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’ SURREPLY
`
`
`
`
`
`
`
`
`
`__________________
`
`
`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’ SURREPLY
`
`
`
`
`
`
`
`
`
`
`
`I.
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`D.
`
`II.
`III.
`
`TABLE OF CONTENTS
`
`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
`
`
`
`
`
`
`i
`
`
`
`
`
`TABLE OF AUTHORITIES
`CASES
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`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
`
`
`
`
`
`ii
`
`
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`
`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
`
`
`
`
`
`
`
`iii
`
`
`
`Nalox-1’s Reply introduces brand-new theories that it claims, without a hint
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`
`
`of irony, support obviousness, even though it took Nalox-1 over a year to arrive at
`
`them. Nalox-1’s new theories fare no better than its old ones. The Board should
`
`reject them all.
`
`Particularly astonishing is how frequently Nalox-1 sets about trying to
`
`discredit its own references. An obviousness case should have the POSA follow
`
`the teachings of its references. Here, at every turn, Nalox-1 would have the POSA
`
`read Wyse and HPE and do precisely what they instruct not to do—try to achieve
`
`high and fast naloxone levels, use BZK, and combine it with EDTA.
`
`In reply, Nalox-1 attempts to discredit Wyse’s BZK teachings based on a
`
`new and incorrect theory that BZK “could not cause the naloxone degradation
`
`reported in Wyse.” Reply 2. Wyse did not conclude that, and Nalox-1’s evidence
`
`does not support it. Nalox-1’s expert contends only that BZK cannot “directly”
`
`react with naloxone to form a particular naloxone degradant—a far cry from
`
`Nalox-1’s blanket assertion of impossibility. And the POSA would know that
`
`BZK could indirectly cause degradation.
`
`Nalox-1 also claims for the first time that the POSA would ignore Wyse and
`
`undertake extensive testing to find some alternate “root cause” of the
`
`degradation—one Nalox-1 is glaringly unable to identify. Nalox-1’s suggestion
`
`that the POSA would try to pull BZK from the reject pile is hindsight at its worst.
`
`
`
`
`
`1
`
`
`
`
`Nalox-1 cannot demonstrate that the POSA would have had an unabiding desire to
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`use BZK as opposed to other preservatives, and by the priority date the POSA
`
`would have known that preservatives were “obsolete,” and disfavored in single-use
`
`nasal products.
`
`Nalox-1 also cannot satisfy its independent obligation to prove that the entire
`
`claimed combination is obvious. After Patent Owners refuted it, Nalox-1 dropped
`
`the argument that it is entitled to a “presumption of obviousness,” never
`
`mentioning it in reply. Nalox-1 is left with significant failures of proof regarding
`
`the selection of various claim elements and amounts.
`
`As to dose, Nalox-1 contends the POSA would seek to fix a “standard of
`
`care” dose that wasn’t broken, by increasing it at the expense of harming patients
`
`and endangering caregivers. This argument too requires ignoring Wyse’s
`
`teachings. Nalox-1’s arguments—whether its original ones or its new, belated
`
`ones—are not supported by the literature or by a clinician.
`
`Finally, overwhelming objective evidence confirms non-obviousness, the
`
`facts of which are undisputed.
`
`The claims should be confirmed.
`
`I.
`
`Nalox-1 Has Not Met Its Burden As To BZK.
`Wyse, HPE, and other prior art teach away from BZK in a single-use
`
`intranasal naloxone formulation.
`
`
`
`
`
`2
`
`
`
`
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`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
`
`using BZK. At institution, the Board properly rejected that argument. Patent
`
`Owners’ Response further rebutted it.
`
`In reply, Nalox-1 pivots to a new theory found nowhere in its Petition: that
`
`BZK cannot cause naloxone degradation. Nalox-1 improperly presented this new
`
`theory for the first time in reply. The Board should decline to consider it under 37
`
`C.F.R. §42.23(b). Intelligent Bio-Sys. v. Illumina Cambridge, 821 F.3d 1359,
`
`1369-70 (Fed. Cir. 2016).
`
`If BZK could not cause naloxone degradation, one would have expected
`
`Nalox-1 to mention it earlier. Wyse, a trained chemist, clearly disagrees. Ex-
`
`2065, 268:3-7. He attributes the degradation to BZK, as did his company in
`
`regulatory filings. POR 10; Ex-2188 pp.9-10.
