UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`v.
`ADAPT PHARMA OPERATIONS LTD., AND
`OPIANT PHARMACEUTICALS, INC.
`Patent Owners
`
`CASE IPR2019-00685
`U.S. Patent No. 9,211,253
`
`Video deposition of STUART ALLEN
`JONES, Ph.D., held remotely via Zoom, on Friday,
`May 1, 2020, commencing at 8:06 a.m., before
`Kathleen McHugh, a Registered Professional
`Reporter, Certified Realtime Reporter, Certified
`Shorthand Reporter-NJ, License No. 30XI00180400,
`and Notary Public.
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`Videoconference Deposition of Stuart Allen Jones, Ph.D., 5/1/2020
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`2
`
`APPEARANCES:
`ARENT FOX LLP
`BY: RICHARD J. BERMAN, ESQUIRE (via Zoom)
` Richard.berman@arentfox.com
`BY: YELEE Y. KIM, ESQUIRE (via Zoom)
` Yelee.kim@arentfox.com
` 1717 K Street, NW
` Washington, DC 20006
` 202-857-6000
` Counsel for Petitioner, Nalox-1
` Pharmaceuticals, LLC
`WILLIAMS & CONNOLLY LLP
`BY: DAVID M. KRINSKY, ESQUIRE (via Zoom)
` dkrinsky@wc.com
`BY: JESSAMYN S. BERNIKER, ESQUIRE (via Zoom)
` jberniker@wc.com
`BY: ANA C. REYES, ESQUIRE (via Zoom)
` areyes@wc.com
`BY: ANTHONY H. SHEH, ESQUIRE (via Zoom)
` asheh@wc.com
`BY: YOULIN YUAN, ESQUIRE (via Zoom)
` Yyuan@wc.com
` 725 Twelfth Street, NW
` Washington, DC 20005
` 202-434-5000
` Counsel for Patent Owner Adapt
` Pharma Operations Limited
`GREEN, GRIFFITH & BORG-BREEN LLP
`BY: JESSICA TYRUS MACKAY, ESQUIRE (via Zoom)
` jmackay@greengriffith.com
` 676 North Michigan Avenue, Suite 3900
` Chicago, Illinois 60611
` 313-883-8000
` Counsel for Patent Owners Adapt
` Pharma Operations Ltd., and
` Opiant Pharmaceuticals, Inc.
`ALSO PRESENT:
` Martin Zinkel, Videographer (via Zoom)
` Joshua Harris (via Zoom)
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`Videoconference Deposition of Stuart Allen Jones, Ph.D., 5/1/2020
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` EXAMINATION INDEX
`
`Dr. Stuart Allen Jones
` BY MR. BERMAN . . . . . . . . . . . . . . 4
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`6
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`Videoconference Deposition of Stuart Allen Jones, Ph.D., 5/1/2020
`4
`1 VIDEOGRAPHER: We are now on the video
`2 record.
`3 This is the video deposition of
`4 Dr. Stuart Allen Jones, taken by plaintiff --
`5 petitioner, in the matter of Nalox-1
`6 Pharmaceuticals, LLC v. Adapt Pharma Operations
`7 Ltd., et al., hearing remotely with the deponent in
`8 Watford, United Kingdom, on Friday, May 1st, 2020,
`9 at 8:06 a.m.
`10 I am Martin Zinkel, the videographer.
`11 The court reporter is Kathy McHugh. We are from
`12 the firm of Advanced Depositions in Philadelphia,
`13 Pennsylvania.
`14 Counsel will be noted on -- the
`15 appearances will be noted on the transcript, and
`16 the reporter will now swear in the witness.
`17 STUART ALLEN JONES, Ph.D., having been
`18 duly sworn, was examined and testified as follows:
`19 EXAMINATION
`20 BY MR. BERMAN:
`21 Q. Hello again, Dr. Jones. My name again
`22 is Rich Berman. I'm counsel for petitioner,
`23 Nalox-1 Pharmaceuticals, LLC.
`24 Let's turn to Exhibit 2300, your
`25 Supplemental Declaration, just the cover page,
`
`1 is oxidative degradation, but there are others.
`2 And I cited in my first report that also naloxone
`3 is prone to photoinstability issues, i.e.,
`4 degradation under light.
`5 Q. If we can go to Nalox 1201, the
`6 Donovan Supplemental Declaration, and paragraph 15.
`7 And you can blow up up until the line
`8 there.
