UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner
`
`v.
`
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owner
`
`_____________________
`
`IRP2019-00690
`Patent No. 9,468,747
`_____________________
`
`DECLARATION OF MAUREEN DONOVAN, Ph.D.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`TABLE OF CONTENTS
`
`I.
`
`OVERVIEW .................................................................................................... 1
`
`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 9
`
`III.
`
`LEGAL STANDARDS ................................................................................. 11
`
`A.
`
`B.
`
`C.
`
`Person of ordinary skill in the art ........................................................ 11
`
`Claim construction .............................................................................. 13
`
`Anticipation or obviousness ................................................................ 15
`
`D. Written description and priority .......................................................... 17
`
`IV.
`
`THE ’747 PATENT AND ITS CLAIMS ...................................................... 18
`
`A.
`
`Background of the art pertinent to the ’747 Patent ............................. 19
`
`1.
`
`2.
`
`3.
`
`Opioid overdose ........................................................................20
`
`Prior intranasal formulations of naloxone ................................21
`
`Development of a new intranasal naloxone formulation. .........23
`
`(a)
`
`(b)
`
`(c)
`
`Physical and chemical properties of naloxone ............... 23
`
`Stability of the formulation............................................. 26
`
`Nasal physiology ............................................................ 29
`
`improved
`for an
`(d) Drug exposure attributes
`intranasal formulation of naloxone ................................. 30
`
`(e)
`
`(f)
`
`(g)
`
`Choice of pharmaceutical excipients to achieve the
`desired exposure and stability attributes ......................... 32
`
`Choice of delivery device ............................................... 49
`
`The properties of the nasal spray delivered by the
`spray device .................................................................... 50
`
`ii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`Independent claims 1 and 30 ............................................................... 57
`
`Dependent claims 2–29 and 31–45 ..................................................... 59
`
`The ’747 patent lacks priority to U.S. Provisional Application
`No. 61/953,379. ................................................................................... 64
`
`Orange Book listing of the ’747 patent ............................................... 67
`
`B.
`
`C.
`
`D.
`
`E.
`
`V.
`
`CLAIM CONSTRUCTION .......................................................................... 67
`
`1.
`
`2.
`
`3.
`
`“pre-primed” .............................................................................68
`
`“delivery time” ..........................................................................69
`
`“90% confidence interval for dose delivered per actuation is
`±about 2.0%,” and “95% confidence interval for dose delivered
`per actuation is ±about 2.5%” ...................................................69
`
`VI.
`
`PUBLIC ACCESSIBILITY OF THE PRIOR ART...................................... 70
`
`VII. BASIS OF MY ANALYSIS WITH RESPECT TO OBVIOUSNESS ......... 70
`
`A.
`
`A Formulator POSA reading Wyse in view of HPE would have
`had ample reason and know-how to arrive at the subject matter of
`claims 1–3, 16–24, and 30–33. ............................................................ 70
`
`1.
`
`Claim 1 ......................................................................................70
`
`(a)
`
`(b)
`
`Preamble: “A method of treatment of opioid
`overdose or a symptom thereof, comprising”................. 71
`
`1.1: “nasally administering to a patient in need
`thereof a dose of naloxone hydrochloride using a
`single-use, pre-primed device adapted for nasal
`delivery of a pharmaceutical composition to a
`patient by one actuation of said device into one
`nostril of said patient, having a single reservoir
`comprising” ..................................................................... 72
`
`iii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`1.2: “a pharmaceutical composition which is an
`aqueous solution of about 100 μL comprising:” ............ 75
`
`1.3: “about 4 mg naloxone hydrochloride or a
`hydrate thereof;” ............................................................. 77
`
`1.4: “between about 0.2 mg and about 1.2 mg of an
`isotonicity agent;” ........................................................... 80
`
`1.5: “between about 0.005 mg and about 0.015 mg
`of a compound which is at least one of a
`preservative,
`a
`cationic
`surfactant, and
`a
`permeation enhancer;” .................................................... 81
`
`1.6: “between about 0.1 mg and about 0.5 mg of a
`stabilizing agent;” ........................................................... 88
`
`1.7: “and an amount of an acid sufficient to
`achieve a pH of 3.5-5.5.” ................................................ 90
`
`(c)
`
`(d)
`
`(e)
`
`(f)
`
`(g)
`
`(h)
`
`2.
