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`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 IPR2019-00694
`U.S. Patent No. 9,629,965
`__________________
`
`PATENT OWNERS’ RESPONSE
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`
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`
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`Case IPR2019-00694
`U.S. Patent No. 9,629,965
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`TABLE OF CONTENTS
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`II.
`
`TABLE OF CONTENTS ............................................................................................ i
`TABLE OF AUTHORITIES ................................................................................... iii
`I.
`The POSA Would Not Have Been Motivated To Use Any
`Preservative At The Claimed Amount, Much Less BZK, Or Had A
`Reasonable Expectation Of Success With BZK. ............................................. 4
`A. Wyse Teaches Away From The Use Of BZK. ...................................... 5
`B. HPE Also Teaches Away From The Claimed Invention. ................... 13
`C.
`The Prior Art As A Whole Also Teaches Away From BZK And
`Preservatives Generally. ...................................................................... 14
`D. Nalox-1 Failed To Prove Motivation To Use The Claimed
`Amount Of Preservative. ..................................................................... 18
`The Claimed 4 Milligram Initial Dose Of Naloxone Was Not
`Obvious. ......................................................................................................... 21
`A.
`The Prior Art Encouraged A “Low and Slow” 2 Milligram
`Intranasal Dose And Discouraged Higher And Faster Naloxone
`Dosing.................................................................................................. 25
`1.
`2 Milligram Intranasal Doses Were Known To Be
`Effective. ................................................................................... 25
`The Prior Art Taught Administration of Naloxone “Low
`and Slow.” ................................................................................. 26
`3. Wyse Used A 2 Milligram Intranasal Dose And Taught
`Away From Higher Doses. ....................................................... 29
`4. Wyse Does Not Disclose A Range of Doses
`Encompassing 4 Milligrams. .................................................... 32
`The POSA Would Have Followed Wyse’s Approach. ............. 34
`5.
`B. Nalox-1’s Argument That The POSA Would Want “Rapid
`Onset” Is Unsupported And Fails to Justify A 4 Milligram
`Dose. .................................................................................................... 36
`1.
`Unsubstantiated Expert Testimony Cannot Support A
`Motivation To Modify The Prior Art. ....................................... 37
`
`2.
`
`i
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`2.
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`3.
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`The POSA Would Use The Lowest Available
`Comparator. ............................................................................... 39
`Nalox-1’s “Simple Math” Is Based On Faulty
`Assumptions. ............................................................................. 43
`III. Nalox-1 Did Not Prove That The Claimed Device And Method of
`Administration Are Obvious. ........................................................................ 47
`IV. Nalox-1 Fails To Show It Would Have Been Obvious To Select And
`Combine The Elements Of The Claimed Invention. ..................................... 48
`V. Objective Indicia Confirm Non-Obviousness Of The Challenged
`Claims. ........................................................................................................... 55
`A.
`The Claimed Invention Has Unexpected Properties ........................... 55
`B. Narcan® Nasal Spray Has Been The Subject Of Significant
`Skepticism. .......................................................................................... 57
`C. Others Failed To Arrive At The Claimed Invention And Copied
`It. .......................................................................................................... 57
`D. Narcan® Nasal Spray Satisfied A Long-Felt But Unmet Need. .......... 58
`E.
`Narcan® Nasal Spray Is A Commercial Success. .............................. 60
`F.