`9 Great.
`10 It says, Wyse discloses that
`11 formulations 7, 9, 14 and 14A contained, quote, an
`12 additional degradant, unquote, one that was not
`13 reported as being found in at least some of the
`14 other disclosed formulations. Since these
`15 formulations were pH adjusted, quote, to accelerate
`16 degradation, unquote, of the naloxone -- and
`17 there's a citation given there -- a Formulator POSA
`18 would have considered that, if the, quote,
`19 additional degradant, unquote, was a naloxone
`20 degradant, it would likely be an oxidation
`21 degradant.
`22 Do you see that?
`23 A. Yes.
`24 MR. KRINSKY: And I'd just like to
`25 note, you only have part of the paragraph on the
`
`5
`
`1 page 1.
`2 And this is the declaration that you
`3 submitted for the '747 patent.
`4 Do you see that?
`5 A. Yes.
`6 Q. And my understanding is that you
`7 submitted this same substantive declaration in all
`8 three IPRs; is that correct?
`9 A. Yes, I believe they're identical.
`10 Q. Okay. If we can go to paragraph 12.
`11 I don't have the page number in front of me.
`12 Oh, there you go. Good.
`13 It starts off --
`14 You can just blow up that paragraph.
`15 It starts off saying, Dr. Donovan
`16 limited the analysis in her second declaration to
`17 oxidative degradation of naloxone.
`18 Do you see that?
`19 A. Yes.
`20 Q. So sitting here today, you don't know
`21 of any mechanism for degradation of naloxone other
`22 than oxidative degradation, correct?
`23 A. I understand that the degradation of
`24 naloxone is a complex process, and it can occur by
`25 many different mechanisms. One of those mechanisms
`
`7
`1 screen. I just wanted to make sure Dr. Jones knew
`2 that he could ask Martin to put up what he needs to
`3 put up if he'd like to look at something else.
`4 BY MR. BERMAN:
`5 Q. Do you agree with Dr. Donovan's
`6 opinion that a POSA would have considered it likely
`7 that the naloxone degradant was an oxidation
`8 degradant?
`9 THE WITNESS: If you could just do --
`10 Martin, I still have to look at the full page,
`11 please. (Witness reviews document.)
`12 Could I just look at the next page of
`13 the document as well, please. (Witness reviews
`14 document.)
`15 If you can go back to the previous
`16 page, please. (Witness reviews document.)
`17 And can I have the question?
`18 BY MR. BERMAN:
`19 Q. Yes. Do you need me to repeat the
`20 question? Okay.
`21 The question is, do you agree with
`22 Dr. Donovan's opinion that a POSA would have
`23 considered it likely that the naloxone degradant
`24 was an oxidation degradant?
`25 A. The POSA would have read Wyse and
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`Videoconference Deposition of Stuart Allen Jones, Ph.D., 5/1/2020
`8
`10
`1 stable. The POSA would not go on to consider the
`1 would have understood from Wyse that benzalkonium
`2 mechanism by which that occurred.
`2 chloride caused the degradation of naloxone.
`3 MR. BERMAN: If we can go to Wyse --
`3 They would have read Wyse and
`4 that's Nalox 1007.
`4 understood Wyse in the wider context of the
`5 MR. KRINSKY: I believe you said Nalox
`5 literature and understand this was a valid
`6 1007.
`6 proposition from Wyse's data and what Wyse actually
`7 MR. BERMAN: Nalox 1007. That's just
`7 said.
`8 the exhibit number. Thanks.
`8 Wyse identified an additional
`9 PDF page 22, we're going to look at
`9 degradant of four formulations containing
`10 Example 5 on columns 26 and 27.
`10 benzalkonium chloride. And, therefore, POSA would
`11 If you could zoom in on where it says
`11 have read Wyse and understood that Wyse showed that
`12 Example 5 above where you are a bit. Right there.
`12 benzalkonium chloride caused naloxone degradation.
`13 Yes.
`13 The POSA would not need to understand
`14 No. Down. Down. Around line 20.
`14 the mechanism by which that would occur because
`15 Yes, there you go. That's fine.
`15 they would have read Wyse and understood Wyse from
`16 BY MR. BERMAN:
`16 what Wyse said and what Wyse did.
`17 Q. Okay. So I'm looking at Wyse Example
`17 Wyse removed benzalkonium chloride in
`18 5 and specifically at -- I'm going to just read
`18 the formulations after finding it caused
`19 from a couple of places and then ask you a couple
`19 instability in the formulations with respect to
`20 of questions.