`
`Claim 2 ......................................................................................91
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`“the isotonicity agent is NaCl;” ...................................... 91
`
`“the preservative is benzalkonium chloride;”................. 91
`
`“the stabilizing agent is disodium edetate;” ................... 95
`
`“and the acid is hydrochloric acid.” ............................... 95
`
`3.
`
`Claim 3 ......................................................................................95
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`“about 4.4 mg naloxone hydrochloride dihydrate;” ....... 95
`
`“about 0.74 mg NaCl;” ................................................... 96
`
`“about 0.01 mg benzalkonium chloride;” ..................... 100
`
`“about 0.2 mg disodium edetate;” ................................ 100
`
`“and an amount of hydrochloric acid sufficient to
`
`iv
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`achieve a pH of 3.5 to 5.5.” .......................................... 101
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 16 ..................................................................................102
`
`Claim 17 ..................................................................................103
`
`Claim 18 ..................................................................................105
`
`Claim 19 ..................................................................................105
`
`Claims 20–23 ..........................................................................107
`
`Claim 24 ..................................................................................111
`
`10. Claim 30 ..................................................................................114
`
`11. Claim 31 ..................................................................................115
`
`12. Claim 32 ..................................................................................115
`
`13. Claim 33 ..................................................................................116
`
`B.
`
`A Formulator POSA reading Wyse in view of Djupesland and
`HPE would have had ample reason and know-how to arrive at the
`subject matter of claims 4–7 and 10–14. ........................................... 117
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Claim 4 ....................................................................................117
`
`Claim 5 ....................................................................................120
`
`Claim 6 ....................................................................................123
`
`Claim 7 ....................................................................................124
`
`Claims 10–11 ..........................................................................125
`
`Claims 12–14 ..........................................................................128
`
`C.
`
`A Formulator POSA reading Wyse in view of Djupesland, HPE,
`and the ’291 patent would have had ample reason and know-how
`to arrive at the subject matter of claims 8–9. .................................... 131
`
`v
`
`

`

`D.
`
`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`A Formulator POSA reading Wang in view of Djupesland, HPE,
`Bahal, and Kushwaha would have had ample reason and know-
`how to arrive at the subject matter of claims 1–7, 16, and 30–33. ... 138
`
`1.
`
`Claim 1 ....................................................................................138
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`(f)
`
`(g)
`
`(h)
`
`Preamble: “A method of treatment of opioid
`overdose or a symptom thereof, comprising”............... 139
`
`1.1: “nasally administering to a patient in need
`thereof a dose of naloxone hydrochloride using a
`single-use, pre-primed device adapted for nasal
`delivery of a pharmaceutical composition to a
`patient by one actuation of said device into one
`nostril of said patient, having a single reservoir
`comprising” ................................................................... 141
`
`1.2: “comprising a pharmaceutical composition
`which is an aqueous solution of about 100 μL
`comprising:” ................................................................. 144
`
`1.3: “about 4 mg naloxone hydrochloride or a
`hydrate thereof;” ........................................................... 147
`
`1.4: “between about 0.2 mg and about 1.2 mg of an
`isotonicity agent;” ......................................................... 150
`
`1.5: “between about 0.005 mg and about 0.015 mg
`of a compound which is at least one of a
`preservative,
`a
`cationic
`surfactant, and
`a
`permeation enhancer;” .................................................. 153
`
`1.6: “between about 0.1 mg and about 0.5 mg of a
`stabilizing agent;” ......................................................... 162
`
`1.7: “and an amount of an acid sufficient to
`achieve a pH of 3.5-5.5.” .............................................. 170
`
`2.
`
`Claim 2 ....................................................................................171
`
`vi
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`“the isotonicity agent is NaCl;” .................................... 171
`
`“the preservative is benzalkonium chloride;”............... 172
`
`“the stabilizing agent is disodium edetate;” ................. 172
`
`“and the acid is hydrochloric acid.” ............................. 172
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`3.
