`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`PAR PHARMACEUTICAL, INC.
`Petitioner
`
`v.
`
`SUMITOMO DAINIPPON PHARMA CO., LTD.
`Patent Owner
`_______________________
`U.S. Patent No. 9,555,027
`
`Title: Pharmaceutical Composition
`_______________________
`
`Inter Partes Review Case No. Unassigned
`_______________________
`
`DECLARATION OF PROFESSOR GRAHAM BUCKTON
`
`
`
`
`
`
`
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 001
`
`

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`
`
`TABLE OF CONTENTS
`
`I.
`
`
`II.
`
`
`Introduction ...................................................................................................... 1
`
`Background and Qualifications ....................................................................... 2
`
`
`
` List Of Documents Considered In Forming My Opinions .............................. 6 III.
`
`
`
` My Understanding of the Relevant Law ......................................................... 9 IV.
`
`A.
`B.
`
`Claim Construction................................................................................ 9
`Obviousness ........................................................................................... 9
`
`V.
`
`
`Level of Ordinary Skill in the Art ................................................................. 12
`
`
`
` Summary of the ’027 Patent Disclosure and Alleged Invention ................... 13 VI.
`
`A.
`B.
`
`The Specification ................................................................................. 13
`The Claims of the ’027 Patent ............................................................. 17
`
`
`
` Claim construction ......................................................................................... 20 VII.
`
`A.
`B.
`
`“Pregelatinized starch” ........................................................................ 21
`“Equivalent dissolution profile across the range of lurasidone” ......... 23
`
`
`
` The State of the Art in 2005 .......................................................................... 25 VIII.
`
`A.
`
`B.
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`Formulation of oral preparations with good disintegration and
`rapid dissolution was well known in the art ........................................ 25
`Lurasidone (and formulations thereof) were known in the art............ 28
`Lurasidone was known to be effective at doses from 5 to
`120 mg ................................................................................................. 31
`It was known to select excipients to improve the dissolution
`rate ....................................................................................................... 33
`It was known that different dosage amounts of a given
`formulation should be proportionally scaled, should have
`acceptable tablet size, and should share equivalent dissolution
`characteristics ...................................................................................... 36
`Pregelatinized starch was a commonly used disintegrant (and
`multifunctional excipient) in oral dosage forms ................................. 40
`Pregelatinized starch was known to impart rapid dissolution and
`disintegration behavior in immediate release oral dosage forms ........ 44
`
`i
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`Par Pharm., Inc.
`Exhibit 1002
`Page 002
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`
`H.
`
`I.
`
`J.
`
`Pregelatinized starch was used in formulations of poorly
`soluble APIs to impart rapid dissolution and disintegration ............... 46
`The beneficial dissolution and disintegration behavior of
`pregelatinized starch was known to apply to formulations with a
`wide range of API loading .................................................................. 48
`Pregelatinized starch was typically used in amounts ranging
`from 1-75% of total weight of the oral dosage form ........................... 49
`
`
`
` Summary of Prior Art .................................................................................... 50 IX.
`
`A.
`B.
`
`C.
`D.
`
`EP 1 327 440 A1 (Ex. 1008, “Fujihara”) ............................................ 50
`PHARMACEUTICS: THE SCIENCE OF DOSAGE FORM DESIGN
`(Michael E. Aulton ed., 1988) (Ex. 1009, “Aulton”) .......................... 58
`U.S. Patent No. 4,911,921 (Ex. 1010, “Denton”) ............................... 62
`Chowdary, K.P.R. and Rama Rao, N., “Formulation and
`Evaluation of Dispersible Tablets with Pregelatinized Starch,”
`Indian Drugs, 35(6):368-371 (1998) (Ex. 1011, “Chowdary”) .......... 64
`
`X.
`
`
`Sumitomo did not fairly Characterize the prior art during prosecution ........ 67
`
`A.
`
`B.
`
`C.
`
`The prior art does not support Sumitomo’s argument that
`pregelatinized starch has unpredictable effects on dissolution ........... 67
`Salpekar does not teach away from the claimed range of
`pregelatinized starch ............................................................................ 72
`One of ordinary skill would consider formulations of other
`poorly soluble APIs relevant to formulations of lurasidone ............... 77
`
`
`
` Overview of my conclusions ......................................................................... 79 XI.
`
` The Challenged Claims would have been Obvious to One of Ordinary XII.
`
`
`Skill in 2005 ................................................................................................... 81
`
`A.
`
`The Challenged Claims were obvious over Fujihara in view of
`Aulton .................................................................................................. 81
`1.
`Fujihara discloses ranges of lurasidone content and
`excipients that overlap with the Challenged Claims ................. 82
`One of ordinary skill would have been motivated to
`increase the dose of lurasidone in Fujihara while
`maintaining equivalent dissolution between doses ................... 84
`One of ordinary skill would have used the higher content
`of lurasidone disclosed in Fujihara ........................................... 86
`
`2.
`
`3.
`
`ii
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`Par Pharm., Inc.
`Exhibit 1002
`Page 003
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`4.
`
`5.
`
`6.
`
`7.
`
`One of ordinary skill was motivated to select a known
`disintegrant in Fujihara ............................................................. 87
`It would have been obvious to combine Fujihara with
`Aulton to select pregelatinized starch as a disintegrant
`because pregelatinized starch was in a small group of
`commonly used disintegrants .................................................... 88
`There is no evidence of unexpected results of the claimed
`ranges ........................................................................................ 93
`Combining Fujihara with Aulton yields every limitation
`of the challenged claims .......................................................... 100
`The Challenged Claims would have been obvious over Fujihara
`in view of Denton and Chowdary ..................................................... 118
`1.
`One of ordinary skill would have been motivated to
`improve the oral preparations of Fujihara to increase the
`dose of lurasidone while maintaining equivalent
`dissolution between doses ....................................................... 118
`One of ordinary skill would have used the higher content
`of lurasidone disclosed in Fujihara ......................................... 119
`To limit tablet size and maintain equivalent dissolution
`profiles between doses across a broad range, one of
`ordinary skill would have looked to Denton’s use of
`pregelatinized starch ............................................................... 119
`One of ordinary skill further would have looked to
`Chowdary to use 10%-20% pregelatinized starch .................. 123
`There is no evidence of unexpected results for the
`claimed ranges ......................................................................... 126
`Combining Fujihara with Denton and Chowdary yields
`every limitation of the Challenged Claims ............................. 127
`Reasonable Expectation of Success .................................................. 133
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`B.
`
`C.
`
`
`
` There Are No Secondary Considerations of Non-Obviousness .................. 136 XIII.
`
`XIV.
`
` Conclusion ................................................................................................... 137
`
`
`
`iii
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 004
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`

