IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`QUALICAPS CO., LTD,
`Patent Owner.
`
`Case IPR2017-00203
`Patent 6,649,180
`
`DECLARATION OF JASON T. MCCONVILLE, PH.D.
`IN SUPPORT OF PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2028 - 1/94
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`
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`QUALICAPS CO., LTD,
`Patent Owner.
`
`Case IPR2017-00203
`Patent 6,649,180
`
`DECLARATION OF JASON T. MCCONVILLE, PH.D.
`IN SUPPORT OF PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2028 - 1/94
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`
`
`
`
`Table of Contents
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`IPR2017-00203
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`Page
`PRELIMINARY STATEMENT ..................................................................... 1
`I.
`ACADEMIC AND PROFESSIONAL QUALIFICATIONS ......................... 1
`II.
`III. RELATIONSHIP TO THE PARTIES ............................................................ 5
`IV. LEVEL OF ORDINARY SKILL IN 1999 ...................................................... 6
`V.
`THE INVENTION OF THE ’180 PATENT ................................................... 8
`A.
`The Problem Discovered and Solved by the Inventors ......................... 8
`B.
`The Criticality of the Claimed MO/HPO Upper Limits ....................... 9
`C.
`The ’180 Patent Claims .......................................................................13
`VI. BACKGROUND OF HARD CAPSULE TECHNOLOGY AND
`HPMC ............................................................................................................ 14
`A.
`State of the Hard Capsule Art in 1999 ................................................14
`B.
`Hydroxypropyl Methylcellulose (“HPMC”) Substitution Types .......17
`VII. THE CITED ART .......................................................................................... 24
`A. Yamamoto ’123 Patent ........................................................................24
`B.
`The Japanese Pharmacopoeia ..............................................................29
`VIII. YAMAMOTO AND THE JP WOULD HAVE TAUGHT A POSA
`THAT ONLY HPMC 2910 WAS ACCEPTABLE FOR HARD
`CAPSULE FILMS ......................................................................................... 29
`A.
`The Prior Art Instructed a POSA to use HPMC 2910 for Film
`Compositions .......................................................................................30
`1.
`Yamamoto’s Reported Optimized Viscosity Confirms
`Using Only HPMC 2910 for Film Compositions. .................... 35
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`B.
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`C.
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`The Unpredictability of the Different Substitution Chemistries
`Confirms Yamamoto’s Use of Only HPMC 2910 for Capsule
`Film Compositions ..............................................................................38
`The Requirements for Preparing Successful Hard Capsules
`Further Directed a POSA to Use Only HPMC 2910 ..........................40
`IX. A POSA WOULD HAVE UNDERSTOOD THAT MO/HPO
`CONTENT IN EACH HPMC SUBSTITUTION TYPE COMPLIED
`WITH THE MANUFACTURER’S DESIGNATION .................................. 45
`X. A POSA WOULD NOT HAVE EXPECTED THAT HPMC 2910
`CAPSULES AVOIDED GELLING AID PRECIPITATION
`DEFECTS ...................................................................................................... 49
`1.
`The Cited Art Does Not Disclose Capsules that
`Inherently Avoided Gelling Aid Precipitation .......................... 54
`XI. CONCLUSION .............................................................................................. 57
`
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`I.
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`IPR2017-00203
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`I, Jason T. McConville, hereby declare and state as follows:
`
`PRELIMINARY STATEMENT
`I have been retained on behalf of Patent Owner Qualicaps Co., Ltd.
`1.
`
`(“Patent Owner” or “Qualicaps”) to provide evidence in Mylan Pharmaceuticals
`
`Inc. v. Qualicaps Co., Ltd, Case IPR2017-00203. I am being compensated at my
`
`usual and customary hourly rate for my services in connection with this Inter
`
`Partes Review proceeding. My compensation is not dependent upon the outcome
`
`of the present Inter Partes review proceeding.
`
`2.
`
`I have reviewed the Petition for Inter Partes Review of Patent No.