`
`Claim 3 ....................................................................................172
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`“about 4.4 mg naloxone hydrochloride dihydrate;” ..... 173
`
`“about 0.74 mg NaCl;” ................................................. 176
`
`“about 0.01 mg benzalkonium chloride;” ..................... 178
`
`“about 0.2 mg disodium edetate;” ................................ 180
`
`“and an amount of hydrochloric acid sufficient to
`achieve a pH of 3.5-5.5.” .............................................. 181
`
`Claim 4 ....................................................................................181
`
`Claim 5 ....................................................................................184
`
`Claim 6 ....................................................................................186
`
`Claim 7 ....................................................................................189
`
`Claim 16 ..................................................................................189
`
`Claim 30 ..................................................................................191
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10. Claim 31 ..................................................................................192
`
`11. Claim 32 ..................................................................................193
`
`12. Claim 33 ..................................................................................194
`
`E.
`
`A Formulator POSA reading Wang in view of Djupesland, HPE,
`Bahal, Kushwaha, and Wyse would have had ample reason and
`know-how to arrive at the subject matter of claims 10–14 and 17–
`
`vii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`24. ...................................................................................................... 194
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Claims 10–11 ..........................................................................195
`
`Claims 12–14 ..........................................................................198
`
`Claim 17 ..................................................................................202
`
`Claim 18 ..................................................................................205
`
`Claim 19 ..................................................................................206
`
`Claims 20–23 ..........................................................................210
`
`Claim 24 ..................................................................................214
`
`F.
`
`G.
`
`A Formulator POSA reading Wang in view of Djupesland, HPE,
`Bahal, Kushwaha, and the ’291 patent would have had ample
`reason and know-how to arrive at the subject matter of claims 8–
`9. ........................................................................................................ 216
`
`A Formulator POSA reading Davies in view of HPE, Bahal, and
`Kushwaha would have had ample reason and know-how to arrive
`at the subject matter of claims 1–4, 16–24, and 30–33. .................... 223
`
`1.
`
`Claim 1 ....................................................................................224
`
`(a)
`
`(b)
`
`Preamble: “A method of treatment of opioid
`overdose or a symptom thereof, comprising”............... 225
`
`1.1: “nasally administering to a patient in need
`thereof a dose of naloxone hydrochloride using a
`single-use, pre-primed device adapted for nasal
`delivery of a pharmaceutical composition to a
`patient by one actuation of said device into one
`nostril of said patient, having a single reservoir
`comprising” ................................................................... 227
`
`(c)
`
`1.2: “a pharmaceutical composition which is an
`aqueous solution of about 100 μL comprising:” .......... 231
`
`viii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`1.3: “about 4 mg naloxone hydrochloride or a
`hydrate thereof;” ........................................................... 233
`
`1.4: “between about 0.2 mg and about 1.2 mg of an
`isotonicity agent;” ......................................................... 235
`
`1.5: “between about 0.005 mg and about 0.015 mg
`of a compound which is at least one of a
`preservative,
`a
`cationic
`surfactant, and
`a
`permeation enhancer;” .................................................. 237
`
`1.6: “between about 0.1 mg and about 0.5 mg of a
`stabilizing agent;” ......................................................... 239
`
`1.7: “and an amount of an acid sufficient to
`achieve a pH of 3.5-5.5.” .............................................. 246
`
`(d)
`
`(e)
`
`(f)
`
`(g)
`
`(h)
`
`2.
`
`Claim 2 ....................................................................................250
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`“the isotonicity agent is NaCl;” .................................... 250
`
`“the preservative is benzalkonium chloride;”............... 250
`
`“the stabilizing agent is disodium edetate;” ................. 251
`
`“and the acid is hydrochloric acid.” ............................. 251
`
`3.
`
`Claim 3 ....................................................................................251
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`“about 4.4 mg naloxone hydrochloride dihydrate;” ..... 252
`
`“about 0.74 mg NaCl;” ................................................. 254
`
`“about 0.01 mg benzalkonium chloride;” ..................... 255
`
`“about 0.2 mg disodium edetate;” ................................ 256
`
`“and an amount of hydrochloric acid sufficient to
`achieve a pH of 3.5-5.5.” .............................................. 257
`
`4.
