`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`
`NALOX-1 PHARMACEUTICALS, LLC,
`
`Petitioner
`
`v.
`
`ADAPT PHARMA OPERATIONS LIMITED, AND
`OPIANT PHARMACEUTICALS, INC.
`Patent Owners
`
`_____________________
`
`IPR2019-00694
`U.S. Patent No. 9,629,965
`_____________________
`
`
`SUPPLEMENTAL DECLARATION OF GÜNTHER HOCHHAUS, Ph.D.
`
`
`
`
`
`
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`TABLE OF CONTENTS
`
`
`
`I.
`
`OVERVIEW .................................................................................................... 1
`
`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 8
`
`III. LEGAL STANDARDS ................................................................................. 11
`
`IV. THE CLAIMED DOSE OF 4 MG OF NALOXONE WOULD HAVE
`BEEN OBVIOUS TO A POSA..................................................................... 12
`
`A. Wyse discloses a range of naloxone content that includes 4 mg,
`and does not “teach away” from such a dose. ..................................... 12
`
`B. A Pharmacologist POSA seeking to develop a community-use
`intranasal naloxone formulation would have been motivated to
`choose a naloxone dose of greater than 2 mg. .................................... 15
`
`C.
`
`Concerns over inducing acute withdrawal would not have
`outweighed administering a less than effective dose of naloxone. ..... 21
`
`D. A Pharmacologist POSA would have tried to achieve a rapid
`onset of action and high drug exposure with an IN naloxone
`formulation, and would have known that a naloxone dose higher
`than 2 mg could achieve these goals. .................................................. 24
`
`E.
`
`F.
`
`A Pharmacologist POSA would not have expected
`the
`differences in drug concentration and excipients between Wyse’s
`IN formulations and the formulation of the claims to have
`unpredictable effects on pK. ................................................................ 28
`
`A Pharmacologist POSA would have reasonably expected that
`the IN exposure parameters disclosed with Wyse’s 2 mg
`administration would remain dose proportional at least at 4 mg. ....... 34
`
`G.
`
`The claimed naloxone formulation has fully expected properties. ..... 37
`
`1.
`
`The Cmax differences between Wyse and the claimed
`formulation are not statistically significant. .............................37
`
`
`
`ii
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`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`2.
`
`3.
`
`The relative bioavailability differences between the Wyse
`formulation and the claimed formulation are not statistically
`significant. .................................................................................40
`
`In an “apples-to-apples” comparison, the terminal half-lives of
`the Wyse formulation and the claimed formulation are not
`different. ....................................................................................41
`
`V.
`
`CONCLUSION .............................................................................................. 44
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`iii
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`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`I, Günther Hochhaus, 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 and experience
`
`in the field of clinical pharmacology, in particular with respect to nasal spray
`
`dosage forms. I understand that this Declaration is being submitted in support of
`
`Petitioner Nalox-1 Pharmaceuticals, LLC’s (“Nalox-1”) Reply to Patent Owner’s
`
`Response to the petition for Inter Partes Review (“IPR”) of certain claims of U.S.
`
`Patent No. 9,629,965 (“the 965 patent”) (Nalox1001).
`
`
`
`This is my second Declaration in this proceeding. Previously, I
`
`submitted a Declaration (Nalox1003) in support of Nalox-1’s petition for IPR
`
`challenging the ’965 patent. I refer to that Declaration hereinafter as “my first
`
`Declaration.”
`
`
`
`I have now been asked to supplement the opinions I expressed in my
`
`first Declaration. I have also been asked to respond to certain opinions contained
`
`in the Declarations of Kenneth A. Williams, M.D. (Ex-2001; Ex-2202) and Stuart
`
`A. Jones, Ph.D. (Ex-2201).
`
`
`
`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 addition to the exhibits disclosed in my first Declaration. See Nalox1003, ¶5.
`
`
`
`1
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`Exhibit No.
