UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`
`Petitioner,
`
`v.
`
`ADAPT PHARMA LIMITED,
`OPIANT PHARMACEUTICALS, INC.,
`
`Patent Owners
`
`_____________________
`
`IPR2019-00698
`U.S. Patent No. 9,775,838
`_____________________
`
`DECLARATION OF MAUREEN DONOVAN, Ph.D.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`TABLE OF CONTENTS
`OVERVIEW .................................................................................................... 1
`I.
`II. MY BACKGROUND AND QUALIFICATIONS ....................................... 10
`III.
`LEGAL STANDARDS ................................................................................. 13
`A.
`Person of ordinary skill in the art ........................................................ 13
`B.
`Claim construction .............................................................................. 15
`C.
`Anticipation and obviousness .............................................................. 16
`D. Written description and priority .......................................................... 18
`THE ’838 PATENT AND ITS CLAIMS ...................................................... 19
`A.
`Background of the prior art relevant to the ’838 patent ...................... 20
`1.
`Opioid overdose ........................................................................20
`2.
`Prior intranasal formulations of naloxone ................................22
`3.
`Development of a new intranasal naloxone formulation ..........24
`(a)
`Physical and chemical properties of naloxone ............... 24
`(b)
`Stability of the formulation............................................. 27
`(c)
`Nasal physiology ............................................................ 30
`(d) Drug exposure attributes for an improved
`intranasal formulation of naloxone ................................. 31
`Choice of pharmaceutical excipients to achieve the
`desired exposure and stability attributes ......................... 33
`Choice of delivery device ............................................... 50
`The properties of the nasal spray delivered by the
`spray device .................................................................... 51
`Independent claims 1 and 41 ............................................................... 58
`
`(f)
`(g)
`
`B.
`
`ii
`
`IV.
`
`(e)
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`C.
`D.
`
`V.
`
`VI.
`
`Dependent claims 2–40 and 42–46 ..................................................... 60
`The ’838 patent lacks priority to U.S. Provisional Application
`No. 61/953,379. ................................................................................... 65
`Orange Book listing of the ’838 patent ............................................... 67
`E.
`CLAIM CONSTRUCTION .......................................................................... 68
`1.
`“pre-primed” .............................................................................69
`2.
`“delivery time” ..........................................................................69
`PUBLIC ACCESSIBILITY OF THE PRIOR ART...................................... 69
`A.
`A Formulator POSA exercising reasonable diligence would have
`located Zomig Review......................................................................... 70
`VII. BASIS OF MY ANALYSIS WITH RESPECT TO OBVIOUSNESS ......... 71
`A.
`A Formulator POSA reading Wyse in view of HPE would have
`had a reason and the know-how to arrive at the subject matter of
`claims 1–4, 18–23, 30–34, 36, and 39–40. .......................................... 71
`1.
`Claim 1 ......................................................................................72
`(a)
`Preamble: “A method of treating opioid overdose,
`the method comprising:” ................................................ 72
`1.1: “delivering a 25-200 μL spray of a
`pharmaceutical solution” ................................................ 73
`1.2: “from a pre-primed device into a nostril of a
`patient, wherein the device is adapted for nasal
`delivery,” ........................................................................ 75
`1.3: “wherein the spray delivers between about 4
`mg and about 10 mg naloxone,” ..................................... 78
`1.4: “an isotonicity agent,” ............................................. 80
`1.5: “and between about 0.005% and about 0.015%
`(w/v) of benzalkonium chloride,” ................................... 81
`
`(e)
`(f)
`
`(b)
`
`(c)
`
`(d)
`
`iii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`2.
`3.
`
`Claim 2 ......................................................................................84
`Claim 3 ......................................................................................85
`(a)
`“the spray delivers about 100 μL of the
`pharmaceutical solution comprising” ............................. 86
`“about 4% (w/v) naloxone hydrochloride;” ................... 86
`(b)
`“about 0.74% (w/v) sodium chloride” ............................ 88
`(c)
`“about 0.01% (w/v) benzalkonium chloride” ................. 92
`(d)
`“about 0.1% (w/v) disodium edetate.” ........................... 94
`(e)
`Claim 4 ......................................................................................96
`4.
