UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`COLLEGIUM PHARMACEUTICAL, INC.,
`Petitioner
`v.
`PURDUE PHARMA L.P.,
`PURDUE PHARMACEUTICALS L.P.,
`THE P.F. LABORATORIES, INC.,
`Patent Owners
`____________________
`Case PGR2018-00048
`U.S. Patent No. 9,693,961
`_____________________
`
`SUPPLEMENTAL DECLARATION OF PANAYIOTIS P.
`CONSTANTINIDES, PH.D.
`
`Purdue 2030
`Collegium v. Purdue, PGR2018-00048
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`Declaration of P. Constantinides
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`TABLE OF CONTENTS
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`Case PGR2018-00048 for
`U.S. Patent No. 9,693,961
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`Exhibit List ............................................................................................................... iii
`I.
`Introduction ...................................................................................................... 1
`II.
`Summary of Opinions ...................................................................................... 2
`III. Technical Background ..................................................................................... 3
`A.
`Surfactants, Fatty Acid Esters, and PGGs ............................................. 3
`2.
`Polyglycolyzed glycerides are surfactants .................................. 4
`3.
`The number of PGG grades, known as Gelucires®, is limited
`and their properties were well-known by POSAs ....................... 6
`Solubilizing a Poorly Water-Soluble API ........................................... 10
`B.
`C. Melt Granulation and Melt Extrusion ................................................. 12
`1.
`Dry and Wet Granulation .......................................................... 12
`2. Melt granulation ........................................................................ 13
`3. Melt extrusion ........................................................................... 14
`Response to Dr. Chambliss’s Section, “Abuse of Opiate Drug
`Products and Abuse Deterrent Dosage Forms” ................................... 15
`IV. The ’961 Patent .............................................................................................. 17
`A. Disclosure of the ’961 Patent and Priority Applications ..................... 17
`1.
`Aversive Agents ........................................................................ 17
`2. Matrix Formulations ................................................................. 18
`Claims .................................................................................................. 22
`B.
`Legal Understandings .................................................................................... 25
`A.
`Claim Construction ............................................................................. 25
`B. Written Description ............................................................................. 26
`C.
`Enablement .......................................................................................... 27
`VI. Person of Ordinary Skill in the Art ................................................................ 27
`A.
`Claim Construction “abuse deterrent dosage form” ........................... 28
`B.
`Preamble .............................................................................................. 31
`
`V.
`
`D.
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`Declaration of P. Constantinides
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`VII. The ’961 Patent Is Entitled to Its Priority Dates............................................ 32
`A.
`The Priority Applications Contain Written Description of the ’961
`Claims .................................................................................................. 32
`1.
`The Inventors Were in Possession of the Claimed Abuse-
`Deterrent Dosage Forms ........................................................... 32
`The Inventors Were in Possession of the Claimed
`Combination of Ingredients and Method for Manufacturing a
`Capsule Dosage Form Containing the Same ............................ 35
`The Priority Applications Enable the ’961 Claims ............................. 51
`1.
`The Specification Teaches a POSA How to Use the Claim
`Method of Preparing ................................................................. 51
`The Specification and Knowledge of a POSA Direct the
`POSA to a Reasonable Number of Embodiments .................... 53
`The Specification Enables a POSA to Make and Use the Full
`Scope of the Invention Without Undue Experimentation......... 67
`Summary of Written Description and Enabling Disclosure ............... 78
`C.
`VIII. Conclusion ..................................................................................................... 98
`
`
`
`2.
`
`B.
`
`2.
`
`3.
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`Declaration of P. Constantinides
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`Case PGR2018-00048 for
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`EXHIBIT LIST1
`
`(Exhibits to Purdue’s Preliminary Response)
`
`Exhibit No. Description
`
`2001.
`
`2002.
`
`2003.
`
`2004.
`
`2005.
`
`2006.
`
`2007.
`
`2008.
`
`2009.
`
`2010.
`
`2011.
`
`2012.
`
`2013.
`
`Declaration of Panayiotis P. Constantinides, Ph.D.
