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
`
`_____________________
`
`IPR2019-00694
`U.S. Patent No. 9,629,965
`_____________________
`
`
`SUPPLEMENTAL DECLARATION OF MAUREEN DONOVAN, Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`TABLE OF CONTENTS
`
`
`
`I.
`
`OVERVIEW .................................................................................................... 1
`
`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 6
`
`III. LEGAL STANDARDS ................................................................................... 7
`
`IV. BASIS OF MY ANALYSIS WITH RESPECT TO OBVIOUSNESS ........... 8
`
`A. Wyse would not have directed a Formulator POSA away from
`using benzalkonium chloride
`in an
`intranasal naloxone
`formulation. ........................................................................................... 8
`
`1.
`
`2.
`
`A Formulator POSA would have concluded that naloxone
`degradants in Wyse’s formulations could not have been caused
`by BAC. ...................................................................................... 8
`
`A Formulator POSA would not know from Wyse’s prototyping
`studies that any one ingredient was the cause of naloxone
`degradation. ...............................................................................15
`
`B.
`
`C.
`
`D.
`
`None of the other prior art cited by Dr. Jones would have directed
`a Formulator POSA away from using BAC in an intranasal
`naloxone formulation. ......................................................................... 18
`
`A Formulator POSA would have been highly motivated to use
`BAC as the preservative in an intranasal naloxone formulation. ........ 21
`
`The claimed naloxone formulation does not have “unexpected”
`stability – a Formulator POSA would have been expected the
`claimed formulation to be stable. ........................................................ 23
`
`V.
`
`CONCLUSION .............................................................................................. 24
`
`
`
`
`
`
`ii
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`I, Maureen D. Donovan, Ph.D., do hereby declare as follows:
`
`I.
`
`OVERVIEW
`
`1.
`
`I am over the age of 18 and otherwise competent to make this
`
`Declaration. This Declaration is based on my personal knowledge as an expert in
`
`the field of pharmaceutical formulation, in particular intranasal formulation. I
`
`understand that this Declaration is being submitted in support of Petitioner Nalox-1
`
`Pharmaceuticals, LLC’s (“Nalox-1”) Reply to Patent Owners’ Response to the
`
`petition for Inter Partes Review (“IPR”) of certain claims of U.S. Patent No.
`
`9,629,965 (“the ’965 patent”) (Nalox1001).
`
`2.
`
`This is my second Declaration in this proceeding. Previously, I
`
`submitted a Declaration (Nalox1002) in support of Nalox-1’s petition for IPR
`
`challenging the ’965 patent. I refer to that Declaration hereinafter as “my first
`
`Declaration.”
`
`3.
`
`I have now been asked to supplement the opinions I expressed in my
`
`first Declaration. I have also been asked to respond to certain opinions contained
`
`in the Declaration of Stuart A. Jones, Ph.D. (Ex-2201) and the Declarations of
`
`Kenneth A. Williams, M.D. (Ex-2001 and Ex-2202).
`
`4.
`
`In preparing this Declaration, I have reviewed the ’965 patent and its
`
`file history. I have also considered each of the documents listed in the table below,
`
`in addition to the exhibits disclosed in my first Declaration. See Nalox1002, ¶5.
`
`
`
`
`1
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`Exhibit No.
`
`Description
`
`Nalox1001 U.S. Patent No. 9,629,965 (the ’965 patent)
`
`Nalox1002 Expert Declaration of Maureen Donovan (my first Declaration)
`
`Nalox1007 U.S. Patent No. 9,192,570 (Wyse)
`
`Nalox1010
`
`Djupesland, P., Nasal Drug Delivery Device: Characteristics
`and Performance in a Clinical Perspective – A Review, 3 Drug
`Deliv. & Transl. Res. 42–62 (2013) (Djupesland)
`
`Nalox1012
`
`Handbook of Pharmaceutical Excipients (Rowe, R. et al. eds.,
`6th ed. 2009) (HPE)
`
`Nalox1015 U.S. Patent No. 8,198,291 (the ‘291 patent)
`
`Nalox1022
`
`Bitter, C. et al., Nasal Drug Delivery in Humans, 40 Curr.