`
`Wyse explains, “commonly used excipients including ... benzalkonium
`
`chloride[] were found to increase degradation of naloxone.” Ex-1007, 28:23-27.
`
`In attempting to dispute this unequivocal statement, Nalox-1 and Dr. Donovan
`
`argue only that BZK cannot directly cause naloxone’s oxidative degradation.
`
`When asked if BZK could “cause oxidative degradation of naloxone,” Dr.
`
`Donovan answered only that BZK does not “participate directly in redox or
`
`
`
`
`
`3
`
`
`
`
`reduction/oxidation reactions,” and she consistently limited her testimony to the
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`purported direct effects of BZK on naloxone. Ex-2215, 477:5-18; id. 477:19-478:9
`
`(“I didn’t anticipate that there would be any direct interactions….”), 478:21-479:8
`
`(“[I]t’s not going to be directly causing the oxidation….”), 482:8-483:9 (“[BZK]
`
`was unlikely to cause a direct degradative interaction….”), 496:7-498:3 (“[I]t’s my
`
`opinion that [BZK] can’t directly cause naloxone degradation….”) (emphases
`
`added); id. 483:10-484:9, 488:19-489:22.
`
`Nalox-1 and Dr. Donovan studiously ignore that BZK could have indirect
`
`effects on naloxone. Wyse refers to BZK “increas[ing] degradation of naloxone,”
`
`Ex-1007, 28:28, and the POSA would know that “[e]xcipients may affect drug
`
`stability via various mechanisms”—as reactants or by catalyzing reactions or
`
`affecting other formulation attributes. Ex-2301 p.119; see Ex-2300 ¶¶1-14;
`
`Ex-2302 p.5; Ex-2303 p.2; Ex-2304 p.6; Ex-2305 p.38; Ex-2306 pp.10-11.
`
`Surfactants, like BZK, are particularly known to facilitate drug degradation.
`
`Ex-1206 p.1, 11-12, 19; Ex-2301 pp.127-28; Ex-2307 p.1; Ex-2308 pp.5-7;
`
`Ex-2309 p.1. BZK’s surfactant properties could indirectly increase naloxone
`
`degradation in various ways, such as by solubilizing oxygen in lipophilic micelles
`
`or by extracting reactive impurities from container components. Ex-2300 ¶¶15-24;
`
`Ex-1231 pp.1-6; Ex-1208 p.3; Ex-2306 pp.15-17; Ex-2308 pp.5-6; Ex-2315 p.1;
`
`Ex-2317 pp.1-2; Ex-2318 pp.2-3; Ex-2319 pp.3-9; Ex-2320 pp.14-19; Ex-2321
`
`
`
`
`
`4
`
`
`
`
`pp.4–5; Ex-2322 p.2; Ex-2323 p.1. Because of the possibility of such indirect
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`interactions, the POSA would not ignore Wyse’s teaching that BZK increases
`
`naloxone degradation.
`
`Further, Nalox-1 argues only that Wyse’s naloxone degradant “would likely
`
`be an oxidation degradant.” Reply 5 (emphasis added). Dr. Donovan was even less
`
`confident. Ex. 2215, 502:11-503:2. Nalox-1 focuses on Impurity E, but Wyse
`
`never identifies the degradant, Ex-2215, 437:12-19, and Nalox-1 has not
`
`established that any of the six other impurities in the European Pharmacopeia,
`
`Ex-2079 p.11—much less all other possible naloxone degradants—form only
`
`through oxidation, Ex-2065, 236:16-237:6, 237:23-238:3.1
`
`B. Wyse Discourages Using BZK With Naloxone.
`In arguing that Wyse’s experiments “could not permit a conclusion that any
`
`one ingredient was responsible for the stability problems,” Reply 2, Nalox-1
`
`ignores the legal standard. As the Board explained, Wyse need not have
`
`“conclusively determine[d]” BZK caused instability to “‘criticize, discredit, or
`
`otherwise discourage’” its use. Paper 11 p.20 (quoting In re Fulton, 391 F.3d
`
`
`1 Nalox-1 relies on a non-prior-art document that it claims “identifie[s]” the
`
`degradant as Impurity E, but it identifies Impurity E as only one of the “impurities”
`
`associated with BZK. Reply 5 (citing Ex-2188 p.10); Ex-2215, 507:15-508:4.