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`
`
`I, Professor Graham Buckton, hereby declare as follows.
`
`I.
`
`
`INTRODUCTION
`
`1.
`
`I am over the age of eighteen and otherwise competent to make this
`
`declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Par
`
`Pharmaceutical, Inc. (“Par”) 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 £375 per hour for my work on this matter. I also am
`
`reimbursed for travel and other direct expenses. I have no personal or financial
`
`interest in the outcome of this proceeding.
`
`3.
`
`I understand that this declaration is being submitted in support of a
`
`petition for IPR of U.S. Patent No. 9,555,027 (Ex. 1001, “the ’027 Patent”), which
`
`issued from U.S. Application No. 14/512,189 (“the ’189 application”) on January
`
`31, 2017. The ’027 Patent names Kazuyuki Fujihara as inventor. I further
`
`understand that, according to USPTO records, the ’027 Patent is currently assigned
`
`to Sumitomo Dainippon Pharma Co., Ltd. (“Patent Owner”).
`
`4.
`
`The cover page of the ’027 Patent indicates that it was filed as the
`
`’189 application on October 10, 2014. The cover page of the ’027 Patent also
`
`claims priority to two related U.S. patent applications, U.S. Non-provisional
`
`Application No. 14/183,283 (“the ’283 application,” filed on February 18, 2014),
`
`1
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 005
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`

