`_____________________
`
`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
`_____________________
`
`PETITIONER NALOX-1 PHARMACEUTICALS, LLC’s
`MOTION FOR OBSERVATIONS ON THE SECOND DEPOSITION OF
`PATENT OWNERS’ EXPERT DR. STUART ALLEN JONES
`
`
`
`IPR2019-00694 – U.S. Patent No. 9,629,965
` Petitioner’s Motion for Observations of Second Deposition
`of Patent Owners’ Expert Dr. Stuart Allen Jones
`
`Pursuant to 77 Fed. Reg. 48,767-68, Petitioner Nalox-1 Pharmaceuticals,
`
`LLC (“Petitioner”) submits this motion for observations regarding cross-
`
`examination of Patent Owners’ sur-reply declarant Dr. Stuart Allen Jones,
`
`following his deposition on May 1, 2020 (Nalox1252).
`
`Observation 1: Relevant to Patent Owners’ argument that, “Surfactants, like
`
`BZK [benzalkonium chloride], are particularly known
`
`to facilitate drug
`
`degradation.” Paper 47 at 4.
`
`Dr. Jones testified:
`
`Q. …[Tsuji (Exhibit 2309)] says, [t]he previous and present studies
`revealed a marked stability of penicillins in acid solutions with
`both cationic and nonionic micelles. Do you see that?
`A. Yes, I see those words on the page.
`Q. And then three lines down, starting “These stabilization,” it
`says, These stabilization effects are attributed to incorporation of
`the penicillin molecules into both types of micelles. Do you see
`that?
`A. Yes, I see those words on the page.
`Q. Tsuji states that using cationic and nonionic surfactant micelles
`stabilized penicillins, correct?
`. . . .
`A. So what Tsuji has shown here is that certain types of chemicals
`can be stabilized to a certain degree by ionic and nonionic
`micelles, but other chemicals are not stabilized. And what Tsuji
`says is this is dependent upon how much of the molecule is
`incorporated within the micelle. And those chemicals which are
`not incorporated within the micelle are not stabilized. And those
`2
`
`
`
`IPR2019-00694 – U.S. Patent No. 9,629,965
` Petitioner’s Motion for Observations of Second Deposition
`of Patent Owners’ Expert Dr. Stuart Allen Jones
`
`which are incorporated into the micelle to a high degree seem to
`show some stability in this particular study.
`Nalox1252 at 41:19–43:25 (emphases added).
`
`Dr. Jones also testified:
`
`Q. [Yoshioka (Exhibit 2301)] says . . . [t]he observation that
`hydrolysis
`of
`acetylcholine
`is
`alkaline
`decreased
`by
`dodecyltrimethylammonium chloride (DTAC) as shown in Figure
`114, has been explained by assuming that the drug molecule
`penetrates the micellar phase and is shielded from the attack of
`hydroxide ion. Do you see that?
`A. Yes.
`Q. And then two lines down, it says, Alkaline hydrolysis of
`benzocaine
`is
`inhibited by cetyltrimethylammonium chloride
`(CTAC). Do you see that?
`A. Yes.
`Nalox1252 at 49:15–50:3 (emphases added).
`
`The preceding testimony contradicts Patent Owners’ argument that,
`
`“Surfactants, like BZK, are particularly known to facilitate drug degradation,”
`
`(Paper 47 at 4), because it demonstrates the knowledge in the prior art that various
`
`cationic surfactants (including the quaternary ammonium compounds DTAC and
`
`CTAC) were shown to enhance drug stability. This testimony is also relevant
`
`because the proposed mechanism by which the surfactants are stated to enhance
`
`drug protection in the prior art—i.e., incorporation of the drug into the micellar
`
`phase—is the same mechanism proposed by Dr. Jones for BZK’s degradation of
`
`3
`
`
`
`IPR2019-00694 – U.S. Patent No. 9,629,965
` Petitioner’s Motion for Observations of Second Deposition
`of Patent Owners’ Expert Dr. Stuart Allen Jones
`
`naloxone (see Nalox1252 at 98:23–100:1), further undermining Dr. Jones’s
`
`opinion that BZK facilitated naloxone degradation.
