UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner
`
`v.
`
`ADAPT PHARMA LTD.,
`OPIANT PHARMACEUTICALS,
`
`Patent Owners
`
`_____________________
`
`IPR2019-00691
`U.S. Patent No. 9,561,177
`_____________________
`
`DECLARATION OF MAUREEN DONOVAN, Ph.D.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit 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 .......................................................... 19
`THE ’177 PATENT AND ITS CLAIMS ...................................................... 19
`A.
`Background of the art pertinent to the ’177 patent ............................. 21
`1.
`Opioid overdose ........................................................................21
`2.
`Prior intranasal formulations of naloxone ................................23
`3.
`Development of a new intranasal naloxone formulation ..........24
`(a)
`Physical and chemical properties of naloxone ............... 25
`(b)
`Stability of the formulation............................................. 28
`(c)
`Nasal physiology ............................................................ 31
`(d) Drug exposure attributes for an improved
`intranasal formulation of naloxone ................................. 32
`Choice of pharmaceutical excipients to achieve the
`desired exposure and stability attributes ......................... 34
`Choice of delivery device ............................................... 51
`The properties of the nasal spray delivered by the
`spray device .................................................................... 52
`Independent claims 1, 12, and 22 ........................................................ 59
`
`(f)
`(g)
`
`B.
`
`ii
`
`IV.
`
`(e)
`
`

`

`V.
`
`VI.
`
`C.
`D.
`
`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`Dependent claims 2–11, 13–21, and 23–30 ........................................ 62
`The ’177 patent lacks priority to U.S. Provisional Application
`No. 61/953,379. ................................................................................... 65
`Orange Book listing of the ’177 patent ............................................... 67
`E.
`CLAIM CONSTRUCTION .......................................................................... 67
`1.
`“pre-primed” .............................................................................68
`2.
`“wherein no more than about [x]% of the droplets have a
`diameter less than 10 μm,” “wherein the median droplet size is
`between about [x] μm and about [y] μm,” and “wherein
`approximately 90% of droplets have a diameter less than about
`100 μm” .....................................................................................69
`PUBLIC ACCESSIBILITY OF THE PRIOR ART...................................... 71
`A.
`A Formulator POSA exercising reasonable diligence would have
`located Zomig Review......................................................................... 71
`VII. BASIS OF MY ANALYSIS WITH RESPECT TO OBVIOUSNESS ......... 72
`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 1–5. ........................................................................................... 72
`1.
`Claim 1 ......................................................................................73
`(a)
`Preamble: “A method of treating opioid overdose,
`the method comprising:” ................................................ 74
`1.1: “delivering a 25-200 μL spray of a
`pharmaceutical solution” ................................................ 75
`1.2: “from a pre-primed device into a nostril of a
`patient, wherein the device is adapted for nasal
`delivery,” ........................................................................ 77
`1.3: “and wherein the pharmaceutical solution
`comprises about 4 mg naloxone hydrochloride or a
`hydrate thereof,” ............................................................. 79
`
`(b)
`
`(c)
`
`(d)
`
`iii
`
`

`

`2.
`3.
`
`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`(e)
`1.4: “between about 0.005% and about 0.015%
`(w/v) of benzalkonium chloride” .................................... 81
`1.5: “and an isotonicity agent.” ...................................... 84
`(f)
`Claim 2 ......................................................................................85
`Claim 3 ......................................................................................86
`(a)
`“the pharmaceutical solution further comprises
`between about 0.1% and about 0.5% (w/v) of a
`stabilizing agent” ............................................................ 87
`“the pharmaceutical solution further comprises . . .
`an amount of an acid sufficient to achieve a pH
`between about 3.5 and about 5.5.” ................................. 88
`Claim 4 ......................................................................................89
`(a)
`“the isotonicity agent is sodium chloride;” .................... 90
`(b)
`“the stabilizing agent is disodium edetate;” ................... 90
`(c)
`“and the acid is hydrochloric acid.” ............................... 90
`Claim 5 ......................................................................................91
`(a)
`“about 4% (w/v) naloxone hydrochloride;” ................... 91
`(b)
`“about 0.74% (w/v) sodium chloride;” ........................... 93
`(c)
`“about 0.01% (w/v) benzalkonium chloride;” ................ 97
`(d)
`“and about 0.2% (w/v) disodium edetate.” ..................... 99
`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 6–9.............................................................. 101
`1.
`Claim 6 ....................................................................................101
`2.
`Claim 7 ....................................................................................104
`3.
`Claim 8 ....................................................................................106
`
`4.
`
`5.
`
`(b)
`
`B.
`
`iv
`
`

