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 GÜNTHER HOCHHAUS, Ph.D.
`
`

`

`IV.
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`TABLE OF CONTENTS
`OVERVIEW .................................................................................................... 1
`I.
`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 6
`III.
`LEGAL STANDARDS ................................................................................... 9
`A.
`Person of ordinary skill in the art ........................................................ 10
`B.
`Claim construction .............................................................................. 12
`C.
`Anticipation and obviousness .............................................................. 13
`D. Written description and priority .......................................................... 15
`THE ’253 PATENT AND ITS CLAIMS ...................................................... 15
`A.
`Independent claim 1 ............................................................................ 17
`B.
`Claims 2–29 ......................................................................................... 17
`C.
`The ’253 patent lacks priority to U.S. Provisional Application
`No. 61/953,379. ................................................................................... 20
`Orange Book listing of the ’253 patent ............................................... 21
`D.
`STATE OF THE ART ................................................................................... 21
`V.
`VI. MOTIVATION TO DESIGN A NALOXONE NASAL
`FORMULATION HAVING HIGH BIOAVAILABILITY, WITH A
`REASONABLE EXPECTATION OF SUCCESS ........................................ 25
`A.
`Prior art patent applications disclose concentrated solutions of
`naloxone administered intranasally to treat opioid overdose. ............. 26
`1. Wyse (U.S. Patent No. 9,192,570) ............................................27
`2. Wang (Chinese Patent Publication CN 1575795) ....................27
`3.
`Davies (PCT Patent Publication WO 00/62757) ......................28
`In view of the prior art, a Pharmacologist POSA would have been
`motivated to design a concentrated solution of naloxone in a
`ready-to-use nasal delivery device, with a reasonable expectation
`
`B.
`
`ii
`
`

`

`2.
`
`3.
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`of success. ............................................................................................ 28
`1.
`The known physical, chemical, biopharmaceutical and
`pharmacological properties of naloxone and prior art would
`have motivated a Pharmacologist POSA to use a range of 2 to
`10 mg naloxone per dose, if not up to 20 mg per dose, in an
`intranasal solution with a reasonable expectation of success. ..29
`The nasal physiology would have motivated a Pharmacologist
`POSA to use an intranasal solution volume of up to 100 µL per
`dose with a reasonable expectation of success. ........................30
`A Pharmacologist POSA would have been motivated to design
`an intranasal solution of naloxone that met or exceeded the
`exposure levels of the approved Narcan® 2 mg injection
`protocol, and would have determined that approximately 4-6
`mg intranasally would work, with a reasonable expectation of
`success. ......................................................................................32
`A Pharmacologist POSA would have been motivated to design
`an intranasal solution of naloxone that achieved a Tmax within
`about 20-30 minutes, with a reasonable expectation of success.
` ...................................................................................................37
`A Pharmacologist POSA would have been able to choose from
`the routine pharmaceutical excipients disclosed in prior art
`naloxone formulations, to achieve high exposure levels, with a
`reasonable expectation of success. ............................................38
`(a)
`A Pharmacologist POSA would have expected the
`inclusion of sodium chloride in a naloxone
`intranasal formulation to achieve high exposure
`levels, consistent with the Wyse intranasal
`formulations. ................................................................... 39
`(b) A Pharmacologist POSA would have expected the
`inclusion of hydrochloric acid in a naloxone
`intranasal formulation to achieve high exposure
`levels, consistent with the Wyse intranasal
`formulations. ................................................................... 40
`A Pharmacologist POSA would have expected the
`
`(c)
`
`4.
`
`5.
`
`iii
`
`

