UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`CAPSUGEL BELGIUM NV
`Petitioner
`
`v.
`
`INNERCAP TECHNOLOGIES, INC.
`Patent Owner
`of
`Patent No. 8,361,497
`Issued: January 29, 2013
`Filed: January 19, 2010
`Inventor: Fred H. Miller
`Title: Multi-Phase, Multi-Compartment, Capsular Delivery Apparatus and
`Methods for Using the Same
`____________________
`
`Case IPR: Unassigned
`____________________
`
`DECLARATION OF DONALD K. LIGHTFOOT
`
`
`
`
`
`
`
`
`
`
`
`
`Capsugel Exhibit 1037
`
`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`
`
`
`I.
`
`Table of Contents
`
`PERSONAL AND PROFESSIONAL BACKGROUND ................................................. 1
`
`II. MATERIALS REVIEWED AND CONSIDERED ........................................................ 4
`
`III. PERSON OF ORDINARY SKILL IN THE ART ......................................................... 6
`
`IV. BACKGROUND ................................................................................................... 7
`
`A.
`
`Brief History of Capsule-Based Delivery Devices ............................... 8
`
`B. Hard and Soft Capsules ......................................................................... 9
`
`C.
`
`Capsule Fillings ................................................................................... 11
`
`1.
`
`2.
`
`Physical States ........................................................................... 11
`
`Ingredients ................................................................................. 13
`
`D.
`
`Capsule Filling and Coating Techniques ............................................ 14
`
`E. Multi-Compartment Capsules ............................................................. 19
`
`V.
`
`THE ’497 PATENT ........................................................................................... 24
`
`VI. OVERVIEW OF THE CITED PRIOR ART REFERENCES ........................................ 29
`
`A. WO 95/16438 (“Barnwell”) (Ex. 1001) .............................................. 30
`
`B. U.S. Patent No. 5,501,857 (“Zimmer”) (Ex. 1002) ............................ 33
`
`C.
`
`The National Library of Medicine’s Current Medical
`Information for Generic Midol® Complete (“Woonsocket’s
`Generic Midol®”) (Ex. 1003) .............................................................. 35
`
`D. Kline et al., “Enteric-coated, pH-dependent peppermint oil
`capsules for the treatment of irritable bowel syndrome in
`children,” J. Pediatr., 138(1):125-8 (2001) (Abstract) (“Kline”)
`(Ex. 1004) ............................................................................................ 35
`
`E.
`
`The FDA letter from McNeil Consumer Healthcare (“McNeil
`Letter”) (Ex. 1005) .............................................................................. 36
`
`
`
`i
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`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`U.S. Patent No. 5,738,871 (“Story”) (Ex. 1006) ................................. 36
`
`F.
`
`G. Merriam-Webster’s Dictionary Definition of “Elixir” (Ex.
`1007) .................................................................................................... 36
`
`H. Merriam-Webster’s Dictionary Definition of “Spirit” (Ex.
`1008) .................................................................................................... 37
`NORVIR® (Ex. 1009) .......................................................................... 37
`
`I.
`
`J. WO 00/28976 (“Schmidt”) (Ex. 1010) ............................................... 37
`
`K.
`
`The Aaron Company’s Dietary Supplement Catalog (“Aaron
`Co. Catalog”) (Ex. 1011) ..................................................................... 38
`
`VII. SUMMARY OF OPINIONS .................................................................................. 38
`
`VIII. CLAIMS 1-26 OF THE ’497 PATENT DO NOT CONTRIBUTE ANYTHING
`NEW TO THE FIELD IN VIEW OF THE PRIOR ART .............................................. 40
`
`A.
`
`Basis of My Analysis with Respect to Anticipation ........................... 40
`
`1.
`
`Each and Every Element of Claims 1, 2, 4, 5, 11-14, 20,
`21, and 26 of the ’497 Patent is Set Forth in Barnwell
`Such that One Skilled in the Art Could have Arrived At
`the Invention of those Claims Without Undue
`Experimentation ........................................................................ 41
`
`B.
`
`The Basis of my Analysis with Respect to Obviousness .................... 46
`
`1.
`
`2.
`
`3.
