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`
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`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
`_____________________
`
`
`DECLARATION OF PANAYIOTIS P. CONSTANTINIDES, PH.D.
`
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`NAI-1503922984
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`1 of 101
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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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`TABLE OF CONTENTS
`
`Exhibit List ............................................................................................................... iii
`
`I.
`
`Introduction ...................................................................................................... 1
`
`A.
`
`Background, Experience, and Qualifications ........................................ 2
`
`B. Materials Considered ............................................................................. 6
`
`II.
`
`Summary of Opinions ...................................................................................... 7
`
`III. Technical Background ..................................................................................... 8
`
`A.
`
`B.
`
`Surfactants, Fatty Acid Esters, and PGGs ............................................. 8
`
`Solubilizing a Poorly Water-Soluble API ...........................................13
`
`C. Melt Granulation and Melt Extrusion .................................................15
`
`D.
`
`Response to Dr. Chambliss’s Section, “Abuse of Opiate Drug
`Products and Abuse Deterrent Dosage Forms” ...................................18
`
`IV. The ’961 Patent ..............................................................................................19
`
`A. Disclosure of the ’961 Patent and Priority Applications.....................19
`
`B.
`
`Claims ..................................................................................................23
`
`V.
`
`Legal Understandings ....................................................................................27
`
`A.
`
`Claim Construction..............................................................................27
`
`B. Written Description .............................................................................28
`
`C.
`
`Enablement ..........................................................................................28
`
`VI. Person of Ordinary Skill in the Art ................................................................29
`
`VII. Claim Construction ........................................................................................30
`
`A.
`
`B.
`
`C.
`
`“abuse deterrent dosage form” ............................................................30
`
`Preamble ..............................................................................................33
`
`“homogenous mixture” .......................................................................34
`
`VIII. The ’961 Patent Is Entitled to Its Priority Dates............................................37
`
`A.
`
`The Priority Applications Adequately Describe the ’961 Claims ......37
`
`1.
`
`The Inventors Were in Possession of the Claimed Abuse-
`Deterrent Dosage Forms ...........................................................37
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`2.
`
`The Inventors Were in Possession of the Claimed
`Combination of Ingredients and Method for Manufacturing a
`Capsule Dosage Form Containing the Same ............................40
`
`B.
`
`The Priority Applications Enable the ’961 Claims .............................50
`
`1.
`
`2.
`
`3.
`
`The Specification Teaches a POSA How to Use the Claim
`Method of Preparing .................................................................50
`
`The Specification and Knowledge of a POSA Direct the
`POSA to a Reasonable Number of Embodiments ....................52
`
`The Specification Enables a POSA to Make and Use the Full
`Scope of the Invention Without Undue Experimentation.........66
`
`C.
`
`Summary of Written Description and Enabling Disclosure ...............77
`
`IX. Conclusion .....................................................................................................96
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`
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`EXHIBIT LIST1
`
`(Exhibits to Purdue’s Preliminary Response)
`
`Exhibit No. Description
`
`2001.
`
`2002.
`
`2003.
`
`Declaration of Panayiotis P. Constantinides, Ph.D.
`
`Curriculum Vitae of Panayiotis P. Constantinides (June 2018)
`
`Isaacs et al., ed., A Dictionary of Science, Oxford Univ. Press (4th ed.
`1999).
`
`2004.
`
`’722 application, 4/8/2016 office action
`
`2005.
`
`’722 application, 11/2/2016 office action
`
`2006.
`
`2007.
`
`’722 application, 5/17/2017 notice of allowability
`
`Gattefossé, Oral Route Excipients (2004)
`
`2008.
`
`FDA’s 1996 Inactive Ingredient Guide
`
`2009.
`
`’275 application, 8/2/2017 amendment
`
`2010.
`
`Material safety data sheet for myristic acid (July 6, 2010) (COLL1080872-
`74)
`
`2011.
`
`Material safety data sheet for myristic acid (December 11, 1990)
`
`2012.
`
`Material safety data sheet for stearic acid
`
`2013.
`
`Statement Regarding Suspension of 160 mg OxyContin® Tablets (May
`11, 2001)
`
`
`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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`2014.
`
`2015.
`
`2016.
`
`2017.
`
`2018.
`
`Knothe et al., A Comprehensive Evaluation of the Melting Points of Fatty
`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)
`
`Improving Drug
`for
`Constantinides, P.P. Lipid Microemulsions
`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)
`
`2019.
`
`U.S. Patent No. 9,592,200
`
`2020.
`
`U.S. Patent No. 7,771,707
`
`2021.
`
`2022.
`
`2023.
`
`2024.