`

`6.
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`inclusion of disodium EDTA in a naloxone
`intranasal formulation to achieve high exposure
`levels, consistent with the Wyse intranasal
`formulations. ................................................................... 41
`(d) A Pharmacologist POSA would have expected the
`inclusion of benzalkonium chloride (BAC) in a
`naloxone intranasal formulation to achieve high
`exposure levels, and may serve to slightly improve
`the exposure seen with the Wyse formulations. ............. 41
`A Pharmacologist POSA would have been motivated employ a
`single-dose device for an intranasal formulation of naloxone,
`with a reasonable expectation of success. .................................42
`VII. CLAIM CONSTRUCTION .......................................................................... 43
`A.
`“patient” ............................................................................................... 44
`VIII. PUBLIC ACCESSIBILITY OF THE APRIL 12, 2012 FDA
`MATERIALS ................................................................................................ 44
`IX. CLAIMS 15 AND 25–29 OF THE ’253 PATENT ARE OBVIOUS
`IN VIEW OF THE PRIOR ART ................................................................... 46
`A.
`Claim 15 is obvious in view of the prior art........................................ 47
`1.
`The additional limitations of claim 15 are obvious over Wyse.
` ...................................................................................................47
`The additional limitations of claim 15 are obvious over Wang
`in view of the knowledge of a Pharmacologist POSA. ............49
`The additional limitations of claim 15 are obvious over
`Wermeling 2013. .......................................................................50
`Claims 25 and 28 are obvious over Wyse. .......................................... 51
`B.
`Claims 26 and 29 are obvious over Wyse. .......................................... 53
`C.
`Claim 27 is obvious over Wyse........................................................... 55
`D.
`SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS .............. 57
`
`X.
`
`2.
`
`3.
`
`iv
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`No teaching away ................................................................................ 58
`A.
`No unexpected superior results ........................................................... 59
`B.
`XI. CONCLUSION .............................................................................................. 60
`
`v
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`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 together with a
`
`petition for inter partes Review (“IPR”) of claims 1–29 of U.S. Patent No.
`
`9,211,253 (the “’253 patent”).
`
`I have been retained 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, I have been informed 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 Günther Hochhaus, Ph.D. (Exhibit 1003)
`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.
`
`Nalox-1
`Exhibit No.
`
`Description
`
`Nalox1005
`
`Nalox1001 U.S. Patent No. 9,211,253 (the ’253 Patent)
`Nalox1002 Expert Declaration of Maureen Donovan
`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)
`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)
`Nalox1013 Kushwaha, S. et al., Advances in Nasal Trans-Mucosal Drug
`Delivery, (1)7 J. Applied Pharm. Sci. 21–28 (2011) (Kushwaha)
`Nalox1014 U.S. Patent No. 5,866,154 (Bahal)
`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)
`
`Nalox1016
`
`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)
`
`2
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`
`Description
`
`Nalox-1
`Exhibit No.
`Nalox1022 Bitter, C. et al., Nasal Drug Delivery in Humans, 40 Curr.
`Probl. Dermatol. 20–35 (2011) (Bitter)
`Nalox1025 Excerpt of Commonwealth of Kentucky, Kentucky Patient Care
`Protocols (Mar. 13, 2015) (Kentucky Patient Care Protocols)
`
`Nalox1026
`
`Nalox1027
`
`Costantino, H. et al., Intranasal Delivery: Physiochemical and
`Therapeutic Aspects, 337 Int’l. J. of Pharm. 1–24 (2007)
`(Constantino)
`
`Dowling, J. et al., Population Pharmacokinetics of Intravenous,
`Intramuscular, and Intranasal Naloxone in Human Volunteers,
`30(4) Ther. Drug. Monit. 490–96 (2008) (Dowling)
`
`Nalox1030
`
`Freise, K. et al., Naloxone Reversal of an Overdose of a Novel,
`Long-Acting Transdermal Fentanyl Solution in Laboratory
`Beagles, 35(2) J. Vet. Pharmacol. Therap. 45–51 (2012) (Freise)
`Nalox1032 Hertz, S., Naloxone for Outpatient Use: Data Required to
`Support an NDA, PowerPoint Presentation (Hertz Presentation)
`
`Nalox1034
`
`Nalox1035
`
`Nalox1036
`
`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)
`
`Kerr, D. et al., Intranasal Naloxone for the Treatment of
`Suspected Heroin Overdose, 103 Addiction 379–86 (2008)
`(Kerr 2008)
`
`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)
`
`3
`
`