`
`6,649,180 (“the ’180 patent”) filed by Mylan Pharmaceuticals Inc. (“Petitioner”),
`
`including Dr. Kibbe’s Declaration (Ex. 1011), as well as the exhibits and articles
`
`cited in those documents. I have also reviewed the articles and documents cited in
`
`this declaration.
`
`3.
`
`I am aware of information generally available to, and relied upon by,
`
`persons of ordinary skill in the art at the relevant times. Some statements below
`
`are expressly based on such awareness.
`
`II. ACADEMIC AND PROFESSIONAL QUALIFICATIONS
`I am an Associate Professor of Pharmaceutics at the University of
`4.
`
`New Mexico College of Pharmacy and an Adjunct Professor at the University of
`
`Bonn, in the Department of Pharmaceutical Technology, in Bonn, Germany.
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`5.
`
`I received my Bachelor of Science, with Honors, in Applied
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`Chemistry from Coventry University, in Coventry, United Kingdom in 1994. From
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`1994 to 1999, I was a Research Technician in Pharmaceutics at the Centre for Drug
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`Formulation Studies at the University of Bath, in Bath, United Kingdom. My main
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`research project pertained to controlled release drug delivery, and specifically
`
`hydrophilic gel formation and drug release. My responsibilities included
`
`preparation and testing of pharmaceutical formulations. These were done under the
`
`direction of the Principal Investigator, who provided the instruction on which
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`materials to use in the formulations. I did not devise new combinations of materials
`
`or new uses for known materials. I would primarily consult manufacturer-provided
`
`information on specific substances and, with regard to testing methodology, the
`
`relevant pharmacopoeia in effect at the time. Additionally, I would refer to current
`
`literature for experimental guidance on standardized methods. I relied on labels
`
`and other identifying information on containers of materials I used to be certain I
`
`was using the correct materials.
`
`6.
`
`I subsequently earned my Ph.D. in Pharmaceutics from the University
`
`of Strathclyde, in Glasgow, United Kingdom in 2002. My Ph.D. dissertation was
`
`titled “Pulsed-Release Drug Delivery and Development of the Time-Delayed
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`Capsule.” After earning my Ph.D., I was a Post-Doctoral Fellow at the University
`
`of Texas at Austin College of Pharmacy from 2002 to 2006.
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`7.
`
`In 2006, I joined the faculty at the University of Texas at Austin as an
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`Assistant Professor of Pharmaceutics in the College of Pharmacy. I assumed my
`
`present positions at the University of New Mexico and the University of Bonn in
`
`2012.
`
`8.
`
`I am a member of several professional societies, including the
`
`American Association of Colleges of Pharmacy and the American Association of
`
`Pharmaceutical Scientists. Within the American Association of Pharmaceutical
`
`Scientists I am a member of two specialized Sections: Formulation Design &
`
`Development; and Physical Pharmacy & Biopharmaceutics.
`
`9.
`
`I have taught many courses related to pharmaceutical dosage form,
`
`design, and development. For example, I have taught Biopharmaceutics to students
`
`since 2007. This course includes instruction on all routes of drug delivery and
`
`formulation, including oral delivery systems such as tablets, capsules formed of
`
`film compositions, and oral suspensions. I have also been an advisor to 28
`
`graduate and Pharm.D. students and have been on the dissertation committee for
`
`14 students.
`
`10.
`
`I have performed practical design, development, and manufacturing
`
`work related to a wide variety of capsule and other solid oral dosage forms over the
`
`last 22 years, including forming a variety of capsules from film compositions for
`
`experimental use. Further, during my doctoral studies, I worked extensively with
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`capsule formulations, including gelatin capsules and cellulose ether capsule
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`formations.
`
`11.
`
`I have co-authored more than 50 articles, more than 120 abstracts, and
`
`many book chapters, including on the topics of oral dosage design, formulation,
`
`and delivery. I have also been an invited speaker or workshop participant on at
`
`least 39 occasions.
`
`12.