`
`Description
`
`Nalox1001 U.S. Patent No. 9,629,965 (the ’965 patent)
`
`Nalox1002 Expert Declaration of Maureen Donovan
`
`Nalox1003 Expert Declaration of Günther Hochhaus (my first Declaration)
`
`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)
`
`Nalox1016
`
`Wermeling, D., A Response to the Opioid Overdose Epidemic:
`Naloxone Nasal Spray, 3 Drug Deliv. & Transl. Res. 63–74
`(2013) (Wermeling 2013)
`
`Nalox1017
`
`Alabama Department of Public Health, Alabama EMS Patient
`Care Protocols (7th ed., Oct. 2013) (Alabama EMS Protocols)
`
`Nalox1020
`
`Barton, E. et al., Intranasal Administration of Naloxone by
`Paramedics, 6 Prehosp. Em. Care 54–58 (Barton 2002)
`
`Nalox1023
`
`Boyer, E., Management of Opioid Analgesic Overdose, 367(2)
`N. Engl. J. Med. 146–55 (2012) (Boyer)
`
`Nalox1025
`
`Excerpt of Commonwealth of Kentucky, Kentucky Patient Care
`Protocols (Mar. 13, 2015) (Kentucky Patient Care Protocols)
`
`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)
`
`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)
`
`
`
`2
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`Exhibit No.
`
`Description
`
`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)
`
`Nalox1037
`
`Kleiman-Wexler, R. et al., Pharmacokinetics of Naloxone-An
`Insight into the Locus of Effect on Stress-Ulceration, 251(2) J.
`Pharmacol. Exp. Ther. 435–38 (1989) (Kleiman-Wexler)
`
`Nalox1040
`
`Merlin, M. et al., Intranasal Naloxone Delivery is an
`Alternative to Intravenous Naloxone for Opioid Overdoses, 28
`Am. J. Emerg. Med. 296–303 (2010) (Merlin)
`
`Nalox1044
`
`Physicians’ Desk Reference, NARCAN [Naloxone
`Hydrochloride Injection, USP], IMITREX Nasal Spray
`[Sumatriptan], 1300–02, 1546–50 (57th ed., 2003) (PDR 2003)
`
`Nalox1047
`
`Robertson, T. et al., Intranasal Naloxone is a Viable Alternative
`to Intravenous Naloxone for Prehospital Narcotic Overdose, 13
`Prehosp. Emerg. Care 512–15 (2009) (Robertson 2009)
`
`Nalox1049
`
`Role of Naloxone in Opioid Overdose Fatality Prevention FDA
`Meeting Transcript (Apr. 12, 2012) (2012 FDA Meeting)
`
`Nalox1203
`
`Agency for Healthcare Research & Quality, H.H.S.,
`Comparative Effectiveness Review, Management of Suspected
`Opioid Overdose With Naloxone by Emergency Medical
`Services Personnel No. 193 (2017) (AHRQ 2017)
`
`Nalox1204
`
`Asali, L.A. & Brown, K.F., Naloxone Protein Binding in Adult
`and Foetal Plasma, 27 Eur. J. Clin. Pharmacol. 459–63 (1984)
`(Asali)
`
`Nalox1207
`
`Committee on Drugs, American Academy of Pediatrics,
`Naloxone Dosage and Route of Administration for Infants and
`Children: Addendum to Emergency Drug Doses for Infants and
`Children, 66(3) Pediatrics 484–85 (1990) (Pediatrics 1990)
`
`
`
`3
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`Exhibit No.