`20 naloxone, and, therefore, the POSA would have
`21 Around line 29, it says, The
`21 followed Wyse's teaching away from using
`22 formulations were at pH 5.0 to accelerate
`22 benzalkonium chloride in the formulation and would
`23 degradation.
`23 not go on to think about the mechanism of
`24 Do you see that?
`24 degradation.
`25 A. Yes.
`25 Q. But do you agree with Dr. Donovan's
`
`9
`1 opinion that a POSA would have considered it likely
`2 that the naloxone degradant was an oxidation
`3 degradant?
`4 MR. KRINSKY: Objection. Asked and
`5 answered.
`6 THE WITNESS: The POSA would have read
`7 Wyse and understood from Wyse that benzalkonium
`8 chloride caused naloxone degradation.
`9 Wyse produced a series of experiments
`10 whereby he tested naloxone's compatibility in a
`11 series of different intranasal formulations, and he
`12 showed from that series of experiments that,
`13 indeed, benzalkonium chloride caused naloxone
`14 degradation.
`15 He identified an additional naloxone
`16 degradation peak in four formulations which
`17 contained benzalkonium chloride and went on to
`18 state in a number of places in Wyse's patent that
`19 benzalkonium chloride caused the degradation of
`20 naloxone.
`21 The POSA would have read this and read
`22 what Wyse did subsequent to defining this finding
`23 in that he removed benzalkonium chloride from his
`24 subsequent formulation testing and went on to make
`25 an intranasal formulation that was chemically
`
`11
`1 Q. And then going on -- if you can leave
`2 that up, and then go on to the next column, 27.
`3 And then just go from the top down to
`4 about line 30.
`5 Yep. Perfect.
`6 And here around line 20, it says,
`7 Increasing the pH of the solution accelerated the
`8 degradation of naloxone HCL resulting in the
`9 formation of a major degradant at a relative
`10 retention time, RRT, of 0.52. However, it was
`11 found that decreasing the pH minimizes the
`12 formation of potential oxidative degradants.
`13 Do you see that?
`14 A. Yes.
`15 Q. So in this Example 5 test, Wyse
`16 increased the pH of the solution to accelerate the
`17 degradation of naloxone, correct?
`18 MR. KRINSKY: Object to the form of
`19 the question.
`20 THE WITNESS: (Witness reviews
`21 document.)
`22 Could you reask the question, please?
`23 BY MR. BERMAN:
`24 Q. Sure.
`25 In this example, Wyse increased the pH
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`Videoconference Deposition of Stuart Allen Jones, Ph.D., 5/1/2020
`12
`14
`
`1 of the solution to accelerate the degradation of
`2 naloxone, correct?
`3 A. In Example 5 Wyse took naloxone and a
`4 series of formulation excipients and generated some
`5 prototypes. Wyse took naloxone and made intranasal
`6 formulations with a series of excipients.
`7 Those prototype formulations he
`8 subjected, as he said in his test, to 60 degrees
`9 and some of the formulations were at pH 5 and some
`10 of the formulations were -- were at pH 4 or 4.5.
`11 He performed a stability test. And
`12 from that stability test, he found benzalkonium
`13 chloride caused naloxone instability. He showed
`14 that the formulations -- four of the formulations
`15 that had benzalkonium chloride in, there was an
`16 additional peak in the HPLC chromatogram, and he
`17 attributed this to naloxone instability caused by
`18 benzalkonium chloride.
`19 The POSA would have read this and
`20 understood this was a normal screening study and
`21 would have accepted from this that benzalkonium
`22 chloride caused naloxone instability and would,
`23 therefore, have taken this teaching and generated a
`24 formulation which didn't include benzalkonium
`25 chloride because the POSA would know that they
`
`13
`
`1 didn't need even a preservative inside the
`2 formulation, and the prior art taught away from
`3 using preservatives, so that they could then
`4 produce a preservative-free formulation.
`5 And if for some reason they needed a
`6 preservative, then they could use benzyl alcohol,
`7 which Wyse subsequently taught was a suitable
`8 preservative for naloxone intranasal formulations.
`9 Q. Are you familiar with an oxidative
`10 stress test, with what that is?
`11 MR. KRINSKY: I'm sorry, you cut out
`12 there. Can you repeat the question?
`13 MR. BERMAN: Yes.
