`
`
`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.
`_____________________
`
`CASE IPR2019-00688
`U.S. Patent No. 9,468,747
`_____________________
`
`PETITIONER NALOX-1 PHARMACEUTICALS, LLC’S REPLY
`TO PATENT OWNERS’ RESPONSE
`
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`

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`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`TABLE OF CONTENTS
`
`
`I.
`
`INTRODUCTION ............................................................................................1
`
`II.
`
`THE CHALLENGED CLAIMS ARE UNPATENTABLE .............................2
`
`A. Wyse would not have directed a POSA away from using BAC
`in an intranasal naloxone formulation. ................................................... 2
`
`1.
`
`2.
`
`A POSA would have known that naloxone degradants in
`Wyse’s formulations could not have been caused by
`BAC, and therefore would have dismissed Wyse’s
`conclusion. ...................................................................................3
`
`A POSA would have known that Wyse’s prototyping
`studies were not designed
`to
`identify any single
`ingredient as the cause of naloxone degradation, and
`would have further investigated the root cause of the
`degradation. ..................................................................................6
`
`B.
`
`C.
`
`D.
`
`No other prior art cited by Adapt would have directed a POSA
`away from using BAC in an intranasal naloxone formulation............... 9
`
`A POSA would have been highly motivated to use BAC as a
`preservative in an intranasal naloxone formulation. ............................ 11
`
`The claimed dose of 4 mg of naloxone would have been
`obvious to a POSA. .............................................................................. 12
`
`1. Wyse discloses a range of naloxone content that includes
`4 mg, and does not teach away from such a dose. .................... 12
`
`2.
`
`3.
`
`4.
`
`A POSA seeking to develop a community-use intranasal
`naloxone formulation would have been motivated to
`choose a naloxone dose of greater than 2 mg. .......................... 13
`
`Concerns over inducing acute withdrawal would not have
`outweighed the risks of administering a less than
`effective dose of naloxone. ....................................................... 15
`
`A POSA would have tried to achieve a rapid onset of
`action and high drug exposure with an intranasal
`naloxone formulation, and would have known that a
`naloxone dose higher than 2 mg could achieve these
`goals. ......................................................................................... 16
`
`
`
`ii
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`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`5.
`
`A POSA would not have expected substantial differences
`in pK between Wyse’s intranasal formulations and the
`claimed formulation, and would have expected Wyse’s
`exposure parameters to remain dose proportional at least
`at 4 mg. ...................................................................................... 17
`
`E.
`
`The claimed naloxone formulation does not have unexpected
`properties. ............................................................................................. 18
`
`1.
`
`2.
`
`3.
`
`The claimed naloxone formulation does not have
`“unexpected” stability – a POSA would have expected
`the claimed formulation to be stable. ........................................ 18
`
`The Cmax and relative bioavailability differences between
`Wyse and the claimed formulation are not statistically
`significant. ................................................................................. 19
`
`In an “apples-to-apples” comparison, the terminal half-
`lives of
`the Wyse formulation and
`the claimed
`formulation are not different. .................................................... 20
`
`F.
`
`Adapt’s evidence of “skepticism” and alleged “failure of
`others” is based on hearsay or irrelevant facts, and should be
`ignored. ................................................................................................. 20
`
`G. Adapt has not shown commercial success and satisfaction of a
`long-felt need because Narcan’s adoption by the community
`and sales are attributable to factors other than the claims.................... 22
`
`III. CONCLUSION .............................................................................................. 25
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`iii
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`

`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`TABLE OF EXHIBITS
`
`Exhibit No.