`
`Curriculum Vitae of Panayiotis P. Constantinides (June 2018)
`
`OXFORD DICTIONARY OF SCIENCE (Alan Isaacs et al. eds., 4th ed. 1999)
`
`’722 application, 4/8/2016 office action
`
`’722 application, 11/2/2016 office action
`
`’722 application, 5/17/2017 notice of allowability
`
`Gattefossé, Oral Route Excipients (2004)
`
`FDA’s 1996 Inactive Ingredient Guide
`
`’275 application, 8/2/2017 amendment
`
`Material safety data sheet for myristic acid (July 6, 2010) (COLL1080872-
`74)
`
`Material safety data sheet for myristic acid (December 11, 1990)
`
`Material safety data sheet for stearic acid (February 24, 2005)
`
`Statement Regarding Suspension of 160 mg OxyContin® Tablets (May 11,
`2001)
`
`2014.
`Knothe et al., A Comprehensive Evaluation of the Melting Points of Fatty
`
`1 Unless otherwise noted, all exhibits (including exhibits to Collegium’s petition) are
`
`cited by their original page, paragraph, or column numbers.
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`Case PGR2018-00048 for
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`2015.
`
`2016.
`
`2017.
`
`2018.
`
`2019.
`
`2020.
`
`2021.
`
`2022.
`
`2023.
`
`2024.
`
`2025.
`
`2026.
`
`2027.
`
`Acids and Esters Determined by Differential Scanning Calorimetry, J. AM.
`OIL CHEM. SOC., 86:843-56 (2009)
`
`International Publication No. WO 99/63971
`
`Breitenbach, J. Melt extrusion: from process to drug delivery technology,
`54 EUR. J. PHARM. & BIOPHARM. 107-17 (2002)
`
`Constantinides, P.P. Lipid Microemulsions for Improving Drug Dissolution
`and Oral Absorption: Physical and Biopharmaceutical Aspects, PHARM.
`RES., 12(11):1561-72 (1995)
`
`Crew, M. The Second Quadrant: Analysis of the Historical Use of
`Solubilization Techs., DRUG. DEVEL. & DELIVERY, 14(2):22-25 (March
`2014)
`
`U.S. Patent No. 9,592,200
`
`U.S. Patent No. 7,771,707
`
`Orange Book listing for Xtampza 9 mg (last accessed 7/3/2018)
`
`Purdue OxyContin HCl TR (OTR) 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg
`Tablets Pharmaceutical Development Report (CONFIDENTIAL)
`
`Semjonov, K. et al., The formation and physical stability of two-phase solid
`dispersion systems of indomethacin in supercooled molten mixtures with
`different matrix formers, EURO. J. PHARM. SCI. 97:237-46 (2017)
`
`Hearing transcript, Purdue Pharma L.P. v. Collegium Pharmaceuticals,
`Inc., C.A. No. 15-13099-FDS (D. Mass. June 1, 2017)
`
`HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (6th ed. 2009)
`
`HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (Ainley Wade & Paul J.
`Weller eds., 2nd ed. 1994)
`
`S. Hulsmann et al., Melt Extrusion-An Alternative Method For Enhancing
`The Dissolution Rate of 17β-estradiol Hemihydrate, 49 EUROPEAN
`JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS 237-242 (2000)
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`2028.
`
`2029.
`
`2030.
`
`2031.
`
`2032.
`
`2033.
`
`
`
`
`
`Manish K. Gupta et al., Hydrogen Bonding With Absorbent During Storage
`Governs Drug Dissolution From Solid-Dispersion Granules, 19(11)
`PHARMACEUTICAL RESEARCH, 1663-1762 (2002)
`
`Deposition Transcript of Walter G. Chambliss, Ph.D. (Jan. 9, 2019)
`
`Supplemental Declaration of Panayiotis P. Constantinides, Ph.D.
`
`Paul W.S. Heng et al., Role Of Surfactant On Drug Release From Tablets,
`16(6) DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 951-962 (1990)
`
`U.S. Patent No. 6,267,985
`
`U.S. Patent No. 5,635,159
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`Declaration of P. Constantinides
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`I, Panayiotis P. Constantinides, hereby declare:
`
`I.