`Claim 18 ....................................................................................98
`5.
`Claim 19 ....................................................................................99
`6.
`Claim 20 ..................................................................................101
`7.
`Claim 21 ..................................................................................101
`8.
`Claims 22–23 ..........................................................................103
`9.
`10. Claim 30 ..................................................................................106
`11. Claim 31 ..................................................................................107
`12. Claim 32 ..................................................................................108
`(a)
`“the pharmaceutical solution further comprises
`between about 0.1% and about 0.5% (w/v) of a
`stabilizing agent” .......................................................... 108
`“and an amount of an acid sufficient to achieve a
`pH between about 3.5 and about 5.5.” .......................... 110
`13. Claim 33 ..................................................................................111
`(a)
`“the isotonicity agent is sodium chloride;” .................. 111
`(b)
`“the stabilizing agent is disodium edetate;” ................. 112
`
`(b)
`
`iv
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`“and the acid is hydrochloric acid.” ............................. 112
`(c)
`14. Claim 34 ..................................................................................112
`15. Claim 36 ..................................................................................113
`16. Claims 39–40 ..........................................................................117
`A Formulator POSA reading Wyse in view of HPE and Wang
`would have had a reason and the know-how to arrive at the
`subject matter of claims 5–12............................................................ 120
`1.
`Claims 5–9 ..............................................................................120
`2.
`Claims 10–12 ..........................................................................124
`A Formulator POSA reading Wyse in view of HPE and the ’291
`patent would have had a reason and the know-how to arrive at the
`subject matter of claims 13–17 and 41. ............................................. 127
`1.
`Claims 13–17 ..........................................................................127
`2.
`Claim 41 ..................................................................................131
`(a)
`“wherein the patient is in a lying, supine, or
`recovery position.” ........................................................ 133
`“the patient experiences a geometric mean
`naloxone Cmax not less than about 3 ng/mL
`following a single spray.” ............................................. 136
`A Formulator POSA reading Wyse in view of HPE and
`Djupesland would have had a reason and the know-how to arrive
`at the subject matter of claims 24, 35, and 37 ................................... 137
`1.
`Claim 24 ..................................................................................137
`2.
`Claim 35 ..................................................................................140
`3.
`Claim 37 ..................................................................................143
`A Formulator POSA reading Wyse in view of HPE, Djupesland,
`and Zomig Review would have had a reason and the know-how
`to arrive at the subject matter of claim 38. ........................................ 145
`
`(b)
`
`v
`
`B.
`
`C.
`
`D.
`
`E.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`(f)
`
`A Formulator POSA reading Wang in view of HPE and
`Djupesland would have had a reason and the know-how to arrive
`at the subject matter of claims 1–2, 4–12, 18, 24, 30–31, 35 and
`37. ...................................................................................................... 152
`1.
`Claim 1 ....................................................................................152
`(a)
`Preamble: “A method of treating opioid overdose,
`the method comprising:” .............................................. 153
`1.1: “delivering a 25-200 μL spray of a
`pharmaceutical solution” .............................................. 154
`1.2: “from a pre-primed device into a nostril of a
`patient, wherein the device is adapted for nasal
`delivery,” ...................................................................... 158
`1.3: “wherein the spray delivers between about 4
`mg and about 10 mg naloxone,” ................................... 161
`1.4: “an isotonicity agent.” ........................................... 162
`1.5: “and between about 0.005% and about 0.015%
`(w/v) of benzalkonium chloride,” ................................. 164
`Claim 2 ....................................................................................172
`2.
`Claims 4–9 ..............................................................................174
`3.
`Claims 10–12 ..........................................................................176
`4.
`Claim 18 ..................................................................................179
`5.
`Claim 24 ..................................................................................180
`6.
`Claim 30 ..................................................................................183
`7.
