`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`CATALENT PHARMA SOLUTIONS, INC.
`Petitioner
`
`v.
`
`PATHEON SOFTGELS INC.
`Patent Owner
`
`_____________________
`
`Case IPR2018-00422
`Patent 9,693,979
`_____________________
`
`DECLARATION OF MANSOOR KHAN, R.PH., PH.D.
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`PSG2001
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`I.
`II. MY BACKGROUND AND QUALIFICATIONS ......................................... 2
`III. DOCUMENTS I CONSIDERED IN FORMULATING MY OPINIONS ..... 6
`IV. PERSON OF ORDINARY SKILL IN THE ART ........................................10
`V.
`CLAIM CONSTRUCTION ..........................................................................11
`VI. STATE OF THE ART BEFORE MARCH 8, 2005 ......................................17
`A.
`The art contradicts Mr. Draper’s implication that disclosures of
`“naproxen” are synonymous with “naproxen sodium”—on the
`contrary, naproxen and naproxen sodium are two different drugs. ....17
`B. Artisans knew that dissolving naproxen sodium in polyethylene glycol
`resulted in formation of naproxen-polyethylene glycol esters,
`producing unacceptable impurities and reduced naproxen
`bioavailability. .....................................................................................19
`C. Mr. Draper’s analyses depend on selecting a particular capsule size
`from a myriad of options. ....................................................................23
`D. Mr. Draper’s analyses depend on selecting a particular naproxen
`sodium dosage amount from a myriad of options. ..............................25
`The art contradicts Mr. Draper’s assertion that lactic acid and citric
`acid are “functional equivalents.” .......................................................26
`VII. MR. DRAPER’S DECLARATION IGNORES THE STATE OF THE ART
`AND MISCHARACTERIZES DISCLOSURES IN THE ASSERTED
`REFERENCES. .............................................................................................31
`A. Mr. Draper mischaracterizes the disclosures in Chen. ........................31
`1. Mr. Draper’s assessment of Chen is based on unfounded
`assumptions. ..............................................................................32
`2. Chen discloses using lactic acid in a different context from the
`’979 patent and does not suggest a composition in which lactic
`acid is used as claimed. .............................................................35
`B. Mr. Draper mischaracterizes the disclosures in Kim. .........................38
`1. Kim does not disclose compositions comprising lactic acid. ....38
`2. Mr. Draper relies on Kim’s dexibuprofen formulations to
`calculate naproxen sodium dosage amounts. ............................39
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
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`C. Mr. Draper mischaracterizes the disclosures in Schoenhard. .............40
`1.
`Schoenhard does not disclose lactic acid as a deionizing agent.
` ...................................................................................................41
`2. Mr. Draper’s assessment of Schoenhard is based on unfounded
`and erroneous assumptions. ......................................................42
`VIII. MR. DRAPER MISCHARACTERIZES THE ’979 PATENT INVENTORS’
`UNEXPECTEDLY SUPERIOR RESULTS. ................................................45
`IX. CONCLUSION ..............................................................................................47
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`I, Mansoor Khan, hereby declare as follows.
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of PATHEON
`
`SOFTGELS INC. (“Patheon”) for the above-captioned inter partes review (IPR). I am
`
`being compensated for my time in connection with this IPR at my standard
`
`consulting rate, which is $640 per hour. I understand that the petition for inter
`
`partes review involves U.S. Patent No. 9,693,979 (“the ’979 Patent”), EX1003. I
`
`understand that the petition was filed by CATALENT PHARMA SOLUTIONS, INC.
`
`(“Catalent”).
`
`3.
`
`I understand that the ’979 patent resulted from U.S. Application No.