`
`I have served on the editorial board for three scientific journals,
`
`including Drug Development and Industrial Pharmacy. I have also served as a
`
`reviewer for at least 15 journals and publishers, including International Journal of
`
`Pharmaceutics, Journal of Controlled Release, and Pharmaceutical Research.
`
`These publishers and journals publish, among other things, research about drug
`
`delivery formulations including hydroxypropyl methylcellulose and dosage forms
`
`such as capsules formed of film compositions. In addition, I have served as a
`
`Scientific Advisor for Drug Delivery to the Lungs (DDL) conference, as well as a
`
`reviewer for the conference proceedings at the 2017 Annual Meeting of the
`
`International Pharmaceutical Excipient Council, which included publications on
`
`hydroxypropyl methylcellulose.
`
`13.
`
`I have received several honors and awards for my research and
`
`teaching activities, including the Outstanding Poster Presentation Award for
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`“Microwave Dielectric Analysis of Wet Granulations for Erodible HPMC tablets,”
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`the Editor’s Choice Award for “Design and Evaluation of a Restraint-Free Small
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`IPR2017-00203
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`Animal Inhalation Dosing Chamber,” selection as Member of the Society for
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`Teaching Excellence at the University of Texas at Austin, and a nomination for
`
`University of Texas System Regents’ Outstanding Teaching Award. Additionally, I
`
`have contributed 17 invited articles for journals in various aspects of drug delivery
`
`including hydroxypropyl methylcellulose and controlled release.
`
`14.
`
`I am a named inventor on ten patents or patent applications.
`
`15. My curriculum vitae, which includes a list of my publications, and a
`
`separate list of all prior matters on which I have consulted as an expert, including
`
`testifying at deposition or trial, are attached to this Declaration.
`
`III. RELATIONSHIP TO THE PARTIES
`I served as an expert witness for Patent Owner Qualicaps Co., Ltd. in
`16.
`
`Eastern District of Texas litigations concerning the ’180 patent, captioned Warner
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`Chilcott (US), LLC et al. v. Mylan Pharmaceuticals, Inc. et al., Civil Action No.
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`2:15-cv-01740 (E.D. Tex.) and Warner Chilcott (US), LLC et al. v. Teva
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`Pharmaceuticals USA, Inc. et al., Civil Action No. 2:15-cv-01471 (E.D. Tex.). I
`
`understand those litigations are related to the present Inter Partes Review
`
`proceeding.
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`IV. LEVEL OF ORDINARY SKILL IN 1999
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`17. Dr. Kibbe states that “at time [sic] of the earliest effective filing date
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`of the ’180 Patent,” which I understand is 1999, a POSA was “someone with at
`
`least a bachelor’s degree in chemistry, chemical engineering, material engineering,
`
`pharmacy, or the equivalent technical degree, and at least two years of industry
`
`experience in pharmaceutical formulation.” Ex. 1011 ¶ 41. I further understand that
`
`the Board has adopted Dr. Kibbe’s definition. For the purposes of this Declaration,
`
`I will apply Dr. Kibbe’s definition of a 1999 POSA. However, I reserve the
`
`opportunity to provide opinions based on a higher level of skill in the art, as
`
`specifically pointed out in the relevant sections of this Declaration.
`
`18.
`
`I note that Dr. Kibbe’s definition of a POSA does not limit the
`
`specific industry experience. My opinions are consistent with Dr. Kibbe’s
`
`definition regardless of whether the specific industry experience was focused in
`
`capsule formulation. Under Dr. Kibbe’s definition, if the POSA in 1999 had
`
`industry experience in capsule formulation, their experience would have
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`predominantly or entirely involved hard gelatin capsules. As I describe below, in
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`1999, gelatin capsules were the established standard for hard capsules in the
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`industry. See below ¶ 34.
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`19. Based on my qualifications and experience, I consider myself
`
`qualified to provide opinions on the understanding of a person of ordinary skill in
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`the relevant art during 1999 as it pertains to hard capsule technology, specifically
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`the formulation of hard capsules, including preparations based on HPMC film
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`compositions, and drug delivery aspects of such capsules.