`
`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)
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`I, Panayiotis P. Constantinides, hereby declare:
`
`I.
`
`INTRODUCTION
`
`1.
`
`2.
`
`I am a U.S. citizen and a resident of Illinois.
`
`I am the Founder and Principal/President of Biopharmaceutical &
`
`Drug Delivery Consulting, LLC, in Gurnee, Illinois.
`
`3.
`
`I have been retained in this proceeding by Jones Day, counsel for
`
`patent owner Purdue, to consider petitioner Collegium’s Amended Petition for
`
`Post-Grant Review of U.S. Patent No. 9,693,961, including the Amended
`
`Declaration of Walter G. Chambliss, Ph.D. I make this declaration in support of
`
`Purdue’s Preliminary Response to Collegium’s Amended Petition and in response
`
`to Dr. Chambliss’s declaration.
`
`4.
`
`The 1000-series exhibit cites in this declaration are to the exhibits to
`
`Collegium’s petition. The 2000-series exhibits cites are to the exhibits to Purdue’s
`
`Preliminary Response. I also make use of the abbreviations listed in the Table of
`
`Abbreviations in the Preliminary Response.
`
`5.
`
`I am being compensated $500 per hour (other than time spent
`
`testifying) and $600 per hour (for time spent testifying) for my work on this
`
`proceeding. My compensation does not depend in any way on the substance of my
`
`testimony or on the outcome of this or any other proceeding.
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`A. Background, Experience, and Qualifications
`
`6.
`
`I received a University Diploma in Chemistry from the National and
`
`Kapodistrian University of Greece in Athens Greece in 1977. From there, I
`
`attended Brown University, where I received a Ph.D. in Biochemistry (physical) in
`
`1983. After that, I attended Yale University, where I completed a Postdoctoral
`
`Fellowship in Pharmacology and Cancer Research in 1985 and then continued as
`
`an Associate Research Scientist for two years. I have held adjunct faculty
`
`positions with Roosevelt University, School of Pharmacy, Department of
`
`Biopharmaceutical Sciences in Schaumburg, Illinois; the University of Washington
`
`Department of Pharmaceutics in Seattle, Washington; and the University of
`
`Tennessee, Department of Biochemistry in Knoxville, Tennessee.
`
`7.
`
`In 1987, I entered the biotech and pharmaceutical industry and
`
`progressed through a number of research and development positions of increasing
`
`responsibility with small biotech and large pharmaceutical companies, including
`
`SmithKline Pharmaceuticals (now GlaxoSmithKline) and Abbott, Pharmaceutical
`
`Products Division. In 2004, I founded Biopharmaceutical & Drug Delivery
`
`Consulting, LLC, in Gurnee, Illinois, serving as its Principal/President and
`
`providing consulting services to the biotech and pharmaceutical industry.
`
`8.
`
`Since 2005, my research and drug-development experience has
`
`included development of new molecular entities, small molecules, and peptide
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`therapeutics for oral (liquid, semi-solid, and solid), parenteral, and topical
`
`formulations, as well as for reformulations of already approved/marketed drugs.
`
`Within the area of my involvement and expertise is also salt screening and
`
`selection using both inorganic and organic acid salts, as well as drug complexation
`
`and ion-pair formation, particularly lipophilic complexes and ion pairs of a drug
`
`with fatty acids and other lipid excipients. As for solid oral dosage forms, my
`
`experience includes micro- and nanoparticulate drug products. I have worked with
`
`immediate- and controlled-release dosage forms. My expertise extends to
`
`functional excipient development and qualification, including novel excipients for
`
`pharmaceutical development and new and non-traditional uses of existing
`
`pharmaceutical excipients. Furthermore, I am experienced with processing and
`
`manufacturing drug formulations, including in vitro drug dissolution and release
`
`and correlation to in vivo performance.
`
`9. More
`
`specifically,
`
`I
`
`have
`
`broad
`
`experience
`
`in
`
`oral,
`
`sustained/controlled-release
`
`technologies
`
`and
`
`dosage
`
`forms
`
`employing
`
`multiparticulate systems and manufactured with various processes, including melt
`
`granulation and melt extrusion.
`
` My experience with microparticles
`
`(multiparticulates) includes pellets and granules that can be directly filled into
`
`capsules or compressed into tablets, such as pellets or granules coated with an
`
`inner hydrophobic layer and an outside hydrophilic layer. For example, I have
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`worked with dual matrix capsule/tablet formulations of various proprietary
`
`molecules incorporating an outside fast-release hydrophilic layer followed by a
`
`slower-release inner hydrophobic core.
`
`10.