`
`Any Differences between Claims 1, 2, 4, 5, 11-14, 20, 21,
`and 26 of the ’497 Patent and Barnwell Would Have
`Been Obvious to One of Ordinary Skill in the Art ................... 47
`
`Claims 1 and 26 are Obvious over Zimmer in view of
`Barnwell .................................................................................... 51
`
`a. Motivation to Combine ................................................... 53
`
`Claims 1-5, 7, 8, 10-14, 17, 18, 20, 21, and 26 are
`Obvious over Barnwell in view of Zimmer .............................. 55
`
`
`
`ii
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`

`

`4.
`
`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`Dependent Claims 6, 9, 15, 16, 19, and 22-25 are
`Obvious over Barnwell Alone (or Barnwell in View of
`Zimmer) in View of Various Prior Art References .................. 59
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`g.
`
`Claim 6 is Obvious over Barnwell alone (or
`Barnwell in view of Zimmer) in view of the
`National Library of Medicine’s Current Medical
`Information for Generic Midol® Complete (Ex.
`1003) ............................................................................... 60
`
`Claim 9 is Obvious over Barnwell alone (or
`Barnwell in view of Zimmer) in view of the Kline
`et al. Abstract (Ex. 1004) ................................................ 61
`
`Claims 15 and 16 are Obvious over Barnwell alone
`(or Barnwell in view of Zimmer) in view of the
`McNeil Letter (Ex. 1005) ............................................... 62
`
`Claim 19 is Obvious over Zimmer in view of
`Barnwell and Further in view of Story (Ex. 1006) ......... 63
`
`Claims 22 and 23 are Obvious over Barnwell alone
`(or Barnwell in view of Zimmer) in view of the
`NORVIR® Label (Ex. 1009) ........................................... 64
`
`Claim 24 is Obvious over Barnwell alone (or
`Barnwell in view of Zimmer) in view of Schmidt
`(Ex. 1010) ....................................................................... 65
`
`Claim 25 is Obvious over Barnwell alone (or
`Barnwell in view of Zimmer) in view of the Aaron
`Company’s Dietary Supplement Catalog (Ex.
`1011) ............................................................................... 66
`
`IX. CONCLUSION ................................................................................................... 67
`
`
`
`
`
`iii
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`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`
`
`I, Donald K. Lightfoot, declare:
`
`1.
`
`I have been retained by Finnegan, Henderson, Farabow, Garrett &
`
`Dunner, LLP, counsel for Capsugel Belgium NV (“Capsugel”), to submit this
`
`declaration in support of Capsugel’s Petition for Inter Partes Review of claims 1-
`
`26 of U.S. Patent No. 8,361,497 (“the ’497 patent”). I am being compensated for
`
`my time at a rate of $125 per hour or $1000 per day, plus actual expenses. My
`
`compensation is not dependent in any way upon the outcome of Capsugel’s
`
`petition.
`
`2.
`
`From May 31, 2006 through May 31, 2008, I had a consulting
`
`contract with Capsugel. Under the contract, I provided Capsugel with limited
`
`consulting in the areas of capsule dosage forms and development activities relating
`
`to capsules. I currently have no financial relationship with Capsugel.
`
`I.
`
`PERSONAL AND PROFESSIONAL BACKGROUND
`3.
`
`I am an expert in the field of capsular delivery devices. I have
`
`extensive production experience in capsule filling and other processes, including
`
`granulation, tablet compression, tablet coating, pellet coating, and suppository
`
`manufacturing.
`
`4.
`
`I have a Bachelor’s Degree, magna cum laude, from Temple
`
`University. Prior to my retirement, I was a member of several professional
`
`
`
`1
`
`

`

`associations
`
`including
`
`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`the Society of Manufacturing Engineers and
`the
`
`International Society for Pharmaceutical Engineering.
`
`5.
`
`Before becoming an independent pharmaceutical consultant, I spent
`
`46 years at GlaxoSmithKline (SmithKline Beecham Corporation, Smith Kline &
`
`French Laboratories). From 1993-2005, I was Director of GSK’s North America
`
`Clinical Trial Supplies Manufacturing. As Director, I managed a group of more
`
`than 60 R&D scientists at the Pennsylvania, North Carolina, and Canada Pilot
`
`Plant Sites involved in clinical supply manufacturing of solid dosage forms and
`
`parenterals for phase I through phase IIIB project compounds and phase IV
`
`Product Line Extensions. I also managed the Validation & Facilities Groups
`
`supporting the GMP Clinical Manufacturing operations, and the Materials
`
`Management group responsible for inventory, allocation and supply of drug
`
`substance, excipients, components and bulk drug product, comparator sourcing,
`
`and shipping of bulk clinical supplies.