`

`Nalox-1
`Exhibit No.
`
`Nalox1038
`
`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`
`Description
`
`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)
`
`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)
`
`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)
`
`Nalox1042
`
`Nalox1044
`
`Nalox1046
`
`Nalox1047
`
`Nalox1048
`
`Monitto, C. et al., The Optimal Dose of Prophylactic
`Intravenous Naloxone in Ameliorating Opioid-Induced Side
`Effects in Children Receiving Intravenous Patient-Controlled
`Analgesia Morphine for Moderate to Severe Pain: A Dose
`Finding Study, 113(4) Anesthesia & Analgesia 834–42 (2011)
`(Monitto)
`
`Physicians’ Desk Reference, NARCAN [Naloxone
`Hydrochloride Injection, USP], IMITREX Nasal Spray
`[Sumatriptan], 1300–02, 1546–50 (57th ed., 2003) (PDR 2003)
`
`Robertson, T. et al., Intranasal Versus Intravenous Naloxone for
`Prehospital Narcotic Overdose, Abstract, 12(5)(1) Acad.
`Emerg. Med. 166–67 (2005) (Robertson 2005)
`
`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)
`
`Role of Naloxone in Opioid Overdose Fatality Prevention;
`Public Workshop; Request for Comments, 76 Fed. Reg. 71,348
`(Nov. 17, 2011) (Role of Naloxone Fed. Reg. Notice)
`
`4
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`
`Nalox-1
`Exhibit No.
`Nalox1049 Role of Naloxone in Opioid Overdose Fatality Prevention FDA
`Meeting Transcript (Apr. 12, 2012) (2012 FDA Meeting)
`
`Description
`
`Nalox1051
`
`Nalox1059
`
`Nalox1060
`
`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)
`
`Wermeling, D., Opioid Harm Reduction Strategies: Focus on
`Expanded Access to Intranasal Naloxone, 30(7)
`Pharmacotherapy 627–31 (2010) (Wermeling 2010)
`
`Loimer, N. et al, Nasal Administration of Naloxone is as
`Effective as the Intravenous Route in Opiate Addicts, 29(6) Int’l
`J. of Addictions 819–27 (1994) (Loimer)
`
`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
`
`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 of clinical
`
`pharmacology (“Pharmacologist POSA”) would have had a reason and the know-
`
`how to arrive at the subject matter recited in claims 15 and 25–29 of the ’253
`
`patent, as discussed in this Declaration below, with a reasonable expectation of
`
`success.
`
`5
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`II. MY BACKGROUND AND QUALIFICATIONS
`I received my undergraduate degree in pharmacy from Westf.
`
`Wilhelms Universität, Münster, FRG in 1979. I attended practical pharmacy
`
`education at Elisabeth Apotheke, Detmold, FRG prior to receiving my Ph.D. from
`
`the Institute of Pharmaceutical Chemistry. After receiving my Ph.D. in 1984, I
`
`conducted my postdoctoral research as a Pharmacologist in the Department of
`
`Pharmaceutical Chemistry, School of Pharmacy, University of California, San
`
`Francisco (“UCSF”) with Group Leader Professor Dr. W. Sadee. I subsequently
`
`joined the University of Florida in July 1987 and currently serve as Professor in
`
`the Department of Pharmaceutics.
`
`During my time at UCSF, I focused on research related to the mode
`
`of action of opioids, characterized opioid receptors, including the interaction of
`
`the receptor with naloxone, and developed sensitive methods to detect opioids in
`
`the bloodstream. After joining the University of Florida, I designed and tested new
`
`pharmacological agents suitable to reduce the development of opiate tolerance and
`
`withdrawal symptoms.
`
`My current research focuses on the clinical pharmacology of drugs
`
`after nasal and pulmonary administration, including the design of drug/device
`
`combinations with improved pharmacokinetic properties. I have led research
`
`assessing the pharmacokinetic properties of nasal sprays, especially to evaluate the
`
`6
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`pharmacokinetics of a solution based nasal spray, and have written review articles
`
`about the clinical pharmacology of nasal drug delivery. For example, the outcome
`
`of one of the projects suggested a distinct advantage of administering asthma
`
`rescue medication through the nasal route in patients unable to inhale. This
`
`represented an alternative to injecting the drugs while a fast absorption and onset
`
`of action was insured.
`
`I am, and have been a consultant for more than 40 generic and
`
`branded companies and helped within this capacity designing pharmacokinetic
`
`studies for nasal and inhalation drugs. Because of my interest in the assessment
`
`and development of nasal and pulmonary drugs, I have been involved in
`
`discussions about ways to test the bioequivalence of this group of drugs (including
`
`methods to test whether a generic formulation is similar to the branded product,
`
`after nasal and pulmonary delivery). I served as a consultant for the Brazilian drug
`
`agency Anvisa when Anvisa drafted its bioequivalence guidance for nasal