`Claim 31 ..................................................................................185
`8.
`Claim 35 ..................................................................................187
`9.
`10. Claim 37 ..................................................................................190
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`
`vi
`
`F.
`
`G.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`2.
`
`3.
`
`Bahal, and Kushwaha would have had a reason and the know-
`how to arrive at the subject matter of claims 3 and 32–34. .............. 192
`1.
`Claim 3 ....................................................................................192
`(a)
`“the spray delivers about 100 μL of the
`pharmaceutical solution comprising” ........................... 193
`“about 4% (w/v) naloxone hydrochloride;” ................. 195
`(b)
`“about 0.74% (w/v) sodium chloride” .......................... 197
`(c)
`“about 0.01% (w/v) benzalkonium chloride” ............... 200
`(d)
`“about 0.1% (w/v) disodium edetate.” ......................... 202
`(e)
`Claim 32 ..................................................................................210
`(a)
`“the pharmaceutical solution further comprises
`between about 0.1% and about 0.5% (w/v) of a
`stabilizing agent” .......................................................... 211
`“and an amount of an acid sufficient to achieve a
`pH between about 3.5 and about 5.5.” .......................... 211
`Claim 33 ..................................................................................213
`(a)
`“the isotonicity agent is sodium chloride;” .................. 213
`(b)
`“the stabilizing agent is disodium edetate;” ................. 213
`(c)
`“and the acid is hydrochloric acid.” ............................. 214
`Claim 34 ..................................................................................214
`4.
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`and Wyse would have had a reason and the know-how to arrive
`at the subject matter of claims 19–23, 36, and 39–40. ...................... 215
`1.
`Claim 19 ..................................................................................215
`2.
`Claim 20 ..................................................................................219
`3.
`Claim 21 ..................................................................................219
`
`(b)
`
`vii
`
`H.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`I.
`
`J.
`
`K.
`
`L.
`
`2.
`
`Claims 22–23 ..........................................................................222
`4.
`Claim 36 ..................................................................................226
`5.
`Claims 39–40 ..........................................................................231
`6.
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`and the ’291 patent would have had a reason and the know-how
`to arrive at the subject matter of claims 13–17. ................................ 234
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`and Zomig Review would have had a reason and the know-how
`to arrive at the subject matter of claim 38. ........................................ 238
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`the ’291 patent, and Wyse would have had a reason and the
`know-how to arrive at the subject matter of claim 41. ...................... 243
`1.
`“wherein the patient is in a lying, supine, or recovery position”
` .................................................................................................245
`“and wherein the patient experiences a geometric mean
`naloxone Cmax not less than about 3 ng/mL following a single
`spray.” .....................................................................................247
`A Formulator POSA reading Davies in view of HPE would have
`had a reason and the know-how to arrive at the subject matter of
`claims 1–2, 4, 18–23, 30–31, and 39–40........................................... 248
`1.
`Claim 1 ....................................................................................248
`(a)
`Preamble: “A method of treating opioid overdose,
`the method comprising:” .............................................. 249
`1.1: “delivering a 25-200 μL spray of a
`pharmaceutical solution” .............................................. 251
`1.2: “from a pre-primed device into a nostril of a
`patient, wherein the device is adapted for nasal
`delivery,” ...................................................................... 253
`1.3: “wherein the spray delivers between about 4
`mg and about 10 mg naloxone,” ................................... 256
`
`(b)
`
`(c)
`
`(d)
`
`viii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`(e)
`(f)
`
`1.4: “an isotonicity agent.” ........................................... 258
`1.5: “and between about 0.005% and about 0.015%
`(w/v) of benzalkonium chloride,” ................................. 259
`Claim 2 ....................................................................................261
`2.
`Claim 4 ....................................................................................263
`3.
`Claim 18 ..................................................................................264
`4.
`Claim 19 ..................................................................................265
`5.
`Claim 20 ..................................................................................267
`6.
`Claim 21 ..................................................................................268
`7.
`Claims 22–23 ..........................................................................270
`8.