`Third Parties Have Extensively Praised Narcan® Nasal Spray. ......... 62
`VI. CONCLUSION .............................................................................................. 62
`
`
`ii
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`TABLE OF AUTHORITIES
`
`CASES
`
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) .......................................................................... 22
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) ..................................................15, 52, 53, 54, 56
`
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) .............................................................. 38, 39, 40
`
`AstraZeneca v. Anchen,
`2012 WL 1065458 (D.N.J. Mar. 29, 2012),
`aff’d, 498 F. App’x 999 (Fed. Cir. 2013) ........................................................... 48
`
`Avanir Pharm. v. Actavis,
`36 F. Supp. 3d 475 (D. Del. 2014),
`aff’d, 612 F. App’x 613 (Fed. Cir. 2015) ..................................................... 41, 42
`
`Bayer Pharma AG v. Watson Labs, Inc.,
`212 F. Supp. 3d 489 (D. Del. 2016).................................................................... 51
`
`E.I. DuPont de Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) .................................................................. 3, 23, 49
`
`Galderma v. Tolmar,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 49
`
`Genetics Inst., LLC v. Novartis,
`655 F.3d 1291 (Fed. Cir. 2011) .................................................................... 52, 53
`
`Henny Penny v. Frymaster,
`938 F.3d 1324 (Fed. Cir. 2019) .......................................................................... 61
`
`Horizon Pharma Ireland Ltd. v. Actavis Labs., UT, Inc.,
`2017 WL 2703785 (D.N.J. May 12, 2017),
`aff’d, 940 F.3d 680 (Fed. Cir. 2019) ................................................................... 51
`
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) ............................................................................ 49
`
`iii
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`
`In re Applied Materials,
`692 F.3d 1289 (Fed. Cir. 2012) .............................................................. 49, 51, 53
`
`In re Carlson,
`983 F.2d 1032 (Fed. Cir. 1992) .......................................................................... 25
`
`In re Cyclobenzaprine,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 58
`
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) .......................................................... 7, 10, 31, 32
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) ........................................................................ 10, 14
`
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .......................................................................... 20
`
`InTouch Techs. v. VGO Commc’ns,
`751 F.3d 1327 (Fed. Cir. 2014) .................................................................... 12, 13
`
`K/S HIMPP v. Hear-Wear Techs., LLC,
`751 F.3d 1362 (Fed. Cir. 2014) .......................................................................... 39
`
`Knoll Pharm. Co. v. Teva Pharm. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004) .......................................................................... 58
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 48, 53
`
`Millennium Pharms., Inc. v. Sandoz, Inc.
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 55
`
`Orexo AB v. Actavis Elizabeth LLC,
`903 F.3d 1265 (Fed. Cir. 2018) .................................................................... 57, 58
`
`Tec Air, Inc. v. Denso Mfg. Michigan Inc.,
`192 F.3d 1353 (Fed. Cir. 1999) ...................................................................... 8, 18
`
`Valeant Pharm. Int’l v. Mylan Pharm.,
`2018 WL 2023537 (D.N.J. May 1, 2018) ........................................................... 51
`
`iv
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`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 61
`
`Winner Int’l Royalty Corp. v. Wang,
`202 F.3d 1340 (Fed. Cir. 2000) .................................................................... 21, 36
`
`v
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`The claims of U.S. Patent 9,629,965 (“the ’965 patent,” Ex-1001) are
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`directed to a specific formulation of intranasal naloxone to treat opioid overdose,
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`as well as methods and devices for administering that formulation. Priced
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`affordably to ensure widespread access, Patent Owners’ Narcan® Nasal Spray
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`product, which embodies the claimed invention, has revolutionized the treatment
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`of opioid overdose, allowing non-medically-trained people all over the country to
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`administer naloxone to overdose victims. It has been credited with saving the lives
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`of countless people around the country. It is no accident that Narcan® Nasal Spray
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`went from approval to over 95% market share in just three-and-a-half years—it
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`satisfied an enormous long-felt need for a needle-free community-use naloxone
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`product.
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`Contrary to Petitioner Nalox-1 Pharmaceuticals, LLC’s unsupportable
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`rhetoric, the challenged claims were anything but obvious. Even though injectable
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`naloxone had been available for decades, and numerous companies tried to create
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`an FDA approved intranasal naloxone product, no one but the inventors arrived at
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`the claimed invention or succeeded in obtaining FDA approval.
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`With the improper benefit of hindsight, Nalox-1’s experts try to cobble
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`together arguments that the art suggested each of the claim limitations. But
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`Nalox-1’s primary reference, Wyse, leads away from the invention. As the Board
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`recognized upon institution, Wyse expressly teaches away from the use of
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`1
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`benzalkonium chloride (“BZK”)—a requirement of most of the claims—because
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`BZK “increase[s] degradation of naloxone.” Ex-1007 at 28:27. The person of
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`ordinary skill in the art (“POSA”) would not have used BZK. And that dooms the
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`Petition as to all the claims, not just the BZK-specific ones, because Nalox-1’s
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`arguments as to the concentrations of a “preservative” that independent claim 20
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`recites also hinge on the purported obviousness of using BZK in particular.
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`Nalox-1 has failed to show that any other preservative would have been used at the
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`concentrations the claims require.