`
`Description
`
`Nalox1002 Expert Declaration of Maureen Donovan
`
`Nalox1003 Expert Declaration of Günther Hochhaus
`
`Nalox1007 U.S. Patent No. 9,192,570 (Wyse)
`
`Nalox1009 PCT International App. Pub. No. WO00/62757 (Davies)
`
`Nalox1010 Djupesland, P., Nasal Drug Delivery Device: Characteristics
`and Performance in a Clinical Perspective - A Review, 3 Drug
`Deliv. & Transl. Res. 42–62 (2013) (Djupesland)
`
`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)
`
`Nalox1015 U.S. Patent No. 8,198,291 (the ’291 patent)
`
`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)
`
`Nalox1044 Physicians’ Desk Reference, NARCAN [Naloxone
`Hydrochloride Injection, USP], IMITREX Nasal Spray
`[Sumatriptan], 1300–02, 1546–50 (57th ed., 2003) (PDR 2003)
`
`Nalox1049 Role of Naloxone in Opioid Overdose Fatality Prevention FDA
`
`Meeting Transcript (Apr. 12, 2012) (2012 FDA Meeting)
`
`Nalox1201 Supplemental Expert Declaration of Maureen Donovan
`
`Nalox1202 Supplemental Expert Declaration of Günther Hochhaus
`
`
`
`iv
`
`

`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`Exhibit No.
`
`Description
`
`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)
`
`Nalox1205
`
`Intentionally Left Blank
`
`Nalox1206
`
`Bureš, F., Quaternary Ammonium Compounds: Simple in
`Structure, Complex in Application, 377(14) Topics in Current
`Chemistry (2019) (Bureš)
`
`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, 86(3) Pediatrics 484–85 (1990) (Pediatrics 1990)
`
`Nalox1208
`
`Connors, K. et al., Oxidation and Photolysis, in Chemical
`Stability of Pharmaceuticals: A Handbook for Pharmacists 82–
`114 (2d ed. 1986) (Connors)
`
`Nalox1209
`
`Intentionally Left Blank
`
`Nalox1210
`
`Ehrick, J. et al., Considerations for the Development of Nasal
`Dosage Forms, in Sterile Product Development: Formulation,
`Process, Quality and Regulatory Considerations 99–144 (Parag
`Kolhe, et al., eds., 2013) (Ehrick)
`
`Nalox1211
`
`Exploring Naloxone Uptake and Uses, FDA Meeting Transcript
`(July 1, 2015) (2015 FDA Meeting)
`
`Nalox1212
`
`Intentionally Left Blank
`
`
`
`v
`
`

`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`Exhibit No.
`
`Description
`
`Nalox1213
`
`FDA, Center for Drug Evaluation and Research, Guidance for
`Industry, Q8(R2) Pharmaceutical Development (Revision 2
`2009) (2009 FDA Guidance)
`
`Nalox1214
`
`Hiom, S., Preservation of Medicines and Cosmetics, in
`Principles and Practice of Disinfection, Preservation &
`Sterilization 484–514 (Fraise, A.P. et al., eds., 4th ed. 2004)
`(Hiom)
`
`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)
`
`Nalox1219
`
`Inactive Ingredient Search for Approved Drug Products, Search
`Names Beginning with B, U.S. FDA (Mar. 3, 2020, 12:08 PM),
`https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm?event
`=browseByLetter.page&Letter=B (FDA B Names)
`
`
`
`vi
`
`

`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`Exhibit No.
`
`Description
`
`Nalox1220
`
`Inactive Ingredient Search for Approved Drug Products:
`Frequently Asked Questions, U.S. FDA (Mar. 3, 2020, 12:12
`PM), https://www.fda.gov/drugs/drug-approvals-and-
`databases/inactive-ingredient-search-approved-drug-products-
`frequently-asked-questions (FDA FAQ)
`
`Nalox1221
`
`Jambhekar S. & Breen, P., Extravascular Routes of Drug
`Administration, in Basic Pharmacokinetics, 97-124 (2009)
`(Jambhekar)
`
`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)
`
`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)
`
`Nalox1227
`
`Marx, D. et al., Intranasal Drug Administration – An Attractive
`Delivery Route for Some Drugs, InTech Open (2015) (Marx)
`
`
`
`vii
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`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`Exhibit No.
