`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ADAPT PHARMA OPERATIONS LIMITED, and
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owners.
`__________________
`
`Case IPR2019-00688
`U.S. Patent No. 9,468,747
`__________________
`
`PATENT OWNERS’ RESPONSE
`
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`Case IPR2019-00688
`U.S. Patent No. 9,468,747
`
`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. ............................................. 5
`A. Wyse Teaches Away From The Use Of BZK. ...................................... 6
`B. HPE Also Teaches Away From The Claimed Invention. ................... 14
`C.
`The Prior Art As A Whole Also Teaches Away From BZK And
`Preservatives Generally. ...................................................................... 15
`D. Nalox-1 Failed To Prove Motivation To Use The Claimed
`Amount of Preservative. ...................................................................... 19
`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.” ................................................................................. 27
`3. Wyse Used A 2 Milligram Intranasal Dose And Taught
`Away From Higher Doses. ....................................................... 30
`4. Wyse Does Not Disclose A Range of Doses
`Encompassing 4 Milligrams. .................................................... 33
`The POSA Would Have Followed Wyse’s Approach. ............. 35
`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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`

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`Case IPR2019-00688
`U.S. Patent No. 9,468,747
`
`
`
`2.
`
`3.
`
`The POSA Would Use The Lowest Available
`Comparator. ............................................................................... 40
`Nalox-1’s “Simple Math” Is Based On Faulty
`Assumptions. ............................................................................. 44
`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 The 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. .......................................................................................................... 58
`D. Narcan® Nasal Spray Satisfied A Long-Felt But Unmet Need. .......... 59
`E.
`Narcan® Nasal Spray Is A Commercial Success. .............................. 61
`F.
`Third Parties Have Extensively Praised Narcan® Nasal Spray. ......... 62
`VI. CONCLUSION .............................................................................................. 63
`
`
`ii
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`

`

`Case IPR2019-00688
`U.S. Patent No. 9,468,747
`
`
`
`TABLE OF AUTHORITIES
`
`CASES
`
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) .......................................................................... 23
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) ........................................... 16, 52, 53, 55, 56, 57
`
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) .......................................................................... 39
`
`AstraZeneca v. Anchen,
`2012 WL 1065458 (D.N.J. Mar. 29, 2012),
`aff’d, 498 F. App’x 999 (Fed. Cir. 2013) ........................................................... 49
`
`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) .................................................................. 4, 23, 50
`
`Galderma v. Tolmar,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 50
`
`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) .......................................................................... 62
`
`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, 52
`
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) ............................................................................ 49
`
`iii
`
`

`

`Case IPR2019-00688
`U.S. Patent No. 9,468,747
`
`
`In re Applied Materials,
`692 F.3d 1289 (Fed. Cir. 2012) .............................................................. 50, 51, 54
`
`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) .......................................................... 8, 10, 11, 32
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) ........................................................................ 10, 14
`
`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, 49, 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
`
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .................................................................... 61, 62
`
`iv
`
`

`

`
`Winner Int’l Royalty Corp. v. Wang,
`202 F.3d 1340 (Fed. Cir. 2000) .................................................................... 22, 36
`
`Case IPR2019-00688
`U.S. Patent No. 9,468,747
`
`
`
`v
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`

`

`Case IPR2019-00688
`U.S. Patent No. 9,468,747
`
`
`
`The claims of U.S. Patent 9,468,747 (“the ’747 patent,” Ex-1001) are
`
`directed to specific formulations of intranasal naloxone and methods of treating
`
`opioid overdose using them. Priced affordably to ensure widespread access, Patent
`
`Owners’ Narcan® Nasal Spray product, which embodies the claimed invention,
`
`has revolutionized the treatment of opioid overdose, allowing non-medically-
`
`trained people all over the country to administer naloxone to overdose victims. It
`
`has been credited with saving the lives of countless people around the country. It
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`is no accident that Narcan® Nasal Spray went from approval to over 95% market
`
`share in just three-and-a-half years—it satisfied an enormous long-felt need for a
`
`needle-free community-use naloxone product.
`
`Petitioner Nalox-1 Pharmaceuticals, LLC was formed on December 12,
`
`2018, and appears to have been created for the sole purpose of challenging the
`
`validity of Patent Owners’ patents. Petitioner has not applied to the FDA to make
`
`a generic version of Narcan® Nasal Spray or any other pharmaceutical product.
`
`Contrary to Nalox-1’s unsupportable rhetoric, the challenged claims were
`
`anything but obvious. Even though injectable naloxone had been available for
`
`decades, and numerous companies tried to create an FDA approved intranasal
`
`naloxone product, no one but the inventors arrived at the claimed invention or
`
`succeeded in obtaining FDA approval.
`
`1
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`

