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`__________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________________
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`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ADAPT PHARMA OPERATIONS LIMITED, and
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owners.
`__________________
`
`Case IPR2019-00694
`U.S. Patent No. 9,629,965
`__________________
`
`PATENT OWNERS’ SURREPLY
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`I.
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`Case IPR2019-00694
`U.S. Patent 9,629,965
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`D.
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`II.
`III.
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`TABLE OF CONTENTS
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`Nalox-1 Has Not Met Its Burden As To BZK. ................................................ 2
`A.
`The POSA Would Recognize That BZK Could Cause Naloxone
`Degradation. .......................................................................................... 3
`B. Wyse Discourages Using BZK With Naloxone. ................................... 5
`C.
`Nalox-1 Offers No Plausible Reason To Use BZK, And Other
`Art Also Discourages It. ........................................................................ 6
`The POSA Had No Reason To Conduct Further Testing To
`Investigate The “Root Cause” Of Wyse’s Degradation. ....................... 8
`The “Preservative” Limitations Are Non-Obvious. ...................................... 11
`It Would Not Be Obvious To Select And Combine The Claim
`Elements. ....................................................................................................... 11
`IV. The Claimed 4 Milligram Dose Is Non-Obvious. ......................................... 12
`A. Dr. Hochhaus Is Unqualified To Address Clinical Motivations. ........ 13
`B. Wyse Does Not Teach A 4 Milligram Dose. ...................................... 14
`C. Wyse Teaches Away From “High and Fast” Doses. .......................... 15
`D. Nalox-1’s Pharmacokinetics Arguments Are Flawed. ........................ 17
`E.
`Nalox-1’s New Motivations Do Not Support Obviousness. ............... 19
`V. Objective Indicia Confirm Non-Obviousness. .............................................. 22
`A.
`Failure of Others, Skepticism, Copying .............................................. 22
`B.
`Unexpected Properties ......................................................................... 24
`C.
`Praise, Commercial Success, Long-Felt Need .................................... 27
`VI. Conclusion ..................................................................................................... 28
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`i
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`TABLE OF AUTHORITIES
`CASES
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`Case IPR2019-00694
`U.S. Patent 9,629,965
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`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 15
`Bayer Schering Pharma AG v. Barr Labs., Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) .......................................................................... 10
`Bone Care Int’l, LLC v. Roxane Labs, Inc.,
`2012 WL 2126896 (D. Del. June 11, 2012) ....................................................... 10
`
`Daubert v. Merrell Dow Pharms., Inc.,
`509 U.S. 579 (1993) ............................................................................................ 14
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 16
`Henny Penny Corp. v. Frymaster LLC,
`938 F.3d 1324 (Fed. Cir. 2019) .......................................................................... 19
`In re Armodafinil Patent Litig.,
`939 F. Supp. 2d 456 (D. Del. 2013) ...................................................................... 9
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) ............................................................................ 5
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) ................................................................................ 6
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ...................................................................... 3, 19
`
`Juniper Networks, Inc. v. Chrimar Sys., Inc.,
`2017 WL 6549892 (P.T.A.B. Dec. 20, 2017) ..................................................... 23
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 10, 12
`Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ............................................................................ 23
`
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`ii
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`Skky, Inc. v. MindGeek, s.a.r.l.,
`859 F.3d 1014 (Fed. Cir. 2017) .......................................................................... 14
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 28
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`iii
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`Nalox-1’s Reply introduces brand-new theories that it claims, without a hint
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`
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`of irony, support obviousness, even though it took Nalox-1 over a year to arrive at
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`them. Nalox-1’s new theories fare no better than its old ones. The Board should
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`reject them all.
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`Particularly astonishing is how frequently Nalox-1 sets about trying to
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`discredit its own references. An obviousness case should have the POSA follow
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`the teachings of its references. Here, at every turn, Nalox-1 would have the POSA
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`read Wyse and HPE and do precisely what they instruct not to do—try to achieve
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`high and fast naloxone levels, use BZK, and combine it with EDTA.