`
`15/159,972 (“the ’972 application”), filed on May 20, 2016, naming Nachiappan
`
`Chidambaram and Aqeel Fatmi as inventors. I understand that the ’972 application
`
`is a continuation application that relates to a series of previous applications. I also
`
`understand that the earliest possible priority date for the ’979 Patent is March 8,
`
`2005, the filing date of U.S. Provisional Patent Application No. 60/659,679, and I
`
`refer to this date throughout this declaration. The ’979 patent was issued on July 4,
`
`2017, from the ’972 application. I further understand that, according to the USPTO
`
`records, the ’979 patent is currently assigned to Patheon.
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`4.
`
`In preparing this Declaration, I have reviewed the ’979 patent and
`
`each of the documents cited herein in light of the general knowledge in the art
`
`before March 8, 2005. In formulating my opinions, I have relied upon my
`
`experience, education, and knowledge in the relevant art. In formulating my
`
`opinions, I have also considered the viewpoint of a person of ordinary skill in the
`
`art (“POSA”)—i.e., a person of ordinary skill in the field of oral formulations
`
`including soft gelatin capsules—prior to March 8, 2005.
`
`II. MY BACKGROUND AND QUALIFICATIONS
`I am currently Professor and Vice Dean of the College of Pharmacy at
`5.
`
`Texas A&M University (College Station, TX). I am also interim Department Head
`
`of Pharmaceutical Sciences and the Director of the Formulations Design and
`
`Development Core Laboratory at Texas A&M. My qualifications and credentials
`
`are more fully set forth in my curriculum vitae, provided as PSG1002.
`
`6.
`
`I am an expert in the field of pharmaceutical formulations—including
`
`soft gelatin capsules—and have been since before March 8, 2005. I have been
`
`actively working in the field of pharmaceutical formulations since the 1980s, and
`
`have gained significant experience in the field while studying and carrying out the
`
`design of numerous types of formulations. My expertise includes thorough
`
`knowledge and understanding of soft gelatin capsule formulations.
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`7.
`
`I obtained a Ph.D. in Industrial Pharmacy from St. John’s University
`
`(Queens, NY) in 1992. Before earning a Ph.D., I earned two Masters degrees: one
`
`M.S. degree in Pharmaceutical Technology from Andhra University (India) in
`
`1984 and a second M.S. degree in Pharmaceutics from Idaho State University
`
`(Pocatello, Idaho) in 1988. I earned a B.S. degree in Pharmacy from Kakatiya
`
`University (India) in 1982. I also have an active license as a pharmacist.
`
`8. My work history includes industrial, U.S. Federal government, and
`
`academic work. Early in my career, I worked as a research and development
`
`scientist for Biological Evans Pharmaceutical Company, and then later for Novartis
`
`Pharmaceuticals, Inc. in oral dosage forms development.
`
`9.
`
`Upon completion of my Ph.D. at St. John’s University, I joined the
`
`faculty at the University of Louisiana (UL) Monroe College of Pharmacy as an
`
`Assistant Professor of Pharmaceutics in 1992. I was promoted to Associate
`
`Professor of Pharmaceutics in 1996, and continued to serve as an Associate
`
`Professor until 1998. At UL Monroe, I routinely taught pharmaceutics, physical
`
`pharmacy, industrial pharmacy, and drug stability to professional, masters and PhD
`
`students. I have carried out research on oral drug formulations, graduated three
`
`PhD, and one MS student as their major advisor. I was tenured at ULM Monroe. In
`
`1998, I joined the faculty at Texas Tech University as an Associate Professor of
`
`Pharmaceutics and the Director of the Graduate Program. I was promoted to
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`Professor of Pharmaceutics (and obtained tenure ) in 2000, and continued to serve
`
`as Professor and Director of the Graduate Program until 2004. While at Texas
`
`Tech, I routinely taught drug delivery systems, product formulation, industrial
`
`pharmacy, and drug stability to Pharm.D., MS, and Ph.D. students, performed
`
`research and mentored post-doctoral fellows and doctoral students in solid orals
`
`including soft gels research. I also served as dissertation advisor for six Ph.D.
`
`graduates.
`
`10.