`Probl. Dermatol. 20–35 (2011) (Bitter)
`
`Nalox1028
`
`FDA, Center for Drug Evaluation and Research, Guidance for
`Industry, Nasal Spray and Inhalation Solution, Suspension, and
`Spray Drug Products – Chemistry, Manufacturing, and Controls
`Documentation (2002) (2002 FDA Guidance)
`
`Nalox1031
`
`Glende, O., Development of non-injectable naloxone for pre-
`hospital reversal of opioid overdose: A Norwegian project and
`a review of international status (May 2016) (unpublished M.A.
`thesis, Norwegian University of Science and Technology) (on
`file with Norwegian University of Science and Technology)
`(Glende)
`
`Nalox1044
`
`Physicians’ Desk Reference, NARCAN [Naloxone
`Hydrochloride Injection, USP], IMITREX Nasal Spray
`[Sumatriptan], 1300–02, 1546–50 (57th ed., 2003) (PDR 2003)
`
`Nalox1206
`
`Bureš, F., Quaternary Ammonium Compounds: Simple in
`Structure, Complex in Application, 377(14) Topics in Current
`Chemistry (2019) (Bureš)
`
`
`
`
`2
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`Exhibit No.
`
`Description
`
`Nalox1208
`
`Connors, K. et al., Oxidation and Photolysis, in Chemical
`Stability of Pharmaceuticals: A Handbook for Pharmacists 82–
`114 (2d ed. 1986) (Connors)
`
`Nalox1210
`
`Ehrick, J. et al., Considerations for the Development of Nasal
`Dosage Forms, in Sterile Product Development: Formulation,
`Process, Quality and Regulatory Considerations 99–144 (Parag
`Kolhe, et al., eds., 2013) (Ehrick)
`
`Nalox1213
`
`FDA, Center for Drug Evaluation and Research, Guidance for
`Industry, Q8(R2) Pharmaceutical Development (Revision 2
`2009) (2009 FDA Guidance)
`
`Nalox1214
`
`Hiom, S., Preservation of Medicines and Cosmetics, in
`Principles and Practice of Disinfection, Preservation &
`Sterilization 484–514 (Fraise, A.P. et al., eds., 4th ed. 2004)
`(Hiom)
`
`Nalox1218
`
`Hsu, H. et al., Effect of Formulation Variables on the Nasal
`Permeability and Stability of Naloxone Intranasal
`Formulations, 20(232) AAPS PharmaSciTech (2019) (Hsu)
`
`Nalox1219
`
`Inactive Ingredient Search for Approved Drug Products, Search
`Names Beginning with B, U.S. FDA (Mar. 3, 2020, 12:08 PM),
`https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm?event
`=browseByLetter.page&Letter=B (FDA B Names)
`
`Nalox1220
`
`Inactive Ingredient Search for Approved Drug Products:
`Frequently Asked Questions, U.S. FDA (Mar. 3, 2020, 12:12
`PM), https://www.fda.gov/drugs/drug-approvals-and-
`databases/inactive-ingredient-search-approved-drug-products-
`frequently-asked-questions (FDA FAQ)
`
`Nalox1227
`
`Marx, D. et al., Intranasal Drug Administration – An Attractive
`Delivery Route for Some Drugs, InTech Open (2015) (Marx)
`
`
`
`
`3
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`Exhibit No.
`
`Description
`
`Nalox1231
`
`Quarry, M. et al., Investigation of 4,5-epoxymorphinan
`Degradation During Analysis by HPLC, 30 J. Pharm. Biomed.