`
`INTRODUCTION
`
`Case PGR2018-00048 for
`U.S. Patent No. 9,693,961
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`1.
`
`I am the same Panayiotis P. Constantinides, Ph.D. who submitted a
`
`declaration in support of Patent Owner’s Preliminary Response to Petition for Post
`
`Grant Review (“Preliminary Declaration”) on July 10, 2018.
`
`2. My background, education, training, compensations, and professional
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`experience are set forth in my Preliminary Declaration, and are incorporated by
`
`reference as if fully set forth herein.
`
`3.
`
`I have considered Collegium’s petition, the non-confidential exhibits
`
`accompanying that petition, including the ’961 patent and Dr. Chambliss’s
`
`declaration and the Board’s October 4, 2018 Institution Decision. I have also
`
`considered all materials cited in this declaration. Finally, I considered relevant
`
`portions of the prosecution history of the ’961 patent.
`
`4.
`
`Although I was not provided with Collegium’s confidential exhibits, I
`
`understand that those exhibits were created years after the 2001/2002 priority dates
`
`at issue. I further understand that the issues on which I am opining relate to the
`
`meaning of the specification to a POSA as of those 2001/2002 dates, whereas
`
`Collegium’s confidential exhibits relate generally to experiments performed by
`
`Collegium in developing Xtampza and testing of Xtampza and OxyContin. Further,
`
`Dr. Chambliss cites only one of those exhibits (Ex. 1048) and does so in connection
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`Declaration of P. Constantinides
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`with his anticipation opinions for a reference (the ’943 publication) that is not prior
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`art based on my opinions. Such materials would not affect my opinions on the
`
`specification of the 2001/2002 priority applications.
`
`II.
`
`SUMMARY OF OPINIONS
`
`5.
`
`I understand that the ’961 patent is the subject of the instituted PGR, in
`
`which Collegium alleges, among other things, that the ’961 patent is not entitled to
`
`its 2001 and 2002 priority dates due to a lack of written description and enablement.
`
`I understand that, prior to evaluating priority, the claims need to be construed.
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`6.
`
`I have been asked to provide my opinions on technology relating to the
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`’961 patent and the state of the art around August 2001/2002, when the provisional
`
`and earliest non-provisional applications (the ’534 and ’412 applications,
`
`respectively) were filed. I have also been asked to provide my opinions on claim
`
`construction. I have further been asked to provide my opinion on whether the ’534
`
`and ’412 priority applications (the “Priority Applications”) adequately describe and
`
`enable the ’961 claims. Finally, I have been asked to respond to the opinions in Dr.
`
`Chambliss’s declaration.
`
`7.
`
`In summary, with respect to claim construction, it is my opinion that,
`
`as used in the ’961 claims:
`
`
`
`“abuse deterrent dosage form” means “a dosage form having a reduced
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`potential for abuse” and
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`
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`the preamble language “an abuse deterrent controlled release dosage
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`form” of the independent claims is limiting and means “a controlled-
`
`release dosage form having a reduced potential for abuse”.
`
`However, my remaining opinions are unchanged even if Collegium’s/Dr.
`
`Chambliss’s constructions are adopted.
`
`8.
`
`It is also my opinion that the ’534 and ’412 applications adequately
`
`describe and enable the ’961 claims and, therefore, the ’961 claims are entitled to
`
`their 2001 and 2002 priority dates.
`
`9.
`
`I explain these opinions below. While doing so, I explain various
`
`disagreements I have with Dr. Chambliss. My silence on a particular opinion of Dr.
`
`Chambliss does not mean that I agree with that opinion.
`
`III. TECHNICAL BACKGROUND
`
`10.
`
`In this section, I provide a background on certain areas of technology
`
`relevant to my opinions. I also provide additional technical background as needed
`
`throughout my declaration.
`
`A.
`
`Surfactants, Fatty Acid Esters, and PGGs
`1.