`
`I have extensive expertise with surfactants, and their applications in
`
`liquid, semi-solid, and solid oral dosage forms, as solubilizers, dissolution and
`
`bioavailability enhancers, and gelling agents, including within hydrophobic
`
`matrices
`
`in controlled-release dosage forms.
`
` With respect
`
`to viscosity
`
`modifying/thickening and gelling agents, I have worked with lipid-based agents
`
`(e.g., fatty acids, fatty acid esters, fatty acid glycerides, polyglycolyzed glycerides
`
`(PGGs), polyglycerol fatty acid esters, cetyl and stearyl alcohols, beeswax,
`
`carnauba wax, and other waxes), high-molecular-weight PEGs
`
`(MW
`
`approximately
`
`1,000-20,000
`
`daltons),
`
`hydrocolloids
`
`(pectin,
`
`alginates,
`
`carrageenan, xanthan gum, and other polysaccharides), starches, cellulosic
`
`polymers, and silicates. Fabrication of such matrix systems to achieve targeted in
`
`vitro drug release (dissolution) and in vivo pharmacokinetic profiles is within my
`
`working knowledge.
`
`11.
`
`I also have been involved with surfactant toxicity, including irritation
`
`and strategies to overcome it.
`
`12. As set forth in more detail in my curriculum vitae (Ex. 2002), I have
`
`more than thirty years of experience in the development of pharmaceutical
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`products, including oral drug products, with an in-depth understanding of drug
`
`formulation and drug delivery. As both a full-time employee with various
`
`biotech/pharma companies and as a consultant, I have contributed to several drug
`
`products on the market and in advanced clinical development. I have authored/co-
`
`authored over 50 original research papers, review articles, book chapters,
`
`commentaries, and interview publications and have spoken at more than 100
`
`invited talks worldwide in the areas of drug delivery and formulation development
`
`of small molecules and peptide therapeutics, traditional and non-traditional uses of
`
`pharmaceutical excipients, pharmaceutical nanotechnology, R&D strategies, and
`
`collaboration models. I have also been an editorial board member and referee for
`
`peer-reviewed journals, and am currently serving as Associate Editor of the
`
`recently launched American Association of Pharmaceutical Scientists (“AAPS”)
`
`Open journal (published by Springer), which provides a global forum for the rapid
`
`and barrier-free publication of reports of original research and other significant
`
`scientific work in the pharmaceutical sciences.
`
`13.
`
`I am an inventor/co-inventor on 12 U.S. patents, 4 European patents,
`
`17 international applications published under the Patent Cooperation Treaty, and
`
`several additional patent applications.
`
`14.
`
`I have received numerous awards and honors, including the Browne-
`
`Coxe Postdoctoral Fellowship at Yale University School of Medicine, employment
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`awards, and AAPS leadership awards and recognitions. I was elected AAPS
`
`Fellow in 2010, and I have held various leadership roles within AAPS, including
`
`Chair of the Formulation Design and Development section and Chair of the Lipid-
`
`Based Drug Delivery Systems and Nanotechnology Focus Groups.
`
`15.
`
`I have testified as an expert in the following two matters: Alnylam v
`
`Tekmira, No. 50 122T 0072613 (ICDR New York) (on behalf of Alnylam) and
`
`Sanofi-Aventis Canada v Hospira, No T-2080-07 (Federal Court of Canada,
`
`Ottawa, Canada) (on behalf of Sanofi-Aventis).
`
`B. Materials Considered
`
`16.
`
`I have considered Collegium’s petition and the non-confidential
`
`exhibits accompanying that petition, including the ’961 patent and Dr. Chambliss’s
`
`declaration. I have also considered all materials cited in this declaration. Finally, I
`
`further considered the prosecution history of the ’961 patent.
`
`17. 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
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`connection with his anticipation opinions for a reference (the ’943 publication) that
`
`is not prior 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
`
`18.
`
`I understand that the ’961 patent is the subject of the present 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.
`
`19.
`
`I have been asked to provide my opinions on technology relating to
`
`the ’961 patent and the state of the 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 adequately describe and enable the ’961 claims.
`
`Finally, I have been asked to respond to the opinions in Dr. Chambliss’s
`
`declaration.
`
`20.
`
`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
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`reduced potential for abuse”;
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`Case PGR2018-00048 for
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`
`
`the preamble language “an abuse deterrent controlled release dosage
`
`form” of the independent claims is limiting and means “a controlled-
`
`release dosage form having a reduced potential for abuse”; and
`
`
`
`“homogenous mixture” does not include a “two-phase mixture.”
`
`However, my remaining opinions are unchanged even if Collegium’s/Dr.
`
`Chambliss’s constructions are adopted.
`
`21.
