UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ADAPT PHARMA OPERATIONS LIMITED, and
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owners.
`__________________
`
`Case IPR2019-00694
`U.S. Patent No. 9,629,965
`__________________
`
`DECLARATION OF STUART A. JONES, PH.D.
`
`Opiant Exhibit 2208
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`

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`DECLARATION OF STUART A. JONES
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ............................................................................................ i
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND AND QUALIFICATIONS ................................................. 6
`
`THE ADAPT PATENTS ............................................................................... 13
`
`LEGAL PRINCIPLES OF OBVIOUSNESS ................................................ 16
`
`PERSON OF ORDINARY SKILL IN THE ART ........................................ 19
`
`VI. CONSTRUCTION OF CLAIMS .................................................................. 23
`
`VII. SCIENTIFIC AND TECHNICAL BACKGROUND ................................... 23
`
`A.
`
`B.
`
`C.
`
`Formulation Basics .............................................................................. 23
`
`Pharmacokinetic Basics ....................................................................... 25
`
`Best Practices in Drug Development .................................................. 28
`
`VIII. THE CHALLENGED CLAIMS WOULD NOT HAVE BEEN
`OBVIOUS ...................................................................................................... 29
`
`A.
`
`The POSA’s Goals Would Not Have Led To The Claimed
`Invention. ............................................................................................. 29
`
`B. Wyse Leads Away From, Not Towards, The Claimed
`Invention. ............................................................................................. 33
`
`C.
`
`The Claimed Use Of A Preservative, And Specifically BZK
`And EDTA, Was Not Obvious. ........................................................... 37
`
`1. Wyse Taught Away From The Use Of BZK, Or BZK
`And EDTA, In A Naloxone Formulation. ................................ 37
`
`2.
`
`Other Prior Art Also Taught Away From The Use Of
`BZK, BZK And EDTA, And Preservatives Generally. ............ 66
`
`i
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
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`DECLARATION OF STUART A. JONES
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`
`3.
`
`4.
`
`5.
`
`The Prior Art Provided Many Other Options For
`Preservatives And Excipients. .................................................. 79
`
`The POSA Would Not Have Had Reasonable
`Expectation That A Formulation With BZK Or BZK And
`EDTA Would Be Stable. ........................................................... 84
`
`Dr. Donovan Has Not Demonstrated That The POSA
`Would Have Used Any Preservative Other Than BZK At
`The Claimed Concentration Ranges. ........................................ 85
`
`D.
`
`The Claimed Dose Of 4 Milligrams Was Not Obvious. ..................... 93
`
`1.
`
`2.
`
`The Prior Art Practice Was To Administer A Low Initial
`Dose Of Naloxone And Increase That Dose Slowly Over
`Time Only if Needed. ............................................................... 93
`
`The Prior Art Taught That An Initial Intranasal Dose Of
`2 Milligrams Or Less Was Effective And Discouraged
`Higher Doses. ............................................................................ 96
`
`3. Wyse Taught A Dose Of 2 Milligrams And Taught Away
`From A Product That Delivered Higher Amounts Of
`Naloxone Faster. ..................................................................... 102
`
`4.
`
`5.
`
`6.
`
`Neither Of Nalox-1’s Experts Identified Anything About
`Wyse’s Final Formulation That The POSA Would Have
`Wanted To Change.................................................................. 120
`
`The POSA Would Not Have Wanted To Increase The
`Dose To Match The Pharmacokinetic Exposure Of An
`Injection Dose Of More Than 0.4 Milligrams. ....................... 124
`
`Davies and Wang Did Not Teach A Dose Of 4
`Milligrams And Would Not Have Provided A
`Reasonable Expectation of Success With Such A Dose. ........ 141
`
`Administering Intranasal Naloxone In A Single Spray In One
`Nostril Was Not Obvious. ................................................................. 145
`
`The Claimed Device Limitations Would Not Have Been
`Obvious. ............................................................................................ 146
`
`E.
`
`F.
`
`ii
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
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`DECLARATION OF STUART A. JONES
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`The Claimed Combination Would Not Have Been Obvious. ........... 148
`
`G.
`
`IX. OBJECTIVE INDICIA DEMONSTRATE THE NON-
`OBVIOUSNESS OF THE CHALLENGED CLAIMS. .............................. 151
`
`A.