`
`Polyglycolyzed glycerides are an example of fatty acid esters
`
`Dr. Chambliss is correct that PGGs are mixtures of mono-, di-, and triesters
`
`of glycerol with mono- and diesters of PEG, and that PGGs are sometimes referred
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`Declaration of P. Constantinides
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`to as “polyoxylglycerides.” (Ex. 1002 ¶ 40 (citing Ex. 1069 (HPE-7th) at 630-34).)2
`
`As HPE-7th points out, PGGs are also sometimes referred to as “macrogolglycerides”
`
`(in Europe). (Ex. 1069 at 630.)
`
`Regardless of the terminology used, PGGs are mixtures of two types of esters:
`
`fatty acid esters of glycerol (i.e., fatty acid glycerides) and fatty acid esters of PEG
`
`(“PEGEs”). PGGs, therefore, are fatty acid esters. Also, PGGs contain fatty acid
`
`glycerides. Due to the fact that PGGs are mixtures of different fatty acid esters,
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`PGGs play a multifunctional role in oral dosage forms as surfactants, gelling agents
`
`and enhancers of drug solubility, dissolution and bioavailability.
`
`2.
`
`Polyglycolyzed glycerides are surfactants
`
`11. Surfactants (surface-active agents) are substances that lower the surface
`
`tension between two liquids, a gas and a liquid, or a liquid and a solid. They can be
`
`classified by their HLB (hydrophile-lipophile balance) value as hydrophilic (HLB >
`
`10) or lipophilic (HLB < 10).
`
`12. Fatty acid esters, such as PGG, represent a major class of hydrophilic
`
`
`2 Although HPE-7th is dated years after the ’961 patent’s 2001 priority date, with
`
`respect to the cited information on PGGs, a POSA would have had such knowledge
`
`as of August 2001. In citing HPE-7th’s discussion of PGGs, Dr. Chambliss appears
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`to agree.
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`and lipophilic surfactants. Fatty acid glycerides, i.e., fatty acid esters of glycerol,
`
`are a subclass of fatty acid esters, having HLB values less than 10 and mostly
`
`between 1 and 5. Transesterification products of vegetable oils with PEG (PGGs)
`
`known under the trade name Labrafil® (Labrafil® M 2125 CS, M 1966 CS, M 1944
`
`CS, M 1980 CS, M 1969 CS, M 2130 BS, M 2130 CS, and M 2735 CS) are lipophilic
`
`surfactants with HLB values of 4 (Labrafil® WL 2609 BS has a HLB value of 6-7).
`
`(See Ex. 2032 at Table 6.) Labrafac® CM 6 and Labrafac® CM 8, which have HLB
`
`values of 6 and 8, respectively, are also lipophilic PGG surfactants. (Ex. 2033 at
`
`1:66-2:23.) On the other hand, transesterification products of vegetable oils with
`
`PEG known by the trade name Gelucire® (Gelucire® 44/14 and Gelucire® 50/13)
`
`are hydrophilic surfactants with HLB values of 14 and 13, respectively. Labrasol®
`
`(PEG-8 caprylic/capric glycerides or capryloylcaproyl macrogol-8-glycerides) is
`
`also a hydrophilic PGG, with a HLB value of 12, as is Labrafac® CM 10, Labrafac®
`
`CM 12 and Labrafac® CM 14, with HLB values of 10, 12 and 14, respectively. (Id.)
`
`However, of all these PGGs, only Gelucire® 44/14 and Gelucire® 50/13 are solid at
`
`ambient and physiological temperature, i.e. 37 °C, and used in immediate and
`
`sustained/controlled release dosage forms as drug solubilizers, surfactants and
`
`gelling agents The Labrafil®, Labrasol® and Labrafac® CM class of PGGs are
`
`liquid at ambient temperature and used for solubility and bioavailability
`
`enhancement in immediate release dosage forms, such as in self-emulsifying drug
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`Declaration of P. Constantinides
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`Case PGR2018-00048 for
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`delivery systems (SEDDS), which are discussed in Section III.B below.
`
`13.