`Anal. 99–104 (2002) (Quarry)
`
`Nalox1241
`
`Yu, L. et al., Understanding Pharmaceutical Quality by Design,
`16(4) The AAPS J. 771–83 (2014) (Yu)
`
`Nalox1243
`
`Astepro Label (Aug. 31, 2009), U.S. FDA Drug Label Database
`(Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022
`203s003lbl.pdf (ASTEPRO)
`
`Nalox1244
`
`Patanase Label (Feb. 22, 2012) U.S. FDA Drug Label Database
`(Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021
`861s009lbl.pdf (PATANASE)
`
`Nalox1245
`
`Nasacort Allergy 24H Label (July 2, 2013), U.S. FDA Drug
`Label Database (Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020
`468s033s034lbl.pdf (NASACORT)
`
`Nalox1246
`
`Flonase Sensimist Label (Aug. 2, 2016), U.S. FDA Drug Label
`Database (Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022
`051Orig1s013lbl.pdf (FLONASE)
`
`Nalox1247
`
`Xhance Label (Sept. 18, 2017), U.S. FDA Drug Label Database
`(Mar. 2, 2020)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209
`022s000lbl.pdf (XCHANCE)
`
`PROTECTIVE ORDER MATERIAL
`
`Nalox1248
`
`February 21, 2020 Transcript of Deposition of Dr. Stuart Allen
`Jones (Jones Dep.)
`
`Nalox1249
`
`Handbook of Pharmaceutical Excipients, 579–81 (Rowe, R. et
`al. eds. 6th ed. 2009) (HPE Potassium Sorbate)
`
`
`
`
`4
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`Exhibit No.
`
`Description
`
`Ex-2001
`
`Declaration of Kenneth A. Williams (First Williams
`Declaration)
`
`Ex-2051
`
`European Pharmacopoeia 6.0, Vol. 2 (6th ed. Jan. 2008)
`(European Pharmacopoeia 6.0)
`
`Ex-2069
`
`Eric Bechgaard et al., Reversibility and clinical relevance of
`morphological changes after nasal application of ephedrine
`nasal drops 1%, 152 Int’l J. Pharms. 67-73 (1997) (Bechgaard)
`
`Ex-2188
`
`NDA No. 205678 Module 3.2.P.2, Pharmaceutical
`Development (Naloxone HCl Nasal Spray, 0.9 mg/Spray, Nasal
`Spray) (Indivior NDA Module 3.2.P.2)
`
`Ex-2201 Declaration of Stuart A. Jones (Jones Declaration)
`
`Ex-2202
`
`Declaration of Kenneth Williams (Second Williams
`Declaration)
`
`
`5.
`
`It remains my opinion that a person of ordinary skill in the art
`
`(“POSA”) reading Wyse (Nalox1007) in view of Handbook of Pharmaceutical
`
`Excipients (“HPE”) (Nalox1012) would have had ample reason and know-how to
`
`arrive at the subject matter of claims 1-2, 9-12, 17-22, 25-26, and 29-30 of the ’965
`
`patent with a reasonable expectation of success, as discussed in my first
`
`Declaration and this Declaration below.
`
`6.
`
`It remains my opinion that a POSA reading Wyse in view of
`
`Djupesland (Nalox1010) and HPE would have had ample reason and know-how to
`
`arrive at the subject matter of claims 23-24 of the ’965 patent with a reasonable
`
`
`
`
`5
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`expectation of success, as discussed in my first Declaration and this Declaration
`
`below.
`
`7.
`
`It remains my opinion that a POSA reading Wyse in view of HPE, and
`
`the ’291 patent (Nalox1015) would have had ample reason and know-how to arrive
`
`at the subject matter of claims 27-28 of the ’965 patent with a reasonable
`
`expectation of success, as discussed in my first Declaration and this Declaration
`
`below.
`
`II. MY BACKGROUND AND QUALIFICATIONS
`
`8.
`
`In my first Declaration, I discussed my background and qualifications.
`
`See Nalox1002, ¶¶17–23. To address certain points raised by Dr. Williams and Dr.
