UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner
`
`v.
`
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owner
`
`_____________________
`
`IPR2019-00694
`U.S. Patent No. 9,629,965
`_____________________
`
`DECLARATION OF MAUREEN DONOVAN, Ph.D.
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`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 ..................................................... 11
`B.
`Claim construction .............................................................................. 13
`C.
`Anticipation and obviousness .............................................................. 14
`D. Written Description and priority ......................................................... 16
`THE ’965 PATENT AND ITS CLAIMS ...................................................... 17
`A.
`Background of the Prior Art Relevant to the ’965 Patent ................... 18
`1.
`Opioid overdose ........................................................................18
`2.
`Prior intranasal formulations of naloxone ................................20
`3.
`Development of a new intranasal naloxone formulation ..........22
`(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
`Independent claims 1 and 20 ............................................................... 56
`
`(f)
`(g)
`
`B.
`
`ii
`
`IV.
`
`(e)
`
`

`

`C.
`D.
`
`V.
`
`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Dependent claims 2–19 and 21–30 ..................................................... 58
`The ’965 patent lacks priority to U.S. Provisional Application
`No. 61/953,379. ................................................................................... 61
`Orange Book listing of the ’965 Patent ............................................... 64
`E.
`CLAIM CONSTRUCTION .......................................................................... 64
`1.
`“pre-primed” .............................................................................65
`2.
`“delivery time” ..........................................................................66
`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%” ...................................................66
`PUBLIC ACCESSIBILITY OF THE PRIOR ART...................................... 67
`VI.
`VII. BASIS OF MY ANALYSIS WITH RESPECT TO OBVIOUSNESS ......... 67
`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 1–2, 9–12, 17–22, 25–26, and 29–30 ....................................... 67
`1.
`Claim 1 ......................................................................................67
`(a)
`Preamble: “A pharmaceutical formulation for
`intranasal administration comprising, in an
`aqueous solution of not more than about 140 μL:” ........ 68
`1.1: “about 4 mg naloxone hydrochloride;” ................... 70
`1.2: “about 0.74 mg NaCl;” ............................................ 72
`1.3: “about 0.01 mg benzalkonium chloride;” ............... 75
`1.4: “about 0.2 mg disodium edetate;” ........................... 79
`1.5: “and an amount of hydrochloric acid sufficient
`to achieve a pH of 3.5-5.5.” ............................................ 80
`Claim 2 ......................................................................................81
`
`(b)
`(c)
`(d)
`(e)
`(f)
`
`2.
`
`iii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Claim 9 ......................................................................................82
`3.
`Claims 10–12 ............................................................................83
`4.
`Claim 17 ....................................................................................86
`5.
`Claim 18 ....................................................................................87
`6.
`Claim 19 ....................................................................................89
`7.
`Claim 20 ....................................................................................89
`8.
`Claims 21, 22, and 26 ...............................................................93
`9.
`10. Claim 25 ....................................................................................94
`11. Claims 29–30 ............................................................................96
`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 23–24............................................................ 98
`1.
`Claim 23 ....................................................................................99
`2.
`Claim 24 ..................................................................................101
`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 27–28 .................................................... 104
`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 1–2, 9–12, 17, and
`20-26. ................................................................................................. 111
`1.
`Claim 1 ....................................................................................111
`(a)
`Preamble: “A pharmaceutical formulation for
`intranasal administration comprising, in an
`aqueous solution of not more than about 140 μL:” ...... 112
`1.1: “about 4 mg naloxone hydrochloride;” ................. 115
`
`(b)
`
`iv
`
`B.
`
`C.
`
`D.
`
`

`

`(c)
`(d)
`(e)
`(f)
`
`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`1.2: “about 0.74 mg NaCl;” .......................................... 116
`1.3: “about 0.01 mg benzalkonium chloride;” ............. 119
`1.4: “about 0.2 mg disodium edetate;” ......................... 128
`1.5: “and an amount of hydrochloric acid sufficient
`to achieve a pH of 3.5-5.5.” .......................................... 136
`Claim 2 ....................................................................................138
`2.
`Claim 9 ....................................................................................138
`3.
`Claims 10–12 ..........................................................................140
`4.
`Claim 17 ..................................................................................144
`5.
`Claim 20 ..................................................................................145
`6.
`Claims 21, 22, and 26 .............................................................150
`7.
`Claim 23 ..................................................................................151
`8.
`Claim 24 ..................................................................................153
`9.
`10. Claim 25 ..................................................................................156
`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 18–19 and 29–
`30. ...................................................................................................... 158
`1.
`Claim 18 ..................................................................................158
`2.
`Claim 19 ..................................................................................162
`3.
`Claims 29–30 ..........................................................................163
`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
`27–28. ................................................................................................ 165
`A Formulator POSA reading Davies in view of HPE, Bahal, and
`v
`
`E.
`
`F.
`
`G.
`
`