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`In reply, Nalox-1 attempts to discredit Wyse’s BZK teachings based on a
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`new and incorrect theory that BZK “could not cause the naloxone degradation
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`reported in Wyse.” Reply 2. Wyse did not conclude that, and Nalox-1’s evidence
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`does not support it. Nalox-1’s expert contends only that BZK cannot “directly”
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`react with naloxone to form a particular naloxone degradant—a far cry from
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`Nalox-1’s blanket assertion of impossibility. And the POSA would know that
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`BZK could indirectly cause degradation.
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`Nalox-1 also claims for the first time that the POSA would ignore Wyse and
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`undertake extensive testing to find some alternate “root cause” of the
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`degradation—one Nalox-1 is glaringly unable to identify. Nalox-1’s suggestion
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`that the POSA would try to pull BZK from the reject pile is hindsight at its worst.
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`1
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`Nalox-1 cannot demonstrate that the POSA would have had an unabiding desire to
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`use BZK as opposed to other preservatives, and by the priority date the POSA
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`would have known that preservatives were “obsolete,” and disfavored in single-use
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`nasal products.
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`Nalox-1 also cannot satisfy its independent obligation to prove that the entire
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`claimed combination is obvious. After Patent Owners refuted it, Nalox-1 dropped
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`the argument that it is entitled to a “presumption of obviousness,” never
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`mentioning it in reply. Nalox-1 is left with significant failures of proof regarding
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`the selection of various claim elements and amounts.
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`As to dose, Nalox-1 contends the POSA would seek to fix a “standard of
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`care” dose that wasn’t broken, by increasing it at the expense of harming patients
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`and endangering caregivers. This argument too requires ignoring Wyse’s
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`teachings. Nalox-1’s arguments—whether its original ones or its new, belated
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`ones—are not supported by the literature or by a clinician.
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`Finally, overwhelming objective evidence confirms non-obviousness, the
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`facts of which are undisputed.
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`The claims should be confirmed.
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`I.
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`Nalox-1 Has Not Met Its Burden As To BZK.
`Wyse, HPE, and other prior art teach away from BZK in a single-use
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`intranasal naloxone formulation.
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`2
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`A. The POSA Would Recognize That BZK Could Cause Naloxone
`Degradation.
`In its Petition, Nalox-1 argued that Wyse would not deter the POSA from
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`using BZK. At institution, the Board properly rejected that argument. Patent
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`Owners’ Response further rebutted it.
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`In reply, Nalox-1 pivots to a new theory found nowhere in its Petition: that
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`BZK cannot cause naloxone degradation. Nalox-1 improperly presented this new
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`theory for the first time in reply. The Board should decline to consider it under 37
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`C.F.R. §42.23(b). Intelligent Bio-Sys. v. Illumina Cambridge, 821 F.3d 1359,
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`1369-70 (Fed. Cir. 2016).
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`If BZK could not cause naloxone degradation, one would have expected
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`Nalox-1 to mention it earlier. Wyse, a trained chemist, clearly disagrees. Ex-
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`2065, 268:3-7. He attributes the degradation to BZK, as did his company in
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`regulatory filings. POR 10; Ex-2188 pp.9-10.
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`Wyse explains, “commonly used excipients including ... benzalkonium
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`chloride[] were found to increase degradation of naloxone.” Ex-1007, 28:23-27.
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`In attempting to dispute this unequivocal statement, Nalox-1 and Dr. Donovan
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`argue only that BZK cannot directly cause naloxone’s oxidative degradation.
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`When asked if BZK could “cause oxidative degradation of naloxone,” Dr.
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`Donovan answered only that BZK does not “participate directly in redox or
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`3
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`reduction/oxidation reactions,” and she consistently limited her testimony to the
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`purported direct effects of BZK on naloxone. Ex-2215, 477:5-18; id. 477:19-478:9
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`(“I didn’t anticipate that there would be any direct interactions….”), 478:21-479:8
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`(“[I]t’s not going to be directly causing the oxidation….”), 482:8-483:9 (“[BZK]
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`was unlikely to cause a direct degradative interaction….”), 496:7-498:3 (“[I]t’s my
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`opinion that [BZK] can’t directly cause naloxone degradation….”) (emphases
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`added); id. 483:10-484:9, 488:19-489:22.