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`
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`and U.S. Non-provisional Application No. 11/919,678 (“the ’678 application,”
`
`filed as application No. PCT/JP2006/310571 on May 26, 2006). The ’027 Patent
`
`also claims priority to Japanese Application No. (JP) 2005-153508, filed on May
`
`26, 2005.
`
`5.
`
`In preparing this Declaration, I have reviewed the ’027 Patent, its
`
`file history and those of its parent patents, and considered each of the documents
`
`cited herein, in light of the general knowledge in the field as of May 26, 2005. In
`
`forming my opinions, I have relied upon my more than 30 years of experience,
`
`education, and knowledge in the relevant art. In forming my opinions, I have also
`
`considered the viewpoint of a person of ordinary skill in the art as of May 26,
`
`2005.
`
` BACKGROUND AND QUALIFICATIONS II.
`
`
`I am an Emeritus Professor of Pharmaceutics in the UCL School of
`6.
`
`Pharmacy of the University of London. I was employed at the School of Pharmacy
`
`of the University of London from 1988 to 2015, initially as Lecturer, then Senior
`
`Lecturer, Reader, and Professor, during which time I served as the Head of the
`
`Department of Pharmaceutics between January 2001 and April 2007. I served as
`
`Chair of the Master of Sciences in Pharmacy (MPharm) Exam Board between
`
`2002 and 2012, and have been an MPharm (or Bachelors in Pharmacy, BPharm)
`
`Examiner at Queens University of Belfast, Cardiff University, University of
`
`2
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 006
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`

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`
`
`Nottingham, Kings College (University of London), University of Colombo (Sri
`
`Lanka), Robert Gordon University, and the University of East Anglia. I received
`
`my Ph.D. in Pharmaceutics from Kings College London in 1985.
`
`7.
`
`In 2000 I founded a contract services company called Pharmaterials
`
`Ltd. I sold the majority stake to a U.S. company, Pharmaceutics International Inc.
`
`(PII), in 2008 and the remaining stake in 2012, at which time I exited. I was Chief
`
`Executive Officer from 2000-2012. Pharmaterials carries out materials
`
`characterization, salt selection, polymorph screening, preformulation, formulation
`
`development, assay development and clinical trial manufacture.
`
`8.
`
`I have served on the Committee on Safety of Medicines (CSM),
`
`which is the body in the UK that grants (and revokes) marketing authorizations
`
`(the equivalent of the FDA in the US), and I chaired its Chemistry, Pharmacy and
`
`Standards (CPS) sub-committee. I remain a member of CPS of the Commission on
`
`Human Medicines (a renamed version of CSM). I have been a member of the
`
`British Pharmacopoeia Commission and have been a member of working parties
`
`for the European and the United States Pharmacopoeias.
`
`9.
`
`I am the Managing Director of Buckton Consulting. I offer
`
`consulting services in the following areas: (1) physical form, formulation
`
`development, GMP manufacturing, and regulatory considerations, (2) company
`
`strategy review and management, (3) due diligence, and (4) expert witness
`
`3
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 007
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`

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`
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`services. As a consultant to industrial companies, I advise on materials science,
`
`formulation (various products, including inhalation and oral delivery), and
`
`regulatory standards.
`
`10.
`
`I have been Course Director and have lectured on the Royal
`
`Pharmaceutical Tableting Technology Course for every year since its inception in
`
`1989, teaching many of those working in tablet development and manufacture in
`
`the UK and Europe during that time. I lecture on materials properties, granulation,
`
`tablet formulation, dissolution, and controlled release.
`
`11. My research has focused on investigating the behavior of
`
`pharmaceutical materials, especially interfacial interactions between two or more
`
`material surfaces, and their use in processing and drug delivery. Applications of
`
`my research include formulation of drug dosage forms including solid oral dosage
`
`forms, studies of surface interactions, and adaptation of physical properties of
`
`powders by physical manipulation such as milling.
`
`12. My research has been funded by such organizations as the
`
`Engineering and Physical Sciences Research Council (EPSRC), Pfizer,
`
`AstraZeneca, GSK, and Novartis, as well as other foundations and companies in
`
`the industry.
`
`13.
`
`I served a 10 year term as Editor of the International Journal of
`
`Pharmaceutics and have been a member of the editorial boards of a number of
`
`4
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 008
`
`

`

`
`
`journals, including Pharmaceutical Research, the AAPS Journal, and AAPS Pharm
`
`SciTec.
`
`14.
`
`I have authored a book on Interfacial Phenomena in Drug Delivery
`
`and Targeting. I have also authored or co-authored over 180 peer reviewed journal
`
`articles, of which numerous articles present original research related to solid
`
`dosage forms. In addition, I have authored or co-authored more than 100 abstracts
`
`and book reviews. I am listed as an inventor on six patents or patent applications.
`
`Additionally, I have lectured at over 130 conferences, seminars, and symposia
`
`around the world.
`
`15.
`
`I have received numerous awards and honors, specifically, the
`
`appointment in 2003 as the Science Chairman for the British Pharmaceutical
`
`Conference, the first recipient of the Academy of Pharmaceutical Sciences Medal
`
`in 2000, the 1998 Stig Sunner Award, the 1998 Foss Near Infrared European Users
`
`Group Award, the 1993 British Pharmaceutical Conference Science Medal, and the
`
`1992 Pfizer Award for “excellence in published research.”
`
`16.
`
`A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, Exhibit
`
`1003, a copy of which is separately submitted.
`
`5
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 009
`
`