`14 BY MR. BERMAN:
`15 Q. Are you familiar with what an
`16 oxidative stress test is?
`17 MR. KRINSKY: Object to the form of
`18 the question. Vague.
`19 THE WITNESS: I'm familiar with the
`20 concept of oxidative stress testing in formulation
`21 development in what we call preformulation studies
`22 to understand chemical stability of drugs that we
`23 might want to formulate into medicines, yes.
`24 BY MR. BERMAN:
`25 Q. Would a POSA have considered Wyse's
`
`1 experiment in Example 5 to be an oxidative stress
`2 test?
`3 A. A POSA would have read Example 5 in
`4 Wyse and understood that what Wyse did was combined
`5 naloxone with a series of formulation excipients,
`6 and the purpose of that was to understand the
`7 chemical stability of naloxone in a series of
`8 prototype formulations.
`9 The POSA would have read that and
`10 understood that the outcome of that test was that
`11 benzalkonium chloride caused the instability of
`12 naloxone, and Wyse showed this by identifying four
`13 formulations where there was additional peak in the
`14 HPLC chromatogram. He identified that in the
`15 naloxone peak.
`16 The POSA would have read and
`17 understood the experiments and then understood to
`18 exclude benzalkonium chloride from future studies.
`19 And the POSA could, therefore, have formulated an
`20 intranasal naloxone product without a preservative
`21 because there didn't need to be one, and
`22 interpreted in these studies, they would understand
`23 that the Example 5 was an accelerated stability
`24 test.
`25 Q. What's the difference, in your mind,
`
`15
`
`1 between an accelerated stability test and an
`2 oxidative stress test?
`3 MR. KRINSKY: Object to the form of
`4 the question. Vague.
`5 BY MR. BERMAN:
`6 Q. Let me, actually, rephrase it.
`7 Is there a difference between an
`8 accelerated stability test and an oxidative stress
`9 test, in your understanding?
`10 A. In the development of medicines for
`11 human use, it is important to understand the
`12 chemical stability of the active. And in that
`13 context, when making a medicine to deliver a drug,
`14 an active compound, then one would want to
`15 understand the chemical stability of the drug in
`16 the presence of the formulation excipients, and
`17 there could be several formulation excipients.
`18 And in that context what one usually
`19 does is expose that system to an accelerated
`20 stability test. An accelerated stability test is
`21 usually using heat to accelerate the stability
`22 and/or pH.
`23 And this is distinctly different to an
`24 oxidative stress test. An oxidative stress test
`25 particularly looks for oxidation. And in those
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`Videoconference Deposition of Stuart Allen Jones, Ph.D., 5/1/2020
`16
`18
`
`1 tests, they will stress the formulations by using
`2 oxygen that will drive the oxidation of the drug,
`3 yes.
`4 MR. BERMAN: If -- I see -- I'm sorry
`5 to interrupt. I see Youlin Yuan keeps coming in.
`6 Can you mute your microphone, please.
`7 Thank you. I think that's what's
`8 causing the issue.
`9 BY MR. BERMAN:
`10 Q. Are you finished with your answer?
`11 A. Yes.
`12 Q. Okay. Thank you.
`13 So here, looking at paragraph 27
`14 again, Wyse said, Increasing the pH of the solution
`15 accelerated the degradation of the naloxone HCL.
`16 You see that, right?
`17 A. Yes.
`18 Q. And then it says, However, it was
`19 found that decreasing the pH minimizes the
`20 formation of potentially oxidative degradants.
`21 Do you see that?
`22 A. Yes.
`23 Q. So increasing the pH of the solution
`24 accelerated the formation of oxidative degradants,
`25 correct, according to Wyse?
`
`17
`
`1 A. Wyse stated in this particular
`2 example, which is related to Example 5, in which he
`3 tested a series of formulation excipients with the
`4 active drug naloxone and showed that benzalkonium
`5 chloride caused the degradation of naloxone by
`6 showing that benzalkonium chloride induced an
`7 additional peak in four of the formulations that
`8 benzalkonium chloride was present.
`9 In that context, he has written some
`10 text of both, and that text says increasing the pH
`11 in the solution accelerated the degradation of
`12 naloxone HCL, resulting in the formation of a major
`13 degradant at the relative retention time of 0.52.
`14 Q. Were you finished with your answer?
`15 A. Yes.
`16 Q. If we can go back to your declaration
`17 where we were in paragraph 12, Exhibit 2300.