`
`The Unexpected Properties. .............................................................. 151
`
`1.
`
`2.
`
`The Claimed Invention Displays Unexpected Stability
`Compared To Wyse. ............................................................... 151
`
`The Claimed Invention Displays Superior
`Pharmacokinetics Compared To Wyse. .................................. 154
`
`B.
`
`The Failure Of Others To Arrive At A Dose Of More Than 2
`Milligrams, Or To Arrive At The Entire Claimed Invention,
`Demonstrates Nonobviousness. ........................................................ 158
`
`1.
`
`2.
`
`AntiOp/Indivior Failed To Secure FDA Approval For
`Their 1.8 Milligram Nasal Naloxone Product. ....................... 159
`
`Amphastar Failed To Secure FDA Approval For A 2
`Milligram Nasal Naloxone Product. ....................................... 160
`
`3. Mundipharma Developed A 2 Milligram Nasal Naloxone
`Product But Did Not Seek FDA Approval. ............................ 161
`
`C. Others Copying The Claimed Dose Demonstrates
`Nonobviousness................................................................................. 161
`
`D.
`
`There Is A Nexus Between The Challenged Claims And
`Objective Indicia Of Nonobviousness. ............................................. 162
`
`E.
`
`Narcan® Nasal Spray Embodies The Claimed Invention. ............... 165
`
`1.
`
`2.
`
`Limitation-by-Limitation Analysis ......................................... 165
`
`Narcan® Nasal Spray Embodies The Claims Of The
`’253, ’747, And ’965 Patents .................................................. 167
`
`Table of Exhibits .................................................................................................... 173
`
`Appendix A: Dependent Claim Embodiment Analysis ............................ Appendix 1
`
`iii
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`Opiant Exhibit 2208
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
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`DECLARATION OF STUART A. JONES
`
`
`I, Stuart A. Jones, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION
`
`
`
`I am an expert in the field of drug development, which includes the
`
`fields of drug formulation, drug delivery, dosage form design, dose selection,
`
`formulation, manufacturing, and pharmacokinetics, including as applied to the
`
`development of intranasal and inhalation products. I am currently a Reader, an
`
`academic position equivalent to a U.S. professorship, in Pharmaceutics at King’s
`
`College London. I have held this position since 2019. I was previously a Senior
`
`Lecturer from 2010 and a Lecturer from 2005. Since 2009, I have been the
`
`Director of two Masters of Science programs, in Drug Development Science and
`
`Clinical Pharmacology. My complete curriculum vitae is found at Exhibit 2200.
`
`
`
`On behalf of Patent Owners Adapt Pharma Operations Limited and
`
`Opiant Pharmaceuticals, Inc. (collectively, “Adapt”), I have been asked to provide
`
`my opinion as to whether the claims of U.S. Patent Nos. 9,211,253 (“the ’253
`
`patent”), 9,468,747 (“the ’747 patent”), and 9,629,965 (“the ’965 patent”)
`
`(collectively, “the Adapt patents” or “the challenged patents”), would have been
`
`obvious to the hypothetical person of ordinary skill (“POSA”) in the art as of
`
`March 16, 2015. I have also been asked to respond to opinions and testimony
`
`offered by Dr. Maureen Donovan and Dr. Günther Hochhaus concerning the
`
`validity of the Adapt patents, both in their declarations and at their depositions.
`
`1
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
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`
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`I am over the age of 18 and otherwise competent to make this
`
`DECLARATION OF STUART A. JONES
`
`
`declaration. I am being compensated at my customary hourly rate of £320.00, as
`
`well as reimbursement of reasonable business expenses. My compensation is not
`
`contingent upon the outcome of these proceedings or the opinions I reach.
`
`
`
`I understand that Nalox-1 Pharmaceuticals, LLC (“Nalox-1”) has
`
`challenged the validity of claims 1–29 of the ’253 patent, claims 1–45 of the ’747
`
`patent, and claims 1–30 of the ’965 patent (“the challenged claims”) on the ground
`
`that the claims are unpatentable as obvious.
`
`
`
`I understand that this declaration is being submitted in support of
`
`Adapt’s patent owners’ responses to petitions for inter partes review (“IPR”) filed
`
`by Nalox-1, Case Nos. IPR2019-00685, IPR2019-00688, and IPR2019-00694.