`
`Claim 4 ....................................................................................257
`
`ix
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`Claim 16 ..................................................................................260
`
`Claim 17 ..................................................................................262
`
`Claim 18 ..................................................................................265
`
`Claim 19 ..................................................................................265
`
`Claims 20–23 ..........................................................................268
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10. Claim 24 ..................................................................................272
`
`11. Claim 30 ..................................................................................275
`
`12. Claim 31 ..................................................................................276
`
`13. Claim 32 ..................................................................................277
`
`14. Claim 33 ..................................................................................278
`
`H.
`
`A Formulator POSA reading Davies in view of Djupesland, HPE,
`Bahal, and Kushwaha would have had ample reason and know-
`how to arrive at the subject matter of claims 5–7 and 10–14. .......... 278
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claim 5 ....................................................................................279
`
`Claim 6 ....................................................................................282
`
`Claim 7 ....................................................................................287
`
`Claims 10–11 ..........................................................................288
`
`Claims 12–14 ..........................................................................291
`
`I.
`
`A Formulator POSA reading Davies in view of Djupesland, HPE,
`Bahal, Kushwaha, and the ’291 patent would have had ample
`reason and know-how to arrive at the subject matter of claims 8–
`9. ........................................................................................................ 294
`
`VIII. SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ............ 301
`
`A.
`
`No teaching away .............................................................................. 302
`
`x
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`No commercial success ..................................................................... 304
`
`No long-felt but unmet need or failure of others............................... 304
`
`No unexpected superior results ......................................................... 307
`
`B.
`
`C.
`
`D.
`
`IX. CONCLUSION ............................................................................................ 308
`
`xi
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`I, Maureen D. Donovan, Ph.D., do hereby declare as follows:
`
`I.
`
`OVERVIEW
`I am over the age of 18 and otherwise competent to make this
`
`Declaration. This Declaration is based on my personal knowledge as an expert in
`
`the fields of pharmaceutical formulation, in particular intranasal formulation. I
`
`understand that this Declaration is being submitted together with a petition for
`
`Inter Partes Review (“IPR”) of certain claims of U.S. Patent No. 9,468,747 (“the
`
`’747 patent”).
`
`I have been retained as an expert witness on behalf of Nalox-1
`
`Pharmaceuticals, LLC (“Nalox-1”) for this IPR.
`
`I understand that the ’747 patent issued on October 18, 2016, and
`
`resulted from U.S. Patent Application No. 14/950,707, filed on November 24,
`
`2015. I also understand that the U.S. Patent and Trademark Office (“USPTO”)
`
`records state that the ’747 patent is currently assigned to Opiant Pharmaceuticals,
`
`Inc. (“Patent Owner”)
`
`The face page of the ’747 patent lists other patent applications. I
`
`understand that the ’747 patent is related to two separate patent applications,
`
`which were filed on March 14, 2014 and March 16, 2015. As discussed below, it
`
`is my opinion that the ’747 patent cannot claim priority to the March 14, 2014
`
`1
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`application, and that the earliest application to which it can claim priority has a
`
`filing date of March 16, 2015.
`
`In preparing this Declaration, I have reviewed the ’747 patent and its
`
`file history. I have also considered each of the documents listed in the table below,
`
`in light of general knowledge in the art as of March 16, 2015.
`
`Exhibit No.