`
`6.
`
`Prior to directing GSK’s North America Clinical Trial Supplies
`
`Manufacturing, I managed GSK’s Capsule Operations Department for more than
`
`17 years. As Manager, I was responsible for granulation, tablet compression,
`
`tablet coating, capsule filling, pellet coating, and liquid, ointment, and suppository
`
`manufacturing. I was responsible for molding up to 1.1B hard gelatin capsules per
`
`year; printing, filling, sealing, and inspecting 750MM capsule drug products per
`
`
`
`2
`
`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`year; and molding of 20MM plastic bottles per year. I implemented capsule
`
`sealing technology, introduced electronic color inspection of filled capsules, and
`
`managed a staff of 80 manufacturing personnel.
`
`7.
`
`Selected accomplishments
`
`from my
`
`time at GSK
`
`include:
`
`implementation of capsule sealing technology and a plastic bottle injection blow
`
`molding operation at SmithKline & French; team leader of a trans-national group
`
`of Clinical Manufacturing Scientists involved in the development of Single Quality
`
`Standards of manufacturing for the global Pharmaceutical Technology sites; and
`
`collaboration with UK Clinical Manufacturing colleagues in developing and
`
`successfully implementing a trans-national Clinical Manufacturing Strategic Plan.
`
`8.
`
`I have authored many peer-reviewed articles in Tablets & Capsules
`
`Magazine, and a textbook chapter on capsule filling techniques. See, e.g.,
`
`“Answers to 10 Common Questions about Capsule Filling”; “A Rising Tide/Liquid
`
`Filled Capsules”; “An Overview of Capsule Checkweighers”; “An Overview of
`
`Capsule Sealing Equipment”; and “Multiparticulate Encapsulation Equipment and
`
`Process” in “Multiparticulate Oral Drug Delivery,” Marcel Decker Inc., 1994. As
`
`listed in my curriculum vitae (Appendix A), I have also received numerous awards
`
`pertaining to my lecturing and expertise.
`
`9.
`
`In addition to gaining expertise via my educational training and
`
`professional experiences described above, I have kept abreast of the field of
`
`
`
`3
`
`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`capsular delivery devices by reading scientific literature, and by attending and
`
`presenting at conferences. I am currently a member of the Technical Advisory
`
`Board for Tablets and Capsules magazine. As a board member, I am responsible
`
`for commenting on submitted articles as well as authoring one or more articles per
`
`year as requested by the publisher.
`
`10. As an expert in the field of capsular delivery devices, I am qualified to
`
`provide an opinion as to what a person of ordinary skill in the field would have
`
`understood, known, or concluded as of April 2002, which I understand is the
`
`earliest effective filing date of the ’497 patent. In formulating my opinions
`
`expressed herein, I have relied on my training, knowledge, and experience
`
`discussed above, and as further detailed in my curriculum vitae.
`
`II. MATERIALS REVIEWED AND CONSIDERED
`11.
`In connection with my work on this matter, I have reviewed and
`
`considered United States Patent No. 8,361,497 (Ex. 1038), and the following
`
`documents:
`
`Exhibit
`1001
`1002
`1003
`
`1004
`
`1005
`
`Description
`International Patent Publication No. WO 95/16438
`U.S. Patent No. 5,501,857
`Printout of the United States National Library of Medicine
`National Institutes of Health Daily Med entry for generic Midol®
`Kline, R.M. et al., “ Enteric-coated, pH-dependent peppermint oil
`capsules for the treatment of irritable bowel syndrome in
`children,” 2001, J. Pediatr., 138(1):125-128 (Abstract)
`FDA Letter from McNeil Consumer Healthcare dated Aug
`19,1999
`
`
`
`4
`
`

`

`1006
`1007
`1008
`1009
`1010
`1011
`
`1012
`
`1013
`1014
`1015
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`1022
`1023
`1024
`1025
`1026
`1027
`1028
`1029
`1030
`1031
`
`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`U.S. Patent No. 5,738,871
`Definition of “elixir” - Merriam-Webster Online
`Definition of “spirit” - Merriam-Website Online
`Norvir® label
`International Patent Publication No. WO 00/28976
`Printout of Vitamins And More From Aaron Co. Colloidal Silver
`Specialists
`Alptekin N.O. et al., “Effects on the clinical indices and gingival
`crevicular fluid enzyme activities of the cyclical regimen of low-
`dose doxycycline therapy for adult periodontitis,” J. Int. Acad.