`
`Because there are a number of common issues in the IPR proceedings, I am
`
`providing a single declaration across all three IPR proceedings.
`
`
`
`In this declaration, I provide opinions regarding the Adapt patents, the
`
`challenged claims, the prior art, the level of skill of the person of ordinary skill in
`
`that art, and how such a person would understand the prior art. The bases and
`
`reasons for my opinions, including the particular references I am relying upon for
`
`the opinions in this declaration, are set forth herein. 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 using a name; a chart of the relevant exhibit numbers in each
`
`2
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 6
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`DECLARATION OF STUART A. JONES
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`those depositions. I have also considered the materials cited herein, including the
`
`declarations submitted by Dr. Kenneth Williams (“Williams POPR Decl.” and
`
`“Williams Decl.”). I have also relied upon my professional judgment and
`
`expertise.
`
`
`
`As set forth in greater detail in this declaration, the POSA would not
`
`have regarded the challenged claims of the Adapt patents as obvious, over the
`
`combination of references identified by Nalox-1 or any other prior art, as of March
`
`16, 2015, for at least the following reasons:
`
`a.
`
`The POSA would have recognized that there were a vast
`
`number of potential options for an intranasal naloxone product,
`
`including many different possible nasal administration
`
`approaches, formulation types, excipients, devices, and
`
`methods of administration, and among these options the
`
`specific claimed invention’s dose, formulation, device, and
`
`method of administration were just one of many. Nothing in
`
`the art led toward the particular claimed combination.
`
`b. Wyse taught away from the use of benzalkonium chloride
`
`(“BZK”), or a combination of BZK and EDTA, in a naloxone
`
`formulation. Based on testing Wyse conducted, he reported
`
`that BZK resulted in instability of the naloxone active
`
`ingredient. The HPE also taught away from the use of BZK in
`
`combination with EDTA in a nasal formulation because it
`
`taught that this would result in irritation. And several
`
`4
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`IPR2019-00694
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`DECLARATION OF STUART A. JONES
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`
`references also taught away from the use of BZK in nasal
`
`formulations because of effects on the cilia, among other things.
`
`c.
`
`The POSA would have understood that there was no need for a
`
`preservative in a single-use product, that there were many
`
`reasons to avoid a preservative, and that the art taught away
`
`from using a preservative in nasal formulations. The POSA
`
`would have understood that there were available formulation
`
`and device options that would have obviated the need for a
`
`preservative.
`
`d.
`
`The POSA would have recognized that an intranasal dose of
`
`naloxone of 2 mg or less was effective to treat opioid overdose,
`
`even when delivered via the improvised kits containing the
`
`“Mucosal Atomization Device” (“MAD”), and thus the POSA
`
`would not have recognized a problem with the existing 2 mg or
`
`less intranasal naloxone dose or have any reason to increase the
`
`dose.
`
`e. Wyse and other prior art references taught away from
`
`increasing the dose of intranasal naloxone because of serious
`
`withdrawal and other side effects.
`
`f.
`
`No prior art reference, including Wyse, reported on the
`
`administration of an initial naloxone dose of more than 2 mg, or
`
`specifically an initial 4 mg dose, to overdosing patients. Nor
`
`did Wyse recommend an initial 4 mg dose to treat opioid
`
`overdose.
`
`5
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 9
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`DECLARATION OF STUART A. JONES
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`g.
`
`There was a long-felt need for an easy-to-use, needle-free
`
`naloxone product for community use, and Narcan® Nasal
`
`Spray, an embodiment of the claimed invention, filled that
`
`need.
`
`h.
`
`The other companies working to develop an intranasal naloxone
`
`product all decided on a dose of 2 mg or less and failed to arrive
`
`at the claimed invention. The two other companies that sought
`
`FDA approval for their products failed to achieve it.
`
`i.
`
`After the publication of the Adapt patents, the only other
`
`company with an FDA-approved community-use naloxone
`
`product copied the claimed invention by increasing their dose.
`
`j.
`
`The entire unique combination of device and formulation
`
`claimed in the challenged patents and embodied in Narcan®
`
`Nasal Spray resulted in the approval of Narcan® Nasal Spray
`
`by the FDA, and produced the unique benefits that have made it
`
`a commercial success.
`
`k.