`Claim 30 ..................................................................................274
`9.
`10. Claim 31 ..................................................................................277
`11. Claims 39–40 ..........................................................................278
`M. A Formulator POSA reading Davies in view of HPE, Bahal, and
`Kushwaha would have had a reason and the know-how to arrive
`at the subject matter of claims 3 and 32–34. ..................................... 281
`1.
`Claim 3 ....................................................................................282
`(a)
`“wherein the spray delivers about 100 μL of the
`pharmaceutical solution comprising” ........................... 282
`“about 4% (w/v) naloxone hydrochloride;” ................. 285
`(b)
`“about 0.74% (w/v) sodium chloride;” ......................... 286
`(c)
`“about 0.01% (w/v) benzalkonium chloride;” .............. 287
`(d)
`“and about 0.1% (w/v) disodium edetate.” ................... 289
`(e)
`Claim 32 ..................................................................................296
`(a)
`“wherein the pharmaceutical solution further
`
`2.
`
`ix
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`3.
`
`(b)
`
`comprises between about 0.1% and about 0.5%
`(w/v) of a stabilizing agent” ......................................... 296
`“and an amount of an acid sufficient to achieve a
`pH between about 3.5 and about 5.5.” .......................... 297
`Claim 33 ..................................................................................300
`(a)
`“the isotonicity agent is sodium chloride;” .................. 301
`(b)
`“the stabilizing agent is disodium edetate;” ................. 301
`(c)
`“and the acid is hydrochloric acid.” ............................. 301
`Claim 34 ..................................................................................302
`4.
`A Formulator POSA reading Davies in view of HPE and Wang
`would have had a reason and the know-how to arrive at the
`subject matter of claims 5–12............................................................ 302
`1.
`Claim 5–9 ................................................................................303
`2.
`Claims 10–12 ..........................................................................306
`A Formulator POSA reading Davies in view of HPE, Djupesland,
`and the ’291 patent would have had a reason and the know-how
`to arrive at the subject matter of claims 13–17. ................................ 308
`A Formulator POSA reading Davies in view of HPE and
`Djupesland would have had a reason and the know-how to arrive
`at the subject matter of claims 24, 35, and 37. .................................. 312
`1.
`Claim 24 ..................................................................................313
`2.
`Claim 35 ..................................................................................316
`3.
`Claim 37 ..................................................................................319
`A Formulator POSA reading Davies in view of HPE and Wyse
`would have had a reason and the know-how to arrive at the
`subject matter of claim 36. ................................................................ 323
`A Formulator POSA reading Davies in view of HPE, Djupesland,
`and Zomig Review would have had a reason and the know-how
`
`x
`
`N.
`
`O.
`
`P.
`
`Q.
`
`R.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`2.
`
`S.
`
`to arrive at the subject matter of claim 38. ........................................ 328
`A Formulator POSA reading Davies in view of HPE, Djupesland,
`the ’291 patent, and Wyse would have had a reason and the
`know-how to arrive at the subject matter of claim 41. ...................... 334
`1.
`“wherein the patient is in a lying, supine, or recovery position,”
` .................................................................................................336
`“and wherein the patient experiences a geometric mean
`naloxone Cmax not less than about 3 ng/mL following a single
`spray.” .....................................................................................339
`VIII. SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ............ 339
`A.
`No teaching away .............................................................................. 340
`B.
`No commercial success ..................................................................... 342
`C.
`No long-felt but unmet need or failure of others............................... 342
`D.
`No unexpected superior results ......................................................... 345
`IX. CONCLUSION ............................................................................................ 346
`
`xi
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`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. 9,775,838 (the
`
`“’838 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 ’838 patent issued on October 3, 2017, and
`
`resulted from U.S. Patent Application No. 15/589,090, filed on May 8, 2017. I
`
`also understand that the U.S. Patent and Trademark Office (“USPTO”) records
`
`state that the ’838 patent is currently assigned to Adapt Pharma Ltd. and Opiant
`
`Pharmaceuticals (“Patent Owners”).