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`Nalox-1 and Dr. Donovan studiously ignore that BZK could have indirect
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`effects on naloxone. Wyse refers to BZK “increas[ing] degradation of naloxone,”
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`Ex-1007, 28:28, and the POSA would know that “[e]xcipients may affect drug
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`stability via various mechanisms”—as reactants or by catalyzing reactions or
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`affecting other formulation attributes. Ex-2301 p.119; see Ex-2300 ¶¶1-14;
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`Ex-2302 p.5; Ex-2303 p.2; Ex-2304 p.6; Ex-2305 p.38; Ex-2306 pp.10-11.
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`Surfactants, like BZK, are particularly known to facilitate drug degradation.
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`Ex-1206 p.1, 11-12, 19; Ex-2301 pp.127-28; Ex-2307 p.1; Ex-2308 pp.5-7;
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`Ex-2309 p.1. BZK’s surfactant properties could indirectly increase naloxone
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`degradation in various ways, such as by solubilizing oxygen in lipophilic micelles
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`or by extracting reactive impurities from container components. Ex-2300 ¶¶15-24;
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`Ex-1231 pp.1-6; Ex-1208 p.3; Ex-2306 pp.15-17; Ex-2308 pp.5-6; Ex-2315 p.1;
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`Ex-2317 pp.1-2; Ex-2318 pp.2-3; Ex-2319 pp.3-9; Ex-2320 pp.14-19; Ex-2321
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`4
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`pp.4–5; Ex-2322 p.2; Ex-2323 p.1. Because of the possibility of such indirect
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`interactions, the POSA would not ignore Wyse’s teaching that BZK increases
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`naloxone degradation.
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`Further, Nalox-1 argues only that Wyse’s naloxone degradant “would likely
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`be an oxidation degradant.” Reply 5 (emphasis added). Dr. Donovan was even less
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`confident. Ex. 2215, 502:11-503:2. Nalox-1 focuses on Impurity E, but Wyse
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`never identifies the degradant, Ex-2215, 437:12-19, and Nalox-1 has not
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`established that any of the six other impurities in the European Pharmacopeia,
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`Ex-2079 p.11—much less all other possible naloxone degradants—form only
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`through oxidation, Ex-2065, 236:16-237:6, 237:23-238:3.1
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`B. Wyse Discourages Using BZK With Naloxone.
`In arguing that Wyse’s experiments “could not permit a conclusion that any
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`one ingredient was responsible for the stability problems,” Reply 2, Nalox-1
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`ignores the legal standard. As the Board explained, Wyse need not have
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`“conclusively determine[d]” BZK caused instability to “‘criticize, discredit, or
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`otherwise discourage’” its use. Paper 10 p.23 (quoting In re Fulton, 391 F.3d
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`1 Nalox-1 relies on a non-prior-art document that it claims “identifie[s]” the
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`degradant as Impurity E, but it identifies Impurity E as only one of the “impurities”
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`associated with BZK. Reply 5 (citing Ex-2188 p.10); Ex-2215, 507:15-508:4.
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`5
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`1195, 1201 (Fed. Cir. 2004)); POR 9-10. Wyse is the only prior art that describes
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`testing of formulations containing naloxone and BZK, and the POSA would rely
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`on Wyse’s teachings. Ex-2201 ¶¶79-112; Ex-2300 ¶¶25-29.
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`That BZK caused naloxone degradation is the only reasonable conclusion
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`from Wyse. POR 8-12. BZK was the only excipient (apart from sodium chloride)
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`in all four formulations Wyse identified as unstable due to BZK. POR 10.
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`Nalox-1 still cannot identify any alternate theory that explains the “additional
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`degradant” in all four unstable formulations. Dr. Donovan’s far-fetched theories
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`require “an additional degradant” to refer to at least two different substances.