`
`In 2004, I went to work for the U.S. Food and Drug Administration’s
`
`Center for Drug Evaluation and Research (CDER). There, I served as the Director
`
`of the Division of Product Quality Research and also the highest-ranking
`
`formulations scientist in the Senior Biomedical Research Service (SBRS). In my
`
`work at the FDA, I helped developed policies for approval of drug products
`
`including soft gels, evaluated technical merits of new and generic formulations,
`
`reviewed new and generic products for approvals, and recommended post
`
`marketing corrections for products that were approved but caused problems in
`
`patients. I worked for the FDA until 2015, when I joined the faculty at Texas A&M
`
`University, where I currently serve as Professor and Vice Dean in the College of
`
`Pharmacy, Interim Department Head of Pharmaceutical Sciences and the Director
`
`of the Formulations Design and Development Core Laboratories. At Texas A&M, I
`
`carry out formulations research, teach professional students, and supervise over 40
`
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`faculty and staff. I also oversee the Formulations Design and Development Core
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`Laboratory.
`
`11. My work has resulted in the publication of nearly 300 peer-reviewed
`
`journal articles, as well as books and book chapters in the field of pharmaceutical
`
`formulations. I am a listed inventor on U.S. patents and patent applications related
`
`to drug delivery systems and pharmaceutical formulations. I have been an invited
`
`speaker for over 200 conferences or meetings in the field of pharmaceutical
`
`formulations, and have had over 30 grant applications funded in which I am the
`
`principal investigator or investigator.
`
`12. Throughout my career, I have received numerous honors, such as 18
`
`different FDA/CDER awards including the Scientific Achievement award (2006),
`
`Team Excellence awards (2005, 2007, 2010, 2012, 2015), Group Recognition
`
`Awards (2012, 2013), the CDER Center Director’s Special Citation Award,
`
`Regulatory Science Excellence Award (2014), a Special Recognition Award
`
`(2015), and an Excellence Award (2015). In 2012, I received the Formulations
`
`Design and Development Award from the American Association of
`
`Pharmaceutical Scientists (AAPS). This award is considered the highest AAPS
`
`achievement on formulations design and development and is given only to one
`
`scientist every other year for a national/international expert with proven
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`accomplishments. I have also been elected as the founding Chair of the AAPS
`
`Formulations Design and Development Section.
`
`13.
`
`I also serve on the editorial advisory boards for five different research
`
`journals and serve as a manuscript reviewer for at least 20 different research
`
`journals. I have also served or currently serve as consultant to more than a dozen
`
`pharma or generic drug companies, and as an expert witness or consultant to
`
`Federal Agencies (FDA and FTC).
`
`14.
`
`In addition to my educational training, and professional and research
`
`experiences described above, I have kept abreast of the field of pharmaceutical
`
`formulations by reading scientific literature, conferring with colleagues in the field,
`
`attending and presenting at scientific conferences, and presenting at invited
`
`lectures.
`
`15. Accordingly, I am an expert in the pharmaceutical formulations—
`
`including soft gelatin capsule formulations—and have been since prior to March 8,
`
`2005. For that reason, I am qualified to provide an opinion as to what a person of
`
`ordinary skill in the art would have understood, known, or concluded before March
`
`8, 2005.
`
`III. DOCUMENTS I CONSIDERED IN FORMULATING MY OPINIONS
`In formulating my opinions, I considered all of the references cited in
`16.
`
`this Declaration, including the documents listed below.
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`Description
`Declaration of Peter Draper
`U.S. Patent No. 9,693,979
`Prosecution History of U.S. Patent No. 9,693,978 and U.S. Patent
`No. 9,693,979 (App. No. 60/659,679)
`Prosecution History of U.S. Patent No. 9,693,978 and U.S. Patent
`No. 9,693,979 (App. No. 11/367,238)
`Prosecution History of U.S. Patent No. 9,693,978 and U.S. Patent
`No. 9,693,979 (App. No. 14/977,808)
`Prosecution History of EP 1863458 (Counterpart of U.S. Patent No.