`

`(b)
`(c)
`(d)
`(e)
`(f)
`
`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Kushwaha would have had ample reason and know-how to arrive
`at the subject matter of claims 1–2, 9–12, 17–23, 25–26 and 29–
`30. ...................................................................................................... 172
`1.
`Claim 1 ....................................................................................173
`(a)
`Preamble: “A pharmaceutical formulation for
`intranasal administration comprising, in an
`aqueous solution of not more than about 140 μL:” ...... 173
`1.1: “about 4 mg naloxone hydrochloride;” ................. 175
`1.2: “about 0.74 mg NaCl” ........................................... 177
`1.3: “about 0.01 mg benzalkonium chloride;” ............. 178
`1.4: “about 0.2 mg disodium edetate;” ......................... 180
`1.5: “and an amount of hydrochloric acid sufficient
`to achieve a pH of 3.5-5.5.” .......................................... 187
`Claim 2 ....................................................................................191
`2.
`Claim 9 ....................................................................................193
`3.
`Claims 10–12 ..........................................................................195
`4.
`Claim 17 ..................................................................................198
`5.
`Claim 18 ..................................................................................198
`6.
`Claim 19 ..................................................................................201
`7.
`Claim 20 ..................................................................................202
`8.
`Claims 21, 22, and 26 .............................................................207
`9.
`10. Claim 23 ..................................................................................208
`11. Claim 25 ..................................................................................211
`12. Claims 29–30 ..........................................................................211
`A Formulator POSA reading Davies in view of HPE, Bahal,
`vi
`
`H.
`
`