`
`Nalox-1 failed to show a motivation to select and combine the
`
`claimed dose, formulation, device, and method of
`
`administration from the prior art. Thus, the specific
`
`combination of features claimed in the challenged patents
`
`would not have been obvious to the POSA.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`
`
`I received my Ph.D. in Drug Delivery from King’s College London in
`
`2005. My doctoral work focused on the design of inhaled dosage forms for
`
`6
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`IPR2019-00694
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`DECLARATION OF STUART A. JONES
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`respiratory disease and involved the formulation design, aerosol testing, and
`
`respiratory system deposition modelling of novel metered dose inhaler
`
`formulations. Prior to my Ph.D., I received a Masters degree in Pharmacy from the
`
`University of Nottingham. My Masters research, which I completed between 1997
`
`and 2001, included the development of analytical methods for the detection of
`
`analytes in biological fluids. I also hold a Masters degree in Academic Practice
`
`from Kings College London.
`
` As a Reader at Kings College London, I regularly teach university
`
`courses on pharmaceutical sciences and drug development to students enrolled in
`
`the Pharmacy, Pharmaceutical Science, and Drug Development Science/Clinical
`
`Pharmacology programs. For the Masters program in Drug Development
`
`Science/Clinical Pharmacology, I teach lectures to a mixture of medically qualified
`
`professionals and basic scientists on Clinical Pharmaceutics; Drug Formulation;
`
`Inhaled Drug Delivery, and Solution Formulations. In these lectures, I cover a
`
`range of topics within the field of drug development, including nasal drug delivery,
`
`transmucosal delivery, pharmacokinetics of intranasal drugs, drug physicochemical
`
`properties, drug absorption, formulation selection, formulation design, adverse
`
`drug reactions, and preformulation development. In addition, as a lecturer in
`
`courses including Physical Pharmaceutics, Formulation Analysis, Medicines
`
`Discovery and Development, and Gastrointestinal System and Dermatology, I
`
`7
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`DECLARATION OF STUART A. JONES
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`teach first through fourth-year pharmacy students the fundamentals of formulation
`
`science, covering topics such as colloids & gels, colligative properties, electrolytes,
`
`dissolution, experimental design, and drug delivery to the nose, lung, and skin.
`
` As Director of the Masters of Science program in Drug Development
`
`Science and Clinical Pharmacology, I am actively involved in curriculum
`
`development and in ensuring our academic courses address recent advances in drug
`
`development and clinical pharmacology. This curriculum development involves
`
`an annual focus group meeting with a panel of industry experts who inform the
`
`academic team of changes in the pharmaceutical sector. In addition, I have
`
`previously served as Director of the Masters of Science program in Pharmaceutical
`
`Technology, Director of Pharmaceutical Science Postgraduate Studies (including 3
`
`MSc programs in the Department of Pharmacy), Chair of the Industrial Impact
`
`Group in the School of Health and Biomedical Science, and Chair of the
`
`Postgraduate exam board in Pharmaceutical Sciences.
`
` My research currently focuses on understanding the delivery and
`
`absorption of drugs across biological barriers including the nasal epithelium, the
`
`respiratory epithelium, the brain, the skin, and the oral mucosa. I have been
`
`awarded research grants on topics including “In Vivo Safety and Particokinetics of
`
`Inhaled Nanomedicines” (2010–2013); “Mucus penetrating nanoparticles – a novel
`
`8
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`DECLARATION OF STUART A. JONES
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`targeting strategy for the treatment of respiratory disease” (2009–2013); and “A
`
`novel intranasal microencapsulated nanoparticle formulation” (2006–2008).
`
`
`
`I also supervise graduate students and post-doctoral researchers. I
`
`have supervised the work of six post-doctoral researchers, thirty Ph.D. students,
`
`and forty-two Masters students on a wide variety of research projects, including
`
`research relating to intranasal drug formulation and delivery, e.g., the Ph.D. project
`
`entitled ‘Harnessing nanotechnology for nasal drug delivery,’ which was
`
`completed in 2009.
`
`
`
`I have received awards and honors including an Honorary Fellowship
`
`from the Faculty of Pharmaceutical Medicine in 2019, the 2010 GSK Emerging
`
`Scientist Award, and the 2005 King’s College London Ph.D. Award, which is
`
`awarded for the best Ph.D. thesis in a given academic year. I am a Member of the
`
`Royal Pharmaceutical Society of Great Britain, a Fellow of the Higher Education
`
`Academy, and a Member of the General Pharmaceutical Council of Great Britain.
