UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner
`
`v.
`
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owner
`
`_____________________
`
`IPR2019-00687
`U.S. Patent No. 9,211,253
`_____________________
`
`DECLARATION OF MAUREEN DONOVAN, Ph.D.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`TABLE OF CONTENTS
`OVERVIEW .................................................................................................... 1
`I.
`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 8
`III.
`LEGAL STANDARDS ................................................................................. 10
`A.
`Person of ordinary skill in the art ........................................................ 10
`B.
`Claim construction .............................................................................. 12
`C.
`Anticipation and obviousness .............................................................. 13
`D. Written description and priority .......................................................... 16
`THE ’253 PATENT AND ITS CLAIMS ...................................................... 16
`A.
`Background of the art pertinent to the ’253 Patent ............................. 18
`1.
`Opioid overdose ........................................................................18
`2.
`Prior intranasal formulations of naloxone ................................20
`3.
`Development of a new intranasal naloxone formulation ..........21
`(a)
`Physical and chemical properties of naloxone ............... 22
`(b)
`Stability of the Formulation. ........................................... 25
`(c)
`Nasal physiology. ........................................................... 28
`(d) Drug exposure attributes for an improved
`intranasal formulation of naloxone. ................................ 29
`Choice of pharmaceutical excipients to achieve the
`desired exposure and stability attributes. ........................ 31
`Choice of delivery device ............................................... 48
`The properties of the nasal spray delivered by the
`spray device. ................................................................... 49
`Claim 1 of the ’253 patent ................................................................... 56
`
`(f)
`(g)
`
`B.
`
`ii
`
`IV.
`
`(e)
`
`

`

`C.
`D.
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Dependent claims 2–29 of the ’253 patent .......................................... 57
`The ’253 patent lacks priority to U.S. Provisional Application
`No. 61/953,379. ................................................................................... 60
`Orange Book listing of the ’253 patent ............................................... 62
`E.
`CLAIM CONSTRUCTION .......................................................................... 63
`1.
`“pre-primed” .............................................................................64
`2.
`“delivery time” ..........................................................................64
`3.
`“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%” ...................................................64
`PUBLIC ACCESSIBILITY OF THE PRIOR ART...................................... 65
`VI.
`VII. BASIS OF MY ANALYSIS WITH RESPECT TO OBVIOUSNESS ......... 65
`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 and 16–24. ......................................................................... 65
`1.
`Claim 1 ......................................................................................66
`(a)
`Preamble: “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” ........................................... 67
`1.1: “a pharmaceutical composition which is an
`aqueous solution of about 100 μL comprising:” ............ 69
`1.2: “about 4 mg naloxone hydrochloride or a
`hydrate thereof;” ............................................................. 71
`1.3: “between about 0.2 mg and about 1.2 mg of an
`isotonicity agent;” ........................................................... 73
`1.4: “between about 0.005 mg and about 0.015 mg
`of a preservative;” ........................................................... 74
`
`V.
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`iii
`
`

`

`2.
`
`3.
`
`(f)
`(g)
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`1.5: “about 0.2 mg of a stabilizing agent;” ..................... 81
`1.6: “an amount of an acid sufficient to achieve a
`pH of 3.5-5.5.” ................................................................ 83
`Claim 2 ......................................................................................84
`(a)
`“the isotonicity agent is NaCl;” ...................................... 84
`(b)
`“the preservative is benzalkonium chloride;”................. 84
`(c)
`“the stabilizing agent is disodium edetate;” ................... 88
`(d)
`“and the acid is hydrochloric acid.” ............................... 88
`Claim 3 ......................................................................................88
`(a)
`“about 4.4 mg naloxone hydrochloride dihydrate;” ....... 88
`(b)
`“about 0.74 mg NaCl;” ................................................... 89
`(c)
`“about 0.01 mg benzalkonium chloride;” ....................... 93
`(d)
`“about 0.2 mg disodium edetate;” .................................. 93
`(e)
`“and an amount of hydrochloric acid sufficient to
`achieve a pH of 3.5-5.5.” ................................................ 93
`Claim 16 ....................................................................................94
`4.
`Claim 17 ....................................................................................95
`5.
`Claim 18 ....................................................................................97
`6.
`Claim 19 ....................................................................................97
`7.
`Claims 20–23 ............................................................................99
`8.
`Claim 24 ..................................................................................103
`9.
`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. ........................................... 105
`1.
`Claim 4 ....................................................................................106
`
`iv
`
`B.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Claim 5 ....................................................................................108
`2.
`Claim 6 ....................................................................................111
`3.
`Claim 7 ....................................................................................112
`4.
`Claims 10–11 ..........................................................................113
`5.
`Claims 12–14 ..........................................................................115
`6.
`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. .................................... 118
`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, 12–14, and 16. ... 125
`1.
`Claim 1 ....................................................................................125
`(a)
`Preamble: “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” ......................................... 126
`1.1: “a pharmaceutical composition which is an
`aqueous solution of about 100 μL comprising:” .......... 129
`1.2: “about 4 mg naloxone hydrochloride or a
`hydrate thereof;” ........................................................... 132
`1.3: “between about 0.2 mg and about 1.2 mg of an
`isotonicity agent;” ......................................................... 135
`1.4: “between about 0.005 mg and about 0.015 mg
`of a preservative;” ......................................................... 137
`1.5: “about 0.2 mg of a stabilizing agent;” ................... 146
`1.6: “an amount of an acid sufficient to achieve a
`pH of 3.5-5.5.” .............................................................. 154
`Claim 2 ....................................................................................155
`
`(e)
`
`(f)
`(g)
`
`2.
`
`C.
`
`D.
`
`(b)
`
`(c)
`
`(d)
`
`v
`
`