`
`Jones, I supplement this discussion as follows.1 I received my Bachelor of Science
`
`in Pharmacy from the University of Minnesota in 1983, and my Ph.D. from the
`
`University of Michigan Rackham School of Graduate Studies in 1989. I am
`
`currently a faculty member at the University of Iowa, with over 30 years of
`
`experience teaching undergraduate, professional and graduate students about the
`
`
`
`1 Dr. Jones and Dr. Williams criticize my opinion because neither I nor Dr.
`Hochhaus consulted with a clinician in conjunction with our Declarations. See Ex-
`2201, ¶¶238-240; Ex-2202, ¶39. While it remains my opinion that, in this case, a
`POSA would comprise a team of individuals including, inter alia, professionals
`with clinical expertise (see Nalox1002, ¶¶26-27), I disagree that consultation with
`a clinician was required in order to form my opinions in my first Declaration and
`herein. Nevertheless, I have the qualifications of a POSA under Dr. Jones’s and
`Dr. Williams’s definitions. See Ex-2201, ¶¶38-41; Ex-2001, ¶¶13-16.
`
`
`
`
`6
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`fundamental physicochemical principles used in formulation design and the
`
`application of those principles to extemporaneous compounding activities
`
`performed by pharmacists. I actively practiced as a pharmacist from 1983-1988. In
`
`my professional activities as a pharmacist, I provided information to patients
`
`regarding the actions of their prescription medications, the correct use and
`
`administration techniques for their medications, and I assisted patients in the
`
`selection of non-prescription medications. I also provided information to
`
`physicians and other prescribers regarding drug interactions, patient status or
`
`concerns, new drug products, and
`
`the potential for and advantages of
`
`individualized therapy from extemporaneously compounded medications.
`
`III. LEGAL STANDARDS
`
`9.
`
`In my first Declaration, I discussed the legal standards relevant to this
`
`IPR. See Nalox1002, ¶¶24–36. These paragraphs are incorporated by reference
`
`herein. In addition to these legal standards, it has been explained to me by counsel
`
`for Petitioner that the following legal principles are applicable to patent validity
`
`and I have relied upon these legal principles in forming the opinions set forth in
`
`this Declaration.
`
`10.
`
`I understand from counsel that a POSA must consider the totality of
`
`the teachings in the prior art. I also understand from counsel that a POSA would
`
`not simply accept the conclusions stated in a prior art reference if a POSA knew of
`
`
`
`
`7
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`or was alerted to potential shortcomings, or found incomplete evidence for those
`
`conclusions causing the POSA to question them or, at the very least, pursue further
`
`research to confirm those conclusions.
`
`IV. BASIS OF MY ANALYSIS WITH RESPECT TO OBVIOUSNESS
`
`A. Wyse would not have directed a Formulator POSA away from
`using benzalkonium chloride
`in an
`intranasal naloxone
`formulation.
`
`11.
`
`In my first Declaration, I opined that Wyse would not have directed a
`
`Formulator POSA away from using benzalkonium chloride (“BAC” or “BZK”) in
`
`an intranasal naloxone formulation. See Nalox1002, ¶¶67–78. I provide additional
`
`detail below as to why Wyse would not have directed a Formulator POSA away
`
`from using BAC in an intranasal naloxone formulation.
`
`1.
`
`A Formulator POSA would have concluded that naloxone
`degradants in Wyse’s formulations could not have been
`caused by BAC.
`
`12. Dr. Jones opines that “[t]he POSA would have concluded from
`
`reading Wyse that in fact BZK caused naloxone degradation.” Ex-2201, ¶93; see
`
`also Nalox1248 at 70:11-14; 88:1-89:5.2 I disagree. A Formulator POSA would
`
`have been alerted to the shortcomings in Wyse’s stability studies and, more
`
`
`
`2 Dr. Jones testified, “I can’t think of any reason for the POSA to question
`Wyse’s conclusion.” Nalox1248 at 139:8-11. I disagree, for the reasons
`discussed, infra.