`
` Throughout my career, I have authored and co-authored more than 75
`
`peer-reviewed research publications and book chapters, published in, among other
`
`journals: Journal of Controlled Release, Journal of Pharmacy and Pharmacology;
`
`Journal of Drug Delivery Science and Technology; Pharmaceutical Research;
`
`International Journal of Pharmaceutics; European Journal of Pharmaceutics and
`
`Biopharmaceutics; Molecular Pharmaceutics; Drug Delivery: Journal of Delivery
`
`9
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`DECLARATION OF STUART A. JONES
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`and Targeting of Therapeutic Agents; Journal of Pharmaceutical and Biomedical
`
`Analysis; and Inhalation Toxicology. These include numerous articles examining
`
`aspects of inhaled and nasal drug development, including nasal drug formulation,
`
`absorption, delivery, and pharmacokinetics, such as:
`
`
`
`
`
`
`
`
`
`
`
`Zhao, Y., Brown, M.B., Khengar, R.H., Traynor, M.J., Barata,
`
`P., & Jones, S.A. “Pharmacokinetic evaluation of intranasally
`
`administered vinyl polymer-coated lorazepam microparticles in
`
`rabbits” (2012), AAPS Journal, 14 (2), pp. 218-24
`
`Grainger, C.I., Saunders, M., Buttini, F., Telford, R., Merolla,
`
`L.L., Martin, G.P., Jones, S.A., & Forbes, B. “Critical
`
`characteristics for corticosteroid solution metered dose inhaler
`
`bioequivalence” (2012), Molecular Pharmaceutics, 9 (3), pp.
`
`563-69
`
`Jones, S.A. “Suspension versus solution metered dose inhalers:
`
`Different products, different particles?” (2011) Journal of Drug
`
`Delivery Science and Technology, 21 (4), pp. 319-22
`
`Jones, S.A. & Kalia, M. “Inhaled formulation development:
`
`Back to basics? (2010) Pharmaceutical Manufacturing and
`
`Packing Sourcer (WINTER), pp. 52-56
`
`Jones, S.A., Reid, M.L., & Brown, M.B. “Determining degree
`
`of saturation after application of transiently supersaturated
`
`metered dose aerosols for topical delivery of corticosteroids”
`
`(2009), Journal of Pharmaceutical Sciences, 98 (2), pp. 543-54
`
`10
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`DECLARATION OF STUART A. JONES
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`
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`Jones, S.A., Martin, G.P., & Brown, M.B. “High-pressure
`
`aerosol suspensions - A novel laser diffraction particle sizing
`
`system for hydrofluoroalkane pressurised metered dose
`
`inhalers” (2005), International Journal of Pharmaceutics, 302
`
`(1-2), pp. 154-65
`
`
`
`I am currently an Associate Editor for the Journal of Pharmacy and
`
`Pharmacology, a position I have held since 2008. Between 2008 and 2015, I
`
`served as an Associate Editor for Pulmonary Pharmacology and Therapeutics. I
`
`also serve as a peer reviewer for journals including: ACS Nanomedicine; Journal
`
`of Controlled Release; Advanced Drug Delivery Reviews; Nanomedicine:
`
`Nanotechnology; Biology and Medicine; Molecular Pharmaceutics;
`
`Pharmaceutical Research; International Journal of Pharmaceutics; European
`
`Journal of Pharmaceutics; European Journal of Pharmaceutics and
`
`Biopharmaceutics; Journal of Pharmacy and Pharmacology; Pulmonary Pharmacy
`
`and Pharmacology; Toxicology Letters; American Journal of Pharmaceutical
`
`Science; Pharmaceutical Sciences; and APS Pharmaceutical Science and
`
`Technology. As a peer reviewer, I am often called upon to read and evaluate
`
`manuscripts relating to the development of nasal drugs.
`
`
`
`I stay knowledgeable about current research in the field of drug
`
`development by attending scientific conferences, presenting posters and lectures at
`
`conferences and other events, and reading scientific literature.