`

`C.
`
`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`Claim 9 ....................................................................................108
`4.
`A Formulator POSA reading Wyse in view of HPE and the ’291
`patent would have had ample reason and know-how to arrive at
`the subject matter of claims 12–15, 17–27, and 29. .......................... 112
`1.
`Claim 12 ..................................................................................113
`2.
`Claim 13 ..................................................................................119
`3.
`Claim 14 ..................................................................................120
`4.
`Claim 15 ..................................................................................120
`5.
`Claim 17 ..................................................................................124
`6.
`Claim 18 ..................................................................................128
`7.
`Claim 19 ..................................................................................132
`8.
`Claim 20 ..................................................................................137
`9.
`Claim 21 ..................................................................................139
`10. Claim 22 ..................................................................................141
`(a)
`“A method of treating narcotic-induced respiratory
`depression,” .................................................................. 143
`“delivering a 25-200 μL spray . . . in a manner that
`delivers the pharmaceutical solution in a round
`spray plume with an ovality ratio less than about
`2.0 when measured at 3 cm,” ........................................ 144
`“the patient experiences a geometric mean
`naloxone Cmax not less than about 3 ng/ml,
`following a single spray.” ............................................. 145
`11. Claim 23 ..................................................................................146
`12. Claim 24 ..................................................................................146
`13. Claim 25 ..................................................................................147
`
`(b)
`
`(c)
`
`v
`
`

`

`D.
`
`E.
`
`F.
`
`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`14. Claim 26 ..................................................................................148
`15. Claim 27 ..................................................................................149
`16. Claim 29 ..................................................................................150
`A Formulator POSA reading Wyse in view of HPE, the ’291
`patent, Djupesland, and Zomig Review would have had ample
`reason and know-how to arrive at the subject matter of claim 30. ... 153
`A Formulator POSA reading Wang in view of HPE and
`Djupesland would have had ample reason and know-how to
`arrive at the subject matter of claims 1–2. ........................................ 159
`1.
`Claim 1 ....................................................................................159
`(a)
`Preamble: “A method of treating opioid overdose,
`the method comprising:” .............................................. 160
`1.1: “delivering a 25-200 μL spray of a
`pharmaceutical solution” .............................................. 161
`1.2: “from a pre-primed device into a nostril of a
`patient, wherein the device is adapted for nasal
`delivery,” ...................................................................... 165
`1.3: “and wherein the pharmaceutical solution
`comprises about 4 mg naloxone hydrochloride or a
`hydrate thereof,” ........................................................... 168
`1.4: “between about 0.005% and about 0.015%
`(w/v) of benzalkonium chloride,” ................................. 171
`1.5: “and an isotonicity agent.” .................................... 179
`(f)
`Claim 2 ....................................................................................182
`2.
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`Bahal and Kushwaha would have had ample reason and know-
`how to arrive at the subject matter of claims 3–8. ............................ 184
`1.
`Claim 3 ....................................................................................185
`(a)
`“the pharmaceutical solution further comprises
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`vi
`
`

`

`2.
`
`3.
`
`(b)
`
`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`between about 0.1% and about 0.5% (w/v) of a
`stabilizing agent.” ......................................................... 185
`“the pharmaceutical solution further comprises . . .
`an amount of an acid sufficient to achieve a pH
`between about 3.5 and about 5.5.” ............................... 193
`Claim 4 ....................................................................................194
`(a)
`“the isotonicity agent is sodium chloride;” .................. 194
`(b)
`“the stabilizing agent is disodium edetate;” ................. 195
`(c)
`“and the acid is hydrochloric acid.” ............................. 195
`Claim 5 ....................................................................................195
`(a)
`“about 4% (w/v) naloxone hydrochloride;” ................. 196
`(b)
`“about 0.74% (w/v) sodium chloride;” ......................... 198
`(c)
`“about 0.01% (w/v) benzalkonium chloride;” .............. 201
`(d)
`“and about 0.2% (w/v) disodium edetate.” ................... 203
`Claim 6 ....................................................................................204
`4.
`Claim 7 ....................................................................................207
`5.
`Claim 8 ....................................................................................209
`6.
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`Bahal, Kushwaha, and Wyse would have had ample reason and
`know-how to arrive at the subject matter of claim 9. ........................ 210
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`and the ’291 patent would have had ample reason and know-how
`to arrive at the subject matter of claims 12–15 and 21. .................... 216
`1.
`Claim 12 ..................................................................................217
`2.
`Claim 13 ..................................................................................224
`3.
`Claim 14 ..................................................................................225
`
`vii
`
`G.
`
`H.
`
`