`
`20. A person having a bachelor’s degree in one of the relevant disciplines
`
`plus two years of industry experience would be a research technician. I know this
`
`because I personally had this level of education and experience when I worked as a
`
`Research Technician in pharmaceutics in the late 1990s. I also know this because I
`
`worked with research technicians in my graduate and postdoctoral laboratories.
`
`These research technicians invariably have a bachelor’s degree in a relevant field
`
`and typically up to a few years of experience.
`
`21. A research technician typically does not perform independent
`
`research. Rather, a research technician works under the supervision of an
`
`investigator, or sometimes a postdoctoral fellow or a graduate student. Research
`
`technicians do not devise their own experiments or develop novel formulations;
`
`instead, they carry out experiments they are instructed to carry out and prepare
`
`formulations as directed by a supervisor. In other words, research technicians go
`
`“by the book,” following instructions and employing conventional techniques and
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`materials. I know this because it describes my own work as a Research Technician
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`(see above at ¶ 5), as well as the work of all the other research technicians I have
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`known.
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`V. THE INVENTION OF THE ’180 PATENT
`A. The Problem Discovered and Solved by the Inventors
`22. During the course of their research on cellulose ether films as gelatin
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`substitutes for hard capsules, the inventors of the ’180 patent reported that
`
`cellulose ethers themselves presented a significant problem. See ’180 patent at
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`1:10–67 (Ex. 1001). They discovered that “sometimes, cloud spots rather than [a]
`
`uniform cloud” developed as visual defects in the hard capsules during long-term
`
`storage. Id. at 2:1–6. The inventors reported the cause: precipitation of the gelling
`
`aid used in the cellulose ether film composition that forms the capsule. Id. at 1:57–
`
`67.
`
`23. As I discuss below, if a POSA in 1999 had encountered gelling aid
`
`precipitation in hard capsules, they would have considered it to be a significant
`
`defect. See below ¶¶ 101–102; ASHP Guidelines for Selecting Pharmaceutical
`
`Manufacturers and Suppliers, 48 Am. J. Hosp. Pharm. 523–24, 523, no. 11 (1991)
`
`(“ASHP Guidelines”) (Ex. 2044) (suppliers are obliged “to enable the pharmacist
`
`to evaluate the products’ physical traits, including pharmaceutical elegance
`
`(appearance and absences of physical deterioration or flaws)”).
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`The Criticality of the Claimed MO/HPO Upper Limits
`B.
`24. The inventors investigated the weight percent contents of methoxyl
`
`(“MO”) and hydroxypropoxyl (“HPO”) in commercial hydroxypropyl
`
`methylcellulose (“HPMC”) material during the course of their experiments on
`
`creating HPMC capsules without gelling aid precipitation defects. See ’180 patent
`
`at 2:16–32; 5:26 to 6:20 (Ex. 1001). The inventors solved the gelling aid
`
`precipitation problem by “controlling the total content of alkoxyl [e.g., methoxyl]
`
`and hydroxyalkoxyl [e.g., hydroxypropoxyl] groups in the cellulose ether,” id. at
`
`6:16–17, to ensure that the hard capsule products were consistently free of such
`
`cloud spotting defects, see id. at 2:16–32; 6:1–14 (Table 1), 18–28. Their solution
`
`was to develop HPMC material restricted to a total MO/HPO weight percent
`
`substitution with a critical upper bound of 37.6%. See id. at 5:26 to 6:20. In their
`
`experimental examples, the inventors measured the weight percent of MO and
`
`HPO contents of two different substitution types of HPMC--2910 and 2208--and
`
`then blended the two substitution grades in various proportions to create a dipping
`
`solution composition. See id. at 5:28–34; 39–48; 50–58. The inventors then
`
`prepared exemplary capsules, resulting in a specific controlled content of MO/HPO
`
`weight percent substitution for each capsule. See id. at 5:34–37; 6:1–20, Table 1.
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`They theorized a mechanism for how controlling MO/HPO content avoided cloud
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`spotting defects:
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`
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`Id. at 2:37–49.