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`Nalox-1’s obviousness arguments also fail for another reason: the POSA
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`would not have been motivated to use more than a 2 mg initial dose of intranasal
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`naloxone, and the claims all require “about 4 mg.” Nalox-1’s experts argue that
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`the POSA would have wanted to administer a high, rapidly-absorbed dose of
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`naloxone to improve its clinical effects against opioid overdose. But, remarkably,
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`they came to that opinion without input from a clinician or a comprehensive review
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`of the clinical literature—even while conceding that the POSA would have clinical
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`experience. The clinical literature Nalox-1 ignores is unequivocal: not only were
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`2 mg intranasal doses universally acknowledged to be effective, even when
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`delivered less than optimally using the improvised Mucosal Atomization Device
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`(“MAD”), but the art also cautioned repeatedly about the dangers of giving too
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`much naloxone too quickly.
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`Here again Nalox-1 is forced to argue that the POSA would do precisely
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`what its own lead reference teaches not to do. Not only does Wyse teach that a 2
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`mg intranasal dose is the appropriate dose (and bioequivalent to an approved
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`injectable dose), it specifically teaches that “high blood levels are associated with
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`inducing more frequent and severe opioid withdrawal effects,” Ex-1007 at 1:55-57,
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`and extols the advantages of a “slower increase in blood serum levels” that
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`minimizes side effects, Ex-1007 at 16:36-40. In other words, it teaches not to
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`administer naloxone “high and fast.” Nalox-1 fails to establish that Wyse’s 2 mg
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`dose of naloxone is a parameter that the POSA following Wyse even would have
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`sought to alter, let alone increased to “about 4 mg.”
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`Nor, for that matter, does Nalox-1 ever identify anything about Wyse’s final
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`formulation that the POSA would have identified as a problem that needed to be
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`solved. Its experts construct a straw-man, identifying a handful of known
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`problems with 2 mg MAD formulations, but then ignore altogether that Wyse itself
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`taught a final formulation that already solved those problems. But Nalox-1’s
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`obviousness ground starts from Wyse, not from the 2 mg MAD.
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`Recognizing the weakness in its motivation case, Nalox-1 also invokes a
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`“presumption of obviousness” that, it argues, arises “when the ranges of a claimed
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`composition overlap the ranges disclosed in the prior art,” E.I. DuPont de Nemours
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`& Co. v. Synvina C.V., 904 F.3d 996, 1006 (Fed. Cir. 2018). No such presumption
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`3
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`arises here because Wyse never mentions a range of doses overlapping 4 mg, and
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`the POSA would not understand the range of concentrations that it does disclose as
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`such a teaching. The doctrine also is inapplicable for a number of other reasons.
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`For a start, the claimed formulations differ from the prior art by more than just the
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`naloxone dose. To arrive at the claimed invention, the POSA would have to make
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`a host of choices, including each of the excipients and concentrations of excipients,
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`the concentration and dose of naloxone, and the method of administration. And, as
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`Nalox-1’s own expert admitted, the parameters that the POSA would have to select
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`interact in unpredictable ways, affecting not just the amount but the speed at which
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`naloxone is absorbed. Dose is therefore not just a single parameter that the POSA
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`could select from within a disclosed range and arrive at the invention. Patent
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`Owners have not claimed all 4 mg intranasal naloxone products, but rather a
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`specific formulation, and Nalox-1’s petition utterly fails to show that the art
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`teaches putting together the claimed combination at the specific claimed amounts.
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`I. The POSA Would Not Have Been Motivated To Use Any Preservative At
`The Claimed Amount, Much Less BZK, Or Had A Reasonable
`Expectation Of Success With BZK.
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`Claims 1-19 and 22 of the challenged patent require about 0.01 mg BZK and
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`about 0.2 mg EDTA. Claims 20 and 23-30 require “between about 0.005 mg and
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`about 0.015 mg of a preservative.” Claim 21 specifies that the preservative is BZK
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`and further requires EDTA. Nalox-1 fails to show the obviousness of any of these
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`limitations and thus of any challenged claim. See Jones (Ex-2201) ¶¶ 77-181.
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`In its Institution Decision, the Board recognized that there is not even a
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`reasonable likelihood that the POSA would have used BZK in an intranasal
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`naloxone formulation due to the teach-away in Wyse. See Paper 10 (Institution
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`Decision) at 22-26; see also Ex-1006 at 13 (Examiner recognizing teach-away in
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`Wyse during patent prosecution). This finding, as well as the lack of any
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`compelling reason to use BZK, dooms Nalox-1’s obviousness argument for all the
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`claims, not just the ones reciting BZK, because Nalox-1’s arguments for
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`obviousness of the recited preservative amounts hinge on establishing that the
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`POSA would have used BZK.