`Periodontol., 2000, 2(1):3-8 (Abstract)
`European Patent Application No. EP0116311A1
`European Patent Application No. EP0130163A1
`European Patent Application No. EP0211079A1
`Printout of the United States National Library of Medicine
`Dietary Supplements Labels Database entry for Lactobacillus
`Probiotic Complex
`Printout of the United States National Library of Medicine
`Dietary Supplements Labels Database entry for Oleic Acid
`Printout of the United States National Library of Medicine
`National Institutes of Health Drug Information Portal Database
`entry for Propanolol
`Cole G.C., “The Mechanical Operations of Filling Hard
`Capsules,” Chapter 9 in Hard Capsules Development and
`Techonology, edited by Ridgway K. (1987)
`Santivarangkna C. et al., “Role of glassy state on stabilities of
`freeze-dried probiotics,” 2011, J. Food Sci., 76(8):R152-6
`(Abstract)
`U.S. Patent No. 6,232,333 B1
`U.S. Patent No. 1,815,902
`U.S. Patent No. 2,340,037
`U.S. Patent No. 5,074,426
`U.S. Patent No. 5,310,555
`U.S. Patent No. 5,466,843
`International Patent Publication No. WO 01/03676 A1
`International Patent Publication No. WO 01/36290 A1
`International Patent Publication No. WO 02/07710 A2
`International Patent Publication No. WO 99/30693
`U.S. Patent No. 7,163,693 B1
`5
`
`
`
`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`Reich G., “Formulation and physical properties of soft capsules,”
`Chapter 11 in Pharmaceutical Capsules, 2nd edition (2004), edited
`by Fridrun Podczeck and Brian E. Jones
`Stegemann S., “Hard gelatin capsules today - and tomorrow,” 2nd
`edition 2002, Capsugel Library
`Lightfoot D.K., “A rising tide: liquid-filled capsules,” Tablets &
`Capsules (2008)
`Lightfoot D.K., “Capsule Sealing,” Tablets & Capsules (2013)
`Lightfoot D.K., “Multiparticulate Encapsulation Equipment and
`Process,” in Multiparticulate Oral Drug Delivery,” Vol. 65,
`edited by Isaac Ghebre-Sellassie (1994)
`
`1032
`
`1033
`
`1034
`
`1035
`1036
`
`
`
`III. PERSON OF ORDINARY SKILL IN THE ART
`12.
`I am informed that patent claims and prior art references should be
`
`understood from the perspective of a person of ordinary skill in the art to which the
`
`patent is related, based on the understanding of that skilled person at the time the
`
`application was filed. I understand that a person of ordinary skill in the art is one
`
`who is presumed to be aware of all pertinent art, thinks along conventional wisdom
`
`in the art, and is a person of ordinary creativity. I have applied this standard
`
`throughout my report.
`
`13.
`
`I have been informed that there are several factors that may be used in
`
`determining the level of ordinary skill in the art, including but not limited to (1) the
`
`education level of the inventor(s), (2) the education level of active workers in the
`
`field, (3) the types of problems encountered in the art, (4) the prior art solutions to
`
`these problems, (5) the rapidity with which innovations are made, and (6) the
`
`sophistication of the technology. I have further been informed that these factors
`6
`
`
`
`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`may not be present in every case and that certain factors may be more relevant in
`
`some cases than others.
`
`14. For the ’497 patent, as of April 2002, the level of skill in the art of
`
`capsular delivery devices was high. In my opinion, a person of ordinary skill in the
`
`art related to the ’497 patent would have held a Bachelor’s degree in Pharmacy,
`
`Chemical Engineering, Pharmaceutical Manufacturing Technology, or have had
`
`equivalent practical experience. In addition, he would have had 8 to 10 years of
`
`practical experience manufacturing and filling capsules for clinical and commercial
`
`products.
`
`15. As reflected in my qualifications set forth above and in my curriculum
`
`vitae, I qualified as a person of more than ordinary skill in the art at the time the
`
`’497 patent was filed. My opinions concerning the ’497 patent claims set forth
`
`herein are from the perspective of a person of ordinary skill in the art, as set forth
`
`above.
`
`IV. BACKGROUND
`16. The ’497 patent relates to multi-phase, multi-ingredient, multi-
`
`compartment capsules. The following paragraphs provide a detailed background
`
`of that technology.