`
`25. The ’180 patent inventors additionally found a critical lower limit,
`
`explaining that “if the total content of alkoxyl and hydroxyalkoxyl groups is too
`
`low, the resulting film may lose flexibility, strength or other performance, which is
`
`inconvenient in some applications.” Id. at 3:22–25.
`
`26. As detailed below, the experiments resulting in Table 1 were valid
`
`methods showing that the inventors achieved a limit of 37.6% MO/HPO for
`
`preventing gelling aid precipitation defects in hard capsules. See below ¶¶ 95–98,
`
`100–101;’180 patent at 5:24 to 6:20. I also understand, as detailed below, that one
`
`of the inventors, Masaru Tanjoh, replicated the results of Table 1 using multiple
`
`gelling aid types and proportions in the films of hard capsules, further showing the
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`validity of the critical 37.6% upper limit. See below ¶¶ 99–101; ’180 patent File
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`History, Declaration of Masaru Tanjoh, filed May 15, 2003 (“Tanjoh Declaration”)
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`(Ex. 1010 at 106–108).
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`27. Research on combining HPMC polymers having different functional
`
`groups to prevent precipitation of gelling aids in hard capsules would have been
`
`beyond the level of skill of anyone below the doctoral level, and even then would
`
`have presented substantial uncertainty in 1999. Commercial manufacturers used
`
`carefully designed synthetic processes for preparing and selling pharmaceutical
`
`grade HPMC material. See below ¶¶ 37–39. Manufacturers classified and sold the
`
`HPMC products according to their different chemistries based on the varying
`
`MO/HPO substitution types. See Dow Methocel Cellulose Ethers Technical
`
`Handbook (1991) (“Dow (1991)”) at 4 (Ex. 2035). This is because HPMC polymer
`
`chains with different substitution ratios of MO groups and HPO groups are distinct
`
`molecules. The MO groups are relatively hydrophobic, while the HPO groups are
`
`relatively hydrophilic. Mitchell, et al., The Influence of Additives on the Cloud
`
`Point, Disintegration and Dissolution of HPMC Gels and Matrix Tablets, 66 Int’l
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`J. Pharm. 233–42, 234, col. 1 (1990) (Ex. 2045). Combining polymers with
`
`different MO and HPO ratios would have led to complex chemical interactions
`
`among the polymer chains, which were not well understood and would have
`
`substantially impacted capsule preparation and performance. See below ¶¶ 44–45,
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`74–76. Recognizing this, manufacturers’ product literature designated each HPMC
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`substitution chemistry for a specific application, and contained nothing on mixing
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`the different substitution chemistries together. See below ¶¶ 39, 43, 62, 72, 76.
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`Further, I am not aware of any publications before April 1999 describing the
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`mixing of different HPMC substitution types. In 1999, a POSA working with
`
`HPMC film compositions would have considered it suitable to vary viscosity, as I
`
`explain below. See below ¶¶ 71–72, 76; Yamamoto at 3:39–51 (Ex. 1004); Dow
`
`(1991) at 23 (Ex. 2035). But the state of the art directed the POSA to vary HPMC
`
`viscosity only within the same substitution type. Dow 1991 at 23 (Ex. 2035);
`
`Yamamoto at 6:44 to 9:47 (Ex. 1004) (exemplifying capsule films made with
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`HPMC products of varying viscosity grades but only one substitution type (2910));
`
`see below ¶¶ 71–72, 76.
`
`28. A research technician in 1999, then, would not have initiated blending
`
`the different HPMC substitution chemistries together. Therefore, I disagree with
`
`Dr. Kibbe’s statements that the inventors “used routine testing to result in the
`
`patented invention.” Ex. 1011 ¶¶ 76, 102. I note Dr. Kibbe does not cite any source
`
`for those statements. Dr. Kibbe references the ’180 patent, which I understand is
`
`not prior art. Id. at ¶¶ 75, 101. Dr. Kibbe does not cite any reports on combining
`
`different HPMC substitution types, which, as I describe above, was a procedure
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`developed by the inventors for their exemplary experiments. See above ¶¶ 24, 26.