`
`In a 1995 article, I provided a table of common excipients (and their
`
`HLB values) used to formulate self-emulsifying lipid formulations of poorly water-
`
`soluble (lipophilic) and water-soluble (hydrophilic) molecules, such as peptides, for
`
`oral drug delivery, such excipients include fatty acid esters. (Ex. 2017 at 1562
`
`(Table 1).) My table does not list solid Gelucires® that are PGGs because, in that
`
`article, I was focused on liquid-filled capsules for immediate drug release and
`
`absorption.
`
`14. The ’961 patent also identifies PGG as a surfactant “commonly used in
`
`the formulation of pharmaceuticals in accordance with the present invention….”
`
`(Ex. 1001 at 28:35-41.)
`
`3.
`
`The number of PGG grades, known as Gelucires®, is
`limited and their properties were well-known by POSAs
`
`15. Dr. Chambliss opines that, as of the provisional filing, “there were at
`
`least sixteen known grades of Gelucire® PGGs used in pharmaceutical compositions
`
`that had different physical-chemical properties.” (Ex. 1002 ¶ 122.) Dr. Chambliss
`
`is wrong. Dr. Chambliss reaches this number by counting the following “Gelucire®”
`
`compounds listed in three references: 62/05, 55/18, 54/02, 53/10, 50/13, 50/02,
`
`48/09, 46/07, 44/14, 43/01, 42/12, 39/01, 37/06, 37/02, 35/10, and 33/01. (Id. ¶ 122
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`(citing Exs. 1018-20); see also id. ¶¶ 40-45.) However, not all of these Gelucires®
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`are PGGs. In fact, I understand that Dr. Chambliss conceded during his deposition
`
`that not all of these compounds are PGGs. (Ex. 2029 at 10:18-12:8.)
`
`16. Dr. Chambliss fails to realize that not all Gelucires® are PGGs. In fact,
`
`based on his own cited references, only three of the Gelucires® he lists as PGGs are
`
`actually PGGs: Gelucires® 53/10, 50/13, and 44/14:
`
`
`
`Ex. 1020 identifies Gelucires® 44/14, 50/13, and 53/10 as “saturated
`
`polyglycolized glycerides” but identifies Gelucire® 33/01 as “semi-
`
`synthetic triglycerides of C8-C18 saturated fatty acids” and Gelucire®
`
`39/01 as “semi-synthetic glycerides.” (Ex. 1020 at 35:41-54.) Thus,
`
`Gelucires® 33/01 and 39/01 are not identified as PGGs.
`
`
`
`Likewise, Ex. 1062 identifes Gelucires® 44/14, 50/13, and 53/10 as
`
`“saturated polyglycolized glycerides” but identifies Gelucire® 33/01
`
`“semi-synthetic triglycerides of C8-C1 [sic] saturated fatty acids” and
`
`Gelucire® 39/01 “semi-synthetic glycerides.” (Ex. 1062 at 11:55-65,
`
`12:39-40.) Thus, again, Gelucires® 33/01 and 39/01 are not identified
`
`as PGGs.
`
`
`
`Ex. 1019 states that Gelucire® 55/18 “does not contain glyceride
`
`species.” (Ex. 1019 at 77.) Thus, Gelucire® 55/18 is not a PGG, rather,
`
`it is prepared by “direct esterification of fatty acids with PEG” (see id.).
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`17. Dr. Chambliss’s over-estimation of the number of PGGs is confirmed
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`Case PGR2018-00048 for
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`by the manufacturer of Gelucires®. Gattefossé’s 2004 “Oral Route Excipients”
`
`guide identifies 44/14 as “Lauroyl macrogol glycerides” and 50/13 as “Stearoyl
`
`macrogol glycerides.” (Ex. 2007 at 6.) These are both types of PGGs identified in
`
`HPE-7th. (Ex. 1069 at 630 (listing “[l]auroyl polyoxlglycerides” and “[s]tearoyl
`
`polyoxyglycerides,” and stating that “[p]olyoxylglycerides are referred to as
`
`macrogolglycerides
`
`in Europe”).)