`
`
`
`7
`
`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`A. Brief History of Capsule-Based Delivery Devices
`17. The capsule is one of the oldest dosage forms in pharmaceutical
`
`history, and was even known to the ancient Egyptians. (Ex. 1033 at p. 3.) The
`
`earliest European reference is contained in a travel account from 1730, which
`
`mentions the pharmacist de Pauli from Vienna, who produced oval-shaped
`
`capsules in the hope of covering up the unpleasant taste of the pure turpentine he
`
`prescribed for people suffering from gout. (Id.)
`
`18. Approximately 100 years later, the first gelatin capsule appeared.
`
`(Id.) The first patent for such a product was granted in 1834 to the pharmacist
`
`Joseph Gérard Auguste Dublanc and the pharmacy student François Achille
`
`Barnabé Mothès. (Id.) Mothès, who ended his collaboration with Dublanc in
`
`1837, continued to work on improving the gelatin capsule and applied for several
`
`patents on the manufacture and use of capsules. (Id.) Mothès’ inventions were so
`
`successful that, by the following year, capsules were being produced in many
`
`different parts of the world. (Id.) Eventually, this resulted in several more
`
`applications for patents on gelatin capsules. (Id.)
`
`19. One such patent was granted in 1846 to Jules Cesar Lehuby for
`
`“medicine coverings,” and describes the principle of hard-gelatin capsule
`
`manufacturing that is still used today. (Id.) Lehuby also was the first to introduce
`
`two-piece capsules, which he produced by dipping silver-coated metal pins into a
`
`
`
`8
`
`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`gelatin solution and then drying them. (Id.) However, technical difficulties in
`
`manufacturing the separate fitted sections (i.e., the body and the cap) halted further
`
`development of this dosage form for another century. (Id.)
`
`20.
`
`In 1931, Arthur Colton, on behalf of Parke, Davis & Co., succeeded in
`
`designing a machine that simultaneously manufactured both bodies and caps and
`
`fitted them together to form hard gelatin capsules. (Id.) That machine still
`
`represents the basic design of today’s machinery—only minor modifications have
`
`been made to it since 1931 to improve product quality and efficiency. (Id.)
`
`B. Hard and Soft Capsules
`21. Capsules generally comprise an envelope wall of a pharmaceutically
`
`acceptable, e.g., orally ingestible, polymer material such as gelatin, although other
`
`materials for capsule walls such as starch and cellulose-based polymers may also
`
`be used. (Ex. 1031 at col. 1, ll. 7-27.) The capsule walls may be made by placing
`
`a film onto a capsule form or die, which is then allowed to dry, or by continuously
`
`feeding films into the space between a pair of die rolls, and compressing the two
`
`films together. (Id.) Alternatively, or in addition, capsule walls may be made by
`
`injection molding. (See, e.g., Ex. 1028.)
`
`22. There are two types of capsules: hard-shelled capsules and soft-
`
`shelled capsules. Indeed, the U.S. Pharmacopeia defines capsules as solid dosage
`
`
`
`9
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`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`forms in which the active ingredients are sealed in a hard or soft container or shell.
`
`(Ex. 1033 at p. 4.)
`
`23. The differences between soft and hard capsules lie in the composition
`
`of the shell and in the production process. (Id. at p. 19.) Hard shelled capsules
`
`consist of virtually pure gelatin, or other suitable polymer, with a sorption water
`
`content of 13% to 16%. (Id.) Soft capsules normally have thicker shells and
`
`contain approximately 20% to 30% of plasticizers, such as glycerol or sorbitol.
`
`(Id.) Due to the high plasticizer content, the water content of soft capsules is
`
`approximately 30% before drying. (Id.) After capsule formation, however, most
`
`of the water is removed by drying, leading to finished capsules with a moisture
`
`content of 4-10%. (Ex. 1032 at p. 201.)
`
`24. There are virtually no differences between soft and hard capsules as
`
`far as the suitability of fillings is concerned, because compatibility of the
`
`formulation with the polymer wall is the main factor to consider. (Ex. 1033 at p.
`
`19.) However, soft capsules are mainly filled with liquids or liquid suspensions.
`
`In addition, the plasticizer and water content of soft capsules lead to higher oxygen
`
`permeability through the shell, which can lead to problems in the formulation of
`
`ingredients for soft capsules. (Id.)