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`U.S. Patent No. 9,468,747
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`
`
`With the improper benefit of hindsight, Nalox-1’s experts try to cobble
`
`together arguments that the art suggested each of the claim limitations. But
`
`Nalox-1’s primary reference, Wyse, leads away from the invention. As the Board
`
`recognized upon institution, Wyse expressly teaches away from the use of
`
`benzalkonium chloride (“BZK”)—a requirement of most of the claims—because
`
`BZK “increase[s] degradation of naloxone.” Ex-1007 at 28:27. The person of
`
`ordinary skill in the art (“POSA”) would not have used BZK. And that dooms the
`
`Petition as to all the claims, not just the BZK-specific ones, because Nalox-1’s
`
`arguments as to the concentrations of a “preservative” that the independent claims
`
`1 and 30 recite also hinge on the purported obviousness of using BZK in particular.
`
`Nalox-1 has failed to show that any other preservative would have been used at the
`
`concentrations the claims require.
`
`Nalox-1’s obviousness arguments also fail for another reason: the POSA
`
`would not have been motivated to use more than a 2 mg initial dose of intranasal
`
`naloxone, and the claims all require about 4 mg. Nalox-1’s experts argue that the
`
`POSA would have wanted to administer a high, rapidly absorbed dose of naloxone
`
`to improve its clinical effects against opioid overdose. But, remarkably, they came
`
`to that opinion without input from a clinician or a comprehensive review of the
`
`clinical literature—even while conceding that the POSA would have clinical
`
`experience. The clinical literature Nalox-1 ignores is unequivocal: not only were
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`2
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`