`

`3.
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`“the isotonicity agent is NaCl;” .................................... 155
`(a)
`“the preservative is benzalkonium chloride;”............... 155
`(b)
`“the stabilizing agent is disodium edetate;” ................. 156
`(c)
`“and the acid is hydrochloric acid.” ............................. 156
`(d)
`Claim 3 ....................................................................................156
`(a)
`“about 4.4 mg naloxone hydrochloride dihydrate;” ..... 157
`(b)
`“about 0.74 mg NaCl;” ................................................. 159
`(c)
`“about 0.01 mg benzalkonium chloride;” ..................... 162
`(d)
`“about 0.2 mg disodium edetate;” ................................ 164
`(e)
`“and an amount of hydrochloric acid sufficient to
`achieve a pH of 3.5-5.5.” .............................................. 164
`Claim 4 ....................................................................................164
`4.
`Claim 5 ....................................................................................167
`5.
`Claim 6 ....................................................................................169
`6.
`Claim 7 ....................................................................................171
`7.
`Claims 12–14 ..........................................................................172
`8.
`Claim 16 ..................................................................................176
`9.
`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 10–11 and 17–
`24. ...................................................................................................... 178
`1.
`Claims 10–11 ..........................................................................179
`2.
`Claim 17 ..................................................................................182
`3.
`Claim 18 ..................................................................................185
`4.
`Claim 19 ..................................................................................186
`
`vi
`
`E.
`
`

`

`F.
`
`G.
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Claims 20–23 ..........................................................................189
`5.
`Claim 24 ..................................................................................193
`6.
`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. ........................................................................................................ 195
`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 and 16–24. ................................. 202
`1.
`Claim 1 ....................................................................................202
`(a)
`Preamble: “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” ......................................... 203
`1.1: “a pharmaceutical composition which is an
`aqueous solution of about 100 μL comprising:” .......... 207
`1.2: “about 4 mg naloxone hydrochloride or a
`hydrate thereof;” ........................................................... 209
`1.3: “between about 0.2 mg and about 1.2 mg of an
`isotonicity agent;” ......................................................... 211
`1.4: “between about 0.005 mg and about 0.015 mg
`of a preservative;” ......................................................... 212
`1.5: “about 0.2 mg of a stabilizing agent;” ................... 214
`1.6: “an amount of an acid sufficient to achieve a
`pH of 3.5-5.5.” .............................................................. 221
`Claim 2 ....................................................................................225
`(a)
`“the isotonicity agent is NaCl;” .................................... 225
`(b)
`“the preservative is benzalkonium chloride;”............... 225
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`(f)
`(g)
`
`2.
`
`vii
`
`

`

`3.
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`“the stabilizing agent is disodium edetate;” ................. 226
`(c)
`“and the acid is hydrochloric acid.” ............................. 226
`(d)
`Claim 3 ....................................................................................226
`(a)
`“about 4.4 mg naloxone hydrochloride dihydrate;” ..... 227
`(b)
`“about 0.74 mg NaCl;” ................................................. 229
`(c)
`“about 0.01 mg benzalkonium chloride;” ..................... 230
`(d)
`“about 0.2 mg disodium edetate;” ................................ 231
`(e)
`“and an amount of hydrochloric acid sufficient to
`achieve a pH of 3.5-5.5.” .............................................. 231
`Claim 4 ....................................................................................231
`4.
`Claim 16 ..................................................................................234
`5.
`Claim 17 ..................................................................................236
`6.
`Claim 18 ..................................................................................238
`7.
`Claim 19 ..................................................................................239
`8.
`Claims 20–23 ..........................................................................241
`9.
`10. Claim 24 ..................................................................................245
`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. .......... 248
`1.
`Claim 5 ....................................................................................249
`2.
`Claim 6 ....................................................................................252
`3.
`Claim 7 ....................................................................................257
`4.
`Claims 10–11 ..........................................................................257
`5.
`Claims 12–14 ..........................................................................260
`
`viii
`
`H.
`
`