`
`25. The main differences between the capsule types are apparent in their
`
`production process and storage requirements. (Id.) Hard capsules require less
`
`
`
`10
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`

`

`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`stringent conditions during manufacture and storage than soft capsules. (Id.) The
`
`production of soft capsules has to be carried out under controlled conditions at
`
`20% to 30% relative humidity at room temperature, while the processing of hard
`
`capsules can be carried out at 40% to 60% relative humidity at room temperature.
`
`(Id.) In addition, soft capsules cannot be filled with ingredients having a
`
`temperature that exceeds the sealing temperature of the capsule. Thus, for
`
`example, formulations to be filled into soft gelatin capsules are typically kept
`
`below 104°F, while hard gelatin capsules can sustain temperatures up to 212°F for
`
`short periods of time. (Id.)
`
`26. An initial disadvantage of hard capsules was their tendency to leak at
`
`the joint between the body and cap. (Id.) By the turn of the twenty-first century,
`
`however, those skilled in the art had developed ways to solve that problem by
`
`applying a gelatin film on the joint (known as banding), or by spraying ethanol and
`
`water between the joint (known as sealing), both of which are discussed in greater
`
`detail below.
`
`C. Capsule Fillings
`1.
`Physical States
`27. Hard and soft-shelled capsules are both suitable for encapsulating
`
`both solid and liquid products. In fact, at the time the ’497 patent was filed, the
`
`possibilities for fill compositions were almost unlimited.
`
`
`
`11
`
`

`

`28. Powders are
`
`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`the most common form for solid capsule fill
`
`compositions. (Ex. 1019 at p. 92.) However, doses over 600 mg in powder form
`
`are virtually impossible to put into capsules of acceptable size. (Ex. 1033 at p. 11.)
`
`It has, though, been possible to produce such doses in capsule form by increasing
`
`the density of the formulation, for instance, by granulation. (Id.) Granulation
`
`usually leads to an improvement of parameters such as product flow. (Id.) It is
`
`also possible to improve the dissolution rate of a substance by granulation, due to
`
`increased dispersion of the drug in the granules. (Id.) Other suitable solid fill
`
`compositions include pellets, beads, tablets, microtablets, and caplets. (See, e.g.,
`
`Ex. 1036 at pp. 161-170.)
`
`29. From a pharmaceutical point of view, however, there are several
`
`advantages to formulating liquid and semi-solid fillings in capsules, as opposed to
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`solids. (Ex. 1033 at p. 18.) For example, drugs with certain characteristics—such
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`as a low melting point, low dose, or critical stability—present problems that make
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`development in solid oral dosage form difficult, but which can be circumvented by
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`formulation as liquid or semi-solid fillings. (Id.)
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`30. The use of soft gelatin capsules as solid oral dosage forms for liquid
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`and semi-solid formulations was well known at the time the ’497 patent was filed.
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`On the other hand, when talking about hard capsules, powder and granular fillings
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`are usually what spring to mind. (Id. at p. 4.) In fact, however, the first hard
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`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`gelatin capsules were actually developed for liquid medicines. (Id.) Thanks to the
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`hard gelatin capsule, it was possible to formulate a new dosage form for liquid
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`balsam copaivae, which was used during the Napoleonic wars as a cure for
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`vascular diseases. (Id.) This was of great importance, as the substance causes
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`severe nausea if taken as an oral solution. (Id.) As discussed in greater detail
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`below, by the time the ’497 patent was filed, several formulations of liquid or
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`semi-solids had been developed and manufactured in hard capsules.
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`Ingredients
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`2.
`In the development of new active ingredients for oral administration,
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`31.
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`there are several problems to be solved, including formulation, stability, and
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`release characteristics. (Id.) The simplicity of capsule formulation and
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`manufacturing, as well as the versatility of these dosage forms, makes them well-
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`suited for dosing active ingredients. (See id.) Indeed, capsules are easier and
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`quicker to formulate and produce compared with other solid oral dosage forms.
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`(See id. at p. 8.) This has considerably expanded the range of possible
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`formulations utilizing capsules as a simple dosage form for oral drug delivery.
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`(See id. at p. 3.)
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`32. Those skilled in the art have long recognized that, in general, any
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`types of ingredients could be used as fill compositions in capsule-based delivery
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`devices. For example, WO 00/28976 teaches that capsules may be used to deliver
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`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`ingredients ranging from medicinal compounds to foodstuffs, and from fertilizers
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`to cosmetics. (Ex. 1010 at p. 1, ll. 13-19.) Thus, by the time the ’497 patent was
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`filed, the selection of suitable capsule fill compositions had become quite routine.