`
`
`
`
`
`5
`
`
`
`
`1195, 1201 (Fed. Cir. 2004)); POR 10-11. Wyse is the only prior art that describes
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`testing of formulations containing naloxone and BZK, and the POSA would rely
`
`on Wyse’s teachings. Ex-2201 ¶¶79-112; Ex-2300 ¶¶25-29.
`
`That BZK caused naloxone degradation is the only reasonable conclusion
`
`from Wyse. POR 8-13. BZK was the only excipient (apart from sodium chloride)
`
`in all four formulations Wyse identified as unstable due to BZK. POR 10.
`
`Nalox-1 still cannot identify any alternate theory that explains the “additional
`
`degradant” in all four unstable formulations. Dr. Donovan’s far-fetched theories
`
`require “an additional degradant” to refer to at least two different substances.
`
`Ex-2215, 440:1-6, 447:6-448:3. And they require that in three of the formulations
`
`the “degradant” is not a degradant, but instead a BZK/citrate ion pair, Ex-2215,
`
`431:3-432:4, even though Wyse refers to “degradation of naloxone” and the
`
`European Pharmacopeia method of identifying naloxone degradants, Ex-1007,
`
`27:43-44, 29:62-66; Ex-2215, 451:4-464:1; POR 10-11.
`
`Wyse’s repeated teach-aways are more than enough to lead the POSA “in a
`
`direction divergent from” BZK. In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
`
`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—
`
`teach away from using BZK in the claimed invention. Paper 11 pp.22-23. Wyse
`
`
`
`
`
`6
`
`
`
`
`teaches that BZK increases naloxone degradation. POR 6-8. Meanwhile, HPE
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`teaches that BZK and EDTA together cause irritation. POR 14-15. Nalox-1’s only
`
`response is to suggest this is acceptable in an emergency-use product, as if the only
`
`options were BZK versus people dying. Reply 9-10. But the actual options were
`
`an irritating BZK formulation versus non-irritating formulations. The literature
`
`teaches to choose the latter, as does common sense. Ex-2201 ¶130; POR 6-18.
`
`Further, HPE teaches that BZK is incompatible with some rubber
`
`components (as in the Aptar device). Ex-1012 p.6; POR 14-15; Ex-2300 ¶¶20-24.
`
`Dr. Donovan admits as much, acknowledging this could be yet another problem
`
`with BZK the POSA would have to try to solve. Ex-2215, 610:7-613:7.
`
`In the face of numerous reasons to avoid BZK, Nalox-1 offers no reason to
`
`use it. That BZK is “widely used” in multi-dose products is immaterial to a single-
`
`dose product. Providing “better potency and a wider range of antimicrobial
`
`activity” than other preservatives, Reply 11 n.5, is of no consequence to the POSA
`
`who, as Dr. Donovan concedes, is only looking for a preservative that is
`
`“effective,” not “most effective,” Ex-2065, 157:5-11. And as Nalox-1 argued in its
`
`Petition and was reflected in the literature, other effective preservatives were used
`
`in FDA-approved intranasal formulations that were not associated with naloxone
`
`degradation. POR 13; Ex-1013 p.4; Ex-1210 p.45; Ex-2215, 602:10-603:7.
`
`
`
`
`
`7
`
`
`
`In fact, Nalox-1 fails to identify a reason why the POSA designing a “single-
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`
`
`use” intranasal naloxone formulation (as claimed) would include any preservative
`
`at all when the art described them as “obsolete” and discouraged them. POR
`
`15-18. Dr. Donovan admits preservatives are not required in a single-use device.
`
`Ex-1002 ¶63; Ex-2065, 165:5-14, 182:13-21. Reference after reference
`
`discouraged their use due to toxicity and device compatibility issues. POR 14-18;
`
`Ex-1210 pp.19-20; Ex-1227 pp.16-17. Nalox-1 is unable to identify any single-use
`
`intranasal product marketed before the priority date that used BZK. See Reply 11;
`
`Ex-2215, 398:7-399:2.
`
`The art teaches away from combining BZK with naloxone, EDTA, and
`
`single-use devices, each of which the claims require.