`
`products using pharmacokinetics as a cornerstone for the assessment.
`
`I am currently leading FDA sponsored research that evaluates the
`
`effect of formulation factors on the pharmacokinetics of nasal sprays. This study
`
`evaluates the ability of pharmacokinetics to detect differences in the composition
`
`of nasal spray drug/device combinations.
`
`7
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`I have published over 210 scientific publications, given over 350
`
`presentations at national or international meetings and attracted more than $4
`
`million in research support.
`
`I am involved in teaching pharmacokinetics, both at the professional
`
`and graduate level. In 1998, I received a Teaching Improvement Award from the
`
`University of Florida for my efforts to introduce modern electronic approaches
`
`(pharmacokinetic simulations) into the teaching of pharmacokinetics.
`
`Currently I am on the Editorial Board of three journals and frequently
`
`serve as reviewer for a number of journals. I am a Fellow of the American College
`
`of Clinical Pharmacology and have been on the Board of Regents of the American
`
`College of Clinical Pharmacology (“ACCP”). I am also a Fellow of the American
`
`Association of Pharmaceutical Scientists (“AAPS”). In addition, I co-chaired the
`
`annual national meeting of the American College of Clinical Pharmacology in
`
`2003, chaired a South-Eastern-regional AAPS meeting and, in March 2014, a
`
`conference organized by the University of Florida (“UF”) and International
`
`Pharmaceutical Aerosol Consortium on Regulation and Science (“IPAC-RS”),
`
`entitled “Orlando Inhalation Conference: Approaches in International Regulation,”
`
`which discussed current scientific and regulatory approaches for development of
`
`orally inhaled and nasal drug products. I am frequently invited as a plenary
`
`8
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`speaker to meetings around the world, mainly focusing on issues related to nasal
`
`and inhalation therapy.
`
`While I am not a formulator, I have worked with formulators as part
`
`of a team, and I have a general understanding of commonly-used excipients that
`
`tend to affect the pharmacokinetic profile of drugs, especially drugs formulated for
`
`nasal, pulmonary, ocular or topical delivery.
`
`My curriculum vitae and list of publications is attached hereto as
`
`Appendix A.
`
`I am being compensated for my work at $500 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
`
`clinical pharmacology, 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
`
`patent validity and I have relied upon these legal principles in forming opinions
`
`set forth in this Declaration.
`
`9
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`Person of ordinary skill in the art
`I understand that a person of ordinary skill in the art (a “POSA”) is a
`
`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 ’253 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 drug development professionals with
`
`clinical, clinical pharmacology, formulation and regulatory expertise relevant to
`
`the design and performance of a drug development strategy for solution-based
`
`dosage forms such as intranasal dosage forms, including testing and/or evaluating
`
`the fate of the drug in the body (i.e., pharmacokinetics, including the physiological
`
`and biopharmaceutical aspects of nasal drug absorption), testing and/or evaluating
`
`10
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`issues of safety and efficacy, and evaluating the regulatory requirements of a new
`
`dosage form. Within the team, the clinical pharmacologist generally serves as a
`
`link between formulators and clinicians, and helps integrate formulation and
`
`clinical aspects of drug development. Such a clinical pharmacologist would
`
`routinely collaborate with others, such as formulators and clinicians, to achieve a
`
`target pharmaceutical profile.
`
`A clinical pharmacologist member of the drug development team
`
`(hereinafter a “Pharmacologist POSA”) would have an advanced degree in
`
`pharmacy, clinical pharmacology, pharmaceutics, or a similar field, and would
`
`have several years of experience in drug development, including the development
`
`of solution-based dosage forms, including nasal spray dosage forms. Such a
`
`person would also have an understanding of drug
`
`formulation/device
`
`combinations, including the selection of excipients and their relationship to drug
`
`exposure and clinical outcomes.
`
`I have at least the ordinary skill of the Pharmacologist POSA who
`
`forms part of the POSA team in the relevant art with respect to the ’253 patent,
`
`and I possessed such ordinary skill as of the 2015 priority date of the ’253 patent,
`
`as well as the 2014 date of the provisional patent application.
`
`11
`
`