`

`I.
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`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. ........................................................................................................ 263
`VIII. SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ............ 270
`A.
`No teaching away .............................................................................. 271
`B.
`No commercial success ..................................................................... 272
`C.
`No long-felt but unmet need or failure of others............................... 273
`D.
`No unexpected superior results ......................................................... 276
`IX. CONCLUSION ............................................................................................ 277
`
`ix
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`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. 9,211,253 (“the
`
`’253 patent”) (Nalox1001).
`
`I have been retained as an expert witness on behalf of Nalox-1
`
`Pharmaceuticals, LLC (“Nalox-1”) for this IPR.
`
`I understand that the ’253 patent issued on December 15, 2015, and
`
`resulted from U.S. Patent Application No. 14/659,472, filed on March 16, 2015. I
`
`also understand that the U.S. Patent and Trademark Office (“USPTO”) records
`
`state that the ’253 patent is currently assigned to Opiant Pharmaceuticals, Inc.
`
`The face page of the ’253 patent lists other patent applications. I
`
`understand that the ’253 patent is related to a patent application which was filed on
`
`March 14, 2014. As discussed below, it is my opinion that the ’253 patent cannot
`
`claim priority to the March 14, 2014 application, and it is only entitled to its filing
`
`date of March 16, 2015.
`
`1
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`In preparing this Declaration, I have reviewed the ’253 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. 9,211,253 (the ’253 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)
`
`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)
`
`2
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`
`Exhibit No.
`
`Description
`
`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)
`
`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)
`
`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)
`
`3
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`
`Exhibit No.
`
`Description
`
`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)
`
`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)
`
`4
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`
`Exhibit No.
`
`Description
`
`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.)
`Nalox1058 U.S. Provisional Patent Appl. No. 61/953,379 (the ’379
`provisional)
`
`Generally, the ’253 patent claims are directed to a single-use, pre-
`
`primed device adapted for nasal delivery of a pharmaceutical composition
`
`comprising naloxone hydrochloride or a hydrate thereof, a preservative, an
`
`5
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`isotonicity agent, a stabilizing agent, and an acid sufficient to achieve a pH of 3.5
`
`to 5.5.
`
`It is my opinion that a person of ordinary skill in the art (“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 1–3
`
`and 16–24 of the ’253 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 ’253 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 ’253 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, 12–14, and 16 of the ’253 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`6
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`It is my opinion that a POSA reading Wang in view of Djupesland,
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`HPE, Bahal, Kushwaha, and Wyse would have had ample reason and know-how to
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`arrive at the subject matter of claims 10–11 and 17–24 of the ’253 patent with a
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`reasonable expectation of success, as discussed in this Declaration below.
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`It is my opinion that a POSA reading Wang in view of Djupesland,
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`HPE, Bahal, Kushwaha, and the ’291 patent would have had ample reason and
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`know-how to arrive at the subject matter of claims 8–9 of the ’253 patent with a
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`reasonable expectation of success, as discussed in this Declaration below.
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`It is my opinion that a POSA reading Davies in view of HPE, Bahal,
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`and Kushwaha would have had ample reason and know-how to arrive at the subject
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`matter of claims 1–4 and 16–24 of the ’253 patent with a reasonable expectation of
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`success, as discussed in this Declaration below.
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`It is my opinion that a POSA reading Davies in view of Djupesland,
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`HPE, Bahal, and Kushwaha would have had ample reason and know-how to arrive
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`at the subject matter of claims 5–7 and 10–14 of the ’253 patent with a reasonable
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`expectation of success, as discussed in this Declaration below.
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`It is my opinion that a POSA reading Davies in view of Djupesland,
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`HPE, Bahal, Kushwaha, and the ’291 patent would have had ample reason and
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`know-how to arrive at the subject matter of claims 8–9 of the ’253 patent with a
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`reasonable expectation of success, as discussed in this Declaration below.
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`7
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`