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`33. When starting to formulate an ingredient in a capsular delivery form,
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`an important aspect to investigate is its compatibility with the capsule shell. (Ex.
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`1033 at p. 10.) Incompatibilities are known to occur, for instance, with gelatin
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`capsules and certain substances that contain reactive aldehydes, because the
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`aldehydes can react with the gelatin by forming crosslinks. Incompatibilities can
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`also occur with highly hygroscopic ingredients, which may absorb water from
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`gelatin capsule shells, leading to brittleness. (Id.) However, by the turn of the
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`twenty-first century, those skilled in the field had developed ways to prevent such
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`adverse reactions by controlling capsule storage conditions (e.g., to minimize
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`extremes in temperature, humidity, and light exposure), by adjusting the pH and/or
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`enzyme activity of the formulation, and/or by adding various diluents and fillers.
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`(Id.) Thus, as capsule technology developed those skilled in the art routinely
`
`designed around undesirable interactions, for example, by selecting different
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`capsule materials and/or different ingredient formulations.
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`D. Capsule Filling and Coating Techniques
`34. Capsule-filling machines are classified into the following categories
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`based on level of automation and type of machine motions: totally manual,
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`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`semiautomatic, automatic-intermittent motion, and automatic-continuous motion.
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`(Ex. 1036 at p. 171.) All hard shell capsule-filling machines perform the same
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`operations in encapsulating a product: (1) line up and rectify the hard gelatin
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`capsules, (2) separate body and cap, (3) fill the body, (4) join cap and body
`
`together (for closing), and (5) eject the filled capsules. (Id. at pp. 159-161.) Soft
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`capsule manufacturing machines perform similar operations: (1) preparing the gel
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`mass, (2) encapsulating the fill material (forming, filling, and sealing the capsule),
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`and (3) drying. (Ex. 1021 at col. 20, ln. 41-col. 21, ln. 8.)
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`35. As indicated above, the development of machinery to mass-produce
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`and fill capsules can be traced back to the early 1900s. Today’s high-speed
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`automatic capsule-filling machinery was developed in the late 1950s. That
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`technology was modified in the 1980’s after capsule tampering incidents led the
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`U.S. Food and Drug Administration (FDA) to mandate that all over-the-counter
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`capsule products must be sealed using tamper-evident technology. (Ex. 1034,
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`second column.) The FDA’s mandate led to the development and availability of a
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`variety of capsule sealing machines that also facilitated the adoption of liquid-filled
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`hard and soft gelatin capsules. (Id.) By the turn of the twenty-first century, fully-
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`automated capsule-filling machines were capable of producing up to 200,000
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`capsules an hour and were also capable of filling a number of different substances
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`in a single process run. (Ex. 1033 at pp. 3-4, 9-10, 13.)
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`Inter Partes Review of U.S. Patent No. 8,361,497
`Declaration of Donald K. Lightfoot (Ex. 1037)
`36. These technological developments probably account for the fact that
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`use of hard gelatin capsules has grown steadily over the years. In 1982, only
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`17.5% of newly-licensed medicinal products were presented as hard gelatin
`
`capsules. (Id. at p. 4.) By 1996, the figure had reached 35%. (Id.)
`
`37. By the turn of the twenty-first century, high-speed filling machines for
`
`encapsulating solid powder ingredients in hard capsules used two main filling
`
`principles: “dosator” and “dosing disk or tamping.” (Id. at p. 9.) The dosator
`
`principle uses a dosing tube that transfers a cohesive plug to the capsule body. In
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`the dosing disk principle, powder flows into the filling chambers followed by a
`
`slight compression by a series of tamping punches. (Id.) In addition, there were
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`four basic methods for filling non-powder solids (i.e., pellets) into hard capsules:
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`(1) direct fill into the capsule body using a feed frame or shoe; (2) use of a vacuum
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`dosator; (3) use of a dosing chamber; and (4) use of a dosing disc without tamping.
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`(See Ex. 1036 at pp. 166-169.)
`
`38. Similarly, various well-established methods existed for manufacturing
`
`and filling soft shell capsules: (1) a seamless capsule method, (2) a rotary method,
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`and (3) methods using a Linear machine or an Accogel machine, and the like. (Ex.
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`1021 at col. 20, ln. 41-col. 21, ln. 8.) All of these methods involve preparing a gel
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`mass by mixing