`
`Observation 2. Relevant to Dr. Jones’s opinion that CTAB (which, Dr.
`
`Jones opined, has “similar properties” as BZK (see Exhibit 2300 at ¶ 16, n.2)) can
`
`enhance drug degradation.
`
`Dr. Jones testified:
`
`Q. You say, CTAB and BZK are both quaternary ammonium
`compounds that the POSA would have recognized as having
`similar properties. Do you see that?
`A. Yes, and I finish then, including with respect to their ability to
`act as surfactants and preservatives, yes.
`. . . .
` Q. …[Yoshioka (Exhibit 2301)] says, [a]s shown in Figure 116,
`acid degradation of propicillin in solutions was inhibited by
`polyoxyethylene 23 lauryl ether, a nonionic surfactant, and CTAB,
`a cationic surfactant. Do you see that?
`A. Yes.
`…
`Q. [Y]ou chose to only include references to CTAB degrading
`drugs, specifically cefaclor and indomethacin, but you chose not to
`include from the same exact reference in the same exact part of the
`reference that you're quoting from, disclosure that the same
`compound, CTAB, could inhibit degradation of a compound, didn't
`you?
`A. I stated in my declaration two quotes from this reference. The
`first was the effect of surfactants on degradation, in quotes, can be,
`in quotes, difficult to interpret. These two quotes give an overall
`
`4
`
`
`
`IPR2019-00694 – U.S. Patent No. 9,629,965
` Petitioner’s Motion for Observations of Second Deposition
`of Patent Owners’ Expert Dr. Stuart Allen Jones
`
`view of the reference. And the reference in a number of places
`provides examples of where surfactants can have an effect on
`degradation and how this can be difficult to interpret. I then go on
`to talk about cefaclor, an aminophenyl cephalosporin, and how the
`degradation was enhanced by CTAB, a well-known surfactant.
`And this was an appropriate example because this does not include
`within micelles, which,
`therefore,
`is appropriate from
`the
`description of BZK surfactant properties increasing naloxone
`degradation because it's not discussing the inclusion of naloxone in
`micelles, rather it’s discussing the inclusion of oxygen in micelles,
`and, therefore, including drugs which themselves go into micelles -
`- discussing drugs which themselves penetrate into micelles and
`are protected from degradation as a consequence to this discussion
`which is moving toward the effect of surfactants to solubilize
`oxygen and, therefore, the oxygen is within the micelles. And,
`therefore, these citations are appropriate within the wider section
`of BZK’s surfactant properties would
`increase naloxone
`degradation observed in Wyse.
`Nalox1252 at 44:19–25; 79:4–82:24 (emphases added) (Patent Owners’ objections
`
`omitted). This testimony is relevant because it contradicts Dr. Jones’s opinion that
`
`CTAB (which, Dr. Jones opined, has “similar properties” as BZK (see Exhibit
`
`2300 at ¶ 16, n.2)) can enhance drug degradation—since the same prior art
`
`reference cited by Dr. Jones shows that CTAB also can enhance drug stability.
`
`Observation 3. Relevant to Patent Owners’ argument that, “BZK’s
`
`surfactant properties could indirectly increase naloxone degradation … by
`
`solubilizing oxygen in lipophilic micelles….” Paper 47 at 4.
`
`Dr. Jones testified:
`
`5
`
`
`
`IPR2019-00694 – U.S. Patent No. 9,629,965
` Petitioner’s Motion for Observations of Second Deposition
`of Patent Owners’ Expert Dr. Stuart Allen Jones
`
`Q. Dr. Jones, did you look for references that disclose that BZK
`specifically can increase oxygen solubility?
`A. In forming my report, I did a literature search which involved
`both 34 known surfactants that are used in intranasal formulations,
`and specifically benzalkonium chloride, and I found clear
`references which showed that surfactants as a group, as a whole,
`irrespective of the head group, would increase oxygen solubility in
`aqueous formulations. And this – these are the references that I
`presented here. But I did do literature searches both for
`benzalkonium chloride and general surfactants.