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`U.S. Patent No. 9,468,747
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`2 mg intranasal doses universally acknowledged to be effective, even when
`
`delivered less than optimally using the improvised Mucosal Atomization Device
`
`(“MAD”), but the art also cautioned time and again about the dangers of giving too
`
`much naloxone too quickly.
`
`Here again Nalox-1 is forced to argue that the POSA would do precisely
`
`what its own lead reference teaches not to do. Not only does Wyse teach that a 2
`
`mg intranasal dose is the appropriate dose (and had pharmacokinetic exposure
`
`comparable to an approved injectable dose), it specifically teaches that “high blood
`
`levels are associated with inducing more frequent and severe opioid withdrawal
`
`effects,” Ex-1007 at 1:55-57, and extols the advantages of a “slower increase in
`
`blood serum levels” that minimizes side effects, Ex-1007 at 16:36-40. In other
`
`words, it teaches not to administer naloxone “high and fast.” Nalox-1 fails to
`
`establish that Wyse’s 2 mg dose of naloxone is a parameter that the POSA
`
`following Wyse even would have sought to alter, let alone increased to about 4 mg.
`
`Nor, for that matter, does Nalox-1 ever identify anything about Wyse’s final
`
`formulation that the POSA would have identified as a problem that needed to be
`
`solved. Its experts construct a straw-man, identifying a handful of known
`
`problems with 2 mg MAD formulations, but then ignore altogether that Wyse itself
`
`taught a final formulation that already solved those problems. But Nalox-1’s
`
`obviousness ground starts from Wyse, not from the 2 mg MAD.
`
`3
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`Recognizing the weakness in its motivation case, Nalox-1 also invokes a
`
`“presumption of obviousness” that, it argues, arises “when the ranges of a claimed
`
`composition overlap the ranges disclosed in the prior art,” E.I. DuPont de Nemours
`
`& Co. v. Synvina C.V., 904 F.3d 996, 1006 (Fed. Cir. 2018). No such presumption
`
`arises here because Wyse never mentions a range of doses overlapping 4 mg, and
`
`the POSA would not understand the range of concentrations that it does disclose as
`
`such a teaching. The doctrine also is inapplicable for a number of other reasons.
`
`For a start, the claimed formulations differ from the prior art by more than just the
`
`naloxone dose. To arrive at the claimed invention, the POSA would have to make
`
`a host of choices, including each of the excipients and concentrations of excipients,
`
`the concentration and dose of naloxone, and the method of administration. And, as
`
`Nalox-1’s own expert admitted, the parameters that the POSA would have to select
`
`interact in unpredictable ways, affecting not just the amount but the speed at which
`
`naloxone is absorbed. Dose is therefore not just a single parameter that the POSA
`
`could select from within a disclosed range and thereby arrive at the invention.
`
`Patent Owners have not claimed all 4 mg intranasal naloxone products, but rather a
`
`specific formulation, and Nalox-1’s petition utterly fails to show that the art
`
`teaches putting together the claimed combination at the specific claimed amounts.
`
`4
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`Case IPR2019-00688
`U.S. Patent No. 9,468,747
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`
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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.
`
`Every claim of the challenged patent requires “between about 0.005 mg and
`
`about 0.015 mg of a compound which is at least one of a preservative, a cationic
`
`surfactant, and a permeation enhancer.” Claims 2-15, 25-29, 32-33, 37-39, and 43-
`
`45 specify that the preservative is BZK and further require EDTA. Nalox-1 fails to
`
`show the obviousness of any of these limitations and thus of any challenged claim.
`
`See Jones (Ex-2201) ¶¶ 77-181.
`
`In its Institution Decision, the Board recognized that there is not even a
`
`reasonable likelihood that the POSA would have used BZK in an intranasal
`
`naloxone formulation due to the teach-away in Wyse. See Paper 11 (Institution
`
`Decision) at 19-23; see also Ex-1006 at 13 (Examiner recognizing teach-away in
`
`Wyse during patent prosecution). This finding, as well as the lack of any
`
`compelling reason to use BZK, dooms Nalox-1’s obviousness argument for all the
`
`claims, not just the ones reciting BZK, because Nalox-1’s arguments for
`
`obviousness of the recited preservative amounts hinge on establishing that the
`
`POSA would have used BZK.
`
`Moreover, the art teaches away from using any preservative in single-use
`
`nasal formulations.
`
`5
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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
`
`with EDTA, in intranasal naloxone formulations. In its Institution Decision, the
`
`Board rejected Nalox-1’s argument on this point, concluding that “Petitioner has
`
`not shown a reasonable likelihood in prevailing in its assertion that these claims
`
`would have been obvious over Wyse and HPE.” Paper 11 at 23. That conclusion
`
`was correct, and the burden of proof Nalox-1 bears now is even higher. Nalox-1
`
`cannot establish the obviousness of these claims by a preponderance of evidence
`
`given the express teach-away in Wyse.