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`11
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`IPR2019-00694
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`DECLARATION OF STUART A. JONES
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`In addition to my academic experience, I have extensive experience in
`
`
`
`the pharmaceutical industry. Prior to my Ph.D. studies, I worked as a Formulation
`
`Scientist for Pfizer Pharmaceuticals. My work at Pfizer included the design and
`
`manufacture of pharmaceutical dosage forms under ‘Good Manufacturing Practice’
`
`conditions at pilot scale. At Pfizer, I used laser diffraction analysis to characterize
`
`the dosage forms and dissolution testing to understand drug release. In 2004, I
`
`joined MedPharm Limited as Head of Research and Development. At MedPharm,
`
`I oversaw research and drug development programs including the development of
`
`nasal, inhaled and topical products. After completing my Ph.D. in 2005, I
`
`continued in a consulting role with MedPharm for four more years, and from 2005
`
`to 2009, I was a consultant with MedPharm. In 2008, I acted as a consultant for
`
`Synairgen Ltd. Also in 2008, I co-founded a small biotechnology company, Porto
`
`Life Science, which specialized in the assessment of drug pharmacokinetics in
`
`animal models. I remained involved with Porto Life Sciences, on a part-time basis,
`
`until 2012. In the last five years, I have acted as a consultant for Syndermix Ltd.
`
` During my years in academia and industry, I have been involved in
`
`over 100 drug development projects. Among other things, I have been involved in
`
`dose selection; designing, testing, and characterizing new formulations and dosage
`
`forms; and evaluating and applying pharmacokinetic data (e.g., absorption,
`
`bioavailability, exposure, Cmax, Tmax, half-life, etc.), with the goals of developing a
`
`12
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`DECLARATION OF STUART A. JONES
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`drug that is effective, safe, and can achieve regulatory approval. One of the
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`products I worked on whilst at MedPharm has been FDA-approved (Aldara), and
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`two others are currently in the process of seeking FDA approval.
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`In addition to my other experience, from 2015 to 2016, I served as a
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`consultant pharmacist in the Directorate of Rational Use of Medicines, Ministry of
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`Health, Oman. My work for the Directorate related to the regulatory review of
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`medicinal products submitted for licensing approval in Oman. In this role, I
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`reviewed and evaluated clinical, pharmacokinetic, and other evidence relating to
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`efficacy, safety, and bioequivalence of medicinal products. I also performed
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`clinical audits, reviewed medicine use, trained clinicians in medicine review and
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`prescribing, and drafted clinical guidelines.
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`III. THE ADAPT PATENTS
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` The Adapt patents relate to Adapt’s product, Narcan® Nasal Spray,
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`which the FDA has approved for the emergency treatment of opioid overdose.
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`Narcan® Nasal Spray Label at 1. Narcan® Nasal Spray is the subject of Adapt’s
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`New Drug Application (“NDA”) No. 208441. As I explain in Section IX.E, infra,
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`Narcan® Nasal Spray embodies the challenged claims. The Adapt patents disclose
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`formulations, devices, and methods for nasal delivery of pharmaceutical
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`compositions comprising naloxone.
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`13
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 17
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`I understand that the Adapt patents are part of a family originating
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`DECLARATION OF STUART A. JONES
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`with U.S. patent application 14/659,472, filed on March 16, 2015, which resulted
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`in the ’253 patent. As such, the Adapt patents contain overlapping specifications.
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` The ’747 patent and the ’965 patent contain identical specifications.
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`They are both continuations of an application (No. 14/942,344) filed on November
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`16, 2015, which was a continuation-in-part of the application that resulted in the
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`’253 patent. See ’747 patent at 1:4–10; ’965 patent at 1:4–11. I understand that a
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`continuation-in-part generally contains the same disclosures as its predecessor, but
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`also contains additional disclosures. The ’747 and ’965 patents contain some
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`additional disclosures with respect to cationic surfactants/permeation enhancers.