`
`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.
`
`22.
`
`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.
`
`III. TECHNICAL BACKGROUND
`
`23.
`
`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
`
`24. Dr. Chambliss opines that, as of the provisional filing, “there were at
`
`least sixteen known grades of PGGs used in pharmaceutical compositions that had
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`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 (citing Exs. 1018-20); see also id. ¶¶ 40-45.) However, not all of these
`
`Gelucires® are PGGs.
`
`25. 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). Fatty acid esters represent a
`
`major class of hydrophilic 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. Fatty acid esters of PEG are a subclass
`
`of fatty acid esters and are hydrophilic, having HLB values greater than 10. 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 including 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.
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`26. 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 to as “polyoxylglycerides.” (Id. ¶ 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. PGGs, therefore,
`
`are fatty acid esters. Also, PGGs contain fatty acid glycerides.
`
`27. 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:
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`
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`Ex. 1020 calls Gelucires® 44/14, 50/13, and 53/10 “saturated
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`polyglycolized glycerides” but calls Gelucire® 33/01 “semi-synthetic
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`triglycerides of C8-C18 saturated fatty acids” and Gelucire® 39/01
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`“semi-synthetic glycerides.”
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` (Ex. 1020 at 35:41-54.)
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` Thus,
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`2 Although HPE-7th is dated years after the ’961 patent’s 2001 priority date, with
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`respect to the cited information on PGGs, a POSA would have had such
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`knowledge as of August 2001. In citing HPE-7th’s discussion of PGGs, Dr.
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`Chambliss appears to agree.
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`Gelucires® 33/01 and 39/01 are not PGGs.
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`
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`Ex. 1062 is the same, with a typo. It calls Gelucires® 44/14, 50/13,
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`and 53/10 as “saturated polyglycolized glycerides” but calls Gelucire®
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`33/01 “semi-synthetic triglycerides of C8-C1 [sic] saturated fatty acids”
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`and Gelucire® 39/01 “semi-synthetic glycerides.” (Ex. 1062 at 11:55-
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`65, 12:39-40.) Thus, again, Gelucires® 33/01 and 39/01 are not PGGs.
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`
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`Ex. 1019 states that Gelucire® 55/18 “does not contain glyceride
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`species.” (Ex. 1019 at 77.) Thus, Gelucire® 55/18 is not a PGG,
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`rather, it is prepared by “direct esterification of fatty acids with PEG”
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`(see id.).
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`28. Dr. Chambliss’s over-counting of PGGs is confirmed by the
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`manufacturer of Gelucires®. Gattefossé’s 2004 “Oral Route Excipients” guide
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`identifies 44/14 as “Lauroyl macrogol glycerides” and 50/13 as “Stearoyl macrogol
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`glycerides.” (Ex. 2007 at 6.) These are both types of PGGs identified in HPE-7th.
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`(Ex. 1069 at 630
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`(listing “[l]auroyl polyoxlglycerides” and “[s]tearoyl
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`polyoxyglycerides,” and stating that “[p]olyoxylglycerides are referred to as
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`macrogolglycerides
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`in Europe”).)
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` The Gattefossé guide also equates
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`“Macrogolglycerides” with “Polyoxylglycerides.” (Ex. 2007 at 6-7). Although it
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`lists other Gelucires®, the guide does not identify any other Gelucires as
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`macrogolglycerides. Instead, Gelucires® 33/01, 39/01, and 43/01 are all identified
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`as “Glycerol esters of fatty acids.” (Id. at 8-9.) Thus, these Gelucires® are not
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`PGGs.
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`29. Of the sixteen purported PGGs identified by Dr. Chambliss, only three
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`can be identified as PGGs based on the materials he cited along with the Gattefossé
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`2004 “Oral Route Excipients” guide. Many of the purported PGGs he identified
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`are clearly not PGGs. Moreover, Gattefossé’s own 2004 guide identifies only two
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`Gelucires® that are PGGs: Gelucires® 50/13 and 44/14. I note that the guide does
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`not list Gelucire® 53/10 at all. Similarly, a prior-art reference using PGGs in a
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`pharmaceutical composition refers only to Gelucire® 44/13 and 50/13. (Ex. 2015
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`at 4:4-9.)
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`30. Dr. Chambliss points to supposed differences in “hydrophilic-
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`lipophilic balance (HLB) (ranging from at least about 2 to 15), and melting point
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`(ranging from at least about 18º C to 60º C).” (Ex. 1002 ¶ 41.) These wide ranges,
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`however, arise because he counts as PGGs compounds that are not actually PGGs.