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`C. The ’180 Patent Claims
`Independent claim 1 and dependent claim 4 of the ’180 patent recite:
`29.
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` 1. A hard capsule formed of a film composition
`comprising a hydroxypropyl methyl cellulose as a base, a
`gelling agent, and a gelling aid, wherein said
`hydroxypropyl methyl cellulose has a content of
`hydroxypropoxyl groups of at least 4% by weight of the
`hydroxypropyl methyl cellulose and a content of
`methoxyl groups and hydroxypropoxyl groups combined
`of 23 to 37.6% by weight of the hydroxypropyl methyl
`cellulose.
`
`. . .
`
` 4. The hard capsule formed of a film of claim 1,
`wherein the content of methoxyl and hydroxypropoxyl
`groups combined is 29 to 37% by weight of the
`hydroxypropyl methyl cellulose.
`
`’180 patent (Ex. 1001) at 6:38–45; 55–58.
`
`30.
`
`I understand that claim 4 depends from independent claim 1.
`
`Therefore, claim 4 includes the features recited in claim 1, including a film
`
`composition comprising HPMC as a base, a gelling agent, and a gelling aid.
`
`31.
`
`I understand that the ’180 patent claims priority to a Japanese patent
`
`application patent application filed on April 14, 1999. I interpret the meaning of
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`the ’180 patent claims in accordance with the knowledge and understanding of a
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`person of ordinary skill in the art (“POSA”) during April 1999, as described below.
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`VI. BACKGROUND OF HARD CAPSULE TECHNOLOGY AND HPMC
`State of the Hard Capsule Art in 1999
`A.
`32. Pharmaceutical capsules had almost always been manufactured
`
`exclusively from gelatin for well over a century prior to the invention of the ’180
`
`patent. See B. E. Jones, Chapter 1: The History of the Gelatin Capsule, in Hard
`
`Capsules: Development & Technology at 1–10, 13 (K. Ridgway ed., 1987)
`
`(“Ridgway”) (Exhibit 2001 at 16–25, 28). But gelatin capsules had significant
`
`problems, including being unacceptable for certain diets, as gelatin is animal-
`
`derived; a medium for bacterial growth; susceptible to degradation when exposed
`
`to hot and humid environments; and drying during shelf storage. See, e.g., id. at 36,
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`39–42; Yamamoto at 1:25–42 (Ex. 1004).
`
`33. The industry attempted to substitute gelatin with cellulose ether
`
`compounds to address the problems associated with gelatin capsules. See Ridgway
`
`at 56–58 (Ex. 2001 at 71–73). These cellulose ether compounds included
`
`hydroxypropyl methylcellulose (“HPMC”), hydroxypropyl cellulose, hydroxyethyl
`
`cellulose, and methylcellulose. Id. at 56, col. 1 (“only one, methylcellulose, has
`
`reached large-scale capsule manufacture”); see, e.g., U.S. Patent No. 4,001,211, to
`
`Sarkar (Jan. 4, 1977) at 4:7–15 (Ex. 2020). However, cellulose ether capsules
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`presented their own difficulties. One problematic issue was developing a
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`formulation that would dissolve in biological fluids at body temperatures, as
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`previous cellulose ether capsules had passed through the body without dissolving
`
`or disintegrating. See Ridgway at 56–58 (Ex. 2001 at 71–73); U.S. Patent No.
`
`5,756,036, to Grosswald, et al. (May 26, 1998) (“Grosswald”) at 1:20–25 (Ex.
`
`2046). As reported by Yamamoto, a reference cited by Dr. Kibbe, cellulose ether
`
`capsules experienced decreased solubility and disintegration compared to gelatin
`
`capsules in the presence of certain food and beverages. Yamamoto at 2:17–35 (Ex.
`
`1004). Further, up through 1998, the industry was reporting that cellulose ether
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`capsules resulted in failures such as breakage, not separating, or jamming in filling
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`machines. Grosswald at 1:34–39 (Ex. 2046).