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` The Adapt patents disclose that, at the time of the invention, naloxone
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`was “being used mainly in emergency departments and in ambulances by trained
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`medical professionals,” who administered naloxone intravenously or
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`intramuscularly. E.g. ’747 patent at 2:15–17, 6:14–17. The Adapt patents disclose
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`that such routes of administration are not ideal for untrained users, because: 1)
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`they typically require “trained medical personnel (for intravenous injection) or a
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`trained carer (for intramuscular injection),” 2) can be challenging to administer to
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`intravenous drug users with damaged veins, and 3) create “a risk of exposure to
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`blood borne pathogens.” E.g. ’747 patent at 6:20–33. “[T]he growing opioid
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`overdose crisis in the US” led to the recognized need for naloxone to be made
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`14
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`IPR2019-00694
`Page 18
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`available in a form “that untrained consumers are able to use safely.” E.g. ’747
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`DECLARATION OF STUART A. JONES
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`patent at 6:42–46.
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`
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`In addition, the Adapt patents disclose that, at the time of the
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`invention, some emergency services programs had developed a method to
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`administer naloxone intranasally by “combin[ing] an FDA-approved naloxone
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`injection product with a marketed, medical device called the Mucosal Atomization
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`Device.” E.g. ’747 patent at 6:49–51. Although this method “appear[ed] to be
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`effective in reversing narcosis,” the emergency services programs recognized its
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`limitations, including that it was “not assembled and ready-to-use” and “the
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`formulation [wa]s not concentrated for retention in the nasal cavity.” E.g. ’747
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`patent at 16:5–14. This led to “loss of drug from the nasal cavity, due either to
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`drainage into the nasopharynx or externally from the nasal cavity.” Id.
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` Against this background, the Adapt patents disclose “improved ready-
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`to-use products specifically optimized, concentrated, and formulated for nasal
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`delivery.” E.g. ’747 patent at 16:14–16. In general, the claims of the Adapt
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`patents fall into three categories: (1) claims directed to pharmaceutical
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`formulations for intranasal administration of an opioid antagonist—in particular,
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`naloxone; (2) claims directed to single-use, pre-primed devices adapted for nasal
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`delivery of such pharmaceutical formulations; and (3) methods of treating opioid
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`overdose and symptoms thereof by nasally administering naloxone using those
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`15
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 19
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`devices and formulations. See, e.g., ’253 patent at 50:36–52:37; ’747 patent at
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`DECLARATION OF STUART A. JONES
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`6:63–7:9; ’965 patent at 6:66–7:12.
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` The formulations described and claimed in the Adapt patents are
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`aqueous solutions generally comprising about 4 mg naloxone hydrochloride or a
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`hydrate thereof, between about 0.2 mg and about 1.2 mg of an isotonicity agent
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`(sometimes specified in the claims as sodium chloride), between about 0.005 mg
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`and about 0.015 mg of a compound that is a preservative, cationic surfactant, or
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`permeation enhancer (sometimes specified in the claims as benzalkonium
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`chloride), and between about 0.1 mg and about 0.5 mg of a stabilizing agent
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`(sometimes specified in the claims as disodium edetate or “EDTA”).
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`IV. LEGAL PRINCIPLES OF OBVIOUSNESS
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`
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`I understand that a patent claim is “obvious,” and thus invalid, if the
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`differences between the subject matter sought to be patented and the prior art are
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`such that the subject matter as a whole would have been obvious at the time the
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`invention was made to a hypothetical person having ordinary skill (“POSA”) in the
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`art to which said subject matter pertains. I understand that factual determinations
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`relevant to the obviousness inquiry include (a) the scope and content of the prior
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`art, (b) the differences between the claimed invention and the prior art, (c) the level
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`of ordinary skill in the art, and (d) any objective indicia of non-obviousness, such
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`16
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 20
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`as unexpected properties, satisfaction of a long-felt yet unmet need, failure of
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`DECLARATION OF STUART A. JONES
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`others, skepticism, and copying.
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`
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`I understand that there is no basis for concluding that an invention
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`would have been obvious to the POSA solely because it is a combination of
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`elements that were known in the art at the time of the invention. Rather, the
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`challenger must show that there is a reason, suggestion, or motivation in the prior
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`art that would lead the POSA to combine the references, with a reasonable
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`expectation of success. I understand that for an invention to be obvious, the POSA
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`who is following the reference or references that purportedly make it obvious must
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`have had a reasonable expectation of success in applying the teachings of the
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`references to arrive at the claimed invention.
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`
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`I understand that the determination of obviousness must be done
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`based on the knowledge possessed by the POSA at the time when the invention
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`was made. In other words, it is impermissible to use hindsight after viewing the
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`claimed invention to determine questions of obviousness. Rel