`
`
`
`
`8
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`importantly, would have known that BAC could not have caused the naloxone
`
`degradation reported by Wyse.3
`
`13. Naloxone is a 4,5-epoxymorphinan. It was known in the art that 4,5-
`
`epoxymorphinans having a hydroxyl group at the 3-position, such as morphine and
`
`naloxone, undergo oxidative degradation in solution. Quarry (Nalox1231) at 1;
`
`Connors (Nalox1208) at 9; see Nalox1002, ¶49. In this reaction, the 4,5-
`
`epoxymorphinan loses a hydrogen atom (or is “oxidized”), while the oxidizing
`
`agent gains a hydrogen atom (or is “reduced”). Connors (Nalox1208) at 4, 9. The
`
`pH of the solution is known to correlate with the extent of the 4,5-epoxymorphinan
`
`oxidative degradation. In alkaline or neutral solutions (at pH of 7 or above),
`
`degradation of the 4,5-epoxymorphinan occurs rapidly at room temperature, while
`
`acidic solutions are more stable. Quarry (Nalox1231) at 1; see also Wyse
`
`(Nalox1007) at 27:23–24 (“[I]t was found that decreasing the pH minimizes the
`
`formation of potentially oxidative degradants.”).
`
`
`
`3 Dr. Jones notes that Wyse is “a reference that a POSA would have
`considered closely,” and “[t]he POSA would have relied on the data and
`discussion in Wyse to determine the acceptability of BZK in an intranasal
`naloxone formulation.” See Ex-2201, ¶¶79–80. I agree that Wyse is the most
`relevant reference in these proceedings, and therefore a Formulator POSA would
`have given close consideration to the data contained in the reference, rather than
`simply accepting Wyse’s conclusions, especially when those conclusions are
`recognizably contrary to a Formulator POSA’s knowledge regarding BAC.
`
`
`
`
`9
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`14. The primary degradation product of 4,5-epoxymorphinan compounds
`
`having a hydroxyl group at the 3-position is the 2,2’-dimer, which forms from the
`
`oxidation of the phenolic group with subsequent condensation to the dimer. Quarry
`
`(Nalox1231) at 1; Connors (Nalox1208) at 9. In the case of naloxone, this primary
`
`degradation product is known as 2,2’-binaloxone or 2,2’-bisnaloxone. Quarry
`
`(Nalox1231) at 2. 2,2’-binaloxone is also known as “Impurity E.” as described by
`
`the European Pharmacopoeia naloxone hydrochloride dihydrate monograph Ex-
`
`2051 at 5.
`
`15. Wyse discloses that formulations 7, 9, 14 and 14A4 contained “an
`
`additional degradant,” one that was not reported as being found in at least some of
`
`the other disclosed formulations.5 Since these formulations were pH-adjusted “to
`
`accelerate degradation” of the naloxone (Nalox1007 at 26:29–30),6 a Formulator
`
`POSA would have considered that, if the “additional degradant” was a naloxone
`
`degradant, it would likely be an oxidation degradant. See supra, ¶13. Indeed, the
`
`
`
`4 Formulation 14A contained the same ingredients as formulation 14, but
`was at pH 4.5 instead of pH 5.0.
`
`5 Dr. Jones relies on a separate document (Indivior NDA Module 3.2.P.2
`(Ex-2188)) that states formulation 12 contains this additional degradant as well,
`and speculates that “[t]he POSA would have assumed that leaving [Formulation
`12] off the unstable list might have been a typographical error . . . .” (Ex-2201,
`¶109). I disagree that a Formulator POSA reading Wyse would have made such an
`assumption.
`
`6 See Nalox1007 at 27:20–21 (“Increasing the pH of the solution accelerated
`the degradation of naloxone HCl….”)
`
`
`
`
`10
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`“additional degradant” in these formulations was apparently identified as Impurity
`
`E, the primary oxidation degradation product of naloxone. See Ex-2188 at 10.7
`
`The presence of Impurity E in formulations subjected to increased pH to accelerate
`
`oxidative degradation of naloxone, would not have been surprising to a Formulator
`
`POSA—on the contrary, it would have been expected. See supra, ¶¶13–14.