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`34. By 1999, therefore, the industry still did not have an established
`
`understanding of successful HPMC capsule applications. See above ¶¶ 32–33;
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`Grosswald at 1–39 (Ex. 2046); see also Ridgway at 56–58 (Ex. 2001 at 71–73).
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`Gelatin capsules were still the industry standard. See Grosswald at 1:18–19 (Ex.
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`2046) (“Pharmaceutical capsules presently in general use are made of gelatin and
`
`the techniques for the manufacture of gelatin capsules are well developed.”);
`
`Yamamoto at 1:18–19 (Ex. 1004) (“Medical hard capsules are conventionally
`
`formed from compositions comprising gelatin. . . .”); id. at 3:5–6 (reporting
`
`obtaining HPMC capsules that “exert[] performance equivalent to conventional
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`15
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`gelatin capsules”); Ridgway at 58, col. 1, 1st para. (“[G]elatin has a universal
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`acceptability [as capsule material] and so also must any other material that is to
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`replace it.”) (Ex. 2001 at 73); id. at 56 (Ex. 2001 at 71).
`
`35. Further, The Japanese Pharmacopoeia, another reference cited by Dr.
`
`Kibbe, identifies only gelatin as a specific capsule material. JP Pharmacopoeia
`
`(13th ed. 1996) (the “JP”) at 750, col. 2 (Ex. 2016 (fuller version of Ex. 1005))
`
`(“Capsules are made of gelatin or a suitable material . . . .). The United States
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`Pharmacopoeia also specifies that capsule “shells are usually formed from gelatin.”
`
`U.S. Pharmacopoeia, Ch. 1151, 4433–4440, 4436 (rev. 23d, 8th Supp. 1998) (Ex.
`
`2047) (providing “they also may be made from starch or other suitable
`
`substance.”). I also note that Dr. Kibbe provides no evidence that there were any
`
`HPMC capsules on the market prior to the ’180 patent. If HPMC capsule
`
`technology had been well-understood prior to the ’180 patent invention, I would
`
`have expected HPMC to have at least been identified as a suitable capsule
`
`substance in the Japanese or United States Pharmacopoeias, or used in marketed
`
`capsules by that time, given the industry’s drive to solve the problems discussed
`
`above with gelatin capsules. See above ¶¶ 32–33.
`
`36. Further, the state of the art in 1999 had not recognized that gelling aid
`
`precipitation was a phenomenon in cellulose ether capsules. I am not aware of
`
`reports on gelling aid precipitation occurring in capsules in 1999, and therefore
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`16
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`gelling aid precipitation would not have been a phenomenon known to a POSA, as
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`IPR2017-00203
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`I discuss below. See below ¶¶ 104–109. I note Dr. Kibbe does not state in his
`
`declaration that gelling aid precipitation was known in 1999. See Ex. 1011 ¶¶ 145–
`
`60.
`
`B. Hydroxypropyl Methylcellulose (“HPMC”) Substitution Types
`37. As I discuss above, by 1999 the industry had attempted to use HPMC
`
`as one of the cellulose ethers for developing a gelatin substitute as a hard capsule
`
`base. See above ¶ 33. HPMC is a polymer molecule with a cellulose backbone,
`
`comprising a chain of repeating anhydroglucose units. Dow Methocel (1991) at 4
`
`(Ex. 2035). Commercial manufacturers synthesize HPMC from cellulose in a
`
`process that substitutes a fraction of the available hydroxyl (OH) groups on the
`
`anhydroglucose units with methoxyl (“MO”) or hydroxypropoxyl (“HPO”) groups
`
`in an etherification reaction. Id.; Grover, Methylcellulose and its Derivatives,
`
`Chap. 18 in Industrial Gums: Polysaccharides and their Derivatives, 475–504, 476
`
`(R. Whistler & J. BeMiller, eds. 3d ed. 1993) (Ex. 2048). During this process,
`
`amounts of methyl chloride and propylene oxide are added to the reaction vessel,
`
`where the etherification takes place. See, e.g., Dow (1991) at 4 (Ex. 2035); Grover
`
`at 476 (Ex. 2048).