`
`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.
`
`§ 42.23(b)) that the POSA would test Wyse’s formulations to determine the
`
`degradation’s “root cause.” According to Dr. Donovan, this process requires
`
`evaluating “each of the excipients and experimental conditions individually and
`
`potentially evaluat[ing] other factors, including the presence of oxygen or the
`
`materials used in the containers during the storage period.” Ex-1201 ¶20. This
`
`argument too is flawed.
`
`
`
`
`
`8
`
`
`
`First, the POSA had no stability problem to solve, and therefore no reason to
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`
`
`undertake testing. Wyse identifies a stable, final formulation containing benzyl
`
`alcohol. Nalox-1 never explains why the POSA would not start (or end) with this,
`
`particularly given the challenges presented by BZK. POR 13. And the POSA
`
`would recognize that other preservative or preservative-free options were
`
`available. The POSA would not bother to determine the “root cause” of
`
`degradation associated with an excipient not chosen for a final formulation.
`
`Ex-2215, 525:21-527:2, 530:19-532:3; Ex-2300 ¶¶25-29.
`
`Second, hypothetical experimentation results cannot form the basis for
`
`obviousness, which must be based on the prior art. In re Armodafinil Patent Litig.,
`
`939 F. Supp. 2d 456, 502 (D. Del. 2013) (“The [challenger] ... cannot establish
`
`obviousness through non-prior art experiments….”). Nalox-1’s position would
`
`turn the law of obviousness on its head. No prior art could ever teach away,
`
`because of the possibility that hypothetical additional testing could disprove that
`
`teaching. Here, Nalox-1 does not even know what the results of its putative “root
`
`
`
`
`
`9
`
`
`
`
`cause” analysis would be, because no one has conducted that testing. Ex-2215,
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`513:21-22.2
`
`Neither of the cases Nalox-1 cites contradicts the fundamental principle that
`
`obviousness cannot be based on hypothetical experimentation. They are also
`
`factually distinguishable. Bayer v. Barr held that the claimed invention would
`
`have been obvious to try under KSR because there were only two options and the
`
`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
`
`that the POSA would not rely on one statement without considering the other.
`
`2012 WL 2126896, at *47-48 (D. Del. June 11, 2012). Here, in contrast, Nalox-1
`
`does not argue the invention was “obvious to try,” the POSA would recognize
`
`
`2 Nalox-1 points to the post-priority Hsu paper, which began with the patent-in-suit
`
`and set about testing the claimed invention to see if its low BZK concentration
`
`caused naloxone degradation. Ex-1218 pp.1-2, 8; Ex-2214, 537:10-16,
`
`542:21-543:3, 580:22-581:17. (Hsu apparently believed BZK could degrade
`
`naloxone.) But Hsu did not test Wyse’s BZK formulations, which contained a
`
`higher BZK concentration, and Hsu never concluded that BZK was “not the
`
`culprit” in those formulations. Reply 2.
`
`
`
`
`
`10
`
`
`
`
`many possible alternatives, and no reference other than Wyse addresses the
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`stability of naloxone with BZK.
`
`Nalox-1’s myopic focus on BZK is improper hindsight and belied by the
`
`record. The POSA would have no reason to go back to Wyse’s discard pile and
`
`undertake extensive experimentation in the hopes of proving Wyse wrong, when
`
`there were many alternatives to BZK that were not associated with degradation,
`
`irritation, or device incompatibility. POR 13; Ex-2201 ¶¶143-65.
`
`II. The “Preservative” Limitations Are Non-Obvious.
`The Board instituted this proceeding, notwithstanding the BZK teach-away,
`
`because claims 1, 16-24, 30-31, 34-36, and 40-42 of the ’747 patent are not limited
`
`to BZK. Critically, Nalox-1’s arguments as to these claims now hinge on the
`
`purported obviousness of BZK because Nalox-1 has not demonstrated that the
`
`POSA would use any other preservative at the claimed concentrations, POR 19-21,
`
`a point Nalox-1 does not address in reply. All the claims should therefore be
`
`confirmed.
`
`III.