`

`I.
`
`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Kushwaha, and Djupesland would have had ample reason and
`know-how to arrive at the subject matter of claim 24. ...................... 214
`A Formulator POSA reading Davies in view of HPE, Bahal,
`Kushwaha, Djupesland, and the ’291 patent would have had
`ample reason and know-how to arrive at the subject matter of
`claims 27–28. ..................................................................................... 218
`VIII. SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ............ 225
`A.
`No teaching away .............................................................................. 225
`B.
`No commercial success ..................................................................... 227
`C.
`No long-felt but unmet need or failure of others............................... 228
`D.
`No unexpected superior results ......................................................... 231
`IX. CONCLUSION ............................................................................................ 232
`
`vii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`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. 9,629,965 (the
`
`“’965 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 ’965 patent issued on April 25, 2017, and
`
`resulted from U.S. Patent Application No. 15/335,145, filed on October 26, 2016.
`
`I also understand that the U.S. Patent and Trademark Office (“USPTO”) records
`
`state that the ’965 patent is currently assigned to Opiant Pharmaceuticals, Inc.
`
`(“Patent Owner”).
`
`The face page of the ’965 patent lists other patent applications. I
`
`understand that the ’965 patent is related to a patent application which was filed
`
`on March 14, 2014. As discussed below, it is my opinion that the ’965 patent
`
`cannot claim priority to the March 14, 2014 application, and that the earliest
`
`application to which it can claim priority has a filing date of March 16, 2015.
`
`1
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`In preparing this Declaration, I have reviewed the ’965 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. 9,629,965 (the ’965 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. 9,629,965
`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. 9,629,965
`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. 9,629,965
`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)
`
`Nalox1063
`
`Excerpt of File History of U.S. Patent No. 9,629,965, March 17,
`2017 Office Action, Notice of Allowance and Fees Due (’965
`Notice of Allowance)
`
`Generally, the ’965 patent claims are directed to pharmaceutical
`
`formulations for intranasal administration of naloxone hydrochloride containing
`
`5
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`sodium chloride, benzalkonium chloride, disodium edetate, and an amount of
`
`hydrochloric acid sufficient to achieve a pH of 3.5–5.5. Also claimed are single-
`
`use, pre-primed devices adapted for nasal delivery of a pharmaceutical solution
`
`having a reservoir containing compositions containing naloxone hydrochloride, an
`
`isotonicity agent, a preservative, a stabilizing agent, and an amount of acid
`
`sufficient to adjust the pH to between 3.5 and 5.5.
`
`It is my opinion that a POSA reading Wyse in view of Handbook of
`
`Pharmaceutical Excipient (“HPE”) would have had ample reason and know-how
`
`to arrive at the subject matter of claims 1–2, 9–12, 17–22, 25–26, and 29–30 of the
`
`’965 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 23–24 of the ’965 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 27–28 of the ’965 patent with a reasonable expectation of
`
`success, as discussed in this Declaration below.
`
`6
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`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 1–2, 9–12, 17, and 20-26 of the ’965 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Wang in view of Djupesland,
`
`HPE, Bahal, Kushwaha, and Wyse would have had ample reason and know-how
`
`to arrive at the subject matter of claims 18–19 and 29–30 of the ’965 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Wang in view of Djupesland,
`
`HPE, Bahal, Kushwaha, and the ’291 patent would have had ample reason and
`
`know-how to arrive at the subject matter of claims 27–28 of the ’965 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Davies in view of HPE, Bahal,
`
`and Kushwaha would have had ample reason and know-how to arrive at the
`
`subject matter of claims 1–2, 9–12, 17–23, 25–26, and 29–30 of the ’965 patent
`
`with a reasonable expectation of success, as discussed in this Declaration below.
`
`It is my opinion that a POSA reading Davies in view of HPE, Bahal,
`
`Kushwaha, and Djupesland would have had ample reason and know-how to arrive
`
`at the subject matter of claim 24 of the ’965 patent with a reasonable expectation
`
`of success, as discussed in this Declaration below.
`
`7
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`It is my opinion that a POSA reading Davies in view of HPE, Bahal,
`
`Kushwaha, Djupesland, and the ’291 patent would have had ample reason and
`
`know-how to arrive at the subject matter of claims 27–28 of the ’965 patent with a
`
`reasonable expectation of success, as discussed in this Declaration below.
`
`I have reviewed the opinion of Dr. Günther Hochhaus, an expert in
`
`clinical pharmacology, and it is my understanding that he has rendered an opinion
`
`that claims 3–8 and 13–16 of the ’965 patent are obvious over the prior art. I offer
`
`no opinion regarding the obviousness of these claims.
`
`II. MY BACKGROUND AND QUALIFICATIONS
`I am a Professor in the Division of Pharmaceutics and Translational
`
`Therapeutics at the University of Iowa College of Pharmacy. I have more than 25
`
`years of experience working and consulting in the field of pharmaceutics. My
`
`curriculum vitae is attached to this report as Exhibit A.
`
`I am an expert in pharmaceutics. I received my Bachelor of Science
`
`in Pharmacy from the University of Minnesota College of Pharmacy in 1983 and
`
`my Ph.D. in Pharmaceutics from the University of Michigan in 1989.
`
`My professional experience includes working as a Staff Pharmacist
`
`for Clark Professional Pharmacy from 1986 until 1989 and as a Visiting Scholar
`
`for SmithKline Beecham Pharmaceuticals in 1991. From 1989 through the
`
`present, I have held various positions at the University of Iowa College of
`
`8
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`Pharmacy. Specifically, in the Division of Pharmaceutics, I was an Assistant
`
`Professor from 1989 until 1996, and an Associate Professor from 1996 until 2008.
`
`I was promoted to the rank of Professor in 2008 in the College of Pharmacy, and I
`