`
`16. A Formulator POSA would have known that BAC could not have
`
`been responsible for the production of any oxidative degradants of naloxone, much
`
`less Impurity E,
`
`the naloxone degradant “notably” found
`
`in
`
`the Wyse
`
`formulations.8 See Ex-2188 at 10. BAC is a quaternary ammonium compound.
`
`
`
`7 In my first Declaration, I opined that a Formulator POSA could not
`conclude from the disclosure in Wyse whether the “additional degradant” observed
`in formulations 7, 9, 14 and 14A was a naloxone degradant. See Nalox1002, ¶74. I
`maintain this opinion, based on the disclosure of the Wyse reference. Dr. Jones’s
`opinion that “[t]he HPLC assay performed by Wyse would not necessarily have
`been capable of detecting other types of impurities,” (Ex-2201, ¶83) is unsupported
`by Wyse, which discloses several “Unknown Impurities” unrelated to naloxone
`that were detected by the HPLC assay. See Nalox1007 at 29:62–30:38. Dr. Jones’s
`further opinion that “Wyse’s use of the term ‘degradant,’ rather than impurity”
`meant that “the POSA would have considered the additional [HPLC] peak to be
`another naloxone degradant” is similarly unsupported in light of Wyse’s use of the
`term “impurities” to refer to both naloxone impurities and unidentified impurities
`(see Nalox1007 at 30:5–37), as well as Wyse’s reference to “degradation” with
`respect to both types of impurities (see id. at 30:9).
`
`Nevertheless, as noted herein, a Formulator POSA would have known that
`BAC could not have been responsible for any oxidative degradants observed in
`Wyse’s formulations, no matter their source, because BAC does not act as an
`oxidizing agent in pharmaceutical formulations.
`
`8 Dr. Jones admitted that, despite his opinion that BAC caused naloxone
`11
`
`
`
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`See HPE (Nalox1012) at 5. Prior to March 16, 2015, and even today, a Formulator
`
`POSA would have known that quaternary ammonium compounds do not act as
`
`oxidizing agents in pharmaceutical formulations. See, e.g., Bureš (Nalox1206) at 4
`
`(“In general, [quaternary ammonium compounds] undergo four type[s] of
`
`reactions: (a) elimination, (b) substitution, (c) rearrangement, and (d) ion exchange
`
`reactions….”). As I mentioned above, in an oxidation reaction involving small
`
`organic molecules, the oxidizing agent gains a hydrogen atom (or is “reduced”).9
`
`Quaternary ammonium compounds such as BAC are permanently positively
`
`charged at the nitrogen, so adding another hydrogen to that portion of the molecule
`
`is not feasible. And since the alkyl chains in BAC are already saturated, no
`
`additional hydrogens can to be added anywhere on the alkyl chains. The aromatic
`
`ring is particularly stable, and it will not be reduced in aqueous media at room
`
`temperature. Therefore, a Formulator POSA would have known that BAC could
`
`not have acted as an oxidizing agent for the naloxone in Wyse’s formulations.10
`
`
`
`instability, he had no idea of the mechanism by which BAC could have caused
`such instability. See Nalox1248 at 123:4-124:18.
`
`9 See Connors (Nalox1208) at 3, which states “Oxidation/reduction (redox)
`reactions involve the transfer of one or more oxygen or hydrogen atoms or the
`transfer of electrons…. In the case of organic compounds and especially the
`oxidation state of carbon, the oxidation state is determined by the number of bonds
`from carbon to oxygen.”
`
`10 Dr. Jones correctly stated that “[t]he POSA would have understood that
`the mechanism of pH-mediated versus BZK-mediated naloxone degradation could
`12
`
`
`
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`17. The above explanation is consistent with a Formulator POSA’s
`
`general knowledge of the chemical behavior of BAC in pharmaceutical
`
`formulations. I am unaware of any reference describing BAC as an oxidizing
`
`agent in pharmaceutical formulations.