`
`Description
`
`Nalox1211
`
`Exploring Naloxone Uptake and Uses, FDA Meeting Transcript
`(July 1, 2015) (2015 FDA Meeting)
`
`Nalox1215
`
`Hochhaus, G. & Derendorf, H., Dose Optimization Based on
`Pharmacokinetic/Pharmacodynamic Modeling, Handbook of
`Pharmacokinetic/Pharmacodynamic Correlation 79-120 (1995)
`(Hochhaus 1995)
`
`Nalox1216
`
`Hochhaus, G. et al., A New Solution-Based Intranasal
`Triamcinolone Acetonide Formulation in Patients with
`Perennial Allergic Rhinitis: How Does the
`Pharmacokinetic/Pharmacodynamic Profile for Cortisol
`Suppression Compare with an Aqueous Suspension-Based
`Formulation?, 42 J. Clin. Pharmacol. 662–69 (2002) (Hochhaus
`2002)
`
`Nalox1217
`
`Hochhaus, G. et al., Pharmacokinetic/Pharmacodynamic
`Aspects of Aerosol Therapy Using Glucocorticoids as a Model,
`37 J. Clin. Pharmacol. 881–92 (1997) (Hochhaus 1997)
`
`Nalox1218
`
`Hsu, H. et al., Effect of Formulation Variables on the Nasal
`Permeability and Stability of Naloxone Intranasal
`Formulations, 20(232) AAPS PharmaSciTech (2019) (Hsu)
`
`Nalox1221
`
`Jambhekar S. & Breen, P., Extravascular Routes of Drug
`Administration, in Basic Pharmacokinetics, 97-124 (2009)
`(Jambehkar)
`
`Nalox1222
`
`Kanaan, M. et al., P-glycoprotein Is Not Involved in the
`Differential Oral Potency of Naloxone and Naltrexone, 23
`Fundamental & Clin. Pharmacol. 543–48 (2009) (Kanaan)
`
`Nalox1223
`
`Kerensky, T. & Walley, A., Opioid Overdose Prevention and
`Naloxone Rescue Kits: What We Know and What We Don’t
`Know, 12(4) Addict. Sci. Clin. Pract. 1–7 (2017) (Kerensky)
`
`
`
`4
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`Exhibit No.
`
`Description
`
`Nalox1224
`
`Kim, S. et al., Longer Occupancy of Opioid Receptors by
`Nalmefene Compared to Naloxone as Measured In Vivo by a
`Dual-Detector System, 38(11) J. Nuclear Med. 1726–31 (1997)
`(Kim)
`
`Nalox1225
`
`Kreiter, P. et al., Pharmacokinetic Interaction between
`Naloxone and Naltrexone Following Intranasal Administration
`to Healthy Subjects, 47(7) Drug Metabolism and Disposition
`690–98 (2019) (Kreiter 2019)
`
`Nalox1226
`
`Krieter, P. et al., Pharmacokinetic Properties and Human Use
`Characteristics of an FDA-Approved Intranasal Naloxone
`Product for the Treatment of Opioid Overdose, 00(0) J. Clin.
`Pharmacol. 1–11 (2016) (Kreiter 2016)
`
`Nalox1228
`
`Melichar, J.K. et al., Naloxone Displacement at Opioid
`Receptor Sites Measured In Vivo in the Human Brain, 459 Eur.
`J. Pharmacol. 217–19 (2003) (Melichar)
`
`Nalox1229
`
`Mueller, S.R., A Review of Opioid Overdose Prevention and
`Naloxone Prescribing: Implications for Translating Community
`Programming into Clinical Practice, 36(2) Subst. Abus. 240–53
`(2015) (Mueller)
`
`Nalox1230
`
`Pace, N.L. et al., Pharmacokinetics of Naloxone and Naltrexone
`in the Dog, 208(2) J. Pharmacol. Experimental Therapeutics
`254–56 (1979) (Pace)
`
`Nalox1233
`
`Sporer, K.A. et al., Out-of-hospital Treatment of Opioid
`Overdoses in an Urban Setting, 3(7) Academic Em. Med. 660–
`67 (1996) (Sporer)
`
`Nalox1234
`
`Suarez, S. et al., Effect of Dose and Release Rate on Pulmonary
`Targeting of Liposomal Triamcinolone Acetonide Phosphate,
`15(3) Pharm. Res. 461–465 (1998) (Suarez)
`
`
`
`5
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`Exhibit No.
`
`Description
`
`Nalox1235
`
`Sugano, K., Estimation of Effective Intestinal Membrane
`Permeability Considering Bile Micelle Solubilisation, 368 Int. J.