`

`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`Claim construction
`I understand from counsel that, prior to conducting an analysis of a
`
`B.
`
`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, specification, and prosecution
`
`history make up the “intrinsic evidence” in light of which the claims are
`
`construed.
`
`Finally, I understand that it is also appropriate to consult other sources
`
`contemporaneous with the filing of the patent (such as dictionaries, published
`
`articles, other patents, or other materials written by those of skill in the art or with
`
`interest in the art to which the patent pertains) that shed light on the proper
`
`meaning of a particular claim term. Such other sources are considered “extrinsic
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`evidence.” It is my understanding that the intrinsic evidence will generally be
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`more pertinent to the construction of a claim term than the extrinsic evidence.
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`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`Anticipation and obviousness
`I understand that a patent claim is unpatentable as “anticipated” when a
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`C.
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`single piece of prior art describes every element of the claimed inventions, either
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`expressly or inherently, arranged in the same way as the claim. I further
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`understand that, for inherent anticipation to be found, it is required that the
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`missing descriptive material is necessarily present in the cited prior art.
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`I also understand that a patent claim is unpatentable as “obvious” if the
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`subject matter of the claim as a whole would have been obvious to a POSA as of
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`the time of the invention at issue. I further understand that the following factors
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`must be evaluated to determine whether the claimed subject matter is obvious: (1)
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`the scope and content of the prior art; (2) the difference or differences, if any,
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`between each claim of the patent and the prior art; (3) the level of ordinary skill in
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`the art at the time of the invention; and (4) “objective indicia of non-obviousness.”
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`As just noted, I understand that the so-called “objective indicia of non-
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`obviousness,” also known as “secondary considerations,” are to be considered, if
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`present, when assessing obviousness. These include commercial success, long-felt
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`but unresolved needs, failure of others to solve the problem that the inventor
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`solved, unexpected results, copying of the invention by others, and industry
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`recognition or expressions of disbelief by experts in the field of the claimed
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`invention. I also understand that a nexus, i.e., a tie, must exist between any
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`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`“secondary considerations” and the novel aspects of the claimed subject matter.
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`Along those same lines, I understand that secondary considerations cannot be
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`based on features (and their related benefits and/or advantages) that were already
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`known in the prior art.
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`I understand that obviousness may be shown by considering more than
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`one prior art reference as well as the POSA’s common knowledge. I further
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`understand that the reason or reasons for combining multiple prior art references
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`can come from a variety of sources, such as the specific teachings in the cited
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`prior art, teachings in the prior art collectively, known needs or problems in the
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`art, substituting one known element in the art for another to obtain predictable
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`results, the use of a known technique or feature to improve a similar devices, a
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`POSA’s common sense, etc. I further understand that a combination of multiple
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`prior art references or teachings needs to have a reasonable expectation of success
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`from the perspective of a POSA. I further understand that, when performing an
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`obviousness analysis, a POSA should be viewed as person of ordinary creativity,
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`not an automaton.
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`I have evaluated the scope and content of the prior art based on the
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`knowledge of a Pharmacologist POSA at the time of the alleged invention date for
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`the ’253 patent. Below in section IX is a comparison of certain prior art references
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`to claims 15 and 25–29 of the ’253 patent. I also considered “secondary
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`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`considerations” as part of my analysis, but for organizational purposes, I placed
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`that discussion in section X below.
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`D. Written description and priority
`I understand from counsel that a patent that claims priority to the filing
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`date of an earlier application can only properly do so if the earlier application
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`provides written description support for the claims of the patent as of the date the
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`earlier application was filed. I further understand that, although the earlier
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`application need not describe exactly the subject matter claimed, the description
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`must allow a POSA to recognize that the applicant invented what is claimed.
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`Further, I understand that, while the description requirement does not demand any
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`particular form of disclosure, or that the earlier application recite the claimed
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`invention in the exact claim terms used, a description that merely renders the
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`invention obvious does not satisfy the requirement. Rather, it is my understanding
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`from counsel that the specification of a patent must have a written description of
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`the invention, and of the manner and process of making and using it, in such full,
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`clear, concise, and exact terms as to enable any person skilled in the art to which it
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`pertains, or with which it is most nearly connected, to make and use the same.
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`IV. THE ’253 PATENT AND ITS CLAIMS
`I understand that this Declaration is being submitted together with a
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`petition for IPR of claims 1–29 of the ’253 patent.
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`15
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`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther Hochhaus, Ph.D. (Exhibit 1003)
`I have considered the disclosure of the ’253 patent in light of the
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`general knowledge in the art as of the priority date of the ’253 patent.
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`The ’253 patent specification is generally directed towards drug
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`products adapted for nasal delivery comprising a pre-primed device and a
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`pharmaceutical composition comprising an opioid
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`receptor antagonist,
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`pharmaceutical compositions comprising an opioid receptor antagonist, and
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`methods of use thereof. Nalox1001 at 1:8–12. In particular, the device is a single-
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`use, pre-primed device adapted for nasal delivery of a pharmaceutical composition
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`to a patient by one actuation of the device into the nostril of the patient. Id. at
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`21:5–8. The pharmaceutical composition, most specifically, is one containing
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`about 4.4 mg naloxone hydrochloride dihydrate, 0.74 mg sodium chloride as an
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`isotonicity agent, 0.01 mg benzalkonium chloride as a preservative, and about 0.2
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`mg disodium edetate as a stabilizing agent, hydrochloric acid in an amount
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`sufficient to achieve a pH between 3.5 and 5.5, in an aqueous solution of about
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`100 µL. See id. at 21:5–39.
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`I have been informed that claim terms are generally interpreted in
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`accordance with the ordinary and customary meaning they would have to a POSA
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`at the time of the invention, as discussed above in section III.B. After reading the
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`’253 patent’s claims, specification, and file history it is my opinion that a
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`Pharmacologist POSA would have understood that all the terms of claims 15 and
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`Inter Partes Review of U.S. Patent No. 9,211,253
`Declaration of Günther H