`9,693,978)
`Prosecution History of U.S. Patent No. 9,693,979 (App. No.
`15/159,972)
`U.S. Patent No. 6,383,471 (“Chen”)
`U.S. Publication No. 20040157928 (“Kim”)
`U.S. Publication No. 20040224020 (“Schoenhard”)
`U.S. Patent No. 5,141,961 (“Coapman”)
`U.S. Patent No. 5,641,512 (“Cimileuca”)
`U.S. Patent No. 5,360,615 (“Yu”)
`U.S. Patent No. 6,383,515 (“Sawyer”)
`U.S. Publication No. 20060099246 (“Tanner”)
`Wikipedia, Conjugate acid
`
`U.S. Publication No. 20050158377 (“Popp”)
`
`U.S. Patent No. 6,066,339 (“Stark”)
`U.S. Patent No. 6,251,426 (“Gullapalli”)
`Banner Pharmacaps, Inc. Citizen Petition to the Food and Drug
`Administration
`
`Exhibit No.
`1001
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`1010
`1011
`1012
`1013
`1014
`1015
`1016
`1017
`
`1018
`
`1019
`1020
`
`1021
`
`
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`Description
`Wikipedia, Robert Pauli Scherer,
`https://en.wikipedia.org/wiki/Robert_Pauli_Scherer
`R.M.C. Dawson et al., Data for Biochemical Research (Oxford:
`Clarendon Press 1959)
`Jarkko Rautio et al., “In Vitro Evaluation of Acyloxyalkyl Esters as
`Dermal Prodrugs of Ketoprofen and Naproxen,” Journal of
`Pharmaceutical Sciences, Vol. 87, No. 12, 1622-1628 (December
`1998)
`Letter from Sharon Hertz, Department Of Health & Human
`Services, to Roche Palo Alto LLC regarding NDA 18-965
`U.S. Patent No. 3,035,973 (“Klotz”)
`H. Sevelius et al., “Bioavailability of Naproxen Sodium and Its
`Relationship to Clinical Analgesic Effects,” 10 Br. J. Clin.
`Pharmac. 259-263 (1980)
`Banner Pharmacaps Inc. NDA 21-920, Naproxen Sodium Capsules
`Robert Thornton Morrison & Robert Neilson Boyd, Organic
`Chemistry (4th ed., Allyn and Bacon, Inc. 1983)
`Serajuddin, A., “Solid Dispersion of Poorly Water-Soluble Drugs:
`Early Promises, Subsequent Problems, and Recent Breakthroughs,”
`J. Pharm. Sci., 88:1058–1066 (1999)
`Patravale, V.B. et al., “Nanosuspensions: a promising drug delivery
`strategy,” J. Pharm. & Pharmacol., 56:827–840 (2004)
`WO 95/31979 to Shelley et al., “Solutions of Aryl or Heteroaryl
`Substituted Alkanoic Acids in Lipophilic Solvents and Soft Gelatin
`Capsules Containing Such Solutions” (Nov. 30, 1995)
`Ranucci et al., “Pharmacokinetic results on naproxen prodrugs
`based on poly(ethyleneglycol)s,” J. Biomater. Sci. Polymer Edn.,
`6:141–147 (1994)
`WO 95/31194 to Shapiro, H., “Compositions for Treatment of
`Chronic Inflammatory Diseases” (Nov. 23, 1995)
`Shah et al., “In Vitro Dissolution Profile of Water-Insoluble Drug
`Dosage Forms in the Presence of Surfactants,” Pharm Res. 6:612-
`618 (1989)
`
`Exhibit No.
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`Description
`Crowley and Martini, “Physicochemical Approaches to Enhancing
`Oral Absorption,” Pharm. Tech. Eur., 16:18-27 (2004)
`Serajuddin et al., “Water Migration from Soft Gelatin Capsule
`Shell to Fill Material and Its Effect on Drug Solubility,” J. Pharm.