`Pharms. 116–22 (2009) (Sugano)
`
`Nalox1236
`
`Suzuki, T. et al., Involvement of an Influx Transporter in the
`Blood-Brain Barrier Transport of Naloxone, 31 Biopharm. &
`Drug Disposition 243–52 (2010) (Suzuki)
`
`Nalox1237
`
`Talton, J. et al., Nano-Thin Coatings for Improved Lung
`Targeting of Glucocorticoid Dry Powders: In-Vitro and In-Vivo
`Characteristics, Respiratory Drug Delivery (2000) (Talton)
`
`Nalox1238
`
`Wanger, K. et al., Intravenous vs Subcutaneous Naloxone for
`Out-of-hospital Management of Presumed Opioid Overdose,
`5(4) Acad. Emerg. Med. 293–99 (1998) (Wanger)
`
`Nalox1239
`
`Weinstein, S. et al., Absorption and Distribution of Naloxone in
`Rats after Oral and Intravenous Administration, 62(9) J. Pharm.
`Sci. 1416–19 (1973) (Weinstein)
`
`Nalox1242
`
`Zuckerman, M. et al., Pitfalls of Intranasal Naloxone, 18(4)
`Prehosp. Em. Care 550–54 (2014) (Zuckerman)
`
`PROTECTIVE ORDER MATERIAL
`
`Nalox1248
`
`February 21, 2020 Transcript of Deposition of Dr. Stuart Allen
`Jones (Jones Dep.)
`
`Nalox1250
`
`Lemiuex, M., Police Dog Saved with Narcan after Accidental
`Exposure to Fentanyl During Drug Bust, Newsweek (Mar. 11,
`2020), https://www.newsweek.com/police-dog-saved-narcan-
`after-accidental-exposure-fentanyl-during-drug-bust-1479419
`(Lemiuex)
`
`Nalox1251 U.S. Patent No. 9,468,747 (the ’747 patent)
`
`Ex-2001
`
`Declaration of Kenneth A. Williams, M.D. (First Williams
`Declaration)
`
`
`
`6
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`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`Exhibit No.
`
`Description
`
`Ex-2003
`
`Christopher T. Aquina et al., OxyContin® Abuse and Overdose,
`Postgraduate Medicine (2009) 121(2):163–67 (Aquina)
`
`Ex-2004
`
`Catherine T. Baca et al., Take-home Naloxone to Reduce Heroin
`Death, Addiction (2005) 100:1823–31
`
`Ex-2006
`
`Ingebjorg Buajordet, Adverse Events After Naloxone Treatment
`of Episodes of Suspected Acute Opioid Overdose, Eur. J. Emerg.
`Med. (2004) 11:19–23
`
`Ex-2011 Goldfrank’s Toxicologic Emergencies 579–85 (9th ed. 2010)
`
`Ex-2012
`
`Ex-2028
`
`Ex-2029
`
`Indivior Receives Complete Response Letter from FDA Not
`Approving Naloxone Nasal Spray New Drug Application for
`Opioid Overdose (Nov. 24, 2015), available at http://www.
`indivior.com/wpcontent/uploads/2015/11/Nasal-Naloxone-
`Final-Release 112415.pdf
`
`A.Y. Walley et al., Opioid Overdose Rates and Implementation
`of Overdose Education and Nasal Naloxone Distribution in
`Massachusetts: Interrupted Time Series Analysis, BMJ (2013)
`346:174
`
`Daniel P. Wermeling, Review of Naloxone Safety for Opioid
`Overdose: Practical Considerations for New Technology and
`Expanded Public Access, Ther. Adv. Drug Safety (2015)
`6(1):20-31
`
`Ex-2096
`
`World Health Organization, Substance Use: Community
`Management of Opioid Overdose (2014)
`
`Ex-2201
`
`PROTECTIVE ORDER MATERIAL
`
`Declaration of Stuart A. Jones, Ph.D. (Jones Declaration)
`
`Ex-2202
`
`Declaration of Kenneth Williams, M.D. (Second Williams
`Declaration)
`
`Ex-2203 Declaration of Thomas Begres (Begres Declaration)
`
`
`
`
`
`7
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`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`
`
`
`
`It remains my opinion that a person of ordinary skill in the art of
`
`clinical pharmacology (“Pharmacologist POSA”) would have had a reason and the
`
`know-how to arrive at the subject matter recited in claims 3-8 and 13-16 of the
`
`’965 patent with a reasonable expectation of success, as discussed in my first
`
`Declaration and this Declaration.