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`Ex-2215, 440:1-6, 447:6-448:3. And they require that in three of the formulations
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`the “degradant” is not a degradant, but instead a BZK/citrate ion pair, Ex-2215,
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`431:3-432:4, even though Wyse refers to “degradation of naloxone” and the
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`European Pharmacopeia method of identifying naloxone degradants, Ex-1007,
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`27:43-44, 29:62-66; Ex-2215, 451:4-464:1; POR 8-9.
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`Wyse’s repeated teach-aways are more than enough to lead the POSA “in a
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`direction divergent from” BZK. In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
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`C. Nalox-1 Offers No Plausible Reason To Use BZK, And Other Art
`Also Discourages It.
`As the Board recognized, Nalox-1’s primary references—Wyse and HPE—
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`teach away from using BZK in the claimed invention. Paper 10 pp.25-27. Wyse
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`6
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`teaches that BZK increases naloxone degradation. POR 6-8. Meanwhile, HPE
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`teaches that BZK and EDTA together cause irritation. POR 13-14. Nalox-1’s only
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`response is to suggest this is acceptable in an emergency-use product, as if the only
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`options were BZK versus people dying. Reply 9-10. But the actual options were
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`an irritating BZK formulation versus non-irritating formulations. The literature
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`teaches to choose the latter, as does common sense. Ex-2201 ¶130; POR 5-18.
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`Further, HPE teaches that BZK is incompatible with some rubber
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`components (as in the Aptar device). Ex-1012 p.6; POR 13-14; Ex-2300 ¶¶20-24.
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`Dr. Donovan admits as much, acknowledging this could be yet another problem
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`with BZK the POSA would have to try to solve. Ex-2215, 610:7-613:7.
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`In the face of numerous reasons to avoid BZK, Nalox-1 offers no reason to
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`use it. That BZK is “widely used” in multi-dose products is immaterial to a single-
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`dose product. Providing “better potency and a wider range of antimicrobial
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`activity” than other preservatives, Reply 11 n.5, is of no consequence to the POSA
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`who, as Dr. Donovan concedes, is only looking for a preservative that is
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`“effective,” not “most effective,” Ex-2065, 157:5-11. And as Nalox-1 argued in its
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`Petition and was reflected in the literature, other effective preservatives were used
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`in FDA-approved intranasal formulations that were not associated with naloxone
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`degradation. POR 12-13; Ex-1013 p.4; Ex-1210 p.45; Ex-2215, 602:10-603:7.
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`7
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`In fact, Nalox-1 fails to identify a reason why the POSA designing a “single-
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`use” intranasal naloxone formulation (as claimed) would include any preservative
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`at all when the art described them as “obsolete” and discouraged them. POR
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`14-18. Dr. Donovan admits preservatives are not required in a single-use device.
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`Ex-1002 ¶62; Ex-2065, 165:5-14, 182:13-21. Reference after reference
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`discouraged their use due to toxicity and device compatibility issues. POR 13-18;
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`Ex-1210 pp.19-20; Ex-1227 pp.16-17. Nalox-1 is unable to identify any single-use
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`intranasal product marketed before the priority date that used BZK. See Reply 11;
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`Ex-2215, 398:7-399:2.
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`The art teaches away from combining BZK with naloxone, EDTA, and
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`single-use devices, each of which the claims require.
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`D. The POSA Had No Reason To Conduct Further Testing To
`Investigate The “Root Cause” Of Wyse’s Degradation.
`Nalox-1 argues for the first time in reply (improperly under 37 C.F.R.
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`§ 42.23(b)) that the POSA would test Wyse’s formulations to determine the
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`degradation’s “root cause.” According to Dr. Donovan, this process requires
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`evaluating “each of the excipients and experimental conditions individually and
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`potentially evaluat[ing] other factors, including the presence of oxygen or the
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`materials used in the containers during the storage period.” Ex-1201 ¶20. This
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`argument too is flawed.