`
`Description
`
`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)
`
`Nalox1231
`
`Quarry, M. et al., Investigation of 4,5-epoxymorphinan
`Degradation During Analysis by HPLC, 30 J. Pharm. Biomed.
`Anal. 99–104 (2002) (Quarry)
`
`Nalox1232
`
`Intentionally Left Blank
`
`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)
`
`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)
`
`
`
`viii
`
`

`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`Exhibit No.
`
`Description
`
`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 VII (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)
`
`Nalox1240
`
`Yeh, S. & Lach, J., Stability of Morphine in Aqueous Solution
`III: Kinetics of Morphine Degradation in Aqueous Solution,
`50(1) J. Pharm. Sci. 35–42 (1961) (Yeh)
`
`Nalox1241
`
`Yu, L. et al., Understanding Pharmaceutical Quality by Design,
`16(4) The AAPS J. 771–83 (2014) (Yu)
`
`Nalox1242
`
`Zuckerman, M. et al., Pitfalls of Intranasal Naloxone, 18(4)
`Prehosp. Em. Care 550–54 (2014) (Zuckerman)
`
`Nalox1243
`
`Astepro Label (Aug. 31, 2009), U.S. FDA Drug Label Database
`(Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022
`203s003lbl.pdf (ASTEPRO)
`
`Nalox1244
`
`Patanase Label (Feb. 22, 2012) U.S. FDA Drug Label Database
`(Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021
`861s009lbl.pdf (PATANASE)
`
`Nalox1245
`
`Nasacort Allergy 24H Label (July 2, 2013), U.S. FDA Drug
`Label Database (Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020
`468s033s034lbl.pdf (NASACORT)
`
`
`
`ix
`
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`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`Exhibit No.
`
`Description
`
`Nalox1246
`
`Flonase Sensimist Label (Aug. 2, 2016), U.S. FDA Drug Label
`Database (Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022
`051Orig1s013lbl.pdf (FLONASE)
`
`Nalox1247
`
`Xhance Label (Sept. 18, 2017), U.S. FDA Drug Label Database
`(Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209
`022s000lbl.pdf (XHANCE)
`
`PROTECTIVE ORDER MATERIAL
`
`Nalox1248
`
`February 21, 2020 Transcript of Deposition of Dr. Stuart Allen
`Jones (Jones Dep.)
`
`Nalox1249
`
`Handbook of Pharmaceutical Excipients, 579–81 (Rowe, R. et
`al. eds. 6th ed. 2009) (HPE Potassium Sorbate)
`
`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)
`
`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-2029 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-2051
`
`European Pharmacopoeia 6.0, Volume 2 (Jan.2008)
`
`
`
`x
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`

`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`
`Exhibit No.
`
`Description
`
`Ex-2069
`
`Eric Bechgaard et al., Reversibility and clinical relevant or
`morphological changes after nasal application of ephedrine
`nasal drops 1%, Int’l J. Pharms. (1997) 152:67–73
`
`Ex-2096 World Health Organization, Substance Use: Community
`Management of Opioid Overdose (2014)
`
`Ex-2188
`
`PROTECTIVE ORDER MATERIAL
`
`NDA No. 205678 Module 3.2.P.2, Pharmaceutical
`Development (Naloxone HCl Nasal Spray, 0.9 mg/Spray, Nasal
`Spray)
`
`Ex-2201
`
`PROTECTIVE ORDER MATERIAL
`
`Declaration of Stuart A. Jones, Ph.D.
`
`Ex-2202 Declaration of Kenneth Williams, M.D.
`
`Ex-2203 Declaration of Thomas Begres
`
`Ex-2204 Declaration of Eric Karas
`
`Ex-2205
`
`PROTECTIVE ORDER MATERIAL
`
`Declaration of Robert L. Vigil, Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`xi
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`

`
`I.