`
`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
`
`combine all claimed elements by arguing for a “presumption of obviousness”
`
`based on ranges in the prior art. Pet. 31-32. On the pre-institution record, the
`
`Board preliminarily agreed that a “presumption of obviousness” existed as to the 4
`
`
`
`
`
`11
`
`
`
`
`mg dose. Paper 11 p.13. After institution, Patent Owners explained why such a
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`presumption is inapplicable. POR 4, 23-24, 50-55. Nalox-1 abandons this
`
`argument in reply, never even mentioning a supposed “presumption.”
`
`Nalox-1 cannot come close to proving the claimed combinations were
`
`obvious. Nalox-1 does not dispute the POSA would have to make at least ten
`
`different selections of elements and amounts from two prior art references. POR
`
`50-51. As explained, Nalox-1 fails to demonstrate that the POSA would have
`
`combined the various claim elements to arrive at the claimed combination.
`
`Further, as to the specific claimed amounts, Nalox-1 argues only that the prior art
`
`discloses BZK concentration ranges, naloxone concentration ranges, intranasal
`
`volume ranges, and other excipient ranges. Therefore, Nalox-1 cannot prevail
`
`because it has not demonstrated that the POSA would have selected the claimed
`
`amounts of each of these elements from within each of the ranges, much less
`
`combined them to arrive at the claimed invention. KSR v. Teleflex, 550 U.S. 398,
`
`418-19 (2007); POR 47-55.
`
`IV. The Claimed 4 Milligram Dose Is Non-Obvious.
`Misreading Wyse and ignoring the rest of the prior art, Nalox-1 argues that
`
`the POSA would arrive at a 4 mg naloxone dose, even though no reference in over
`
`a decade of literature on intranasal naloxone recommended or tested a dose above
`
`2 mg. POR 25-26. Wyse does not teach a 4 mg dose, and neither does any other
`
`
`
`
`
`12
`
`
`
`
`reference. Instead, Wyse teaches away from the “high and fast” pharmacokinetic
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`goal on which Nalox-1 premises its case. Unable to rely on a range-law
`
`presumption, Nalox-1 tries to conjure a motivation for a 4 mg dose through five
`
`new, unfounded arguments in reply, which are unsupported by literature or
`
`testimony from a qualified witness.
`
`A. Dr. Hochhaus Is Unqualified To Address Clinical Motivations.
`Nalox-1 bases its dose arguments on assertions by Dr. Hochhaus about the
`
`POSA’s clinical motivations and assessments of risk. But Dr. Hochhaus is not
`
`qualified to render these opinions. He is not a clinician and has no clinical
`
`experience with naloxone. Ex-2214, 344:12-345:16, 350:14-16, 351:11-14. He
`
`did not consult with a clinician in arriving at his opinions, even though he and
`
`Nalox-1 concede that the POSA team would include a clinician. Pet. 10; Ex-1003
`
`¶22.3 He is not qualified to opine on clinical motivations and risks, and he did not
`
`
`3 In an apparent attempt to obfuscate the record, Nalox-1 asked its experts to
`
`declare that they “have the qualifications of a POSA under Dr. Jones’s and Dr.
`
`Williams’s definitions.” Ex-1201 ¶8 n.1; Ex-1202 ¶6 n.1; see also Reply 1 n.2.
`
`These statements are patently false, as Drs. Jones and Williams also opine the
`
`POSA would have “clinical experience with administering opioid antagonists to
`
`
`
`
`
`13
`
`
`
`
`apply the appropriate methodology to support such opinions. His testimony cannot
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`be credited. See Skky v. MindGeek, 859 F.3d 1014, 1022 (Fed. Cir. 2017); see also
`
`Daubert v. Merrell Dow Pharms., 509 U.S. 579, 592-93 (1993).
`
`By contrast, Patent Owners’ expert, Dr. Williams, has more than thirty
`
`years’ experience in emergency medicine, including treating overdosing patients
`
`with naloxone. Ex-2001 ¶¶2-12. The Board should credit his testimony as to
`
`clinical motivations and concerns because it is effectively unrefuted—Nalox-1
`
`declined to cross-examine Dr. Williams, and its own experts lack the requisite
`
`qualifications.
`
`B. Wyse Does Not Teach A 4 Milligram Dose.
`Wyse does not mention an initial dose higher than 2 mg. Although it
`
`discloses a range of possible concentrations, it does not disclose a range of doses.