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`Moreover, the art teaches away from using any preservative in single-use
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`nasal formulations.
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`A. Wyse Teaches Away From The Use Of BZK.
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`The prior art teaches away from the use of BZK, especially in conjunction
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`with EDTA, in intranasal naloxone formulations. In its Institution Decision, the
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`Board rejected Nalox-1’s argument on this point, concluding that “Petitioner has
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`not shown a reasonable likelihood in prevailing in its assertion that these claims
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`would have been obvious over Wyse and HPE.” Paper 10 at 26. That conclusion
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`was correct, and the burden of proof Nalox-1 bears now is even higher. Nalox-1
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`cannot establish the obviousness of these claims by a preponderance of evidence
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`given the express teach-away in Wyse.
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`1.
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`The evidence of the teach-away is essentially undisputed. The parties
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`agree that the POSA would have wanted an intranasal naloxone formulation to
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`retain “nearly all of the naloxone active ingredient” for a long term and under a
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`variety of conditions. Donovan (Ex-1002) ¶¶46, 50; Donovan (Ex-2065) 200:8-23;
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`Jones (Ex-2201) ¶¶47, 65. The parties agree that the POSA would have known of
`
`naloxone’s propensity to degrade. Donovan (Ex-1002) ¶51; Donovan (Ex-2065)
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`198:15-21; Jones (Ex-2201) ¶78; see Ex-2067 at 1. And there is no dispute that
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`Wyse is the only reference that discloses the results of any stability testing of
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`naloxone with BZK. Jones (Ex-2201) ¶¶69, 79-80.
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`There is also no dispute as to the actual teachings of Wyse. In Example 5,
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`Wyse conducted preliminary formulation screening studies, evaluating thirteen
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`excipient combinations, including combinations involving BZK. Jones (Ex-2201)
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`¶81. After an accelerated stability study, Wyse analyzed the formulations using an
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`assay specifically designed to detect naloxone degradants. Ex-1007 at 29:62-66;
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`see Jones (Ex-2201) ¶¶82-84; Donovan (Ex-2065) 225:4-14. Wyse then reported
`
`that “[t]he results further surprisingly showed that the use of benzalkonium
`
`chloride, a common nasal product preservative, resulted in an additional
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`degradant” in four BZK-containing formulations. Ex-1007 at 27:29-37. Wyse
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`thus concluded that “benzalkonium chloride was not [acceptable] due to increased
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`observed degradation,” id. at 27:41-44, even repeating that “Applicant found that,
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`surprisingly, commonly excipients including . . . benzalkonium chloride, were
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`found to increase degradation of naloxone,” id. at 28:23-27. Wyse also reports that
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`all the tested formulations containing both BZK and EDTA were unstable. See
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`Jones (Ex-2201) ¶¶85-86.
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`And Wyse did not simply teach that BZK, particularly with EDTA, makes
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`naloxone formulations unstable—he acted on that conclusion by excluding BZK
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`from subsequent studies. See Jones (Ex-2201) ¶¶87-89. Example 6 tested four
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`modified formulations, none of which included BZK. Ex-1007 at 28:52-67 (Table
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`14). Example 7 further narrowed down the study to two formulations and arrived
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`at the most preferred formulation 4M, which contained benzyl alcohol as a
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`preservative, id. at 29:25-60. See Jones (Ex-2201) ¶¶90-91. Wyse then proceeded
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`to use Formulation 4M (with the naloxone concentration lowered to 10 mg/mL),
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`identified as “Naloxone Nasal Spray” or “NNS,” in his pharmacokinetic studies.
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`See Ex-1007 at 12:55-13:25; Jones (Ex-2201) ¶91. Each of these facts is also
`
`undisputed.