`18 You can just pull up 12 again, please.
`19 Thank you.
`20 So four lines down, it says -- or
`21 starting on the fifth line, The POSA would have
`22 understood that oxidative degradation mechanisms
`23 can be, quote, complex, unquote, and can therefore
`24 present many opportunities for one ingredient in a
`25 formulation to cause or increase the degradation of
`
`1 another, including in indirect ways.
`2 Do you see that?
`3 A. Yes.
`4 Q. And then you cite Baertschi 2005 at
`5 38.
`6 Do you see that?
`7 A. Yes.
`8 Q. And then there is a quote in
`9 parentheses following that.
`10 Do you see that?
`11 A. Yes.
`12 Q. So I want to look at the quote in
`13 context. Let's go to Exhibit 2305 at page -- PDF
`14 page 38, please.
`15 You can go right under C, the first
`16 paragraph there, starting at C and going down.
`17 Great.
`18 So you had quoted, Oxidative
`19 mechanisms can be quite diverse, and going on. And
`20 that's in the second sentence.
`21 Do you see that?
`22 A. Can you just zoom in -- I'm sorry --
`23 please, just to make sure we're on the right page.
`24 Q. It's PDF page 38.
`25 A. Yeah, okay. Good. Page 38, yes.
`
`19
`
`1 Q. So right above that sentence that you
`2 quoted, there's another sentence that says, It can
`3 be difficult to translate oxidative stress-testing
`4 results into accurate predictions of the
`5 susceptibility of a compound oxidation.
`6 Do you see that?
`7 A. Yes.
`8 Q. Do you agree with that statement?
`9 A. So in the formulation of compounds,
`10 such as naloxone, for intranasal use, one needs to
`11 consider the chemical stability of the drug
`12 naloxone.
`13 And as part of that formulation
`14 process, one needs to understand the chemical
`15 stability in a series -- in combination with the
`16 formulation excipients, and one needs to take steps
`17 to ensure that the drug, the chemical, is
`18 chemically stable before giving it to the patient.
`19 And as part of that, one needs to
`20 perform formulation screening studies. And as part
`21 of that formulation screening study, one needs to
`22 test the chemical stability of the drug, such as
`23 naloxone, like in Wyse when he tested the
`24 formulation stability of naloxone in intranasal
`25 formulations and found that benzalkonium chloride
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`Videoconference Deposition of Stuart Allen Jones, Ph.D., 5/1/2020
`20
`22
`
`1 was incompatible and caused the degradation -- as
`2 part of those -- of naloxone.
`3 As part of those studies, one can use
`4 different stress testings, such as accelerated
`5 stability testing, when you change the pH and/or
`6 the temperature of the test or oxidative stress
`7 testing.
`8 And during oxidative stress testing,
`9 one might use different means to induce oxidation
`10 depending upon the type of oxidation the compound
`11 is susceptible to. And these methods are various.
`12 And the oxidation mechanisms by which compounds can
`13 degrade could be varied.
`14 And, therefore, in that wide context
`15 of generality of thinking about the numerous
`16 different ways of exposing a compound to oxidation,
`17 and some of those means of exposing a compound to
`18 oxidation may be difficult or accurate to predict
`19 from that particular test system the real
`20 susceptibility of a compound to oxidation.
`21 But, likewise, there are other ways
`22 which oxidative stress testing can be quite
`23 predictive for the real situation, and this depends
`24 on the compound, the mechanism, and the way in
`25 which the oxidative stress testing is performed.
`
`21
`
`1 Q. So it might be predictive or it might
`2 not depending on the situation?
`3 A. In a formulation of a product for
`4 human use, when one is trying to understand the
`5 chemical stability of a drug in the presence of
`6 excipients in a formulation, then a compound can be
`7 subject to different chemical degradation pathways.
`8 Those pathways can be numerous, and the ways to
`9 stress that compound can be numerous.
`10 In terms of oxidative stress testing,
`11 then there can be a number of ways in which you can
`12 try and stress the compound in terms of its
`13 oxidative mechanisms. Some of those may be
`14 predictive, and some of them may be not. Some of
`15 them may be in between. There will be a spectrum
`16 by which these different tests are predictive. It
`17 depends upon the drug, the excipients, the actual
`18 conditions of the oxidative stress test, and the
`19 context in which those experiments are performed.
`20 Q. You had also talked about other
`21 degradation tests such as temperature and pH.