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`8
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`First, the POSA had no stability problem to solve, and therefore no reason to
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`undertake testing. Wyse identifies a stable, final formulation containing benzyl
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`alcohol. Nalox-1 never explains why the POSA would not start (or end) with this,
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`particularly given the challenges presented by BZK. POR 12-13. And the POSA
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`would recognize that other preservative or preservative-free options were
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`available. The POSA would not bother to determine the “root cause” of
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`degradation associated with an excipient not chosen for a final formulation.
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`Ex-2215, 525:21-527:2, 530:19-532:3; Ex-2300 ¶¶25-29.
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`Second, hypothetical experimentation results cannot form the basis for
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`obviousness, which must be based on the prior art. In re Armodafinil Patent Litig.,
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`939 F. Supp. 2d 456, 502 (D. Del. 2013) (“The [challenger] ... cannot establish
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`obviousness through non-prior art experiments….”). Nalox-1’s position would
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`turn the law of obviousness on its head. No prior art could ever teach away,
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`because of the possibility that hypothetical additional testing could disprove that
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`teaching. Here, Nalox-1 does not even know what the results of its putative “root
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`9
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`cause” analysis would be, because no one has conducted that testing. Ex-2215,
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`513:21-22.2
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`Neither of the cases Nalox-1 cites contradicts the fundamental principle that
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`obviousness cannot be based on hypothetical experimentation. They are also
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`factually distinguishable. Bayer v. Barr held that the claimed invention would
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`have been obvious to try under KSR because there were only two options and the
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`art taught away from both. 575 F.3d 1341, 1349-50 (Fed. Cir. 2009). Bone Care
`
`v. Roxane involved contradictory statements in the prior art; the court concluded
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`that the POSA would not rely on one statement without considering the other.
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`2012 WL 2126896, at *47-48 (D. Del. June 11, 2012). Here, in contrast, Nalox-1
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`does not argue the invention was “obvious to try,” the POSA would recognize
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`2 Nalox-1 points to the post-priority Hsu paper, which began with the patent-in-suit
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`and set about testing the claimed invention to see if its low BZK concentration
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`caused naloxone degradation. Ex-1218 pp.1-2, 8; Ex-2214, 537:10-16,
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`542:21-543:3, 580:22-581:17. (Hsu apparently believed BZK could degrade
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`naloxone.) But Hsu did not test Wyse’s BZK formulations, which contained a
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`higher BZK concentration, and Hsu never concluded that BZK was “not the
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`culprit” in those formulations. Reply 2.
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`10
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`many possible alternatives, and no reference other than Wyse addresses the
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`stability of naloxone with BZK.
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`Nalox-1’s myopic focus on BZK is improper hindsight and belied by the
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`record. The POSA would have no reason to go back to Wyse’s discard pile and
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`undertake extensive experimentation in the hopes of proving Wyse wrong, when
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`there were many alternatives to BZK that were not associated with degradation,
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`irritation, or device incompatibility. POR 13; Ex-2201 ¶¶143-65.
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`II. The “Preservative” Limitations Are Non-Obvious.
`The Board instituted this proceeding, notwithstanding the BZK teach-away,
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`because claims 1 and 23-30 of the ’965 patent are not limited to BZK. Critically,
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`Nalox-1’s arguments as to these claims now hinge on the purported obviousness of
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`BZK because Nalox-1 has not demonstrated that the POSA would use any other
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`preservative at the claimed concentrations, POR 18-20, a point Nalox-1 does not
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`address in reply. All the claims should therefore be confirmed.
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`III.
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`It Would Not Be Obvious To Select And Combine The Claim Elements.
`Nalox-1’s Petition tried to overcome the lack of motivation to select and
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`combine all claimed elements by arguing for a “presumption of obviousness”
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`based on ranges in the prior art. Pet. 31. On the pre-institution record, the Board
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`preliminarily agreed that a “presumption of obviousness” existed as to the 4 mg
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`dose. Paper 10 p.16. After institution, Patent Owners explained why such a
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`11
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`presumption is inapplicable. POR 3-4, 23, 50-55. Nalox-1 abandons this
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`argument in reply, never even mentioning a supposed “presumption.”