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`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`I have reviewed the opinion of Dr. Günther Hochhaus, an expert in
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`clinical pharmacology, and it is my understanding that he has rendered an opinion
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`that claims 15 and 25–29 of the ’253 patent are obvious over the prior art. I offer
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`no opinion regarding the obviousness of these claims.
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`II. MY BACKGROUND AND QUALIFICATIONS
`I am a Professor in the Division of Pharmaceutics and Translational
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`Therapeutics at the University of Iowa College of Pharmacy. I have more than 25
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`years of experience working and consulting in the field of pharmaceutics. My
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`curriculum vitae is attached to this report as Exhibit A.
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`I am an expert in pharmaceutics. I received my Bachelor of Science in
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`Pharmacy from the University of Minnesota College of Pharmacy in 1983 and my
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`Ph.D. in Pharmaceutics from the University of Michigan in 1989.
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`My professional experience includes working as a Staff Pharmacist
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`for Clark Professional Pharmacy from 1986 until 1989 and as a Visiting Scholar
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`for SmithKline Beecham Pharmaceuticals in 1991. From 1989 through the present,
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`I have held various positions at the University of Iowa College of Pharmacy.
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`Specifically, in the Division of Pharmaceutics, I was an Assistant Professor from
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`1989 until 1996, and an Associate Professor from 1996 until 2008. I was promoted
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`to the rank of Professor in 2008 in the College of Pharmacy, and I currently hold
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`this position. From 2008 until 2013, I was the Division Head for the Division of
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`8
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`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Pharmaceutics. In 2013, I became the Associate Dean for Undergraduate Programs
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`at the College of Pharmacy, and I currently hold this position.
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`I have over 25 years of experience in pharmaceutical research and
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`development
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`including actively
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`teaching drug delivery, pharmaceutical
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`preformulation, and compounding to pharmacy students and graduate students, and
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`directing research programs focused on drug absorption, nasal drug delivery, and
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`alternative routes of drug delivery and delivery systems.
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`I have published numerous articles, book chapters, and abstracts in the
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`area of pharmaceutics, drug absorption, drug delivery, and materials
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`characterization, and have conducted research related to the absorption of
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`compounds from the nasal cavity as well as the properties of nasal sprays that
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`influence the deposition of nasal sprays in the nasal cavity as well as the absorption
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`of active ingredients through nasal tissues. Of particular relevance to this
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`proceeding, I have co-authored numerous publications related to systemic delivery
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`of compounds through intranasal administration, including such papers as
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`• Al-Ghabeish M, Scheetz T, Assem M, Donovan MD. Microarray
`Determination of Expression of Drug Transporters in Humans and Animal
`Species
`Used
`in
`the
`Investigation
`of
`Nasal
`Absorption. Mol. Pharm. 12(8), 2742–54, 2015.
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`• Zhang H, Lin C-W, Donovan MD. Correlation between Nasal Membrane
`Permeability and Nasal Absorption Rate. AAPS PharmSciTech 14(1), 60–
`63, 2013.
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`• Foo M-Y, Cheng Y-S, Su W-C, and Donovan MD. The Influence of
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`9
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`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Spray Geometry on Intranasal Deposition and Distribution. J. Aerosol
`Med. 20 (4), 495–508, 2007
`
`• Chemuturi NV, Hayden P, Klausner M, and Donovan MD. Comparison
`of Human Tracheal/bronchial Epithelial Cell Cultures (EpiAirway) and
`Bovine Nasal Respiratory Explants for Nasal Drug Transport Studies. J.
`Pharm. Sci. 94, 1976–85, 2005.
`I also belong to several professional societies for pharmaceutical science and
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`technology, including the American Association of Pharmaceutical Scientists.
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`I am being compensated for my work at $400 per hour in this matter.
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`No part of this compensation due or received is contingent upon the outcome of
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`this matter or the pending proceeding.
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`In addition to my knowledge, education, and experience in the field of
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`pharmaceutical formulation, in forming the opinions I express in this report, I
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`reviewed the full list of materials cited in paragraph 5 above.
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`III. LEGAL STANDARDS
`I am neither a patent lawyer nor an expert in patent law. It has been
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`explained to me by counsel for Petitioner that the following law is applicable to
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`patent validity and I have relied upon these legal principles in forming opinions set
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`forth in this Declaration.
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`A.
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`Person of ordinary skill in the art
`I understand that a POSA is a hypothetical person who is presumed to
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`be aware of all pertinent art, thinks along conventional wisdom in the art, and is a
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`person of ordinary creativity. A POSA may work as part of a multi-disciplinary
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`10
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`

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`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`team and draw upon not only his or her own skills, but also take advantage of
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`certain specialized skills of others in the team, to solve a given problem. In
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`evaluating who const