`Sci., 75:62-64 (1986)
`Merisko-Liversidge et al., “Nanosizing: a formulation approach for
`poorly-water-soluble compounds,” Eur. J. Pharm. Sci., 18:113-120
`(2003)
`Naprosyn®, Physician’s Desk Reference, 48th ed., 2363–2365
`(1994)
`Anaprox®, Physician’s Desk Reference, 48th ed., 2350–2352 (1994)
`Aleve®, Physician’s Desk Reference, 49th ed., 1910 (1995)
`Naprelan®, Physician’s Desk Reference, 53rd ed., 3335–3337
`(1999)
`FDA Approved Products: Naprosyn®, available at
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=o
`verview.process&ApplNo=017581, last accessed May 19, 2018
`FDA Approved Products: Anaprox®, available at
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=o
`verview.process&ApplNo=018164, last accessed May 19, 2018
`FDA Approved Products: Naprelan®, available at
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=o
`verview.process&ApplNo=020353, last accessed May 19, 2018
`FDA Approved Products: Aleve®, available at
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=o
`verview.process&ApplNo=020204, last accessed May 19, 2018
`FDA Approved Products: Naproxen Sodium Soft Gelatin Capsules,
`available at
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=o
`verview.process&ApplNo=021920, last accessed May 19, 2018
`Tabibi and Gupta, “Soft Gelatin Capsules Development,” in Water
`Insoluble Drug Formulation, Chapter 17, Interpharm Press (2000)
`Seager and Slabaugh, “Acids, Bases, and Salts,” in Introductory
`Chemistry, Chapter 9, Scott, Forsman and Co. (1979)
`
`Exhibit No.
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`Description
`Gennadios, “Soft Gelatin Capsules,” in Protein-Based Films and
`Coatings, Chapter 16, CRC Press LTD (2000)
`International Conference on Harmonisation, “Topic Q3B: ICH
`Harmonised Tripartite Guideline for Impurities in New Medicinal
`Products,” (November 6, 1996)
`The Merck Index, Merck & Co., Inc., 12th Ed. (1996), xii-xvii, 392-
`393, 641-642, 763-764, 911, 1101, 1305, 1320, and 1349
`Chang, R., “Chemistry,” 6th ed., Ch. 15, pp. 597–641, McGraw-Hill
`(1998)
`
`Exhibit No.
`
`2023
`
`2025
`
`2026
`
`2027
`
`
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`I understand that a person of ordinary skill in the art (“POSA”) is a
`17.
`
`hypothetical person who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. A POSA in
`
`the field of pharmaceutical formulations would have had knowledge of the
`
`scientific literature and have skills relating to that field, including the design,
`
`generation, and use of gelatin capsule formulations before March 8, 2005. A POSA
`
`would also have had knowledge of basic formulation principles and techniques,
`
`such as solubility of the active pharmaceutical ingredient, formulation stability,
`
`Brønsted–Lowry acid/base chemistry, and bioavailability/bioequivalence.
`
`18. A POSA would typically have (i) a Ph.D. in pharmaceutical sciences
`
`or a related field and at least two years’ experience formulating, characterizing,
`
`and/or analyzing pharmaceutical products, (ii) a Master’s degree in pharmaceutical
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
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`sciences or a related field and at least four years’ experience in formulating,
`
`characterizing, and/or analyzing pharmaceutical products, or (iii) a Bachelor’s
`
`degree in pharmaceutical sciences or a related field and at least six years’
`
`experience formulating, characterizing, and/or analyzing pharmaceutical products.
`
`19. A POSA also would have had access to and/or collaborate, as needed,
`
`with people in other areas of science, including pharmacology, organic chemistry,
`
`drug development, and medical treatment, such as an M.D.
`
`
`
`V. CLAIM CONSTRUCTION
`I understand that terms of the claims are to be given their broadest
`20.