`
`Description
`
`Nalox1001 U.S. Patent No. 9,468,747 (the ’747 patent)
`
`Nalox1003 Expert Declaration of Günther Hochhaus
`
`Nalox1005
`
`Excerpt of File History of U.S. Patent No. 9,561,177, Oct. 21,
`2016 Amendment and Response to Office Action (Oct. 21,
`2016 Response to Office Action)
`
`Nalox1006
`
`Excerpt of File History of U.S. Patent No. 9,561,177, Dec. 21,
`2016 Office Action, Notice of Allowance and Fees Due (Notice
`of Allowance)
`
`Nalox1007 U.S. Patent No. 9,192,570 (Wyse)
`
`Nalox1008 Chinese Patent No. 1,575,795 (Wang)
`
`Nalox1009 PCT International App. Pub. No. WO00/62757 (Davies)
`
`Nalox1010
`
`Djupesland, P., Nasal Drug Delivery Device: Characteristics
`and Performance in a Clinical Perspective - A Review, 3 Drug
`Deliv. & Transl. Res. 42–62 (2013) (Djupesland)
`
`Nalox1011
`
`Grassin-Delyle, S. et al., Intranasal Drug Delivery: An Efficient
`and Non-invasive Route for Systemic Administration, Focus on
`Opioids, 134 Pharm. & Ther. 366–79 (2012) (Grassin-Delyle)
`
`2
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`
`Exhibit No.
`
`Description
`
`Nalox1012
`
`Handbook of Pharmaceutical Excipients, 56–60, 64–66, 78–81,
`220–22, 242–44, 270-72, 441–45, 517–22, 596–98 (Rowe, R. et
`al. eds., 6th ed. 2009) (HPE)
`Nalox1013 Kushwaha, S. et al., Advances in Nasal Trans-Mucosal Drug
`Delivery, (1)7 J. Applied Pharm. Sci. 21–28 (2011) (Kushwaha)
`
`Nalox1014 U.S. Patent No. 5,866,154 (Bahal)
`Nalox1015 U.S. Patent No. 8,198,291 (the ’291 patent)
`
`Nalox1016
`
`Wermeling, D., A Response to the Opioid Overdose Epidemic:
`Naloxone Nasal Spray, 3 Drug Deliv. & Transl. Res. 63–74
`(2013) (Wermeling 2013)
`
`Nalox1018
`
`Aptar Pharma, Press Release, Aptar Pharma Provides Unit-Dose
`Nasal Spray Technology for Treatment of Opioid Overdose
`(Apr. 20, 2016) (Aptar Press Release)
`
`Nalox1021
`
`Barton, E. et al., Efficacy of Intranasal Naloxone as a
`Needleless Alternative for Treatment of Opioid Overdose in the
`Prehospital Setting, 29(3) J. Emerg. Med. 265–71 (2005)
`(Barton 2005)
`Nalox1022 Bitter, C. et al., Nasal Drug Delivery in Humans, 40 Curr.
`Probl. Dermatol. 20–35 (2011) (Bitter)
`Nalox1023 Boyer, E., Management of Opioid Analgesic Overdose, 367(2)
`N. Engl. J. Med. 146–55 (2012) (Boyer)
`
`Nalox1027
`
`Dowling, J. et al., Population Pharmacokinetics of Intravenous,
`Intramuscular, and Intranasal Naloxone in Human Volunteers,
`30(4) Ther. Drug. Monit. 490–96 (2008) (Dowling)
`
`3
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`
`Exhibit No.
`
`Description
`
`Nalox1028
`
`Nalox1029
`
`FDA, Center for Drug Evaluation and Research, Guidance for
`Industry, Nasal Spray and Inhalation Solution, Suspension, and
`Spray Drug Products – Chemistry, Manufacturing, and
`Controls Documentation (2002) (2002 FDA Guidance)
`
`FDA, Center for Drug Evaluation and Research, Guidance for
`Industry, Bioavailability and Bioequivalence Studies for Nasal
`Aerosols and Nasal Sprays for Local Action (2003) (2003 FDA
`Guidance)
`
`Nalox1031
`
`Glende, O., Development of non-injectable naloxone for pre-
`hospital reversal of opioid overdose: A Norwegian project and
`a review of international status (May 2016) (unpublished M.A.