`
`INTRODUCTION
`
`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`Petitioner Nalox-1 Pharmaceuticals (“Nalox-1”)1 maintains
`
`that
`
`the
`
`Challenged Claims of U.S. Patent No. 9,468,747 (“the ’747 patent”) are
`
`unpatentable in view of the prior art of record, including Wyse (Nalox1007), HPE
`
`(Nalox1012), Djupesland (Nalox1010), and the ’291 patent (Nalox1015). The
`
`Petition (Paper 1) and this Reply, supported by the expert testimony of Dr.
`
`Donovan and Dr. Hochhaus,2 demonstrate that each of the Challenged Claims is
`
`obvious.
`
`Patent Owners Adapt Pharma Operations Limited and Opiant
`
`Pharmaceuticals, Inc. (collectively, “Adapt”) contend that Petitioner has failed to
`
`set forth a proper case of obviousness, focusing on two issues: (1) Wyse allegedly
`
`teaches away from the use of benzalkonium chloride (“BAC”); and (2) a person of
`
`ordinary skill in the art (“POSA”) allegedly would not have been motivated to use
`
`a 4 mg intranasal (“IN”) dose of naloxone. Paper 34, 1-3. However, Adapt’s
`
`
`1 Nalox-1 is a pharmaceutical company currently developing and planning to
`seek FDA approval to market a generic version of Narcan® naloxone nasal spray.
`Contrary to Adapt’s assertion, Nalox-1 was not “created for the sole purpose of
`challenging the validity of [Adapt’s] patents.” See Paper 34, 1.
`
`2 Adapt criticizes Petitioner’s experts’ opinions because they allegedly did
`not involve input from a clinician. See Paper 34, 2. However, Dr. Donovan and
`Dr. Hochhaus each state that they did not need to consult with a clinician to form
`their opinions, and they have the qualifications of a POSA as defined by Adapt.
`See Nalox1201, ¶8, n.1, Nalox1202, ¶6, n.1.
`
`
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`

`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`arguments fall flat. In addition, none of the so-called secondary considerations
`
`overcome Petitioner’s strong case of obviousness.
`
`II. THE CHALLENGED CLAIMS ARE UNPATENTABLE
`
`A. Wyse would not have directed a POSA away from using BAC in
`an intranasal naloxone formulation.
`
`The prior art of record makes obvious an intranasal formulation in an
`
`aqueous solution of about 100 µL, comprising naloxone, an isotonicity agent, a
`
`preservative such as BAC, a stabilizing agent, and an acid in an amount sufficient
`
`to achieve a pH of 3.5-5.5. See Paper 1 at 29-58. Adapt’s main argument is that a
`
`POSA would not have found the claimed formulation obvious in light of Wyse,
`
`because Wyse teaches away from the use of BAC. Adapt’s argument rests on the
`
`proposition that “Wyse singled out [BAC] as responsible for naloxone instability,”
`
`and “Wyse’s express statements that [BAC] caused naloxone degradation” would
`
`have discouraged its use. Paper 34, 10-11. However, a POSA would have known
`
`that BAC could not cause the naloxone degradation reported in Wyse, and
`
`therefore would have dismissed Wyse’s conclusion and investigated other potential
`
`causes of instability. Nalox1201, ¶¶12-17. Further, a POSA would have recognized
`
`Wyse’s experimental design could not permit a conclusion that any one ingredient
`
`was responsible for the stability problems. Id., ¶¶19-21. A POSA would have
`
`further
`
`investigated
`
`the root cause of naloxone degradation, and upon
`
`investigating, would have confirmed that BAC is not the culprit. Id., ¶¶18, 22.
`
`
`
`2
`
`

`

`IPR2019-00688 - U.S. Patent No. 9,468,747
`Petitioner’s Reply to Patent Owners’ Response
`
`Thus, a POSA would not have been deterred by Wyse’s conclusions, and Wyse
`
`would not have directed a POSA away from using BAC in an intranasal naloxone
`
`formulation. Id., ¶11.
`
`1.
`
`A POSA would have known that naloxone degradants in
`Wyse’s formulations could not have been caused by BAC,
`and therefore would have dismissed Wyse’s conclusion.