`
`POR 33-35. Patent Owners’ Response submitted expert evidence that the POSA
`
`would understand that Wyse’s concentration range did not teach appropriate
`
`naloxone doses, and would not use it to select a dose. The POSA would select an
`
`appropriate dose first, and then decide what concentration and volume to use.
`
`Ex-2201 ¶¶219-225. Dr. Jones also explained that the POSA would not read Wyse
`
`
`overdose patients,” Ex-2001 ¶16; Ex-2201 ¶40, and neither of Nalox-1’s experts
`
`do. Ex-2214, 351:11-14; Ex-2215, 358:3-5; POR 37-39.
`
`
`
`
`
`14
`
`
`
`
`to teach that all concentrations in the range are appropriate for use with all of the
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`volumes Wyse separately describes. Id. ¶¶219, 223. Nalox-1 and its experts
`
`ignore these fatal flaws. Reply 12-13.
`
`C. Wyse Teaches Away From “High and Fast” Doses.
`Even if Wyse did disclose a range of doses, evidence of teaching away
`
`would still overcome any presumption of obviousness. Allergan v. Sandoz, 796
`
`F.3d 1293, 1304-06 (Fed. Cir. 2015).
`
`Misconstruing Patent Owners’ argument, Nalox-1 argues that Wyse’s
`
`decision to test intranasal doses of 2 mg or below alone “does not teach away from
`
`a 4 mg dose.” Reply 12-13. Although Wyse’s choice of a 2 mg initial intranasal
`
`dose is certainly significant, that is not the teach-away Patent Owners identified.
`
`POR 31-32.
`
`Nalox-1 attacks this straw man because it has no response to the actual
`
`teach-away: Wyse teaches avoiding high and fast pharmacokinetics in order to
`
`“minimize sudden and severe side effects of rapid reversal of opioid overdose.”
`
`Ex-1007, 3:7-8, 16:29-40; POR 31-32. But in its hundreds of pages of briefing and
`
`declarations, Nalox-1 never addresses this teaching in Wyse, even though the
`
`central premise underlying its dose argument is that the POSA would want a “high
`
`and fast” pharmacokinetic profile and would expect to achieve that with a 4 mg
`
`intranasal dose. Reply 16-17; Ex-1202 ¶31.
`
`
`
`
`
`15
`
`
`
`Wyse says four times that withdrawal effects are “severe,” and makes clear
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`
`
`that his objective is to “minimize” them. Ex-1007, 1:55-57, 2:12-22, 3:3-8, 16:36-
`
`40. And Dr. Hochhaus concedes that higher naloxone doses lead to increased
`
`withdrawal symptoms and side effects. Ex-2214, 450:20-21, 459:8-13, 491:16-
`
`492:1, 494:15-17.4 Wyse, consistent with decades of prior art, discourages raising
`
`the dose to achieve a higher and faster pharmacokinetic profile. POR 27-32.
`
`Wyse’s teach-away is devastating for Nalox-1. Wyse is the instituted
`
`combination’s only dose reference, and “[a]n inference of nonobviousness is
`
`
`4 While Nalox-1 argues (without support from a qualified witness) that withdrawal
`
`and other side effects are “not a medical emergency,” Reply 16, Dr. Hochhaus
`
`admits that some of these side effects are severe and even “life-threatening,” Ex-
`
`2214, 494:3-7, 495:18-498:5; see also id. 348:7-12, 462:6-14, as the literature
`
`repeatedly recognized, POR 27-28; Ex-1044 pp.3-4. Dr. Hochhaus contends that
`
`some of these effects were “rare,” Ex-1202 ¶¶26-28, but ignores others (e.g.,
`
`violence, drug-seeking behaviors, Ex-2001 ¶¶29-35; Ex-2203 ¶15)—and ignores
`
`that low initial naloxone doses were used precisely in order to keep adverse effects
`
`rare, Ex-2001 ¶36; Ex-2203 ¶19. The only expert in the case with experience
`
`treating opioid overdose with naloxone, Dr. Williams, disagrees with Dr.
`
`Hochhaus’s comments on withdrawal. Ex-2202 ¶¶32-37.
`
`
`
`
`
`16
`
`
`
`
`especially strong” where the cited reference “undermine[s] the very reason being
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`proffered” to arrive at the claimed combination. DePuy Spine v. Medtronic
`
`Sofamor Danek, 567 F.3d 1314, 1326 (Fed. Cir. 2009).