`
`
`
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`17
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`38. An HPMC structural formula is shown below:
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`IPR2017-00203
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`
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`HPE (1994) at 229 (Ex. 2003). The above formula depicts two anhydroglucose
`
`units, which would repeat throughout the polymer chain. Each R group is
`
`individually substitutable with an MO or HPO substituent. See Dow (1991) at 4
`
`(Ex. 2035); Grover at 476 (Ex. 2048). The degree of MO/HPO substitution and
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`position of MO/HPO groups are not the same on each anhydroglucose unit
`
`throughout the polymer chain. See, e.g., id.
`
`39. The synthetic process for HPMC involves subjecting the backbone to
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`two simultaneous chemical reactions which compete with one another to make an
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`HPO or MO substitution. Dow Methocel (1991) at 4 (Ex. 2035); see above ¶ 37.
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`As the synthetic process for manufacturing HPMC results in varying degrees of
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`substitution and positions of the MO and HPO groups, manufacturers developed
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`18
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`distinct HPMC products, informing customers that the different chemistries
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`substantially affected product performance. See below ¶ 47; Dow (1991) at 4 (Ex.
`
`2035) (“These products possess varying ratios of [HPO] and [MO] substitution, a
`
`factor which influences organic solubility and the thermal gelation temperature of
`
`aqueous solutions.”); see also Dow Methocel Cellulose Ethers Handbook (1978)
`
`(“Dow (1978)”) at § 3.3 (Ex. 2017).
`
`40. The HPMC material sold by manufacturers conformed to official
`
`reference standards promulgated by pharmaceutical societies or government
`
`authorities. See, e.g., U.S. Pharmacopoeia (rev. 23 1995) (“USP”) (Ex. 2015); JP
`
`(Exs. 1005 & 2015). The HPMC monographs in those standards publications set
`
`forth percent limits to which the HPO and MO substituents must conform. USP at
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`774, col. 2 (Ex. 2015) (“HPMC contains [MO and HPO] groups conforming to the
`
`limits for the types of Hydroxypropyl Methylcellulose set forth in the
`
`accompanying table.”); JP at 800–03 (Ex. 1005). The USP set forth four distinct
`
`HPMC substitution types with their corresponding minimum and maximum
`
`allowable limits of MO and HPO substitutions:
`
`
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`19
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`USP at 775, col. 1 (Ex. 2015).
`
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`41. The Handbook of Pharmaceutical Excipients in effect in 1999 set
`
`forth the same four distinct HPMC substitution types: 1828, 2208, 2906, and 2910.
`
`Handbook of Pharmaceutical Excipients, 229–32 (Wade & Weller eds., 2d ed.
`
`1994) (“HPE (1994)”) at 229, § 9 (Ex. 2003).
`
`42. The HPE (1994) explained the nomenclature of the four HPMC
`
`substitution types: “Hydroxypropyl methylcellulose defined in the USP XXII
`
`specifies the substitution type by appending a four digit number to the
`
`nonproprietary name, e.g. hydroxypropyl methylcellulose 1828. The first two
`
`digits refer to the approximate percentage content of the methoxy group (OCH3).
`
`The second two digits refer to the approximate percentage content of the
`
`hydroxypropoxy group (OCH2CHOHCH3), calculated on a dried basis.” HPE
`
`(1994) at 229, § 4 (Ex. 2003).
`
`43. A POSA in 1999 would have recognized, therefore, that the HPMC
`
`nomenclature identifies the average percentage contents of the MO and HPO
`
`groups. This would have been specified on the manufacturer’s label on the HPMC
`
`bottle, according to the specific substitution type. See USP at 774, col. 2 (Ex.
`
`2015) (HPMC monograph states: “Labeling—Label it to indicate its substitution
`
`type and its viscosity type”). Beyond reading the label to ascertain the HPMC
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`20
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`substitution type, the POSA would not have cared what the substitution percentage
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`of a given batch was.
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`44. A POSA in 1999 would not have understood the significance of
`
`changing MO
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