`
`reasonable interpretation in light of the language of the claims, the specification,
`
`and the file history of the ’979 patent. Independent claims 1, 8, and 17 are directed
`
`to pharmaceutical compositions comprising a soft gelatin capsule encapsulating a
`
`liquid matrix comprising, among other ingredients, “about 5%” lactic acid by
`
`weight of the matrix. EX1003, col. 10–12. For example, claim 1 of the ’979 patent
`
`is copied below:
`
`1. A pharmaceutical composition comprising a soft
`gelatin capsule encapsulating a
`liquid matrix
`comprising:
`(a) naproxen sodium;
`(b) about 5% lactic acid by weight of the matrix;
`(c) one or more polyethylene glycols; and
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
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`comprising
`solubilizers
`or more
`one
`(d)
`polyvinylpyrrolidone,
`propylene
`glycol,
`or
`a
`combination thereof.
`
`21.
`
`I disagree with Mr. Draper’s construction that the broadest reasonable
`
`interpretation of the term “about 5%” means “at least from 2 to 8% lactic acid by
`
`weight of the fill material.” EX1001, ¶82. A POSA considering the language of the
`
`claims and the disclosures in the ’979 patent specification and the patent’s file
`
`history, in light of the general knowledge in the art, would not have arrived at such
`
`a broad interpretation, and would not have found Mr. Draper’s interpretation to be
`
`reasonable. First, Mr. Draper’s construction of “at least from 2 to 8% lactic acid”
`
`encompasses amounts of lactic acid at least 60% lower (i.e., 2%) and at least 60%
`
`higher (i.e., 8%) than the midpoint of “about 5% lactic acid.” Contrary to Mr.
`
`Draper’s construction, a POSA reading the ’979 patent would have applied the
`
`plain and ordinary meaning of “about 5%” to mean “approximately 5%,” and
`
`would not have considered 2% lactic acid or 8% lactic acid to be approximately
`
`5% lactic acid.
`
`22. Second, the exemplary formulations in the ’979 patent would have
`
`confirmed the POSA’s interpretation of “about 5%” to mean “approximately 5%.”
`
`The POSA would have understood from the disclosures in the ’979 patent that the
`
`example formulations comprising lactic acid calculate specific percentages of
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
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`lactic acid by weight of the matrix—calculated out to the hundredths of a percent.
`
`See, e.g., Example 7 (5.27% lactic acid) and Examples 9–12 (5.00% lactic acid).
`
`With this level of specificity in the examples of the ’979 patent, a POSA would not
`
`have considered “about 5%” to include up to 8% and as low as 2% lactic acid.
`
`23. Example 8 of the ’979 patent is the only example comprising lactic
`
`acid that is not presented as a specific percentage. Instead, Example 8 discloses
`
`“0.24–0.35M” lactic acid. EX1003, col. 9:57–65. Mr. Draper asserts that a POSA
`
`would have understood Example 8’s disclosure of “0.24–0.35M” lactic acid to
`
`mean “0.24–0.35 mole equivalents of lactic acid per mole equivalent of naproxen
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`sodium.” EX1001, ¶81. Under Mr. Draper’s interpretation, the amount of lactic
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`acid in Example 8 when presented as a percentage by weight would be 2.1% to
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`3.1% lactic acid by weight of the matrix. These numbers are calculated using the
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`following Calculations I and II, where “LA” represents lactic acid; “Npx”
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`represents naproxen sodium; “W” represents the total weight of the matrix; the
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`molecular weight of lactic acid is 90 g/mol; and the molecular weight of naproxen
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`sodium is 252 g/mol:
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`Calculation I
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`
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`Calculation II
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`
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`24. A POSA, considering the specific amounts of lactic acid disclosed in
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`
`
`
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`Example 7 (5.27%) and Examples 9–12 (5.00%)—again, calculated out to the
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`hundredths of a percent—would not have considered the 2.1% to 3.1% lactic acid
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`in Example 8 to be “about 5% lactic acid.” I understand that the scope of patent
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`claims need not encompass all alternative embodiments in the specification.