`
`Adapt’s expert opines that “[t]he POSA would have concluded from reading
`
`Wyse that in fact [BAC] caused naloxone degradation” (Ex-2201, ¶93) and
`
`testified, “I can’t think of any reason for the POSA to question Wyse’s
`
`conclusion.” Nalox1248 at 139:8-11. However, a POSA would have been alerted
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`to shortcomings in Wyse’s stability studies and would have sought to verify
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`Wyse’s conclusion. Nalox1201, ¶12. See Bayer Schering Pharma AG v. Barr
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`Labs., Inc., 575 F.3d 1341, 1346 (Fed. Cir. 2009) (affirming district court finding
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`that a POSA “would be aware of [a] study’s shortcomings, and would verify [its
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`conclusion].”). More importantly, a POSA would have known that BAC could not
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`have caused the naloxone degradation reported by Wyse. Nalox1201, ¶12.
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`A POSA would have known that BAC could not have caused the disclosed
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`naloxone degradation. Naloxone is a 4,5-epoxymorphinan. It was known in the art
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`that 4,5-epoxymorphinans having a hydroxyl group at the 3-position, such as
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`morphine and naloxone, undergo oxidative degradation in solution. Nalox1231 at
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`1; Nalox1208 at 9; see Nalox1002, ¶50. In this reaction, the 4,5-epoxymorphinan
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`loses a hydrogen atom (or is “oxidized”), while the oxidizing agent gains a
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`hydrogen atom (or is “reduced”). Nalox1208 at 3, 9. The pH of the solution is
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`known to correlate with the extent of the 4,5-epoxymorphinan oxidative
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`degradation. In alkaline or neutral solutions (at pH of 7 or above), degradation of
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`the 4,5-epoxymorphinan occurs rapidly at room temperature, while acidic solutions
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`are more stable. Nalox1231 at 1; see also Nalox1007 at 27:23-24 (“[I]t was found
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`that decreasing the pH minimizes the formation of potentially oxidative
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`degradants.”). Nalox1201, ¶13.
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`The primary degradation product of 4,5-epoxymorphinan compounds having
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`a hydroxyl group at the 3-position is the 2,2’-dimer, which forms from the
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`oxidation of the phenolic group with subsequent condensation to the dimer.
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`Nalox1231 at 1; Nalox1208 at 9. In the case of naloxone, this primary degradation
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`product is known as 2,2’-binaloxone or 2,2’-bisnaloxone. Nalox1231 at 2; Ex-
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`2051 at 5. 2,2’-binaloxone is also known as “Impurity E” as described by the
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`European Pharmacopoeia naloxone hydrochloride dihydrate monograph. Ex-2051
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`at 5. Nalox1201, ¶14.
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`Wyse discloses that formulations 7, 9, 14 and 14A contained “an additional
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`degradant” presumably not found in at least some of the other disclosed
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`formulations.3 Nalox1007 at 27:29-32. Since these formulations were pH-adjusted
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`“to accelerate degradation” of the naloxone (see Nalox1007 at 26:29-30), a POSA
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`would have considered that, if the “additional degradant” was a naloxone
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`degradant, it would likely be an oxidation degradant. Nalox1201, ¶¶13, 15.
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`Indeed, the “additional degradant” in these formulations was identified in a
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`separate document as Impurity E—i.e., 2,2’-binaloxone—the primary oxidation
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`degradation product of naloxone. See Ex-2201, ¶110; Ex-2188 at 10. A POSA
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`would not have been surprised to find Impurity E present in formulations subjected
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`to increased pH to accelerate oxidative degradation of naloxone. Nalox1201, ¶15.
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`Critically, a POSA would have known that BAC could not have been
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`responsible for the production of any oxidative degradants of naloxone, much less
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`Impurity E, the naloxone degradant “notably” found in Wyse’s formulations.
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`Nalox1201, ¶16; see Ex-2188 at 10. BAC is a quaternary ammonium compound.