`thesis, Norwegian University of Science and Technology) (on
`file with Norwegian University of Science and Technology)
`(Glende)
`Nalox1032 Hertz, S., Naloxone for Outpatient Use: Data Required to
`Support an NDA, Powerpoint Presentation (Hertz Presentation)
`
`Nalox1034
`
`Kelly, A-M. et al., Randomised Trial of Intranasal Versus
`Intramuscular Naloxone in Prehospital Treatment for Suspected
`Opioid Overdose, 182(1) Med. J. Austl. 24–27 (2005) (Kelly)
`
`Nalox1035
`
`Kerr, D. et al., Intranasal Naloxone for the Treatment of
`Suspected Heroin Overdose, 103 Addiction 379–86 (2008)
`(Kerr 2008)
`
`Nalox1036
`
`Kerr, D. et al., Randomized Controlled Trial Comparing the
`Effectiveness & Safety of Intranasal & Intramuscular Naloxone
`for the Treatment of Suspected Heroin Overdose, 104 Addiction
`2067–74 (2009) (Kerr 2009)
`
`4
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`
`Exhibit No.
`
`Description
`
`Nalox1038
`
`Marple, B. et al., Safety Review of Benzalkonium Chloride Used
`as a Preservative in Intranasal Solutions: An Overview of
`Conflicting Data and Opinions, 130 Otolaryngol Head Neck
`Surg. 131–41 (2004) (Marple)
`Nalox1039 Merck Index, Isotonic Solutions, MISC-47–69 (Windholz, M. et
`al. eds., 10th ed. 1983) (Merck Index)
`
`Nalox1041
`
`Middleton, L. et al., The Pharmacodynamic & Pharmacokinetic
`Profile of Intranasal Crushed Buprenorphone &
`Buprenorphine/Naloxone Tablets in Opioid Abusers, 106(8)
`Addiction 1460–73 (2011) (Middleton)
`Nalox1043 Pharmacodynamic Agents, in Foye’s Principles of Medicinal
`Chemistry, 670 (Lemke, T. et al. eds., 6th ed. 2008) (Lemke)
`
`Nalox1044
`
`Physicians’ Desk Reference, NARCAN [Naloxone
`Hydrochloride Injection, USP], IMITREX Nasal Spray
`[Sumatriptan], 1300–02, 1546–50 (57th ed., 2003) (PDR 2003)
`Nalox1045 Physicians’ Desk Reference, ZOMIG Nasal Spray
`[Zolmitriptan], 768–78 (64th ed., 2010) (PDR 2010)
`Nalox1049 Role of Naloxone in Opioid Overdose Fatality Prevention FDA
`Meeting Transcript (Apr. 12, 2012) (2012 FDA Meeting)
`
`Nalox1050
`
`Rosanske, T., Morphine, in Chemical Stability of
`Pharmaceuticals: A Handbook for Pharmacists, 604–11
`(Connors, K. et al. eds., 2d ed. 1986) (Rosanske)
`
`Nalox1051
`
`Sabzghabaee, A. et al., Naloxone Therapy in Opioid Overdose
`Patients: Intranasal or Intravenous? A Randomized Clinical
`Trial, 10(2) Arch. Med. Sci. 309–14 (2014) (Sabzghabaee)
`
`5
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`
`Exhibit No.
`
`Description
`
`Nalox1053
`
`Trows, S. et al., Analytical Challenges and Regulatory
`Requirements for Nasal Drug Products in Europe and the U.S.,
`6 Pharm. 195–219 (2014) (Trows)
`Nalox1054 United States Pharmacopeia and National Formulary (USP 36-
`NF 31) Vol 1., 54–55, 930–33 (2013) (USP)
`
`Nalox1055 U.S. Patent Appl. No. 61/918,802 (the ’802 Appl.)
`Nalox1058 U.S. Provisional Patent Appl. No. 61/953,379 (the ’379
`provisional)
`
`Nalox1063
`
`Excerpt of File History of U.S. Patent No. 9,468,747, April 12,
`2016 Office Action, Notice of Allowance and Fees Due (’747
`Notice of Allowance)
`
`Generally, the ’747 patent claims are directed methods of treating
`
`opioid overdose by nasally administering naloxone hydrochloride using a single-
`
`use, pre-primed device adapted for nasal delivery of a pharmaceutical composition
`
`which is an aqueous solution of about 100 μL comprising naloxone hydrochloride
`
`or a hydrate thereof, an isotonicity agent, a compound which is a preservative,
`
`cationic surfactant, or permeation enhancer, and a stabilizing agent along with a
`
`sufficient quantity of acid to adjust the pH to 3.5 to 5.5. The pharmaceutical
`
`composition itself is also claimed.