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`Therefore, it is of no moment that the formulation of Example 8 does not fall
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`within the broadest reasonable interpretation of “about 5%” lactic acid in the ’979
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`patent.
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
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`25. Third, a POSA considering the ’979 patent’s file history would have
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`concluded that construing “about 5%” to mean “at least from 2 to 8%” is
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`unreasonable because such a construction provides nearly the same scope of
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`original claim 10. Thus, Mr. Draper’s construction overlooks the fact that the
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`claims were amended during prosecution. EX1006, at 121, 195. In particular, I
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`understand from my review of the ’979 patent’s file history that the Applicant
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`initially pursued independent claim 10 directed to a pharmaceutical composition
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`comprising “naproxen sodium” and “about 0.2 to about 1.0 mole equivalents of
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`lactic acid per mole of naproxen sodium.” EX1008, at 121. According to the file
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`history, dependent claim 15 at the time—which depended from claim 10 and thus
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`was narrower than claim 10—was directed to the composition of claim 10
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`“wherein the weight percentage of lactic acid is about 5%.” A POSA would have
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`accordingly known that “about 5%” lactic acid by weight is narrower than “about
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`0.2 to about 1.0 mole equivalents of lactic acid per mole of naproxen sodium.”
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`26. Examples 8–12 of the ’979 patent each include 25% naproxen sodium
`
`by weight of the matrix. EX1003, col. 9:57–10:50. If a POSA were to include
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`lactic acid in such formulations in an amount from “about 0.2 to about 1.0 mole
`
`equivalents of lactic acid per mole of naproxen sodium,” the amount of lactic acid
`
`shown as a percentage by weight would be about 1.8% to 8.9% lactic acid by
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`weight of the matrix. These numbers are calculated using the following
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`Calculations III and IV, where “LA” represents lactic acid; “Npx” represents
`
`naproxen sodium; “W” represents the total weight of the matrix; the molecular
`
`weight of lactic acid is 90 g/mol; and the molecular weight of naproxen sodium is
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`252 g/mol:
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`Calculation III
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`Calculation IV
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`
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`27. A POSA considering the ’979 patent’s file history would have
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`concluded that construing “about 5%” to mean “at least from 2 to 8%” is
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`unreasonable because such a construction provides nearly the same scope of
`
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
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`original claim 10 (1.8% to 8.9% lactic acid), overlooking the fact that the claims
`
`were amended during prosecution. EX1008, at 121, 195.
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`28.
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`In summary, in view of the plain language of the claims and the
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`disclosures in the ’979 patent’s specification and prosecution history, a POSA
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`would have given the term “about 5%” its plain and ordinary meaning:
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`“approximately 5%.”
`
`VI. STATE OF THE ART BEFORE MARCH 8, 2005
`A. The art contradicts Mr. Draper’s implication that disclosures of
`“naproxen” are synonymous with “naproxen sodium”—on the
`contrary, naproxen and naproxen sodium are two different drugs.
`29. Mr. Draper states that “combining naproxen sodium with lactic acid is
`
`fundamentally the same as combining naproxen with sodium lactate.” EX1001,
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`¶41. Mr. Draper’s assertion oversimplifies the relationship between naproxen,
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`naproxen sodium, lactic acid, and sodium lactate because it focuses exclusively on
`
`a simple equilibrium equation—not a pharmaceutical formulation. Mr. Draper’s
`
`assertion fails to account for the other ingredients that would be present in a
`
`pharmaceutical formulation (e.g., solubilizers, plasticizers, filling agents, etc.),
`
`which affect the equilibrium. In other words, in a pharmaceutical composition,
`
`combining naproxen with sodium lactate is not simply the same as combining
`
`naproxen sodium with lactic acid.
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`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
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`30.