`

`
`
` LIST OF DOCUMENTS CONSIDERED IN FORMING MY III.
`
`
`OPINIONS
`
`17.
`
`In forming my opinions, I have considered all the references and
`
`documents cited herein, including those listed below.
`
`Exhibit
`No.
`1001
`1006
`1008
`1009
`
`1010
`1011
`
`1012
`1013
`1014
`1015
`1017
`1018
`
`1020
`
`1021
`
`1022
`
`1023
`1024
`1025
`
`Description
`
`U.S. Patent No. 9,555,027
`Declaration of Dr. Adam Kaplin
`EP 1 327 440 A1
`PHARMACEUTICS: THE SCIENCE OF DOSAGE FORM DESIGN (Michael
`E. Aulton ed., 1988)
`U.S. Patent No. 4,911,921
`K.P.R. Chowdary and N. Rama Rao, Formulation and Evaluation of
`Dispersible Tablets with Pregelatinized Starch, 35 INDIAN DRUGS
`368 (1998)
`WO 2004/017973 A1
`File History for U.S. Patent No. 9,555,027
`U.S. Patent No. 8,729,085
`File History for U.S. Patent No. 8,729,085
`Calculated Fujihara Excipient Ranges
`U.S. Food & Drug Admin., Guidance for Industry: Bioavailability
`and Bioequivalence Studies for Orally Administered Drug Products
`— General Considerations (Mar. 2003)
`D. Becker et al., Effectiveness of Binders in Wet Granulation: A
`Comparison Using Model Formulations of Different Tabletability, 23
`DRUG DEVELOPMENT & INDUSTRIAL PHARMACY 791 (1997)
`HANDBOOK OF PHARMACEUTICAL EXCIPIENTS 184 (Raymond C.
`Rowe et al. eds., 4th ed. 2003)
`Rajendra K. Khankari & John Hontz, Chapter 4: Binders and
`Solvents, HANDBOOK OF PHARMACEUTICAL GRANULATION TECH. 59
`(Dilip M. Parikh ed., 1997)
`U.S. Patent Application Publication No. US 2004/0186105
`EP 1 371 646 A1
`Colorcon, Starch 1500: Partially Pregelantinized Maize Starch
`(1999)
`
`6
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 010
`
`

`

`
`
`Exhibit
`No.
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`1032
`1033
`1035
`1036
`1037
`1038
`1039
`1040
`1041
`1042
`
`1043
`
`1044
`
`1045
`
`Description
`
`Mary Kathryn Kottke & Edward M. Rudnic, Chapter 10: Tablet
`Dosage Forms, MODERN PHARMACEUTICS (Gilbert S. Banker &
`Christopher T. Rhodes eds., 4th ed. 2002)
`Ralph F. Shangraw & Dudley A. Demarest Jr., A Survey of Current
`Industrial Practices in the Formulation and Manufacture of Tablets
`and Capsules, 17 PHARMACEUTICAL TECH. 32 (Jan. 1993)
`Joseph B. Schwartz et al., Intragranular Starch: Comparison of
`Starch USP and Modified Cornstarch, 64 J. PHARMACEUTICAL SCI.
`328 (1975)
`Charles R.Cunningham & Laura K. Scattergood, Evaluation of a
`Partially Pregelatinized Starch in Comparison with
`Superdisintegrants in a Direct-Compression Hydrochlorothiazide
`Formulation, (Oct. 1999)
`U.S. Patent No. 4,600,579
`U.S. Patent No. 4,837,031
`U.S. Patent No. 6,150,366
`U.S. Patent No. 5,605,889
`EP 1 695 699 A1
`U.S. Patent No. 6,586,617
`U.S. Patent No. 7,141,249
`U.S. Patent Application Publication No. US 2004/0028741
`U.S. Patent No. 8,883,794
`File History for U.S. Patent No. 8,883,794
`Peter Davies, Chapter 11: Oral Solid Dosage
`Form, PHARMACEUTICAL PREFORMULATION AND FORMULATION 379
`(Mark Gibson ed., 2001)
`Vinod P. Shah et al., In Vitro Dissolution Profile Comparison –
`Statistics and Analysis of the Similarity Factor, f2, 15
`PHARMACEUTICAL RESEARCH 889 (1998)
`Marina Levina & Ali R. Rajabi-Siahboomi, The Influence of
`Excipients on Drug Release from Hydroxypropyl Methylcellulose
`Matrices, 93 J. PHARMACEUTICAL SCI. 2746 (Nov. 2004)
`Chi-Yuan Wu & Leslie Z. Benet, Predicting Drug Disposition via
`Application of BCS: Transport/Absorption/ Elimination Interplay
`and Development of a Biopharmaceutics Drug Disposition
`Classification System, 22 PHARMACEUTICAL RES. 11 (Jan. 2005)
`
`7
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 011
`
`