`
`D. Nalox-1’s Pharmacokinetics Arguments Are Flawed.
`The logic and assumptions underlying Nalox-1’s 4-6 mg dose calculations
`
`are unsupported and flawed.
`
`First, Dr. Hochhaus provides nothing beyond his own say-so to support the
`
`notion that the POSA would seek “rapid onset” and “high drug exposure.” This
`
`position defies Wyse, the clinical literature, and Dr. Williams’s testimony, which
`
`agree that rapidly reversing opioid overdoses should be avoided because “in many
`
`instances” it “can be dangerous both to the patient and to the emergency
`
`responder.” Ex-1007, 2:11-16; supra Section IV.C; POR 27-32.
`
`Second, the POSA would not ignore years of clinical experience establishing
`
`a safe and effective dose of 2 mg or less and instead select a dose on the basis of
`
`pharmacokinetics alone. POR 40-44; Ex-2201 ¶¶252-59. The POSA, like Wyse,
`
`would look to pharmacokinetics only to confirm that the formulation satisfied the
`
`minimum threshold for FDA approval. POR 40-44. Indeed, the POSA would
`
`recognize a disconnect between the available pharmacokinetic and clinical
`
`evidence, such that pharmacokinetics would not usefully predict clinical outcomes.
`
`POR 42-44; Ex-2061; Ex-2066, 90:24-91:22. Nalox-1 does not dispute this, nor
`
`
`
`
`
`17
`
`
`
`
`does it explain why the POSA would increase the intranasal dose to match the
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`pharmacokinetics of a 2 mg intramuscular dose, when the clinical literature
`
`showed that a 2 mg intranasal dose already matched the clinical effect of a 2 mg
`
`intramuscular dose. See Ex-2201 ¶192; Ex-2202 ¶42.
`
`Third, “rapid onset” is an entirely different pharmacokinetic parameter from
`
`exposure (AUC). Nalox-1 still has no explanation for why the POSA, seeking to
`
`match “rapid onset” of a parenteral dose, would perform a calculation to match
`
`AUC instead, as Dr. Hochhaus does. His math does not permit a conclusion that a
`
`4-6 mg intranasal dose would match the rapidity of onset of parenteral products.
`
`POR 44-47; Ex-2201 ¶¶260-67.
`
`Fourth, the POSA would not be able to predict the pharmacokinetic profile
`
`of a different formulation from Wyse’s data. Dr. Hochhaus tries to prove—by
`
`relying on new models not based on real inputs, Ex-2214, 557:8-18, and post-
`
`priority testing of the patented invention, Ex-1218—only that these differences
`
`cannot have significant effects on absorption rate. Ex-1202 ¶¶36-39. Even if true,
`
`this is irrelevant because the metric upon which Dr. Hochhaus and Nalox-1 base
`
`their 4-6 mg “math” is AUC, not absorption rate—and they are “totally different.”
`
`Ex-2066, 125:7-21; Pet. 19-20; Ex-1003 ¶¶65-68. Dr. Hochhaus did not address
`
`AUC in his supplemental declaration, and even held it constant in his modeling.
`
`Ex-1202 ¶34; Ex-2214, 568:14-569:9, 570:2-4, 574:18–577:6. But both sides’
`
`
`
`
`
`18
`
`
`
`
`experts agree that formulation differences—e.g., concentration, excipients, and
`
`Case IPR2019-00688
`U.S. Patent 9,468,747
`
`tonicity—and method of administration can cause significant and unpredictable
`
`changes in AUC. POR 44-47; see Ex-2059 pp.107-08.
`
`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
`
`new motivations for the POSA to use a 4 mg dose and seven new prior-art
`
`references (Exs-1203, 1207, 1224, 1228, 1233, 1238, 1242). Reply 13-15. The
`
`Board should decline to consider these new obviousness arguments and references.
`
`Henny Penny v. Frymaster, 938 F.3d 1324, 1330-31 (Fed. Cir. 2019); Intelligent
`
`Bio-Sys., 821 F.3d at 1369-70; 37 C.F.R. §42.23(b).
`
`In any event, these arguments are wrong.
`
`First, the standard practice as of the priority d
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