`
`II. MY BACKGROUND AND QUALIFICATIONS
`
`
`
`In my
`
`first Declaration,
`
`I discussed my background and
`
`qualifications. See Nalox1003, ¶¶8–19. To address certain points raised by Dr.
`
`Williams and Dr. Jones,1 I supplement this discussion as follows.
`
`
`
`As I mentioned in my first Declaration, I am a member of the
`
`American College of Clinical Pharmacology (“ACCP”). I served two 5-year
`
`terms on the Board of Regents of this organization, an indication that I am
`
`recognized in the field. ACCP’s objectives are to advance the science of clinical
`
`pharmacology in all its phases. The vision and mission of this organization is to
`
`improve health by optimizing therapeutics by providing innovative leadership and
`
`
`
`1 Dr. Jones and Dr. Williams criticize my opinion because neither I nor Dr.
`Donovan consulted with a clinician in conjunction with our Declarations. See Ex-
`2201, ¶¶238-240; Ex-2202, ¶39. While it remains my opinion that, in this case, a
`POSA would comprise a team of individuals including, inter alia, professionals
`with clinical expertise (see Nalox1003, ¶22), I disagree that consultation with a
`clinician was required in order to form my opinions in my first Declaration and
`herein. Nevertheless, I have the qualifications of a POSA under Dr. Jones’s and
`Dr. Williams’s definitions. See Ex-2201, ¶¶38-41; Ex-2001, ¶¶13-16.
`
`
`
`8
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`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`interdisciplinary education that will enable the generation, integration and
`
`translation of scientific knowledge to optimize the research, development and
`
`utilization of medication for the benefit of all.
`
`
`
`I received “Excellence in Achievement” recognition from ACCP in
`
`2019. In addition, I received in the same year “the Bristol-Myers Squibb
`
`Mentorship in Clinical Pharmacology Award” from the ACCP.
`
`
`
`I have knowledge and expertise in optimizing therapeutics, including
`
`dose optimization. I taught a class at the University of Florida called “Basic
`
`Principles of Dose Optimization” for more than 15 years (1999-2014). The course
`
`objectives were
`
`to: 1) understand
`
`the
`
`theoretical background of
`
`the
`
`pharmacokinetic behavior of drugs; 2) understand the influence of dosage forms,
`
`dosing regimens and dose on drug levels and to understand the relationship
`
`between drug concentration, effect and side effects; 3) design optimized dosing
`
`regimens for patient care utilizing drug monitoring techniques and computer
`
`technology; and 4) apply the above principles for pharmacokinetic decision
`
`making and improvement of patient care.
`
` I am currently teaching a course called “Principles of Drug Therapy
`
`Individualization.” The purpose of this course is individualization of drug therapy
`
`by selecting an optimal dose and dosing regimen for the patient. This requires an
`
`understanding of the disease, the mechanism of the drug’s action, and exposure-
`
`
`
`9
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`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`response relationships. The goal of individualization is to optimize the efficacy of
`
`a drug, minimize toxicity, or both, on a patient-by-patient basis.
`
` My research has focused on questions related to dose finding and
`
`optimizing therapy to achieve the best effect-to-side-effect ratio. My expertise in
`
`the area of dose finding is reflected as one example in a chapter that I co-authored
`
`in the book “Handbook of Pharmacokinetic/Pharmacodynamic Correlations”
`
`entitled “Dose Optimization Based on Pharmacokinetic-Pharmacodynamic
`
`Modeling”. Hochhaus 1995 (Nalox1215). This chapter addresses questions such as
`
`“What is the best dose?”, “What is the best dosing regimen?”, “What is the best
`
`route of administration?” and “What is the best dosage form?”. One aspect
`
`focuses on relationships between drug absorption and pharmacological effects and
`
`the relationship between dose and desired effects on one side, versus dose and
`
`undesired side effects on the other side. I frequently consult with a wide range of
`
`pharmaceutical companies on projects that focus on clinical pharmacology
`
`questions, such as the relationship between dose and effects and side effects, as
`
`well as simulation approaches for assessing bioequivalence with the final goal of
`
`identifying suitable doses and study designs to detect differences in the local
`
`performance (e.g. nasal or pulmonary) of generic and innovator products. I have
`
`also evaluated the relationship between dose absorption rate and effects and side
`
`effects for certain nasally and pulmonary administered drugs. See Hochhaus 2002
`
`
`
`10
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`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`(Nalox1216); Hochhaus 1997
`
`(Nalox1217); Talton
`
`(Nalox1237); Suarez
`
`(Nalox1234).