`

`
`
`Exhibit
`No.
`1046
`1047
`1049
`1051
`
`1053
`
`1054
`1055
`
`1057
`
`1058
`
`1059
`
`1060
`1061
`
`1062
`
`1063
`
`1064
`
`1065
`
`1066
`
`Description
`
`BRITISH PHARMACOPOEIA 2001 (2001)
`21 C.F.R. § 320.22 (Apr. 2005)
`U.S. Patent No. 5,047,246
`DrugBank, Acetaminophen,
`https://www.drugbank.ca/drugs/DB00316 (last visited Apr. 16, 2017)
`DrugBank, Valdecoxib, https://www.drugbank.ca/drugs/DB00580
`(last visited Apr. 14, 2017)
`UNITED STATES PHARMACOPEIA (28th ed. 2005)
`PubChem, Norfloxacin,
`https://pubchem.ncbi.nlm.nih.gov/compound/norfloxacin#section=To
`p (last visited Apr. 14, 2017)
`Barry Blackwell, Treatment Adherence, 129 BRITISH J. PSYCHIATRY
`513 (1976)
`Charles R. Cunningham, Maize Starch and Superdisintegrants in a
`Direct-Compression Formulation, 12 PHARMACEUTICAL
`MANUFACTURING REVIEW 23 (Dec. 1999)
`DrugBank, Piroxicam, https://www.drugbank.ca/drugs/DB00554
`(last visited Apr. 14, 2017)
`U.S. Patent No. 5,532,372
`Product Information – Zeldox (ziprasidone hydrochloride) (Feb. 24,
`2016)
`DrugBank, Ibuprofen, https://www.drugbank.ca/drugs/DB01050 (last
`visited Apr. 14, 2017)
`DrugBank, Azithromycin, https://www.drugbank.ca/drugs/ DB00207
`(last visited Apr. 14, 2017)
`DrugBank, Hydrochlorothiazide, https://www.drugbank.ca/drugs/
`DB00999 (last visited Apr. 14, 2017)
`Center for Drug Evaluation and Research, Application No. 200603,
`Chemistry Reviews – LATUDA (Lurasidone Hydrochloride) Tablets
`U.S. Patent No. 7,727,553
`
`8
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 012
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`
` MY UNDERSTANDING OF THE RELEVANT LAW IV.
`
`
`I have been informed by counsel of the legal standards that apply to
`18.
`
`patentability, and I have applied those standards, which I discuss below, in arriving
`
`at my conclusions.
`
`A. Claim Construction
`I understand that the U.S. Patent Trial and Appeal Board (PTAB)
`19.
`
`will construe claim terms using their broadest reasonable construction in view of
`
`the specification and prosecution history of the ’027 Patent. I understand that
`
`claim terms are interpreted based upon their meaning to a person of ordinary skill
`
`in the art at the time of the alleged invention.
`
`B. Obviousness
`I understand that a patent claim is unpatentable as obvious if the
`20.
`
`differences between the subject matter sought to be patented and the prior art are
`
`such that the subject matter as a whole would have been obvious to a person of
`
`ordinary skill in the art at the time the invention was made. I understand that a
`
`person of ordinary skill in the art is presumed to have been aware of all pertinent
`
`prior art at the time of the alleged invention.
`
`21.
`
`I understand that this assessment takes into account (1) the scope
`
`and content of the prior art; (2) the differences between the prior art and the claim
`
`at issue; (3) the level of ordinary skill in the art; and (4) any so called secondary
`
`considerations of non-obviousness, which include (i) long felt but unmet need; (ii)
`
`9
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 013
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`