`
` The Gattefossé guide also equates
`
`“Macrogolglycerides” with “Polyoxylglycerides.” (Ex. 2007 at 6-7). Although the
`
`guide lists other Gelucires®, it does not identify any other Gelucires® as
`
`macrogolglycerides. Instead, Gelucires® 33/01, 39/01, and 43/01 are all identified
`
`as “Glycerol esters of fatty acids.” (Id. at 8-9.) Thus, these Gelucires® are not
`
`PGGs.
`
`18. Similarly, a prior-art reference using PGGs in a pharmaceutical
`
`composition refers only to Gelucire® 44/13 and 50/13. (Ex. 2015 at 4:4-9.)
`
`19. Thus, of the sixteen purported Gelucire® PGGs identified by Dr.
`
`Chambliss, only three can be identified as PGGs that are solid at ambient and
`
`physiological temperature and used as hydrophilic surfactants and gelling agents
`
`based on the materials he cited along with the Gattefossé 2004 “Oral Route
`
`Excipients” guide. Many of the purported PGGs he identified are clearly not PGGs.
`
`Moreover, Gattefossé’s own 2004 guide identifies only two Gelucires® that are
`
`PGGs: Gelucires® 50/13 and 44/14. I note that the guide does not list Gelucire®
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`Declaration of P. Constantinides
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`53/10 at all.
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`Case PGR2018-00048 for
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`20. Dr. Chambliss points to supposed differences in “hydrophilic-lipophilic
`
`balance (HLB) (ranging from at least about 2 to 15), and melting point (ranging from
`
`at least about 18º C to 60º C).” (Ex. 1002 ¶ 41.) These wide ranges, however, arise
`
`because he counts as PGGs compounds that are not actually PGGs or are PGGs that
`
`are liquid at ambient temperature (Labrafil® CS series, BS and WL, Labrafac® CM
`
`series and Labrasol®) and used for solubility and bioavailability enhancement in
`
`immediate release dosage forms.
`
`21. The numbers following the names of Gelucire® compounds are the
`
`melting point (°C) and HLB, respectively, of the particular compound. The melting
`
`points for Gelucires® 44/14, 50/13, and 53/10 are 44, 50, and 53°C, respectively
`
`(i.e., the first number in the ratios in the Gelucire® names). Gattefossé’s literature
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`confirms the melting point of Gelucire® 44/14 is 44°C and that of Gelucire® 50/13
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`is 50°C. (Ex. 2007 at 6.) Thus, the actual range of melting points for the PGGs
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`identified by Dr. Chambliss is 44-53°C, not 18-60°C. This range is narrow, such
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`that the three Gelucires® do not “differ widely.” (See Ex. 1002 ¶ 40.) None of the
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`Gelucires® he identified (even the non-PGGs) has a melting point as low as 18°C,
`
`which is well below the useful melting-point range for their use as gelling agents in
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`controlled-release applications. Thus, it is clear Dr. Chambliss got his numbers by
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`incorrectly including PGGs that are not liquid at ambient temperature and are not
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`Purdue 2030
`Collegium v. Purdue, PGR2018-00048
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`Declaration of P. Constantinides
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`used as gelling agents in controlled release formulations.
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`Case PGR2018-00048 for
`U.S. Patent No. 9,693,961
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`22. The HLBs for Gelucires® 44/14, 50/13, and 53/10 are 14, 13, and 10,
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`respectively (i.e., the second number in the Gelucire® names). Thus, the actual
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`range of HLB for the PGGs identified by Dr. Chambliss is 10-14, not 2-15. Dr.
`
`Chambliss’s Ex. 1018 describes these HLBs as “close together.” (Ex. 1018 at 539.)
`
`I agree.
`
`B.