`
`18. A Formulator POSA would have investigated the cause of the
`
`degradation observed in Wyse’s formulations.11 A Formulator POSA would have
`
`known that a plausible explanation for the presence of naloxone degradants in
`
`Wyse’s BAC-containing formulations is that Wyse may have used raw materials
`
`with unacceptable levels of impurities or other compounds that could contribute to
`
`the formation of degradants. A Formulator POSA would have known that the grade
`
`
`
`be different. . . .” (Ex-2201, ¶98). Dr. Jones goes on to state that the POSA “would
`have expected that BZK could have resulted in formulation [sic] of an additional
`degradant that was different from the pH related degradants.” Id. (emphasis
`added). Dr. Jones thus seems to agree that since Wyse found a pH related
`degradant, Impurity E, in the BAC-containing formulations, a Formulator POSA
`would have recognized that the culprit could not have been BAC.
`
`11 In my first Declaration, I opined that other excipients in formulations 7, 9,
`14 and 14A may have contributed to the degradation. See Nalox1002, ¶¶76-78. Dr.
`Jones criticizes my opinion because I did not “opine that the POSA would have
`drawn this conclusion. . . .” (Ex-2201, ¶102) (emphasis added). As I stated in my
`first Declaration (see Nalox1002, ¶72) and further discuss, infra, a Formulator
`POSA would have had to test each of the excipients individually in order to
`identify the excipient(s) responsible for degradation. Therefore, a Formulator
`POSA would not have drawn any conclusions about the cause or source of the
`degradation, but would have known that further research was necessary to identify
`the culprit(s).
`
`
`
`
`13
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`and purity of a nasal formulation excipient can affect stability,12 and potentially
`
`would have investigated the possibility here due to the unusual stability results that
`
`Wyse observed. Indeed, Wyse does not provide any indication of the commercial
`
`physical grade of sodium citrate, ascorbic acid, hypromellose, polyethylene glycol,
`
`sorbitol, glycerine, propylene glycol, methylparaben, propylparaben, benzalkonium
`
`chloride, and polysorbate 20 that were used in his prototype formulations, and a
`
`Formulator POSA would not have assumed that a pharmaceutical grade raw
`
`material was used by Wyse for his Preliminary Formulation Prototyping Studies.13
`
`A Formulator POSA would not have assumed that any of the degradants observed
`
`in the Wyse formulations were caused by BAC instead of any of the other
`
`components, combination of components, or unknown impurities in the raw
`
`materials. Preferably, a Formulator POSA would have conducted further studies to
`
`determine whether BAC was incompatible with naloxone.14 In light of the known
`
`
`
`12 According to its Guidance for Industry for nasal products, the FDA states
`that “grade of excipient may affect the stability of the drug product.” 2002 FDA
`Guidance (Nalox1028) at 35.
`
`13 I note that Wyse did describe the quality grades of the formulation
`components in his final “NNS” formulation (Table 1), but the same quality
`descriptions are absent from the information in Table 13, which relates to the
`materials used for the Preliminary Formulation Screening Studies. See Nalox1007,
`Tables 1 and 13.
`
`14 As I discuss in further detail, infra, one research team did investigate
`whether BAC was incompatible with naloxone, and found that BAC is not
`incompatible with naloxone. See Hsu (Nalox1218) at 7–8.
`
`
`
`
`14
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`superiority of BAC as an antimicrobial agent (e.g., as an anti-Pseudomonal agent)
`
`compared with other preservatives used in nasal formulations, a Formulator POSA
`
`would not have avoided using the BAC altogether, since BAC plays an important
`
`role in the formulation, and would, instead, investigate the root cause of the
`
`stability problem.15
`
`2.
`
`A Formulator POSA would not know from Wyse’s
`prototyping studies that any one ingredient was the cause of
`naloxone degradation.
`
`19.