`
` Thus, as a clinical pharmacologist, I have vast experience in evaluating
`
`the relationships between dose, concentrations, effects and side effects in the
`
`clinical setting. Expertise in these clinical pharmacological topics are applicable to
`
`all therapeutic areas. For a given disease or condition to be treated, or a specific
`
`therapeutic approach to treatment, I complement my general knowledge by
`
`considering background information and specific clinical results for that disease,
`
`condition or therapeutic approach on which I have been asked to focus. In the case
`
`at hand, having direct clinical experience in treating an opioid overdose victim is
`
`not necessary for me to render opinions on the topic because background
`
`information and relevant clinical information were available in the prior art, which
`
`I incorporated into my clinical pharmacological analysis. A Pharmacologist
`
`POSA, as I defined it in my first Declaration, would have had the same approach.
`
`III. LEGAL STANDARDS
`
` In my first Declaration, I discussed the legal standards relevant to this
`
`IPR. See Nalox1003, ¶¶20-32. These paragraphs are incorporated by reference
`
`herein. In addition to these legal standards, it has been explained to me by counsel
`
`for Petitioner that the following legal principles are applicable to patent validity
`
`
`
`11
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`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`and I have relied upon these legal principles in forming opinions set forth in this
`
`Declaration.
`
` I understand from counsel that the use of patents as references is not
`
`limited to what the patentees describe as their own inventions or to the problems
`
`with which they are concerned, and that they are part of the literature of the art,
`
`relevant for all they contain.
`
` I also understand from counsel that disclosed examples and preferred
`
`embodiments do not constitute a teaching away from a broader disclosure or
`
`nonpreferred embodiments. Furthermore, the prior art’s mere disclosure of more
`
`than one alternative does not constitute a teaching away from any of these
`
`alternatives because such disclosure does not criticize, discredit, or otherwise
`
`discourage the solution claimed.
`
`IV. THE CLAIMED DOSE OF 4 MG OF NALOXONE WOULD HAVE
`BEEN OBVIOUS TO A POSA
`
` Dr. Jones and Dr. Williams opine that the claimed dose of 4 mg was
`
`not obvious for various reasons. See Ex-2201, ¶¶182-276; Ex-2202, ¶¶23-67. I
`
`disagree. Based on the prior art, a 4 mg dose would have been an obvious choice.
`
`A. Wyse discloses a range of naloxone content that includes 4 mg,
`and does not “teach away” from such a dose.
`
` As I stated in my first Declaration, Wyse discloses concentrated
`
`intranasal naloxone solutions for treating opioid overdose containing up to 50
`
`
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`12
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`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`mg/mL. See Nalox1003, ¶58. I have reviewed and agree with Dr. Donovan’s
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`opinion in her first Declaration (see Nalox1002, ¶123), and a Pharmacologist
`
`POSA would understand that Wyse discloses a range of about 0.5 mg to 5 mg
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`naloxone in 100 µL of solution for intranasal (“IN”) administration. See
`
`Nalox1007, claim 1 and at 6:50-65, 10:53-56. Since this range includes 4 mg, a
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`Pharmacologist POSA would have found the claim dose obvious in view of Wyse.