`

`I.
`
`J.
`
`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`Claim 15 ..................................................................................226
`4.
`Claim 21 ..................................................................................229
`5.
`A Formulator POSA reading Wang in view of Djupesland, HPE,
`the ’291 patent, and Wyse would have had ample reason and
`know-how to arrive at the subject matter of claims 17–20, 22–23,
`and 29. ............................................................................................... 232
`1.
`Claim 17 ..................................................................................233
`2.
`Claim 18 ..................................................................................237
`3.
`Claim 19 ..................................................................................241
`4.
`Claim 20 ..................................................................................246
`5.
`Claim 22 ..................................................................................248
`(a)
`“A method of treating narcotic-induced respiratory
`depression,” .................................................................. 249
`“delivering a 25-200 μL spray . . . in a manner that
`delivers the pharmaceutical solution in a round
`spray plume with an ovality ratio less than about
`2.0 when measured at 3 cm,” ........................................ 252
`“the patient experiences a geometric mean
`naloxone Cmax not less than about 3 ng/mL,
`following a single spray.” ............................................. 253
`Claim 23 ..................................................................................254
`6.
`Claim 29 ..................................................................................254
`7.
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`Bahal, Kushwaha, the ’291 patent, and Wyse would have had
`ample reason and know-how to arrive at the subject matter of
`claims 24–27. ..................................................................................... 258
`1.
`Claim 24 ..................................................................................258
`2.
`Claim 25 ..................................................................................259
`
`(b)
`
`(c)
`
`viii
`
`

`

`K.
`
`L.
`
`(c)
`
`(d)
`
`(b)
`
`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`Claim 26 ..................................................................................260
`3.
`Claim 27 ..................................................................................261
`4.
`A Formulator POSA reading Wang in view of HPE, Djupesland,
`the ’291 patent, Zomig Review, and Wyse would have had ample
`reason and know-how to arrive at the subject matter of claim 30. ... 262
`A Formulator POSA reading Davies in view of HPE would have
`had ample reason and know-how to arrive at the subject matter of
`claims 1–2. ......................................................................................... 267
`1.
`Claim 1 ....................................................................................267
`(a)
`Preamble: “A method of treating opioid overdose,
`the method comprising:” .............................................. 268
`1.1: “delivering a 25-200 μL spray of a
`pharmaceutical solution” .............................................. 270
`1.2: “from a pre-primed device into a nostril of a
`patient, wherein the device is adapted for nasal
`delivery,” ...................................................................... 272
`1.3: “and wherein the pharmaceutical solution
`comprises about 4 mg naloxone hydrochloride or a
`hydrate thereof,” ........................................................... 275
`1.4: “between about 0.005% and about 0.015%
`(w/v) of benzalkonium chloride,” ................................. 277
`1.5: “and an isotonicity agent.” .................................... 280
`(f)
`Claim 2 ....................................................................................281
`2.
`M. 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 3–5. ................................................... 281
`1.
`Claim 3 ....................................................................................282
`(a)
`“the pharmaceutical solution further comprises
`between about 0.1% and about 0.5% (w/v) of a
`
`(e)
`
`ix
`
`

`

`2.
`
`3.
`
`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`stabilizing agent.” ......................................................... 282
`“the pharmaceutical solution further comprises . . .
`an amount of an acid sufficient to achieve a pH
`between about 3.5 and about 5.5.” ............................... 290
`Claim 4 ....................................................................................293
`(a)
`“the isotonicity agent is sodium chloride;” .................. 293
`(b)
`“the stabilizing agent is disodium edetate;” ................. 294
`(c)
`“and the acid is hydrochloric acid.” ............................. 294
`Claim 5 ....................................................................................294
`(a)
`“about 4% (w/v) naloxone hydrochloride;” ................. 295
`(b)
`“about 0.74% (w/v) sodium chloride;” ......................... 295
`(c)
`“about 0.01% (w/v) benzalkonium chloride;” .............. 297
`(d)
`“and about 0.2% (w/v) disodium edetate.” ................... 299
`A Formulator POSA reading Davies in view of HPE, Bahal,
`Kushwaha, and Djupesland would have had ample reason and
`know-how to arrive at the subject matter of claims 6–8. .................. 300
`1.
`Claim 6 ....................................................................................300
`2.
`Claim 7 ....................................................................................303
`3.
`Claim 8 ....................................................................................308
`A Formulator POSA reading Davies in view of HPE, Bahal,
`Kushwaha, and Wyse would have had ample reason and know-
`how to arrive at the subject matter of claim 9. .................................. 313
`A Formulator POSA reading Davies in view of HPE, Djupesland,
`and the ’291 patent would have had ample reason and know-how
`to arrive at the subject matter of claims 12–15 and 21. .................... 318
`1.
`Claim 12 ..................................................................................319
`
`(b)
`
`N.
`
`O.
`
`P.
`
`x
`
`