`Q. But you didn’t include a reference that specifically discloses
`that BZK can increase oxygen solubility, correct?
`A. When I found the references cited in my proposal – in my
`declaration, my Supplemental Declaration, regarding oxygen
`solubility, and saw that the effect was general for the class of
`surfactants, I felt – didn’t feel the need to go on with my searches
`for benzalkonium chloride’s effect because the POSA would have
`known that the effect is across surfactants as a whole, and,
`therefore, it would have occurred with surfactants in general.
`Nalox1252 at 89:17–90:18. This testimony is relevant because it contradicts
`
`Patent Owners’ argument that, “BZK’s surfactant properties could indirectly
`
`increase naloxone degradation … by solubilizing oxygen in lipophilic micelles”
`
`(Paper 47 at 4), since Dr. Jones admitted that he did not locate any prior art
`
`reference disclosing that BZK had this property. Further, Dr. Jones’s testimony
`
`that the oxygen solubilizing effects are “across surfactants as a whole” (Nalox1252
`
`at 90:16), is relevant because it contradicts Patent Owners’ argument that,
`
`“Surfactants, like BZK, are particularly known to facilitate drug degradation,”
`
`6
`
`
`
`IPR2019-00694 – U.S. Patent No. 9,629,965
` Petitioner’s Motion for Observations of Second Deposition
`of Patent Owners’ Expert Dr. Stuart Allen Jones
`
`(Paper 47 at 4), since various surfactants (including the quaternary ammonium
`
`compounds DTAC and CTAC) were shown in the prior art to enhance drug
`
`stability (see Observation 1), despite Dr. Jones’s opinion that they have the same
`
`oxygen solubilizing effects as BZK.
`
`Date: May 8, 2020
`
`Respectfully submitted,
`
`/s/ Yelee Y. Kim
`Yelee Y. Kim, Reg. No. 60,088
`ARENT FOX LLP
`1717 K Street, NW
`Washington, DC 20006
`202.857.6000
`Counsel for Petitioner
`Nalox-1 Pharmaceuticals, LLC
`
`7
`
`
`
`IPR2019-00694 – U.S. Patent No. 9,629,965
` Certificate of Service
`
`CERTIFICATION OF SERVICE (37 C.F.R. §§ 42.6(e), 42.105(a))
`The undersigned hereby certifies that the above-captioned “Petitioner Nalox-
`
`1 Pharmaceuticals, LLC’s Motion for Observations on the Second Deposition of
`
`Patent Owners’ Expert Dr. Stuart Allen Jones,” was served in its entirety on May
`
`8, 2020, upon the following parties via e-mail:
`
`Jessamyn S. Berniker (jberniker@wc.com)
`Ana C. Reyes (areyes@wc.com)
`David M. Krinsky (dkrinsky@wc.com)
`Anthony H. Sheh (asheh@wc.com)
`WILLIAMS & CONNOLLY LLP
`725 Twelfth Street, NW
`Washington, DC 20005
`(202) 434-5000
`Counsel for Patent Owner
`Adapt Pharma Operations Limited
`
`Jessica Tyrus Mackay (jmackay@greengriffith.com)
`Ann K. Kotze (akotze@greengriffith.com)
`GREEN, GRIFFITH & BORG-BREEN, LLP
`676 North Michigan Avenue, Suite 3900
`Chicago, IL 60611
`(313) 883-8000
`Counsel for Patent Owner
`Opiant Pharmaceuticals, Inc.
`
`/s/ Yelee Y. Kim
`Yelee Y. Kim, Reg. No. 60,088
`ARENT FOX LLP
`1717 K Street, NW
`Washington, D.C. 20006
`(202) 857-6000
`yelee.kim@arentfox.com
`
`Counsel for Petitioner
`Nalox-1 Pharmaceuticals, LLC
`
`