`
`It is my opinion that a POSA reading Wyse in view of Handbook of
`
`Pharmaceutical Excipients (HPE) would have had ample reason and know-how to
`
`6
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`arrive at the subject matter of claims 1–3, 16–24, and 30–33 of the ’747 patent
`
`with a reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Wyse in view of Djupesland
`
`and HPE would have had ample reason and know-how to arrive at the subject
`
`matter of claims 4–7 and 10–14 of the ’747 patent with a reasonable expectation
`
`of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Wyse in view of Djupesland,
`
`HPE, and the ’291 patent would have had ample reason and know-how to arrive at
`
`the subject matter of claims 8–9 of the ’747 patent with a reasonable expectation
`
`of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Wang in view of Djupesland,
`
`HPE, Bahal, and Kushwaha would have had ample reason and know-how to arrive
`
`at the subject matter of claims 1–7, 16, and 30–33 of the ’747 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Wang in view of Djupesland,
`
`HPE, Bahal, Kushwaha, and Wyse would have had ample reason and know-how
`
`to arrive at the subject matter of claims 10–14 and 17–24 of the ’747 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Wang in view of Djupesland,
`
`HPE, Bahal, Kushwaha, and the ’291 patent would have had ample reason and
`
`7
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`know-how to arrive at the subject matter of claims 8–9 of the ’747 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Davies in view of HPE, Bahal,
`
`and Kushwaha would have had ample reason and know-how to arrive at the
`
`subject matter of claims 1–4, 16–24, and 30–33 of the ’747 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Davies in view of Djupesland,
`
`HPE, Bahal, and Kushwaha would have had ample reason and know-how to arrive
`
`at the subject matter of claims 5–7 and 10–14 of the ’747 patent with a reasonable
`
`expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Davies in view of Djupesland,
`
`HPE, Bahal, Kushwaha, and the ’291 patent would have had ample reason and
`
`know-how to arrive at the subject matter of claims 8–9 of the ’747 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`I have reviewed the opinion of Dr. Günther Hochhaus, an expert in
`
`clinical pharmacology, and it is my understanding that he has rendered an opinion
`
`that claims 15, 25–29, and 34–45 of the ’747 patent are obvious over the prior art.
`
`I offer no opinion regarding the obviousness of these claims.
`
`8
`
`

`

`Inter Partes Review of U.S. Patent No. 9,468,747
`Declaration of Maureen Donovan, Ph.D. (Nalox1002 )
`II. MY BACKGROUND AND QUALIFICATIONS
`I am a Professor in the Division of Pharmaceutics and Translational
`
`Therapeutics at the University of Iowa College of Pharmacy. I have more than 25
`
`years of experience working and consulting in the field of pharmaceutics. My
`
`curriculum vitae is attached to this report as Exhibit A.
`
`I am an expert in pharmaceutics. I received my Bachelor of Science
`
`in Pharmacy from the University of Minnesota College of Pharmacy in 1983 and
`
`my Ph.D. in Pharmaceutics from the University of Michigan in 1989.
`
`My professional experience includes working as a Staff Pharmacist
`
`for Clark Professional Pharmacy from 1986 until 1989 and as a Visiting Scholar
`
`for SmithKline Beecham Pharmaceuticals in 1991. From 1989 through the
`
`present, I have held various positions at the University of Iowa College of
`
`Pharmacy. Specifically, in the Division of Pharmaceutics, I was an Assistant
`
`Professor from 1989 until 1996, and an Associate Professor from 1996 until 2008.
`
`I was promoted to the rank of Professor in 2008 in the College of Pharmacy, and I
`
`currently hold this position. From 2008 until 2013, I was the Division Head for the
`
`Division of Pharmaceutics. In 2013, I became the Associate Dean for
`
`Undergraduate Programs at the College of Pharmacy, and I currently hold this
`
`position.
`
`9
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`Inter Partes Review of U.S. Patent No. 9,468,747
`Decl