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`As the Board recognized, these explicit statements “criticize, discredit, or
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`otherwise discourage” the use of BZK, and BZK with EDTA, in intranasal
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`naloxone formulations. Paper 10 at 23 (quoting In re Fulton, 391 F.3d 1195, 1201
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`7
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`(Fed. Cir. 2004)); see also Tec Air, Inc. v. Denso Mfg. Michigan Inc., 192 F.3d
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`1353, 1360 (Fed. Cir. 1999). The Board was correct in concluding that “Wyse
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`teaches away from using BAC as an excipient here.” Paper 10 at 23; see Jones
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`(Ex-2201) ¶70. The use of BZK would not have been obvious, and the POSA
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`would not have had a reasonable expectation of success in developing a naloxone
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`formulation with BZK.
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`2.
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`Nalox-1’s obviousness argument rests on the untenable assertion that
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`the POSA would ignore Wyse’s testing and conclusions and do exactly what Wyse
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`instructs not to do: put BZK in a naloxone formulation. None of Nalox-1’s
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`attempts to undermine the Wyse teach-away are persuasive. See Jones (Ex-2201)
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`¶¶93-112.
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`Nalox-1 argues that none of Wyse’s experiments indicated that the
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`formulations “specifically resulted in additional naloxone degradation, rather than
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`degradation of another component.” Pet. at 52. This is flatly wrong. Wyse
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`specifically assessed—and repeatedly teaches that he assessed—whether excipients
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`in a naloxone formulation would degrade naloxone itself. Ex-1007 at 27:19-20
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`(examining effect of storage conditions and pH on the “stability of naloxone,”), id.
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`at 27:21 (observing that increasing the pH accelerates the “degradation of
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`naloxone,”), id. at 27:54 (certain excipients “cause increased naloxone
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`degradation.”); Jones (Ex-2201) ¶¶82-84, 94-98. Thus, in summarizing the results
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`8
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`of his first stability studies, Wyse specifically states that “commonly used
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`excipients” including BZK “were found to increase degradation of naloxone.” Ex-
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`1007 at 28:23-27 (emphasis added); see also Jones (Ex-2201) ¶95.
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`This conclusion is supported by the experimental method Wyse used. Wyse
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`reports that he analyzed each formulation in Example 5 for degradants using a
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`specific, compendial “Naloxone RP-HPLC assay for purity,” Ex-1007 at 26:31-34,
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`29:62-66. See Jones (Ex-2201) ¶¶82, 96-97. The POSA would recognize that this
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`assay was designed to detect naloxone and particular naloxone-specific degradants.
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`Jones (Ex-2201) ¶¶82-84, 96-97; see Ex-2079 at 10. As reflected in Table 17, it
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`allowed Wyse to identify and distinguish “Naloxone Related Substances” on the
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`one hand, from “Unknown Impurities” on the other hand. Jones (Ex-2201) ¶97.
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`The POSA would understand that the experiment that Wyse performed showed
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`“degradation of naloxone” specifically. Ex-1007 at 28:27; Jones (Ex-2201)
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`¶¶81-84.
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`Nalox-1 also argues that there is no teach-away because it cannot be
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`“conclusively determined” from Wyse’s testing on “multiple different formulations
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`combining multiple different excipients” that “any individual excipient was
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`responsible for any instability issues.” Pet. at 51. But as the Board recognized,
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`Wyse need not “conclusively determine[]” that BZK caused the instability to
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`“criticize, discredit, or otherwise discourage” the POSA from using BZK in a
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`naloxone formulation. Paper 10 at 23 (citing In re Fulton, 391 F.3d at 1201). To
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`constitute a teach-away, the prior art only needs to “suggest[] that the line of
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`development flowing from the reference’s disclosure is unlikely to be productive.”
`
`In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994) (emphasis added). Wyse
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`undoubtedly met that standard here: Wyse singled out BZK as responsible for
`
`naloxone instability, and said so expressly three times. Ex-1007 at 27:29-37,
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`27:41-44, 28:23-27. Wyse also specifically states that “[a]part from the
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`preservative [i.e., BZK] Formulation 7 was believed to be ideal for nasal delivery.”
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`Ex-1007 at 27:32-34 (emphasis added). And apart from sodium chloride, which
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`was in Wyse’s final, stable formulation, BZK was the only excipient present in the
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`four formulations that Wyse identified as unstable due to BZK. Jones (Ex-2201)
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`¶99; see id. ¶57. Wyse’s express statements that BZK caused naloxone
`
`degradation, coupled with the evidence correlating BZK with instability, is more
`
`than sufficient to “discourage” the use of BZK in intranasal naloxone formulations,
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`In re Fulton, 391 F.3d at 1201, particularly given the other options available.