`

`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`Claim 13 ..................................................................................326
`2.
`Claim 14 ..................................................................................327
`3.
`Claim 15 ..................................................................................328
`4.
`Claim 21 ..................................................................................331
`5.
`A Formulator POSA reading Davies in view of HPE, Djupesland,
`the ’291 patent, and Wyse would have had ample reason and
`know-how to arrive at the subject matter of claims 17–20, 22-23,
`and 29. ............................................................................................... 336
`1.
`Claim 17 ..................................................................................337
`2.
`Claim 18 ..................................................................................342
`3.
`Claim 19 ..................................................................................346
`4.
`Claim 20 ..................................................................................351
`5.
`Claim 22 ..................................................................................353
`(a)
`“A method of treating narcotic-induced respiratory
`depression.” .................................................................. 354
`“delivering a 25-200 μL spray . . . in a manner that
`delivers the pharmaceutical solution in a round
`spray plume with an ovality ratio less than about
`2.0 when measured at 3 cm” ......................................... 357
`“the patient experiences a geometric mean
`naloxone Cmax not less than about 3 ng/ml,
`following a single spray.” ............................................. 358
`Claim 23 ..................................................................................358
`6.
`Claim 29 ..................................................................................359
`7.
`A Formulator POSA reading Davies in view of HPE, Djupesland,
`Bahal, Kushwaha, the ’291 patent, and Wyse would have had
`ample reason and know-how to arrive at the subject matter of
`claims 24–27. ..................................................................................... 362
`
`(b)
`
`(c)
`
`Q.
`
`R.
`
`xi
`
`

`

`S.
`
`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`Claim 24 ..................................................................................363
`1.
`Claim 25 ..................................................................................364
`2.
`Claim 26 ..................................................................................365
`3.
`Claim 27 ..................................................................................366
`4.
`A Formulator POSA reading Davies in view of HPE, Djupesland,
`the ’291 patent, Wyse, and Zomig Review would have had ample
`reason and know-how to arrive at the subject matter of claim 30. ... 367
`VIII. SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ............ 372
`A.
`No teaching away .............................................................................. 373
`B.
`No commercial success ..................................................................... 375
`C.
`No long-felt but unmet need or failure of others............................... 376
`D.
`No unexpected superior results ......................................................... 378
`IX. CONCLUSION ............................................................................................ 380
`
`xii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`I, Maureen 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. 9,561,177 (the
`
`“’177 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 ’177 patent issued on February 7, 2017, and
`
`resulted from U.S. Patent Application No. 15/183,441, filed on June 15, 2016. I
`
`also understand that the U.S. Patent and Trademark Office (“USPTO”) records
`
`state that the ’177 patent is currently assigned to Adapt Pharma Ltd. and Opiant
`
`Pharmaceuticals (“Patent Owners”).
`
`The face page of the ’177 patent lists other patent applications. I
`
`understand that the ’177 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 ’177 patent cannot claim priority to the March 14, 2014
`
`1
`
`

`

`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit 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 ’177 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. 9,561,177 (the ’177 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. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit 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. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit 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
`
`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)
`
`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)
`
`4
`
`

`

`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`
`Exhibit No.
`
`Description
`
`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)
`Nalox1049 Role of Naloxone in Opioid Overdose Fatality Prevention FDA
`Meeting Transcript (Apr. 12, 2012) (2012 FDA Meeting)
`
`Nalox1050
`
`Nalox1051
`
`Rosanske, T., Morphine, in Chemical Stability of Pharmaceuticals:
`A Handbook for Pharmacists, 604–11 (Connors, K. et al. eds., 2d
`ed. 1986) (Rosanske)
`
`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.)
`Nalox1058 U.S. Provisional Patent Appl. No. 61/953,379 (the ’379 provisional)
`
`Generally, the ’177 patent claims are directed methods of treating
`
`opioid overdose or narcotic-induced respiratory depression by delivering a
`
`5
`
`

`

`Inter Partes Review of U.S. Patent No. 9,561,177
`Declaration of Maureen Donovan, Ph.D. (Exhibit Nalox1002)
`pharmaceutical solution containing naloxone, an
`isotonicity agent, and
`
`benzalkonium chloride in the form of a spray to a patient. Other claims are
`
`directed specifically to the mist containing naloxone, an isotonicity agent, and
`
`benzalkonium chloride.
`
`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 arrive at the subject matter of claims 1–5 of the ’177 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
`
`Djupseland would have had ample reason and know-how to arrive at the subject
`
`matter of claims 6–9 of the ’177 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 ample reason and know-how to arrive at the subject
`
`matter of claims 12–15, 17–27, and 29 of the ’177 patent with a reasonable
`
`expect