`
` Wyse does not “teach away” from a 4 mg dose. In the exemplary
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`“pilot study” treatments, Wyse chose to administer 1 mg or 2 mg IN. See
`
`Nalox1007 at 15:15-23:28. In the following study, called “Naloxone 1301 Study,”
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`Wyse chose a 2 mg dose IN to compare with a dose of 0.4 mg administered
`
`intramuscularly (“IM”) (see id. at 23:39-24:51), which is the lowest of the
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`previously-approved 0.4 to 2 mg parenteral starting doses. See PDR 2003
`
`(Nalox1044) at 4.2 But Wyse’s failure to disclose an exemplary IN treatment with
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`a dose higher than 2 mg would not have dissuaded a Pharmacologist POSA from
`
`
`
`2 As I stated in my first Declaration, the FDA stated that, in order to meet
`certain streamlined regulatory requirements, an intranasal naloxone formulation
`must meet or exceed the exposure levels of an approved parenteral naloxone dose
`administered by an approved route (i.e., 0.4 to 2 mg naloxone administered IM, IV
`or SC), and thus, a Pharmacologist POSA would have been motivated to select a
`target parenteral dose of 0.4 to 2 mg, as a comparator to the intranasal
`formulation. See Nalox1003, ¶63. Dr. Jones agrees that a POSA would have been
`motivated to match or exceed the exposure levels of an approved parenteral
`naloxone dose. See Ex-2201, ¶64.
`
`
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`13
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`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`considering Wyse’s disclosure of higher doses or from selecting a higher
`
`comparator parenteral dose.3
`
` Other prior art suggested that the dose range disclosed in Wyse of
`
`about 0.5 mg to 5 mg naloxone in 100 µL of solution could be achieved.4 Thus a
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`Pharmacologist POSA would not have considered Wyse’s dose range far-fetched
`
`or unachievable. In addition, the prior art provided a finite number of identified
`
`choices of an IN dose (Wyse’s range of about 0.5 mg to 5 mg naloxone in 100 µL
`
`of solution) and a comparator parenteral dose (0.4 to 2 mg). Simply because Wyse
`
`picked one of these finite numbers of identified choices to exemplify, a
`
`Pharmacologist POSA would not have been dissuaded from selecting another of
`
`these choices, especially given the fact that (as I discuss below) other prior art
`
`would have motivated a Pharmacologist POSA to select a dose higher than the 2
`
`mg IN dose chosen by Wyse.5
`
`
`
`3 As I stated in my first Declaration, a Pharmacologist POSA would have
`been further motivated to select the 2 mg parenteral comparator dose. See
`Nalox1003, ¶¶63-64; see also, e.g., infra ¶¶ 21-25.
`
`4 See Wang (Nalox1008), claim 9 and at 8:13-14 (disclosing naloxone doses
`of 0.1 to 10 mg and spray volumes between 20 to 200 µL); Davies (Nalox1009) at
`3:2-4 (disclosing naloxone doses of 0.2 to 5 mg and spray volumes between 20 to
`100 µL).
`
`5 Dr. Jones criticizes Dr. Donovan’s opinion that Wyse’s Naloxone 1301
`Study Treatment B (in which 2 mg was administered IN, followed by another 2
`mg IN in five minutes) would provide useful information, and opines, “The POSA
`would not have treated two discrete 2 mg doses administered five minutes apart as
`
`
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`14
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`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`B. A Pharmacologist POSA seeking to develop a community-use
`intranasal naloxone formulation would have been motivated to
`choose a naloxone dose of greater than 2 mg.
`
` A Pharmacologist POSA seeking to develop a community-use
`
`intranasal naloxone formulation6 would have been motivated to choose an
`
`intranasal naloxone dose of greater than 2 mg for a variety of reasons.
`
`
`
`equivalent to a single 4 mg dose administered at one time. Quite the contrary; the
`POSA would have expected the clinical effect and pharmacokinetics of these two
`regimens to be quite different.” See Ex-2201, ¶215 (citing Nalox1002, ¶459). I
`disagree. I ran a simulation using a computer program that I developed in
`conjunction with one of the classes I teach, “Basic Principles of Dose
`Optimization.” This computer program can be found at this website:
`http://copnt13.cop.ufl.edu/pat/pha5127/simulatn.htm (last modified July 1, 2011).