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`Jones (Ex-2201) ¶¶99-107.
`
`Nalox-1 observes that Wyse’s “Formulation 12,” includes BZK but was not
`
`listed with the other formulations containing an additional degradant. Pet. at 52.
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`This omission would not have led the POSA to second-guess Wyse’s explicit
`
`conclusion that BZK caused naloxone degradation, particularly in view of Wyse’s
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`10
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`decision to exclude BZK from his subsequent studies. See Ex-1007 at 28:52-67,
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`29:25-60, 12:55-13:25; Jones (Ex-2201) ¶¶108-09. Rather, the POSA would have
`
`believed that Formulation 12 was likely also unstable, and that its omission could
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`have been a typographical error. Id. In any event, had the POSA conducted
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`further stability testing on Formulation 12—as Dr. Donovan conceded the POSA
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`would have done if interested in pursuing it, Ex-2065 at 241:9-16—the POSA
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`would have confirmed that Formulation 12 was also unstable, as reflected in the
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`FDA submission from Wyse’s company. See Ex-2188 at 9-10; Jones (Ex-2201)
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`¶110. Furthermore, as the Board recognized, Formulation 12 would not have
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`motivated the POSA to use BZK in conjunction with EDTA because Formulation
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`12 did not contain EDTA and because every formulation tested in Wyse that did
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`contain BZK with EDTA exhibited naloxone degradation. Paper 10 at 23; Jones
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`(Ex-2201) ¶111.
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`Finally, having no support that the POSA would ignore the repeated and
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`explicit teach-away in Wyse, Nalox-1 resorts to quoting Glende, a non-prior-art
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`Norwegian graduate thesis, purportedly as evidence that the POSA would not read
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`Wyse to teach away from BZK. Pet. at 52. However, as the Board recognized,
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`Glende reached her conclusion after reviewing the WIPO publication equivalent of
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`a parent application of the ’965 Patent, which disclosed storage-stable BZK-
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`containing formulations. Paper 10 at 24-25; Glende (Ex-1031) at 66, 76; Jones
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`(Ex-2201) ¶100; Donovan (Ex-2065) 245:4-7. Glende’s conclusion was based on
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`knowledge of the patented invention which disclosed the stability of the patentee’s
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`formulations, not what the POSA would have understood from the prior art. See
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`InTouch Techs. v. VGO Commc’ns, 751 F.3d 1327, 1351 (Fed. Cir. 2014) (patent
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`challenger cannot rely on the patent as a “roadmap” leading to the claimed
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`invention).
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`None of the other references relied on by Nalox-1 contradict Wyse’s
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`teaching that BZK causes naloxone instability in any respect. Three of them, the
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`HPE (Ex-1012), Kushwaha (Ex-1013), and Djupesland (Ex-1010), do not even
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`mention naloxone. Jones (Ex-2201) ¶117-20, 127. The remaining references,
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`Bahal (Ex-1014), Davies (Ex-1009), Wang (Ex-1008), and Wermeling ’291 (Ex-
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`1016), contain no data relating to a formulation with naloxone and BZK, let alone
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`data showing that such a formulation is stable. Jones (Ex-2201) ¶114-16, 121-26.
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`3.
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`Even Nalox-1 acknowledges that there is nothing special about BZK.
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`Donovan (Ex-1002) ¶137. The first and foremost preservative option for the
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`POSA would have been benzyl alcohol, the preservative Wyse used in its storage-
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`stable “final” intranasal naloxone formulation. See Jones (Ex-2201) ¶112, 154-56.
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`And Nalox-1 fails to identify any reason at all why the POSA—starting from the
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`reference that Nalox-1 itself advances in its obviousness ground—would have
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`modified the Wyse formulation to substitute a different preservative. The entire
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`point of Wyse’s extensive stability testing was to identify a suitable formulation
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`and it did. Id.
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`But even if the POSA did deviate from the final formulation in Wyse, the
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`POSA would have an abundance of alternatives, as Nalox-1 admits and the HPE
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`demonstrates. See Donovan (Ex-2065) Tr. 322:11-325:20; Jones (Ex-2201) ¶156-
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`65. The evidence is clear that the POSA would not have selected BZK from
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`among the alternatives in the face of Wyse’s teachings regarding its effect on
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`naloxone’s stability, as well as the additional concerns with BZK set forth in
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`Section I.B-C below. Jones (Ex-2201) ¶166.