`
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`commercial success attributable to the claimed invention; (iii) unexpected results
`
`of the claimed invention as compared with the closest prior art; (iv) copying of the
`
`claimed invention by others; (v) failure of others; and (vi) industry praise.
`
`22.
`
`I understand that a claim can be obvious in light of a single prior art
`
`reference or a combination of multiple prior art references.
`
`23.
`
`I also understand that obviousness can be established by combining
`
`or modifying the teachings of the prior art to achieve the claimed invention. I
`
`understand that a reason to combine prior art references must be identified. This
`
`reason to combine can come from a variety of sources, not just the prior art itself or
`
`the specific problem the patentee was trying to solve. I understand that the
`
`references themselves need not provide a specific hint or suggestion of the
`
`alteration needed to arrive at the claimed invention; the analysis may include why
`
`common sense compels a finding of obviousness that does not necessarily require
`
`explanation in any reference. It is also my understanding that where there is a
`
`reason to modify or combine the prior art to achieve the claimed invention, a
`
`person of ordinary skill in the art must also have a reasonable expectation of
`
`success in doing so.
`
`24.
`
`I also understand that as long as the person of ordinary skill in the
`
`art would have been motivated to combine references by the prior art taken as a
`
`whole, it is not necessary that the references be combined for the same reasons
`
`10
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 014
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`