`
`1.
`
`The evidence of the teach-away is essentially undisputed. The parties
`
`agree that the POSA would have wanted an intranasal naloxone formulation to
`
`retain “nearly all of the naloxone active ingredient” for a long term and under a
`
`variety of conditions. Donovan (Ex-1002) ¶¶47, 51; Donovan (Ex-2065) 200:8-23;
`
`Jones (Ex-2201) ¶¶47, 65. The parties agree that the POSA would have known of
`
`naloxone’s propensity to degrade. Donovan (Ex-1002) ¶52; Donovan (Ex-2065)
`
`198:15-21; Jones (Ex-2201) ¶78; see Ex-2067 at 1. And there is no dispute that
`
`Wyse is the only reference that discloses the results of any stability testing of
`
`naloxone with BZK. Jones (Ex-2201) ¶¶69, 79-80.
`
`There is also no dispute as to the actual teachings of Wyse. In Example 5,
`
`Wyse conducted preliminary formulation screening studies, evaluating thirteen
`
`6
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`excipient combinations, including combinations involving BZK. Jones (Ex-2201)
`
`¶81. After an accelerated stability study, Wyse analyzed the formulations using an
`
`assay specifically designed to detect naloxone degradants. Ex-1007 at 29:62-66;
`
`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
`
`degradant” in four BZK-containing formulations. Ex-1007 at 27:29-37. Wyse
`
`thus concluded that “benzalkonium chloride was not [acceptable] due to increased
`
`observed degradation,” id. at 27:41-44, even repeating that “Applicant found that,
`
`surprisingly, commonly excipients including . . . benzalkonium chloride, were
`
`found to increase degradation of naloxone,” id. at 28:23-27. Wyse also reports that
`
`all the tested formulations containing both BZK and EDTA were unstable. See
`
`Jones (Ex-2201) ¶¶85-86.
`
`And Wyse did not simply teach that BZK, particularly with EDTA, makes
`
`naloxone formulations unstable—he acted on that conclusion by excluding BZK
`
`from subsequent studies. See Jones (Ex-2201) ¶¶87-89. Example 6 tested four
`
`modified formulations, none of which included BZK. Ex-1007 at 28:52-67 (Table
`
`14). Example 7 further narrowed down the study to two formulations and arrived
`
`at the most preferred formulation 4M, which contained benzyl alcohol as a
`
`preservative, id. at 29:25-60. See Jones (Ex-2201) ¶¶90-91. Wyse then proceeded
`
`7
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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.
`
`See Ex-1007 at 12:55-13:25; Jones (Ex-2201) ¶91. Each of these facts is also
`
`undisputed.
`
`As the Board recognized, these explicit statements “criticize, discredit, or
`
`otherwise discourage” the use of BZK, and BZK with EDTA, in intranasal
`
`naloxone formulations. Paper 11 at 20 (quoting In re Fulton, 391 F.3d 1195, 1201
`
`(Fed. Cir. 2004)); see also Tec Air, Inc. v. Denso Mfg. Michigan Inc., 192 F.3d
`
`1353, 1360 (Fed. Cir. 1999). The Board was correct in concluding that “Wyse
`
`teaches away from using benzalkonium chloride as an excipient here.” Paper 11 at
`
`20; see Jones (Ex-2201) ¶70. The use of BZK would not have been obvious, and
`
`the POSA would not have had a reasonable expectation of success in developing a
`
`naloxone formulation with BZK.
`
`2.
`
`Nalox-1’s obviousness argument rests on the untenable assertion that
`
`the POSA would ignore Wyse’s testing and conclusions and do exactly what Wyse
`
`instructs not to do: put BZK in a naloxone formulation. None of Nalox-1’s
`
`attempts to undermine the Wyse teach-away are persuasive. See Jones (Ex-2201)
`
`¶¶93-112.
`
`Nalox-1 argues that none of Wyse’s experiments indicated that the
`
`formulations “specifically resulted in additional naloxone degradation, rather than
`
`8
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`U.S. Patent No. 9,468,747
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`degradation of another component.” Pet. at 59. This is flatly wrong. Wyse
`
`specifically assessed—and repeatedly teaches that he assessed—whether excipients
`
`in a naloxone formulation would degrade naloxone itself. Ex-1007 at 27:19-20
`
`(examining effect of storage conditions and pH on the “stability of naloxone,”), id.
`
`at 27:21 (observing that increasing the pH accelerates the “degradation of
`
`naloxone,”), id. at 27:54 (certain excipients “cause increased naloxone
`
`degradation.”); Jones (Ex-2201) ¶¶82-84, 94-98. Thus, in summarizing the results
`
`of his first stability studies, Wyse specifically states that “commonly used
`
`excipients” including BZK “were found to increase degradation of naloxone.” Ex-
`
`1007 at 28:23-27 (emphasis added); see also Jones (Ex-2201) ¶95.
`
`This conclusion is supported by the experimental method Wyse used. Wyse
`
`reports that he analyzed each formulation in Example 5 for degradants using a
`
`specific, compendial “Naloxone RP-HPLC assay for purity,” Ex-1007 at 26:31-34,
`
`29:62-66. See Jones (Ex-2201) ¶¶82, 96-97. The POSA would recognize that this
`
`assay was designed to detect naloxone and particular naloxone-specific degradants.
`
`Jones (Ex-2201) ¶¶82-84, 96-97; see Ex-2079 at 10. As reflected in Table 17, it
`
`allowed Wyse to identify and distinguish “Naloxone Related Substances” on the
`
`one hand, from “Unknown Impurities” on the other hand. Jones (Ex-2201) ¶97.
`
`The POSA would understand that the experiment that Wyse performed showed
`
`9
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`