`
`The face page of the ’838 patent lists other patent applications. I
`
`understand that the ’838 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 ’838 patent cannot claim priority to the March 14, 2014
`
`1
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`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 ’838 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. 9,775,838 (the ’838 patent)
`Nalox1003 Expert Declaration of Günther Hochhaus
`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)
`
`Nalox1005
`
`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)
`Djupesland, P., Nasal Drug Delivery Device: Characteristics
`and Performance in a Clinical Perspective - A Review, 3 Drug
`Deliv. & Transl. Res. 42–62 (2013) (Djupesland)
`
`Nalox1010
`
`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. 9,775,838
`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)
`Wermeling, D., A Response to the Opioid Overdose Epidemic:
`Naloxone Nasal Spray, 3 Drug Deliv. & Transl. Res. 63–74
`(2013) (Wermeling 2013)
`
`Nalox1016
`
`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)
`Nalox1024 CDC, NDA No. 21-450 Clinical Pharmacology &
`Biopharmaceutics Review (2002) (Zomig Review)
`
`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. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`Exhibit No.
`
`Nalox1028
`
`Nalox1029
`
`Description
`
`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
`
`Nalox1038
`
`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)
`
`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)
`
`4
`
`

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`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`Exhibit No.
`
`Description
`
`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)
`
`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.)
`
`5
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`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`Exhibit No.
`
`Description
`
`Nalox1058 U.S. Provisional Patent Appl. No. 61/953,379 (the ’379
`provisional)
`
`Generally, the ’838 patent claims are directed to methods of treating
`
`opioid overdose or narcotic-induced respiratory depression by delivering a
`
`pharmaceutical solution containing naloxone, an
`
`isotonicity agent, and
`
`benzalkonium chloride in the form of a spray to a patient.
`
`It is my opinion that a POSA reading Wyse in view of Handbook of
`
`Pharmaceutical Excipients (“HPE”) would have had a reason and the know-how
`
`to arrive at the subject matter of claims 1–4, 18–23, 30–34, 36, and 39–40 of the
`
`’838 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 HPE and Wang
`
`would have had a reason and the know-how to arrive at the subject matter of
`
`claims 5–12 of the ’838 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 HPE and the
`
`’291 patent would have had a reason and the know-how to arrive at the subject
`
`matter of claims 13–17 and 41 of the ’838 patent with a reasonable expectation of
`
`success, as discussed in this Declaration below.
`
`6
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`It is my opinion that a POSA reading Wyse in view of HPE,
`
`Djupesland, and the Zomig Review would have had a reason and the know-how to
`
`arrive at the subject matter of claim 38 of the ’838 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 HPE and Djupesland would have had a
`
`reason and the know-how to arrive at the subject matter of claims 24, 35, and 37
`
`with a reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Wang in view of HPE and
`
`Djupesland would have had a reason and the know-how to arrive at the subject
`
`matter of claims 1–2, 4–12, 18, 24, 30–31, 35 and 37 of the ’838 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 HPE,
`
`Djupesland, Bahal and Kushwaha would have had a reason and the know-how to
`
`arrive at the subject matter of claims 3 and 32–34 of the ’838 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 HPE,
`
`Djupesland, and Wyse would have had a reason and the know-how to arrive at the
`
`subject matter of claims 19–23, 36, and 39–40 of the ’838 patent with a reasonable
`
`expectation of success, as discussed in this Declaration below.
`
`7
`
`

`

`Inter Partes Review of U.S. Patent No. 9,775,838
`Declaration of Maureen Donovan, Ph.D. (Nalox1002)
`
`It is my opinion that a POSA reading Wang in view of HPE,
`
`Djupesland, and the ’291 patent would have had a reason and the know-how to
`
`arrive at the subject matter of claims 13–17 of the ’838 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 HPE,
`
`Djupesland, and the Zomig Review would have had a reason and the know-how to
`
`arrive at the subject matter of claim 38 of the ’838 p