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`Solubilizing a Poorly Water-Soluble API
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`23. By 2001, the use of solubilization technologies to solubilize poorly
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`water-soluble APIs in oral drug products was on a steady rise. (Ex. 2018 at 24
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`(Figure 1, showing the number of approved products using various solubilization
`
`technologies since the 1980s; Table 1, showing the percent of new molecular entities
`
`(NMEs) using solubilization technologies by decade).) An increasing number of
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`APIs in marketed oral drug products, including immediate- and controlled-release
`
`products, had (and still have) poor water solubility. Thus, there has been a need to
`
`consider and apply strategies to solubilize these poorly water-soluble drugs in an
`
`effort to improve their dissolution from the dosage form and maximize intestinal
`
`absorption and oral bioavailability. As of 2001, the most prominent technologies
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`for solubilizing such APIs were lipid-based systems and solid dispersions,
`
`particularly molecular dispersions. (Id. (Table 1).) The physicochemical properties
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`of the API, particularly its lipophilicity (logP value) and melting point, are relevant
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`Purdue 2030
`Collegium v. Purdue, PGR2018-00048
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`

`

`Declaration of P. Constantinides
`
`
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`Case PGR2018-00048 for
`U.S. Patent No. 9,693,961
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`in properly selecting the solubilization technology or technologies best suited for the
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`particular API.
`
`24. Oral, lipid-based systems for immediate release and absorption contain
`
`oily liquid or semi-solid solutions of API known as self-emulsifying drug-delivery
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`systems (SEDDS). Thus, liquid or semi-solid lipid excipients are used, such as the
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`liquid excipients listed in Table 1 of my 1995 article on Lipid Microemulsions for
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`Oral Drug Delivery. (Ex. 2017 at 1562.) Oral, solid, lipid formulations include self-
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`emulsifying sustained-release capsules and tablets, incorporating granules, pellets,
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`solid dispersions, and micro- and nanoparticles.
`
`25.
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`In a solid dispersion, the API is dispersed as crystalline or amorphous
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`particles in a solid excipient matrix (polymer or lipid). Solid solutions are a subclass
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`of solid dispersions where the API is dispersed at the molecular level in the matrix.
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`As of 2001 (and still today), solid dispersions were (are) manufactured primarily by
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`spray drying or hot-melt extrusion. Spray drying using organic solvents results in
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`powders that can be filled into capsules or compressed into tablets. Hot-melt
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`extrusion, which I discuss in more detail in the following section, results in material
`
`that can be shaped in various ways, including into multiparticulates that can be
`
`placed within a capsule. As of 2001, hot-melt extrusion was already commonly used
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`to form solid solutions (molecular dispersions). (See Ex. 2016 at 107 (“[melt]
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`extrusion represents an efficient manufacturing technology required to disperse
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`- 11 -
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`Purdue 2030
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Declaration of P. Constantinides
`
`
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`Case PGR2018-00048 for
`U.S. Patent No. 9,693,961
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`drugs in a melt up to a true molecular solution of the active agent in the matrix”),
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`113 (“Melt extrusion … makes the solid molecular dispersion approach a viable
`
`option.”) (emphasis added in both).)3
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`C. Melt Granulation and Melt Extrusion
`
`26.
`
`I mentioned melt extrusion in the previous section in the context of
`
`solid dispersions and solid, oral, lipid-based formulations. I explain melt extrusion
`
`and a related process, melt granulation, in more detail in this section. Before I get
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`to melt granulation, though, I begin with more traditional granulation processes, wet
`
`and dry granulation, keeping in mind that the selection of the process to use requires
`
`a thorough understanding of several parameters, including the physicochemical
`
`properties of the drug and excipients, and the required flow and drug release
`
`properties.
`
`1.
`
`Dry and Wet Granulation
`
`27. Dry granulation uses mechanical compression
`
`(slugging) or
`
`compaction (roller compaction) to facilitate the agglomeration of dry powder
`
`
`3 Although this “Review article” was submitted to the journal in February 2002 and
`
`in revised form in April 2002, its discussion of solid dispersions and solid solutions
`
`provides knowledge of a POSA as of August 2001 as well. This article is not
`
`reporting new research, but is summarizing the state of the art.
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`- 12 -
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`Purdue 2030
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Declaration of P. Constantinides
`
`
`
`Case PGR2018-00048 for
`U.S. Patent No. 9,693,961
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`particles containing the API and excipients, while wet granulation uses granulation
`
`liquid (binder/solvent) to facilitate agglomeration by forming a wet mass through
`
`adhesion. Wet granulation was (and still is) a widely used granulation method
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`despite the fact that it involves multiple unit operations, such as wet massing, drying,
`
`and screening, which are complex, timely and resource consuming.