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`See Nalox1012 at 5. Prior to March 16, 2015, and today, a POSA would have
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`known that quaternary ammonium compounds do not act as oxidizing agents in
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`pharmaceutical formulations. Nalox1201, ¶16. In an oxidation reaction involving
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`small organic molecules, the oxidizing agent gains a hydrogen atom (or is
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`3 Adapt’s expert relies on a separate document (Ex-2188) that states
`formulation 12 contains this additional degradant, and speculates “[t]he POSA
`would have assumed that leaving [Formulation 12] off the unstable list might have
`been a typographical error . . . .” (Ex-2201, ¶109). A POSA reading Wyse would
`not have made this assumption. Nalox1201, ¶15, n.5.
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`“reduced”). Nalox1208 at 3. Quaternary ammonium compounds such as BAC are
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`permanently positively charged at the nitrogen, so adding another hydrogen to that
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`portion of the molecule is not feasible. Since the alkyl chains in BAC are already
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`saturated, no additional hydrogens can to be added anywhere on the alkyl chains.
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`Therefore, a POSA would have known that BAC could not have acted as an
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`oxidizing agent for the naloxone in Wyse’s formulations. Nalox1201, ¶¶16-17.
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`Even Adapt’s expert admitted, despite his opinion that BAC caused naloxone
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`degradation, he had no idea of the mechanism by which BAC could have caused
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`such degradation. See Nalox1248 at 123:4-124:18. Because of this knowledge
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`regarding BAC and naloxone, a POSA would have been skeptical of Wyse’s
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`conclusions relating to the use of BAC.
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`2.
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`A POSA would have known that Wyse’s prototyping studies
`were not designed to identify any single ingredient as the
`cause of naloxone degradation, and would have further
`investigated the root cause of the degradation.
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`Further, a POSA would have questioned Wyse’s conclusions, because of the
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`nature of Wyse’s studies. Wyse discloses that his prototyping studies, in which
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`combinations of excipients were tested together, would not permit a conclusion
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`that any one ingredient in the combinations was responsible for naloxone
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`degradation. See Nalox1007 at 28:28-31 (“While some of the excipients might
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`work individually, the combination of many of these was found to be unacceptable
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`for various reasons as outlined above.”) (emphasis added). A POSA would have
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`known that in order to conclude that BAC and naloxone were incompatible, one
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`would need to study the individual combination of the two compounds.
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`Nalox1201, ¶21.4
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`Adapt’s expert opined that “the POSA would not . . . have questioned
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`Wyse’s experimental design, as testing excipients individually would have been
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`impractical.” Ex-2201, ¶100. Antithetically, during pharmaceutical product
`
`development, individual excipients are routinely tested to determine their
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`compatibility with other components in the formulation. Nalox1201, ¶20. A POSA
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`would have known the limitations of prototyping studies—if a particular
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`formulation presents problems, it is not possible to attribute blame to any single
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`agent present in the formulation. Id. To determine the root cause of any problems,
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`a POSA would have to evaluate each excipient and experimental condition
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`individually and potentially evaluate other factors, including the presence of
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`oxygen or materials used in containers during the storage period, to determine the
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`cause of the observed problem. Id. Indeed, FDA regulators have criticized the
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`approach advocated by Adapt’s expert, and prefer “systematic drug-excipient
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`compatibility testing” to, inter alia, “enhanc[e] the understanding of drug-excipient
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`4 Indeed, a 2019 study confirmed that BAC is not incompatible with
`naloxone. See Nalox1218 at 7-8.
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`interactions that can help with root cause analysis should stability problems occur.”
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`See Nalox1241 at 3.