`22 Would those results also vary
`23 depending on the situation?
`24 MR. KRINSKY: Object to the form of
`25 the question. Foundation, and vague.
`
`1 THE WITNESS: When formulating a
`2 medicine for human use, it's important that the
`3 drug that you are using in that medicine is
`4 chemically stable. The formulator will try and
`5 ensure this during the formulation process.
`6 In the context of an intranasal
`7 naloxone formulation, this would involve combining
`8 the drug with a series of excipients that will be
`9 useful for intranasal formulation and testing for
`10 chemical stability.
`11 The formulator would use a number of
`12 tests to test that chemical stability, and this
`13 would depend on the context of that formulation
`14 development process.
`15 Some other tests that they could use
`16 are normal real-time stability studies, accelerated
`17 stability studies, oxidative stress testing, light
`18 stress testing, amongst others.
`19 And these experiments will be used to
`20 inform the formulator of the potential for that
`21 chemical to degrade. Each of those studies form on
`22 pieces of evidence by which the formulator makes
`23 conclusions on the chemical stability of that drug
`24 in the context of the excipients.
`25 BY MR. BERMAN:
`
`23
`
`1 Q. Can it be difficult to translate pH or
`2 temperature stress testing results into accurate
`3 predictions of the susceptibility of a compound to
`4 degradation?
`5 A. When formulating an intranasal
`6 naloxone formulation, one needs to consider the
`7 chemical stability just like Wyse did. And Wyse
`8 tested the naloxone chemical stability in a series
`9 of formulations which are prototype formulations
`10 with different excipients and found that
`11 benzalkonium chloride caused the chemical
`12 instability of naloxone in the formulations.
`13 This is an example, in Wyse, of using
`14 different stress conditions to understand chemical
`15 stability. And the POSA would have understood that
`16 the accelerated chemical -- accelerated stress
`17 testing is a commonly used method to test the
`18 chemical instability of a naloxone product.
`19 This, along with other types of
`20 studies, would inform the formulator of the
`21 susceptibility of the drug to chemical degradation.
`22 And the formulator would take this information and
`23 use it to understand the interactions of the
`24 excipients in the drug and the stability of that
`25 drug and use that to inform their choices to
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`Videoconference Deposition of Stuart Allen Jones, Ph.D., 5/1/2020
`24
`26
`
`1 generate a sound, stable formulation.
`2 Q. Let's go back to your declaration,
`3 Exhibit 2300, at paragraph 14.
`4 And -- yes, you can blow that up.
`5 Great.
`6 Starting at the sentence "Rather," you
`7 say, The POSA would have understood that other
`8 mechanisms -- including indirect physical and/or
`9 chemical interactions involving BZK -- could
`10 explain Wyse's results.
`11 Do you see that?
`12 A. Yes, I see those words.
`13 Q. So it's your opinion that other
`14 mechanisms such as indirect interactions may have
`15 been responsible for naloxone degradation in Wyse's
`16 formulations, correct?
`17 A. The POSA would have read Wyse and
`18 understood from Wyse that benzalkonium chloride
`19 caused naloxone chemical instability.
`20 Wyse performed a series of studies in
`21 which he combined commonly used nasal formulation
`22 excipients with naloxone and showed that naloxone
`23 in the presence of those excipients was subject to
`24 degradation, and four of the formulations that
`25 contained benzalkonium chloride showed an
`
`25
`1 additional peak in the HPLC chromatogram, and Wyse
`2 identified that as a naloxone degradant peak, and
`3 the benzalkonium chloride caused that peak.
`4 My opinion is that the POSA would have
`5 read Wyse and understood from Wyse that they did
`6 not -- that benzalkonium chloride was an unsuitable
`7 formulation excipient to be used with naloxone and,
`8 therefore, the POSA would have chosen not to use a
`9 preservative. They did not need to use a
`10 preservative in intranasal formulation of naloxone,
`11 and, therefore, they would have chosen to do this.
`12 This is my opinion.
`13 However, in response to Dr. Donovan's
`14 opinion that benzalkonium chloride could not cause
`15 naloxone degradation because it could not directly
`16 interact with naloxone, I provided an opinion about
`17 the mechanism -- possible mechanism by which this
`18 could occur. But the POSA would not go on to think
`19 about this mechanism because they would have
`20 believed Wyse.