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`Nalox-1 cannot come close to proving the claimed combinations were
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`obvious. Nalox-1 does not dispute the POSA would have to make at least ten
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`different selections of elements and amounts from two prior art references. POR
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`50. As explained, Nalox-1 fails to demonstrate that the POSA would have
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`combined the various claim elements to arrive at the claimed combination.
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`Further, as to the specific claimed amounts, Nalox-1 argues only that the prior art
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`discloses BZK concentration ranges, naloxone concentration ranges, intranasal
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`volume ranges, and other excipient ranges. Therefore, Nalox-1 cannot prevail
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`because it has not demonstrated that the POSA would have selected the claimed
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`amounts of each of these elements from within each of the ranges, much less
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`combined them to arrive at the claimed invention. KSR v. Teleflex, 550 U.S. 398,
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`418-19 (2007); POR 47-55.
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`IV. The Claimed 4 Milligram Dose Is Non-Obvious.
`Misreading Wyse and ignoring the rest of the prior art, Nalox-1 argues that
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`the POSA would arrive at a 4 mg naloxone dose, even though no reference in over
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`a decade of literature on intranasal naloxone recommended or tested a dose above
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`2 mg. POR 25-26. Wyse does not teach a 4 mg dose, and neither does any other
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`reference. Instead, Wyse teaches away from the “high and fast” pharmacokinetic
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`12
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`goal on which Nalox-1 premises its case. Unable to rely on a range-law
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`presumption, Nalox-1 tries to conjure a motivation for a 4 mg dose through five
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`new, unfounded arguments in reply, which are unsupported by literature or
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`testimony from a qualified witness.
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`A. Dr. Hochhaus Is Unqualified To Address Clinical Motivations.
`Nalox-1 bases its dose arguments on assertions by Dr. Hochhaus about the
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`POSA’s clinical motivations and assessments of risk. But Dr. Hochhaus is not
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`qualified to render these opinions. He is not a clinician and has no clinical
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`experience with naloxone. Ex-2214, 344:12-345:16, 350:14-16, 351:11-14. He
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`did not consult with a clinician in arriving at his opinions, even though he and
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`Nalox-1 concede that the POSA team would include a clinician. Pet. 10; Ex-1003
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`¶22.3 He is not qualified to opine on clinical motivations and risks, and he did not
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`3 In an apparent attempt to obfuscate the record, Nalox-1 asked its experts to
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`declare that they “have the qualifications of a POSA under Dr. Jones’s and Dr.
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`Williams’s definitions.” Ex-1201 ¶8 n.1; Ex-1202 ¶6 n.1; see also Reply 1 n.2.
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`These statements are patently false, as Drs. Jones and Williams also opine the
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`POSA would have “clinical experience with administering opioid antagonists to
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`overdose patients,” Ex-2001 ¶16; Ex-2201 ¶40, and neither of Nalox-1’s experts
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`do. Ex-2214, 351:11-14; Ex-2215, 358:3-5; POR 37-39.
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`13
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`apply the appropriate methodology to support such opinions. His testimony cannot
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`be credited. See Skky v. MindGeek, 859 F.3d 1014, 1022 (Fed. Cir. 2017); see also
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`Daubert v. Merrell Dow Pharms., 509 U.S. 579, 592-93 (1993).
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`By contrast, Patent Owners’ expert, Dr. Williams, has more than thirty
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`years’ experience in emergency medicine, including treating overdosing patients
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`with naloxone. Ex-2001 ¶¶2-12. The Board should credit his testimony as to
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`clinical motivations and concerns because it is effectively unrefuted—Nalox-1
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`declined to cross-examine Dr. Williams, and its own experts lack the requisite
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`qualifications.
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`B. Wyse Does Not Teach A 4 Milligram Dose.
`Wyse does not mention an initial dose higher than 2 mg. Although it
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`discloses a range of possible concentrations, it does not disclose a range of doses.