`
`2. Melt granulation
`
`28. Melt Granulation is an alternative to traditional wet- and dry-
`
`granulation methods and is defined as a process by which agglomeration of solid
`
`particles to form granules can be achieved by the addition of a binder that melts
`
`during the process. Advantages of the melt-granulation process include: (a) fewer
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`processing steps since the wetting and drying steps are eliminated; (b) no solvents
`
`or water are used, which is advantageous for water-sensitive drugs; (c) it produces
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`uniformly dispersed particles that exhibit good stability at various pHs and moisture
`
`levels; and (d) it can be readily applied to oral, sustained-release dosage forms.
`
`Depending on the particular application, both hydrophilic and hydrophobic meltable
`
`binders can be employed in melt granulation. Hydrophilic binders include:
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`Gelucires® 44/14 and 50/13,4 poloxamer 188, PEGs (MW approximately 1,000-
`
`
`4 As explained, these Gelucire® PGGs contain fatty acid esters of PEG (which are
`
`hydrophilic and the main contributor to the overall hydrophilic nature of the
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`Purdue 2030
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Declaration of P. Constantinides
`
`
`
`Case PGR2018-00048 for
`U.S. Patent No. 9,693,961
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`20,000 daltons). Hydrophobic binders include: beeswax and carnauba wax, paraffin
`
`wax, stearic acid, stearyl alcohol, glyceryl monostearate, glyceryl palmitostearate,
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`glyceryl behenate, hydrogenated castor oil, cetyl palmitate, and cetyl alcohol.
`
`3. Melt extrusion
`
`29. Melt extrusion is a process by which materials are mixed intimately
`
`under controlled conditions of temperature, shear, and pressure to generate a wide
`
`variety of in-process and finished products using processing equipment known as an
`
`extruder. Extrusion involves conversion of raw materials into a product of uniform
`
`shape and density by forcing these materials through a die under controlled
`
`conditions. In pharmaceutical melt extrusion, the drug is embedded in a carrier
`
`formulation consisting of one or more meltable excipients and optionally other
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`functional excipients. The meltable excipients can be polymers or waxes, examples
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`of which are provided in the above discussion of melt granulation and also in the
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`’961 patent. (Ex. 1001 at 15:38-16:31; Ex. 1005 at 21-23; Ex. 1006 ¶¶ 96-100.)
`
`Melt extrusion through continuous formulation processes can be used in the
`
`production of granules, pellets, and tablets. One particular application of melt
`
`
`Gelucires®) and fatty acid esters of glycerol (which are hydrophobic/lipophilic).
`
`The overall hydrophilic nature of these Gelucires® is shown by their HLB values
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`being over 10.
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`- 14 -
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`Purdue 2030
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Declaration of P. Constantinides
`
`
`
`Case PGR2018-00048 for
`U.S. Patent No. 9,693,961
`
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`extrusion that would be of interest to a POSA as of the priority dates was the
`
`production of solid dispersions (in particular, solid solutions (molecular
`
`dispersions)) for improving drug solubility and oral bioavailability and for oral,
`
`controlled-release applications. (See generally Ex. 2016.) The advantages of melt
`
`extrusion compared to traditional wet and dry granulation are similar to those listed
`
`above for melt granulation.
`
`D. Response to Dr. Chambliss’s Section, “Abuse of Opiate Drug
`Products and Abuse Deterrent Dosage Forms”
`
`30.
`
`I agree with Dr. Chambliss that, as of the 2001 priority date of the ’961
`
`patent, abuse of opioids was a concern, and there was a need for abuse-deterrent
`
`formulations. (See Ex. 1002 ¶¶ 27-28.) I further agree that there was a specific
`
`concern about the abuse of original (non-abuse-deterrent) OxyContin. (See id. ¶ 28.)
`
`31. Dr. Chambliss appears to characterize the ’961 specification as
`
`disclosing only methods of abuse deterrence known as of August 2001. (Id. ¶ 29.)
`
`Dr. Chambliss presents no evidence in support of such an opinion. I un