`
` In my first Declaration, I opined that, from Wyse’s studies, a
`
`Formulator POSA would not have been able to pinpoint any individual excipient
`
`responsible for any instability issue in Wyse’s formulations. See Nalox1002, ¶72.
`
`Dr. Jones opined that “the POSA would not … have questioned Wyse’s
`
`experimental design, as
`
`testing excipients
`
`individually would have been
`
`impractical.” Ex-2201, ¶100. Dr. Jones extolled the benefits of a so-called
`
`“prototyping study,” where combinations of excipients are tested, as decreasing
`
`costs and providing “information quickly about a broad range of different
`
`excipients without an impractically large number of experiments.” Id., ¶57.
`
`
`
`15 Dr. Jones’s opinion rests on the assumption that “[t]he POSA would not
`have had any doubt what [sic] Wyse had drawn the conclusion that BZK was
`unacceptable in naloxone formulations.” See Ex-2201, ¶85. I agree that Wyse
`drew this conclusion, but as I noted above, a Formulator POSA would have
`questioned Wyse’s conclusion and would have applied his or her knowledge to
`identify the shortcomings in Wyse’s studies.
`
`
`
`
`15
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`20.
`
`I disagree with Dr. Jones’s opinion that testing excipients individually
`
`is “impractical”—on the contrary, it is common practice of a Formulator POSA.
`
`During the pharmaceutical product development process, excipients are routinely
`
`tested to determine their compatibility with other components in the formulation.16
`
`While I agree with Dr. Jones that prototyping studies containing an ad hoc
`
`selection of excipients are useful to obtain information quickly, a Formulator
`
`POSA would also know the limitations of such studies—that if a particular
`
`formulation presents problems, it is not possible to attribute blame to any single
`
`agent present in the formulation. In order to determine the root cause of any
`
`problems, a Formulator POSA would have to evaluate each of the excipients and
`
`experimental conditions individually and potentially evaluate other factors,
`
`including the presence of oxygen or the materials used in the containers during the
`
`storage period, in order to determine the cause of the observed problem.17 FDA
`
`
`
`16 The FDA discusses the importance of testing excipients during
`pharmaceutical product development studies and states, “The compatibility of the
`drug substance with excipients . . . should be evaluated.” 2009 FDA Guidance
`(Nalox1213) at 8. Further, the FDA states, “Compatibility of excipients with other
`excipients, where relevant . . . . should be established. The ability of excipients
`(e.g., antioxidants, penetration enhancers, disintegrants, release controlling agents)
`to provide their intended functionality and to perform throughout the intended drug
`product shelf life should also be demonstrated.” Id. at 8.
`
`17 The FDA states that “[p]harmaceutical development should include, at a
`minimum… [i]dentifying potential critical quality attributes (CQAs) of the drug
`product, so that those product characteristics having an impact on product quality
`can be studied and controlled… [and] [d]etermining the critical quality attributes of
`16
`
`
`
`
`

`

`Inter Partes Review of U.S. Patent No. 9,629,965
`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201)
`
`regulators have criticized the ad hoc approach advocated by Dr. Jones, and prefer
`
`“systematic drug-excipient compatibility testing” to, inter alia, “enhanc[e] the
`
`understanding of drug-excipient interactions that can help with root cause analysis
`
`should stability problems occur.” See Yu (Nalox1241) at 3.
`
`21. Wyse concedes that his experimental design would not permit a
`
`Formulator POSA to conclude that any one ingredient was responsible for stability
`
`problems. See Nalox1007, 28:28–31 (“While some of the excipients might work
`
`individually, the combination of many of these was found to be unacceptable for
`
`various reasons as outlined above.”) (emphasis added). A Formulator POSA
`
`would have known that in order to conclude that BAC and naloxone were
`
`incompatible, one would need to study the individual combination of the two
`
`compounds.18
`
`22.
`
`Indeed, a 2019 study confirmed that BAC is not incompatible with
`
`naloxone. See Hsu (Nalox1218) a