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`POR 32-34. Patent Owners’ Response submitted expert evidence that the POSA
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`would understand that Wyse’s concentration range did not teach appropriate
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`naloxone doses, and would not use it to select a dose. The POSA would select an
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`appropriate dose first, and then decide what concentration and volume to use.
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`Ex-2201 ¶¶219-225. Dr. Jones also explained that the POSA would not read Wyse
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`to teach that all concentrations in the range are appropriate for use with all of the
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`volumes Wyse separately describes. Id. ¶¶219, 223. Nalox-1 and its experts
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`ignore these fatal flaws. Reply 12-13.
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`C. Wyse Teaches Away From “High and Fast” Doses.
`Even if Wyse did disclose a range of doses, evidence of teaching away
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`would still overcome any presumption of obviousness. Allergan v. Sandoz, 796
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`F.3d 1293, 1304-06 (Fed. Cir. 2015).
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`Misconstruing Patent Owners’ argument, Nalox-1 argues that Wyse’s
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`decision to test intranasal doses of 2 mg or below alone “does not teach away from
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`a 4 mg dose.” Reply 12-13. Although Wyse’s choice of a 2 mg initial intranasal
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`dose is certainly significant, that is not the teach-away Patent Owners identified.
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`POR 31.
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`Nalox-1 attacks this straw man because it has no response to the actual
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`teach-away: Wyse teaches avoiding high and fast pharmacokinetics in order to
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`“minimize sudden and severe side effects of rapid reversal of opioid overdose.”
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`Ex-1007, 3:7-8, 16:29-40; POR 31. But in its hundreds of pages of briefing and
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`declarations, Nalox-1 never addresses this teaching in Wyse, even though the
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`central premise underlying its dose argument is that the POSA would want a “high
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`and fast” pharmacokinetic profile and would expect to achieve that with a 4 mg
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`intranasal dose. Reply 16-17; Ex-1202 ¶31.
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`Wyse says four times that withdrawal effects are “severe,” and makes clear
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`that his objective is to “minimize” them. Ex-1007, 1:55-57, 2:12-22, 3:3-8, 16:36-
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`40. And Dr. Hochhaus concedes that higher naloxone doses lead to increased
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`15
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`withdrawal symptoms and side effects. Ex-2214, 450:20-21, 459:8-13, 491:16-
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`492:1, 494:15-17.4 Wyse, consistent with decades of prior art, discourages raising
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`the dose to achieve a higher and faster pharmacokinetic profile. POR 26-32.
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`Wyse’s teach-away is devastating for Nalox-1. Wyse is the instituted
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`combination’s only dose reference, and “[a]n inference of nonobviousness is
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`especially strong” where the cited reference “undermine[s] the very reason being
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`proffered” to arrive at the claimed combination. DePuy Spine v. Medtronic
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`Sofamor Danek, 567 F.3d 1314, 1326 (Fed. Cir. 2009).
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`4 While Nalox-1 argues (without support from a qualified witness) that withdrawal
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`and other side effects are “not a medical emergency,” Reply 16, Dr. Hochhaus
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`admits that some of these side effects are severe and even “life-threatening,” Ex-
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`2214, 494:3-7, 495:18-498:5; see also id. 348:7-12, 462:6-14, as the literature
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`repeatedly recognized, POR 26-28; Ex-1044 pp.3-4. Dr. Hochhaus contends that
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`some of these effects were “rare,” Ex-1202 ¶¶26-28, but ignores others (e.g.,
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`violence, drug-seeking behaviors, Ex-2001 ¶¶29-35; Ex-2203 ¶15)—and ignores
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`that low initial naloxone doses were used precisely in order to keep adverse effects
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`rare, Ex-2001 ¶36; Ex-2203 ¶19. The only expert in the case with experience
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`treating opioid overdose with naloxone, Dr. Williams, disagrees with Dr.
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`Hochhaus’s comments on withdrawal. Ex-2202 ¶¶32-37.
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`D. Nalox-1’s Pharmacokinetics Arguments Are Flawed.