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`Knowing this, a POSA would have investigated the root cause of the
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`naloxone degradation observed in Wyse’s formulations. Nalox1201, ¶18; see Bone
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`Care Int’l, LLC v. Roxane Labs., Inc., 2012 WL2126896 at *46-47 (D. Del. June
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`11, 2012) (“[T]he court agrees with and finds credible [the expert] testimony that a
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`skilled artisan in 1998 would question or, at the very least, would need to pursue
`
`further research to confirm [the prior art’s] conclusions.”). For example, a POSA
`
`would have known that the grade and purity of a nasal formulation excipient can
`
`affect stability, and may have investigated whether the raw materials in Wyse’s
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`formulations had unacceptable levels of impurities or other compounds potentially
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`contributing to degradant formation. Nalox1201, ¶18. In light of a POSA’s
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`knowledge as to how quaternary ammonium compounds such as BAC behave, a
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`POSA would not have blindly assumed that the naloxone degradants observed in
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`Wyse’s formulations were caused by BAC. Id., ¶¶16-18.
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`Instead, a POSA seeking to determine whether BAC was incompatible with
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`naloxone and investigating the cause of naloxone degradation would have
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`conducted further routine excipient studies in order to achieve this goal—and this
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`further investigation would have informed a POSA that BAC does not cause
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`naloxone degradation. Id., ¶¶18, 22.
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`B. No other prior art cited by Adapt would have directed a POSA
`away from using BAC in an intranasal naloxone formulation.
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`Adapt’s expert opines that other prior art taught away from the use of BAC,
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`with or without ethylene diamine
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`tetraacetic acid (“EDTA”), and from
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`preservatives generally, in a single-use nasal formulation. See Ex-2201, ¶¶128-
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`167. This opinion is unsupported.
`
`Adapt’s expert quotes HPE’s (Nalox1012) disclosure that BAC and EDTA
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`“were shown to produce an inflammatory reaction,” and interprets it to mean that a
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`POSA would not have included these excipients in a nasal naloxone formulation.
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`See Ex-2201, ¶129. However, the original reference cited in HPE, Bechgaard,
`
`does not discourage the use of BAC and EDTA in a naloxone formulation.
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`Nalox1201, ¶24. Indeed, Bechgaard states that, for a “formulation meant for acute
`
`treatment in a life-threatening situation,” which a POSA would understand to
`
`include a naloxone formulation (see Nalox1201, ¶24), “local toxicity to the nasal
`
`mucosa…could be accepted.” See Ex-2069 at 6. Thus, neither HPE nor
`
`Bechgaard teach away from using BAC and EDTA in an intranasal naloxone
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`formulation. Nalox1201, ¶24.
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`Adapt’s expert cites Bitter (Nalox1022) to support his opinion that a POSA
`
`would have been dissuaded from the use of any preservatives in an intranasal
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`naloxone formulation. See Ex-2201, ¶141. But, like Bechgaard, while Bitter
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`IPR2019-00688 - U.S. Patent No. 9,468,747
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`recognized that “local mucosal toxicity” was a characteristic to consider for
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`transmucosal nasal drug delivery, the reference noted that “minor damage [is]
`
`tolerable for emergency or single-application use” (see Nalox1022 at 9), which a
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`POSA would understand to apply to a naloxone formulation. Nalox1201, ¶25.
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`Thus, Bitter does not teach away from using BAC in an intranasal naloxone
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`formulation. Id.
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`Finally, Adapt’s expert points out that “Wyse specifically discusses the
`
`possibility of a preservative-free formulation of naloxone.” See Ex-2201, ¶146
`
`(citing Nalox1007 at 9:8-11). However, that “possibility” would not have
`
`dissuaded a POSA from using a preservative in a naloxone formulation.
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`Nalox1201, ¶26. In fact, a POSA would have understood from Wyse that
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`preservatives could be used in a single-use naloxone nasal spray product. Id. Even
`
`Adapt’s expert admitted that, for a single-use product, “An alternative [to
`
`sterilizing the product] is to include an antimicrobial preservative in the
`
`formulation.” See Ex-2201, ¶48.
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`Thus, none of the other prior art cited by Adapt would have directed a POSA
`
`away from using BAC in an intranasal naloxone formulation. Nalox1201, ¶¶23-26.
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`IPR2019-00688 - U.S. Patent No. 9,468,747
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`C. A POSA would have been highly motivated to use BAC as a
`preservative in an intranasal naloxone formulation.