`21 But if for some reason they did, they
`22 would have been well aware that benzalkonium
`23 chloride formed micelles and was -- had
`24 surfactant-like properties and, therefore, would
`25 have known that BZK could have caused naloxone
`
`1 chemical instability through a number of indirect
`2 mechanisms.
`3 MR. KRINSKY: Just so everyone has
`4 it -- I think this is going to come up again --
`5 micelle is a single word, M-I-C-E-L-L-E.
`6 BY MR. BERMAN:
`7 Q. You do not opine that BZK is directly
`8 chemically reacting with naloxone, correct?
`9 A. Can you repeat the question, please?
`10 Q. Sure.
`11 You don't have the opinion that BZK is
`12 directly chemically reacting with naloxone, do you?
`13 A. My opinion is that the POSA would have
`14 read Wyse and would have understood from Wyse from
`15 his experiments where he combined naloxone with a
`16 series of formulation excipients in screening
`17 studies and showed that benzalkonium chloride
`18 caused a naloxone degradant in four of the
`19 formulations in which benzalkonium chloride was
`20 present.
`21 The POSA would have read this and
`22 understood from Wyse that benzalkonium chloride was
`23 an unsuitable excipient to use in naloxone
`24 formulations, and the POSA would have, therefore,
`25 gone on and not used a preservative at all because
`
`27
`
`1 that wasn't needed within a naloxone formulation
`2 that was formulated for intranasal use.
`3 However, if for some reason the POSA
`4 wanted to use some kind of preservative, then they
`5 could have used a preservative such as benzyl
`6 alcohol, which Wyse showed that was suitable in
`7 such a formulation.
`8 Within the hypothetical scenario that
`9 the POSA needed for some reason to understand the
`10 mechanism -- which I didn't -- I don't believe they
`11 would have though, because they would have read
`12 Wyse and taken Wyse's findings, which were clear,
`13 and used those, but for some reason if they wanted
`14 to look further, they would have understood that
`15 there were a number of mechanisms by which
`16 benzalkonium chloride could have caused naloxone
`17 instability.
`18 I cited two indirect mechanisms, and
`19 I've read Dr. Donovan's opinion that she believes
`20 it cannot directly interact with naxolone. I cited
`21 two indirect mechanisms as examples of mechanisms
`22 whereby benzalkonium chloride could degrade
`23 naloxone.
`24 But I do not agree with Dr. Donovan's
`25 opinion that the only mechanism the POSA would have
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`Nalox1252
`Nalox-1 Pharmaceuticals, LLC
`Page 9 of 39
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`Videoconference Deposition of Stuart Allen Jones, Ph.D., 5/1/2020
`28
`30
`1 commonly used intranasal formulation excipients to
`2 form prototype formulations that Wyse was showing
`3 benzalkonium chloride was responsible for naloxone
`4 chemical instability.
`5 The POSA would have read Wyse and seen
`6 that Wyse showed in four formulations benzalkonium
`7 chloride was included, and in those four
`8 formulations there was an additional peak in the
`9 HPLC chromatogram. That additional peak was a
`10 naloxone peak and, therefore, indicated the
`11 chemical instability of naloxone.
`12 Given that information, the POSA would
`13 have chosen not to use benzalkonium chloride in any
`14 intranasal formulations using naloxone, and they
`15 would have chosen instead to generate the
`16 preservative-free formulation, which was a very
`17 viable option to the POSA.
`18 The POSA would have no need to look at
`19 the mechanism of how benzalkonium chloride
`20 interacted with naloxone because Wyse clearly
`21 showed that it caused instability. Benzalkonium
`22 chloride caused instability.
`23 BY MR. BERMAN:
`24 Q. So, in your opinion, the POSA wouldn't
`25 have even been curious to know the mechanism.
`
`1 considered is the direct interaction of naloxone --
`2 of benzalkonium chloride with naloxone.
`3 And I do -- I am not convinced by her
`4 limited analysis of the chemical structure of
`5 naloxone, the peak chemical -- the mechanism of
`6 oxidation that she stipulates, the only form of
`7 interaction that's possible in that system. There
`8 are many possibilities, and I've given two very
`9 viable possibilities by which benzalkonium chloride
`10 could degrade naloxone.
`11 Q. So, in your opinion, a POSA would not
`12 have been curious to know the mechanism by which
`13 the naloxone degraded in Wyse's formulations?
`14 MR. KRINSKY: Objection. Asked and
`15 answered. Vague.
`16 THE WITNESS: The POSA would have read
`17 Wyse and understood from Wyse's exp