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`31. The numbers following the names of Gelucire® compounds are the
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`melting point (°C) and HLB, respectively, of the particular compound. The
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`melting points for Gelucires® 44/14, 50/13, and 53/10 are 44, 50, and 53°C,
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`respectively (i.e., the first number in the ratios in the Gelucire® names).
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`Gattefossé’s literature confirms the melting point of Gelucire® 44/14 is 44°C and
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`that of Gelucire® 50/13 is 50°C. (Ex. 2007 at 6.) Thus, the actual range of melting
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`points for the PGGs identified by Dr. Chambliss is 44-53°C, not 18-60°C. This
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`ranger is narrow, such that the three Gelucires® do not “differ widely.” (See
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`Ex. 1002 ¶ 40.) It is unclear where Dr. Chambliss got his numbers, as none of the
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`Gelucires® he identified (even the non-PGGs) has a melting point as low as 18°C,
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`which is well below the useful melting-point range for their use as gelling agents in
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`controlled-release applications.
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`32. 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 ratios in the Gelucire® names). Thus,
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`the actual range of HLB for the PGGs identified by Dr. Chambliss is 10-13, not 2-
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`15. Dr. Chambliss’s Ex. 1018 describes these HLBs as “close together.”
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`(Ex. 1018 at 539.) I agree.
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`B.
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`Solubilizing a Poorly Water-Soluble API
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`33. 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
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`technologies since the 1980s; Table 1, showing the percent of new molecular
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`entities (NMEs) using solubilization technologies by decade).) An increasing
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`number of APIs in marketed oral drug products, including immediate- and
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`controlled-release products, had (and still have) poor water solubility. Thus, there
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`has been a need to consider and apply strategies to solubilize these poorly water-
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`soluble drugs in an effort to improve their dissolution from the dosage form and
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`maximize intestinal absorption and oral bioavailability. As of 2001, the most
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`prominent technologies for solubilizing such APIs were lipid-based systems and
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`solid dispersions, particularly molecular dispersions. (Id. (Table 1).) The
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`physicochemical properties of the API, particularly its lipophilicity (logP value)
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`and melting point, are relevant in properly selecting the solubilization technology
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`or technologies best suited for the particular API.
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`34. Oral, lipid-based systems for immediate release and absorption
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`contain oily liquid or semi-solid solutions of API known as self-emulsifying drug-
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`delivery systems (SEDDS). Thus, liquid or semi-solid lipid excipients are used,
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`such as the liquid excipients listed in Table 1 of my 1995 article on Lipid
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`Microemulsions for Oral Drug Delivery. (Ex. 2017 at 1562.) Oral, solid, lipid
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`formulations include self-emulsifying sustained-release capsules and tablets,
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`incorporating granules, pellets, solid dispersions, and micro- and nanoparticles.
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`35.
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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
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`subclass of solid dispersions where the API is dispersed at the molecular level in
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`the matrix. As of 2001 (and still today), solid dispersions were (are) manufactured
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`primarily by spray drying or hot-melt extrusion. Spray drying using organic
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`solvents results in powders that can be filled into capsules or compressed into
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`tablets. Hot-melt extrusion, which I discuss in more detail in the following section,
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`results in material that can be shaped in various ways, including
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`into
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`multiparticulates that can be placed within a capsule. As of 2001, hot-melt
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`extrusion was already commonly used to form solid solutions (molecular
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`dispersions). (See Ex. 2016 at 107 (“[melt] extrusion represents an efficient
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`manufacturing technology required to disperse drugs in a melt up to a true
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`molecular solution of the active agent in the matrix”), 113 (“Melt extrusion …
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`makes the solid molecular dispersion approach a viable option.”) (emphasis added
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`in both).)3
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`C. Melt Granulation and Melt Extrusion
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`36.
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`I mentioned melt extrusion in the previous section in the context of
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`solid dispersions and solid, oral, lipid-based formulations. I explain melt extrusion
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`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,
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`wet and dry granulation, keeping in mind that the selection of the process to use
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`3 Although this “Review article” was submitted to the journal in February 2002 and
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`in revised form in April 2002, its discussion of solid dispersions and solid solutions
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`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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`requires a
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`thorough understanding of several parameters,
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`including
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`the
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`physicochemical properties of the drug and excipients, and the required flow and
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`drug release properties.
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`37. Dry and Wet Granulation. Dry granulation uses mechanical
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`compression (slugging) or compaction (roller compaction) to facilitate the
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`agglomeration of dry powder particles containing the API and excipients, while
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`wet granulation uses granulation liquid (binder/solvent) to facilitate agglomeration
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`by forming a wet mass through adhesion. Wet granulation was (and still is) a
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`widely used granulation method despite the fact that