`The computer program creates simulations that predict plasma concentration time
`curves for drugs, based on standard pharmacokinetic (“pK”) compartmental
`models, and such simulations were routinely used by Pharmacologist POSAs
`before March 16, 2015. The simulation I conducted was used to determine any
`pK differences that would be found between two dosing regimens: (1) a single 4
`mg dose (shown in red), and (2) two 2 mg doses administered five minutes apart
`(shown in blue). The simulation showed no substantial pK difference between the
`two regimens:
`
`
`Thus, a POSA would likewise expect no substantial clinical differences between
`the administration of one 4 mg dose and two 2 mg doses.
`
`6 Dr. Jones agrees with Dr. Williams’s opinion that a POSA here was
`seeking to develop a community-use naloxone product. See Nalox1248 at 33:20-
`
`
`
`15
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`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
` First, contrary to Dr. Williams’s opinion,7 prior to March 16, 2015,
`
`emergency medical personnel routinely administered initial doses of 2 mg IM and
`
`IV to opioid overdose patients. Sporer provided a retrospective review of San
`
`Francisco emergency medical systems (EMS) records for presumed-opioid-
`
`overdose patients.8 The EMS protocol instructed paramedics to administer an
`
`initial 2 mg IM or IV dose of naloxone to suspected opioid overdose patients, with
`
`a repeat dose to be administered if no response was seen in 1-2 minutes. See
`
`Sporer (Nalox1233) at 2. Of the 609 patients reviewed in the retrospective study,
`
`“[t]he 2-mg dose of naloxone was used for 58% of the patients, with higher doses
`
`such as 3-4 mg used for 28% and >4mg used for 7% (Table 4).” Sporer
`
`(Nalox1233) at 4.9 Further, Sporer reports that “[o]f the 609 patients with any
`
`initial BP, 575 (94%) readily responded to naloxone by improving to a GCS ≥ 14
`
`and a respiratory rate ≥10 within 5 minutes of administration.” Sporer
`
`(Nalox1233) at 4. Because Sporer reported the routine and effective use of an
`
`
`
`34:1; Ex-2202, ¶33 (“The POSA, seeking to develop a community-use naloxone
`product….”) (emphasis added). However, much of Dr. Williams’s opinion is
`skewed toward prior art treatment of opioid overdose in the medical setting,
`which is not the applicable setting here. See, e.g., Ex-2001, ¶23.
`
`7 See footnote 14, infra.
`
`8 The retroactive review involved presumed-opioid-overdose patients who
`presented in 1993 to the San Francisco EMS system.
`
`9 Table 4 shows that of 609 patients, 353 patients were administered 2 mg,
`172 patients were administered 3-4 mg, and 40 patients were administered >4mg.
`Sporer (Nalox1233) at 4.
`
`
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`16
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`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Günther Hochhaus, Ph.D. (Nalox1202)
`
`initial IM or IV dose of 2 mg of naloxone for opioid overdose patients, a
`
`Pharmacologist POSA would have expected an intranasal dose that correlated with
`
`the exposure parameters of a 2 mg IM or IV dose to be similarly effective. As a
`
`POSA would have recognized that the dose of naloxone in an intranasal
`
`formulation would have to be higher than a 2 mg IM or IV dose, a Pharmacologist
`
`POSA would have been motivated to use higher doses when developing intranasal
`
`formulations.10 In particular, if an initial parenteral (IM or IV) dose of 2 mg was
`
`known to be effective in treating opioid overdose patients, a Pharmacologist
`
`POSA would have understood that intranasal doses of about 4-6 mg would
`
`achieve comparable drug exposure levels and thus be effective for treating opioid
`
`overdose.11
`
` Second, the prior art recognized that, in the medical setting, dose
`
`titration could be accomplished by medical personnel, who are trained in patient
`
`
`
`10 Dr. Donovan states that a Formulator POSA would have recognized that
`an IN naloxone dose targeting the exposure levels of IM, IV, or SC “would have
`to be higher than 2 mg, because the prior art disclosed that prior intranasal
`naloxone formulations had bioavailabilities of no more than ~42%.” See
`Nalox1002, ¶58.
`
`11 See Nalox1002, ¶58, wherein Dr. Donovan states, “In order to achieve
`sufficient drug exposure, a Formulator POSA thus would have considered doses of
`between about 4 and about 6 mg.” Id.; and Nalox1003, ¶6