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`“degradation of naloxone” specifically. Ex-1007 at 28:27; Jones (Ex-2201)
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`Case IPR2019-00688
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`¶¶81-84.
`
`Nalox-1 also argues that there is no teach-away because it cannot be
`
`“conclusively determined” from Wyse’s testing on “multiple different formulations
`
`combining multiple different excipients” that “any individual excipient was
`
`responsible for any instability issues.” Pet. at 59. But as the Board recognized,
`
`Wyse need not “conclusively determine[]” that BZK caused the instability to
`
`“criticize, discredit, or otherwise discourage” the POSA from using BZK in a
`
`naloxone formulation. Paper 11 at 20 (citing In re Fulton, 391 F.3d at 1201). To
`
`constitute a teach-away, the prior art only needs to “suggest[] that the line of
`
`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
`
`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,
`
`27:41-44, 28:23-27. Wyse also specifically states that “[a]part from the
`
`preservative [i.e., BZK] Formulation 7 was believed to be ideal for nasal delivery.”
`
`Ex-1007 at 27:32-34 (emphasis added). And apart from sodium chloride, which
`
`was in Wyse’s final, stable formulation, BZK was the only excipient present in the
`
`four formulations that Wyse identified as unstable due to BZK. Jones (Ex-2201)
`
`¶99; see id. ¶57. Wyse’s express statements that BZK caused naloxone
`
`10
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`Case IPR2019-00688
`U.S. Patent No. 9,468,747
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`
`degradation, coupled with the evidence correlating BZK with instability, is more
`
`than sufficient to “discourage” the use of BZK in intranasal naloxone formulations,
`
`In re Fulton, 391 F.3d at 1201, particularly given the other options available.
`
`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 59.
`
`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
`
`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
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`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 11 at 20; 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 59-60. However, as the Board recognized,
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`Glende reached her conclusion after reviewing the WIPO publication equivalent of
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`the ’253 patent of which the ‘747 patent is a continuation-in-part, which disclosed
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`storage-stable BZK-containing formulations. Paper 11 at 21-22; Glende (Ex-1031)
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`at 66, 76; Jones (Ex-2201) ¶100; Donovan (Ex-2065) 245:4-7. Glende’s
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`conclusion was based on knowledge of the patented invention which disclosed the
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`stability of the patentee’s formulations, not what the POSA would have understood
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`from the prior art. See InTouch Techs. v. VGO Commc’ns, 751 F.3d 1327, 1351
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`(Fed. Cir. 2014) (patent challenger cannot rely on the patent as a “roadmap”
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`leading to the claimed 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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`Dr. Donovan identifies four other preservatives that the POSA allegedly would be
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`motivated to use—benzethonium chloride, benzyl alcohol, methylparaben, and
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`propylparaben. Donovan (Ex-1002) ¶144. The first and foremost preservative
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`option for the POSA would have been benzyl alcohol, the preservative Wyse used
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`in its storage-stable “final” intranasal naloxone formulation. See Jones (Ex-2201)
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`¶112, 154-56. And Nalox-1 fails to identify any reason at all why the POSA—
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`starting from the reference that Nalox-1 itself advances in its obviousness
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`ground—would have modified the Wyse formulation to substitute a different
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`preservative. The entire point of Wyse’s extensive stability testing was to identify
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`a suitable formulation 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 11 at 22; 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) ¶60; 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