`The logic and assumptions underlying Nalox-1’s 4-6 mg dose calculations
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`are unsupported and flawed.
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`First, Dr. Hochhaus provides nothing beyond his own say-so to support the
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`notion that the POSA would seek “rapid onset” and “high drug exposure.” This
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`position defies Wyse, the clinical literature, and Dr. Williams’s testimony, which
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`agree that rapidly reversing opioid overdoses should be avoided because “in many
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`instances” it “can be dangerous both to the patient and to the emergency
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`responder.” Ex-1007, 2:11-16; supra Section IV.C; POR 26-32.
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`Second, the POSA would not ignore years of clinical experience establishing
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`a safe and effective dose of 2 mg or less and instead select a dose on the basis of
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`pharmacokinetics alone. POR 39-43; Ex-2201 ¶¶252-59. The POSA, like Wyse,
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`would look to pharmacokinetics only to confirm that the formulation satisfied the
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`minimum threshold for FDA approval. POR 49-43. Indeed, the POSA would
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`recognize a disconnect between the available pharmacokinetic and clinical
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`evidence, such that pharmacokinetics would not usefully predict clinical outcomes.
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`POR 41-43; Ex-2061; Ex-2066, 90:24-91:22. Nalox-1 does not dispute this, nor
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`does it explain why the POSA would increase the intranasal dose to match the
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`pharmacokinetics of a 2 mg intramuscular dose, when the clinical literature
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`showed that a 2 mg intranasal dose already matched the clinical effect of a 2 mg
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`intramuscular dose. See Ex-2201 ¶192; Ex-2202 ¶42.
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`Third, “rapid onset” is an entirely different pharmacokinetic parameter from
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`exposure (AUC). Nalox-1 still has no explanation for why the POSA, seeking to
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`match “rapid onset” of a parenteral dose, would perform a calculation to match
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`AUC instead, as Dr. Hochhaus does. His math does not permit a conclusion that a
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`4-6 mg intranasal dose would match the rapidity of onset of parenteral products.
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`POR 43-46; Ex-2201 ¶¶260-67.
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`Fourth, the POSA would not be able to predict the pharmacokinetic profile
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`of a different formulation from Wyse’s data. Dr. Hochhaus tries to prove—by
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`relying on new models not based on real inputs, Ex-2214, 557:8-18, and post-
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`priority testing of the patented invention, Ex-1218—only that these differences
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`cannot have significant effects on absorption rate. Ex-1202 ¶¶36-39. Even if true,
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`this is irrelevant because the metric upon which Dr. Hochhaus and Nalox-1 base
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`their 4-6 mg “math” is AUC, not absorption rate—and they are “totally different.”
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`Ex-2066, 125:7-21; Pet. 20-21; Ex-1003 ¶¶65-68. Dr. Hochhaus did not address
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`AUC in his supplemental declaration, and even held it constant in his modeling.
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`Ex-1202 ¶34; Ex-2214, 568:14-569:9, 570:2-4, 574:18–577:6. But both sides’
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`experts agree that formulation differences—e.g., concentration, excipients, and
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`tonicity—and method of administration can cause significant and unpredictable
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`changes in AUC. POR 43-46; see Ex-2059 pp.107-08.
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`E. Nalox-1’s New Motivations Do Not Support Obviousness.
`Violating 35 U.S.C. §312(a)(3), Nalox-1’s reply improperly introduces five
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`new motivations for the POSA to use a 4 mg dose and seven new prior-art
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`references (Exs-1203, 1207, 1224, 1228, 1233, 1238, 1242). Reply 13-15. The
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`Board should decline to consider these new obviousness arguments and references.
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`Henny Penny v. Frymaster, 938 F.3d 1324, 1330-31 (Fed. Cir. 2019); Intelligent
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`Bio-Sys., 821 F.3d at 1369-70; 37 C.F.R. §42.23(b).
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`In any event, these arguments are wrong.
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`First, the standard practice as of the priority date was to administer a 0.4 mg
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`initial parenteral dose, not a 2 mg one. See Ex-220