`currently hold this position. From 2008 until 2013, I was the Division Head for the
`
`Division of Pharmaceutics. In 2013, I became the Associate Dean for
`
`Undergraduate Programs at the College of Pharmacy, and I currently hold this
`
`position.
`
`I have over 25 years of experience in pharmaceutical research and
`
`development
`
`including actively
`
`teaching drug delivery, pharmaceutical
`
`preformulation, and compounding to pharmacy students and graduate students,
`
`and directing research programs focused on drug absorption, nasal drug delivery,
`
`and alternative routes of drug delivery and delivery systems.
`
`I have published numerous articles, book chapters, and abstracts in
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`the area of pharmaceutics, drug absorption, drug delivery, and materials
`
`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
`
`influence the deposition of nasal sprays in the nasal cavity as well as the
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`absorption of active ingredients through nasal tissues. Of particular relevance to
`
`this proceeding, I have co-authored numerous publications related to systemic
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`delivery of compounds through intranasal administration, including such papers as
`
`9
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`• 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.
`
` Correlation between Nasal
`• Zhang H, Lin C-W, Donovan MD.
`Membrane Permeability
`and Nasal Absorption Rate. AAPS
`PharmSciTech 14(1), 60–63, 2013.
`
`• Foo M-Y, Cheng Y-S, Su W-C, and Donovan MD. The Influence of
`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
`
`technology, including the American Association of Pharmaceutical Scientists.
`
`I am being compensated for my work at $400 per hour in this matter.
`
`No part of this compensation due or received is contingent upon the outcome of
`
`this matter or the pending proceeding.
`
`In addition to my knowledge, education, and experience in the field
`
`of pharmaceutical formulation, in forming the opinions I express in this report, I
`
`reviewed the full list of materials cited in paragraph 5 above.
`
`III. LEGAL STANDARDS
`I am neither a patent lawyer nor an expert in patent law. It has been
`
`explained to me by counsel for Petitioner that the following law is applicable to
`
`10
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`patent validity and I have relied upon these legal principles in forming opinions
`
`set forth in this Declaration.
`
`A.
`
`Person of Ordinary Skill in the Art
`I understand that a POSA is a hypothetical person who is presumed to
`
`be aware of all pertinent art, thinks along conventional wisdom in the art, and is a
`
`person of ordinary creativity. A POSA may work as part of a multi-disciplinary
`
`team and draw upon not only his or her own skills, but also take advantage of
`
`certain specialized skills of others in the team, to solve a given problem. In
`
`evaluating who constitutes a POSA, one should take into account the types of
`
`problems encountered in the art, solutions to those problems disclosed in the prior
`
`art, the speed of innovation in the field, the sophistication of the technology, and
`
`the education level of the persons working in the field,
`
`In my opinion, with regard to the ’965 patent, a POSA would
`
`comprise a team of individuals having experience in drug development, and
`
`specifically the development of solution-based dosage forms such as intranasal
`
`dosage forms. Such a team would include at least one formulator with experience
`
`in preformulation testing for and selection of excipients for a solution-based
`
`dosage
`
`form
`
`(including
`
`intranasal dosage
`
`forms)
`
`to achieve a
`
`target
`
`pharmaceutical profile. Such a formulator would likely have a Ph.D. in pharmacy,
`
`pharmaceutics, pharmaceutical chemistry, or a similar
`
`field
`
`involving
`
`11
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`pharmaceutical formulations, and would have several years of experience in
`
`pharmaceutical formulation development, including development of solution-
`
`based dosage forms, including intranasal dosage forms. Alternatively, such a
`
`formulator would have a Bachelor’s or Master’s degree
`
`in pharmacy,
`
`pharmaceutical chemistry, or a similar
`
`field
`
`involving pharmaceutical
`
`formulations, and would have 3–5 years of experience developing and testing
`
`pharmaceutical formulations with specific experience with solution dosage forms,
`
`such as intranasal sprays and drops. Such a formulator would also have an
`
`understanding of the importance, use, and component elements of certain
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`commercially-available delivery systems for dosage forms, including inhalers,
`
`metered-dose nasal sprayers, and single-dose nasal sprayers, as well as the
`
`importance of the properties of the spray emitted from such devices (including
`
`droplet size and spray plume geometry).
`
`Within the POSA “team,” such a formulator would routinely
`
`collaborate with others, such as clinical pharmacologists, to discuss issues
`
`regarding safety, efficacy, and pharmacokinetic profiles and requirements of a
`
`new dosage form, and with mechanical, chemical, or biomedical engineers with
`
`experience in the design and development of new devices for delivering drugs,
`
`such as autoinjectors and spray applicators.
`
`12
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Declaration of Maureen Donovan, Ph.D. (Exhibit 1002)
`I have at least the ordinary skill of the “formulator” who forms part of
`
`the POSA team (i.e., the “Formulator POSA”) in the relevant art with respect to
`
`the ’965 patent, and I possessed such ordinary skill as of the March 16, 2015,
`
`priority date of the ’965 patent, as well as on March 14, 2014 (the date U.S.
`
`Provisional Patent Application No. 61/953,379 was filed).
`
`B.
`
`Claim construction
`I understand from counsel that, prior to conducting an analysis of a
`
`patent claim’s validity, the claim terms must be properly construed. I have been
`
`advised that claim terms are generally interpreted in accordance with the ordinary
`
`and customary meaning they would have to a person of ordinary skill in the art at
`
`the time of the invention. I have also been advised that the skilled person would
`
`read the claim terms in the context of the claims as well as the entire patent,
`
`including the specification of the patent. I further understand that the skilled
`
`person, when interpreting claim terms, would consider the record of a patentee’s
`
`communications with the patent office during prosecution to obtain the patent (the
`
`“prosecution history”). Together, the patent claims, spe