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`Indeed, before March 8, 2005, it was well known in the art that
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`naproxen and naproxen sodium are two different drugs. For example, in 1980
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`Sevelius described a study comparing the bioavailability of naproxen tablets and
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`naproxen sodium tablets in human patients—i.e., two different drugs, not just
`
`formulations. EX1027, abstract. Sevelius reported that patients who received
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`naproxen sodium tablets exhibited “more rapid absorption of the drug,” “achieved
`
`significantly earlier and higher plasma levels” of the active pharmaceutical
`
`ingredient, and had “consistently lower” pain intensity compared with patients who
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`received naproxen tablets. EX1027, at 261. The differences in these two drugs
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`were also evident in that they were approved by the US Food and Drug
`
`Administration as two different drugs and marketed as two different products:
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`Naprosyn® (naproxen) and Anaprox® (naproxen sodium). PSG2012; PSG2013.
`
`31. Before March 8, 2005, both naproxen and naproxen sodium were
`
`formulated in solid dosage forms, such as tablets. For example, naproxen was
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`initially approved in 1976 as a solid tablet (Naprosyn®; Syntex, Inc.), followed by
`
`naproxen sodium approval in 1980, also as a solid tablet (Anaprox®; Syntex, Inc.).
`
`PSG2016; PSG2017. Naproxen and naproxen sodium remained on the market for
`
`nearly 30 years as solid tablet dosages until 2006 when the FDA approved Banner
`
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
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`Pharmacaps’ naproxen sodium softgel capsule formulation, which I understand is
`
`encompassed by claims of the ’979 patent. PSG2018; PSG2019; PSG2020 1.
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`B. Artisans knew that dissolving naproxen sodium in polyethylene
`glycol resulted in formation of naproxen-polyethylene glycol
`esters, producing unacceptable impurities and reduced naproxen
`bioavailability.
`32. Before March 8, 2005, artisans generally understood that soft gelatin
`
`capsule formulations could offer certain advantages over conventional tablet
`
`dosage forms. PSG2010, at 62; PSG2023, at 395–396. Despite these known
`
`advantages, the art failed to provide softgel capsule formulations of a naproxen
`
`salt, as provided in the ’979 patent. Thus, before March 8, 2005, there was a need
`
`for a liquid softgel formulation that offered good active pharmaceutical ingredient
`
`solubility, stability, and bioavailability, such as a naproxen salt liquid softgel
`
`formulation. But the art was unable to provide such a formulation.
`
`
`1 PSG2016, PSG2017, PSG2018, PSF2019, and PSG2020 are true and
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`correct copies of the information available from the FDA’s drug database search
`
`feature at www.fda.gov (search term “naproxen”). The information contained in
`
`the aforementioned exhibits is the type of information an expert in the field of
`
`pharmaceutical formulations would reasonably rely upon when forming opinions
`
`on drug approval dates and dosage types.
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`IPR2018-00422
`Declaration of Mansoor Khan, R.Ph., Ph.D.
`
`33. Artisans knew that, for a drug to be efficiently absorbed and diffuse
`
`across the intestinal lumen, the drug needed to be in solution or solubilized form at
`
`the site of absorption. For example, Shah explained in 1989 that “the drug must be
`
`solubilized in the aqueous environment of the gastrointestinal (GI) tract in order to
`
`be absorbed.” PSG2008, at 612. And as Crowley wrote in 2004, “the drug must be
`
`in the solvated state to diffuse into and across the enterocytes lining the intestinal
`
`lumen.” PSG2009, at 18. For solid drug formulations like tablets, artisans knew
`
`that absorption across the intestinal lumen required dissolution rate-limiting steps
`
`in the absorption process. As Shah explained, “[d]issolution of drugs from solid
`
`oral dosage forms is a necessary criterion for drug bioavailability….” PSG2008, at
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`612.
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`34. With this foundation of general knowledge, artisans logically
`
`understood that the simplest and most efficient way to present a drug to the
`
`gastrointestinal tract for absorption is to administer the drug in solution or in a
`
`solubilized form. By formulating the drug in solution or as a solubilized form (as
`
`oppo