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`B. HPE Also Teaches Away From The Claimed Invention.
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`The other reference Nalox-1 points to for the preservative and BZK
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`limitations, the Handbook of Pharmaceutical Excipients (“HPE”), does not
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`undermine the Wyse teach-away, as it says nothing about naloxone stability. In
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`fact, the HPE also teaches away from the claimed invention.
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`As the Board recognized previously, the HPE teaches that both BZK and
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`EDTA are “known to be local irritants,” and that using them together would
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`“produce an inflammatory reaction.” Paper 10 at 26; see also Jones (Ex-2201)
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`¶129. As Nalox-1 and its experts agree, the POSA would have been motivated to
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`develop a formulation that “minimize[s] irritation.” Pet. at 22; see Donovan (Ex-
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`1002) ¶59; Donovan (Ex-2065) 197:18-198:10; Hochhaus (Ex-2066) 179:19-
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`180:13; see also Jones (Ex-2201) ¶128. In light of this goal, the HPE would have
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`“discouraged” the POSA, and teaches away, from using BZK with EDTA in the
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`claimed formulation. In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994); see Jones
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`(Ex-2201) ¶130.
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`The HPE would also have discouraged the POSA from using BZK due to
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`potential incompatibilities between preservatives and container closures. The HPE
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`discloses that BZK specifically is “[i]ncompatible with . . . some rubber mixes, and
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`some plastic mixes,” Ex-1012 at 6, and the prior art taught that preservatives
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`generally can react with device components, undermining formulation stability.
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`Jones (Ex-2201) ¶¶131-32. The POSA would have recognized BZK’s
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`incompatibility with rubber mixes to be particularly problematic because nasal
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`delivery devices—including the Aptar Unitdose device Nalox-1 contends the
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`POSA would have been motivated to use, Pet. at 23—have rubber components that
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`can come into contact with the formulation. Jones (Ex-2201) ¶133; Ex-2091 at 21-
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`22. This further teaches away from using BZK, and preservatives more generally.
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`C. The Prior Art As A Whole Also Teaches Away From BZK And
`Preservatives Generally.
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`In addition to the teach-aways in the two references Nalox-1 relies upon, the
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`prior art also provides other reasons why the POSA would have steered away from
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`the claimed invention. See Jones (Ex-2201) ¶¶134-42. The parties agree the
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`POSA would be mindful of “the impact of local toxicity of a formulation,”
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`Donovan (Ex-2065) 143:23-144:2; see Jones (Ex-2201) ¶135, and the prior art
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`included numerous teachings away from the use of BZK, or any preservative at all,
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`due to toxicity concerns.
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`The art described a longstanding debate over the use of BZK in nasal
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`products because of its toxic effects, including studies showing irreversible “halted
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`mucociliary transport,” “irreversible ciliostatis,” and “surfactant properties” that
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`“might be expected to be toxic to cilia.” Ex-2092 at 8; Ex-2049 at 4; Ex-2070 at 3;
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`Ex-2081 at 3; see Jones (Ex-2201) ¶135. Because of these safety and toxicity
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`issues, there were longstanding regulatory concerns. See Jones (Ex-2201) ¶140;
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`Ex-2094 at 5 (“In Germany, the use of benzalkonium chloride (BKC) was banned
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`in nasal products.”). Concern for toxicity and resulting difficulty in obtaining
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`regulatory approval “would have discouraged” and thus taught away from the use
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`of BZK in an intranasal naloxone formulation. See Allergan, Inc. v. Sandoz Inc.,
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`796 F.3d 1293, 1305 (Fed. Cir. 2015) (affirming that art taught away from claimed
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`BZK concentration because “known side effects would have discouraged [the
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`POSA] from using higher concentrations of [BZK] in [the claimed] formulation”).
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`The concerns expressed in the art, moreover, were not limited to BZK—a
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`fact that undermines Nalox-1’s arguments as to all the claims, not just the ones that
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`recite BZK. See Jones (Ex-2201) ¶¶141-53. Rizzo summed up the state of the art,
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`explaining that “nowadays, when preservative-free alternatives are available,
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`preserved nasal sprays are obsolete.” Ex-2049 at 5. Nalox-1’s references say the
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`same thing. Bitter taught that: “Due to the ubiquitous reports on preservative-
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`mediated intolerance, th