`

`
`
`contemplated by the inventor or to address the specific problem solved by the
`
`invention.
`
`25.
`
`I understand that a combination of familiar elements according to
`
`known methods is likely to be obvious when it does no more than yield predictable
`
`results.
`
`26.
`
`I understand that when a skilled person would have reached the
`
`claimed invention through routine optimization, the invention may be deemed
`
`obvious.
`
`27.
`
`I also understand that a patent claim may be proven obvious by
`
`showing that the combination of elements was “obvious to try.” I understand that
`
`when there is a design need or market pressure to solve a problem and there are a
`
`finite number of identified, predictable solutions, a skilled person has good reason
`
`to pursue the known options within his or her technical grasp. I understand that if
`
`this leads to the anticipated outcome, then that outcome is likely a product not of
`
`innovation, but of ordinary skill and common sense, and therefore is considered
`
`obvious. I understand that obviousness therefore exists when a finite, and in the
`
`context of the art, small or easily traversed, number of options would convince an
`
`ordinarily skilled artisan of obviousness. Accordingly, I understand that a patent
`
`claim may be obvious where a technique has been used to improve one thing, and a
`
`11
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`Par Pharm., Inc.
`Exhibit 1002
`Page 015
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`person of ordinary skill in the art would recognize that the technique would
`
`improve similar things in the same way.
`
` LEVEL OF ORDINARY SKILL IN THE ART V.
`
`
`I understand that a person of ordinary skill in the art is a hypothetical
`28.
`
`person who is presumed to be aware of all pertinent art at the time of the invention,
`
`and also is a person of ordinary creativity.
`
`29.
`
`I have assumed for the purposes of this declaration that the relevant
`
`timeframe for assessing the patentability of the claims of the ’027 Patent is May
`
`26, 2005, the earliest effective filing date of the application that led to the ’027
`
`Patent. Unless otherwise specifically noted, all of my opinions expressed herein
`
`regarding a person of ordinary skill in the art apply to a person of ordinary skill in
`
`the art as of May 26, 2005. By virtue of my education, experience, and training, I
`
`am familiar with the ordinary level of skill in the art of the ’027 Patent as of May
`
`26, 2005.
`
`30.
`
`In my opinion, a person of ordinary skill in the art as of May 26,
`
`2005, would be a formulator with a Ph.D. in pharmaceutics or in a drug delivery
`
`relevant field of a related discipline such as physical chemistry, or could have a
`
`bachelor’s degree in pharmaceutics or in a related field, plus two to five years of
`
`relevant experience in developing solid oral drug formulations. This description is
`
`approximate, and a higher level of education or skill might make up for less
`
`12
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`Par Pharm., Inc.
`Exhibit 1002
`Page 016
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`experience, and vice versa. This person of ordinary skill may consult with others
`
`from an interdisciplinary team, such as a clinician with experience in treating
`
`and/or dosing schizophrenic patients.
`
` SUMMARY OF THE ’027 PATENT DISCLOSURE AND ALLEGED VI.
`
`
`INVENTION
`A. The Specification
`The ’027 Patent is directed to certain oral preparations of lurasidone
`31.
`
`hydrochloride (“lurasidone”),1 a poorly-soluble2 active pharmaceutical ingredient
`
`(“API,” or more commonly, “drug”).
`
`1 As in the specification of the ’027 Patent, I refer to lurasidone hydrochloride,
`
`which is the form discussed and claimed in the ’027 Patent, as “lurasidone.” See
`
`Ex. 1001, ’027 Patent at 2:55-58 (noting that the hydrochloride form is “hereinafter
`
`referred to as lurasidone”).
`
`2 Generally, a drug with a solubility of 1 mg/ml or less is considered to be poorly
`
`soluble in water. See, e.g., Ex. 1009, PHARMACEUTICS: THE SCIENCE OF DOSAGE
`
`FORM DESIGN (Michael E. Aulton ed., 1988) (“Aulton”), Ch. 13 (Preformulation)
`
`at 247 (“for any drug whose aqueous solubility is poor ( <1 mg ml-1)”); see also id.
`
`at 226 (“A solubility of less than 1 mg ml-1 indicates the need for a salt,
`
`particularly if the drug will be formulated as a tablet or capsule”). I note that this
`
`is not a hard-and-fast rule, since whether something is poorly soluble is relative,
`
`
`
`13
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`Page 017
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`and at the priority date it was also usual to consider solubility in relation to the
`
`dose of API that was to be administered. However, for the purposes of this
`
`declaration, I will refer to drugs with a solubility less than about 1 mg/ml as poorly
`
`soluble.
`
`Lurasidone is described in the ’027 Patent as being a poorly soluble API. See Ex.
`
`1001,’027 Patent at 2:17-18 (“for such a slightly water-soluble active ingredient as
`
`lurasidone”). This was known in the prior art. See Ex. 1008, EP 1 327 440 A1
`
`(“Fujihara”) at [0008] (referring to lurasidone as “slightly water-soluble”); id. at
`
`[0098] (“it was found that the solubility of [lurasidone] within 15 minutes
`
`measured by the method for determination of solubility disclosed in the
`
`Pharmacopoeia of Japan was quite low”). One of ordinary skill in the art also
`
`could (and would) readily have determined the solubility of lurasidone, which is
`
`0.224 mg/ml (with maximum solubility of 0.349 mg/ml in pH 3.5 buffer). See Ex.
`
`1065, Center for Drug Evaluation and Research, Application No. 200603,
`
`Chemistry Reviews – LATUDA (Lurasidone Hydrochloride) Tablets at 9
`
`(http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200603Orig1s000Chem
`
`R.pdf). In any event, both the figures reported in Fujihara and the actual solubility
`
`of lurasidone as later reported to FDA fall below the general 1 mg/ml cutoff in the
`
`art for poorly soluble drugs.
`
`14
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`Exhibit 1002
`Page 018
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`32.
`
`The lurasidone formulations of the ’027 Patent contain
`
`pregelatinized starch (sometimes called “PGS” in the art), other specified
`
`excipients, and varying amounts of API (including 20, 40, 80, and 120 mg tablets).
`
`See, e.g., Ex. 1001, ’027 Patent at 21:60-63, 23:1-35 (Table 38).
`
`33.
`
`The ’027 Patent also purports to disclose oral preparations that have
`
`“equivalent dissolution profile[s] of the active ingredient even though contents of
`
`the active ingredient therein are varied,” although as I will describe when I discuss
`
`the claims, most claims do not actually require this. See Ex. 1001, ’027 Patent at
`
`1:19-23 (“Technical Field”). I note that the motivation to maintain consistent
`
`dissolution behavior of the API across various doses was common in the art, and I
`
`discuss this further below in Section VIII.E.
`
`34.
`
`The “Background” section of the ’027 Patent discusses another well-
`
`known motivation in the field at the time, namely to increase drug loading whilst
`
`preventing the tablet from being too large. See Ex. 1001, ’027 Patent at 2:14-17
`
`(characterizing prior art as requiring either “administering multiple tablets at one
`
`time or using a tablet having a big size which is difficult to administer.”)
`
`However, other than this general desire to increase API content, the ’027 Patent
`
`provides no explanation or justification for why its claimed range (20-45%
`
`lurasidone content by weight) is important. See Ex. 1001, ’027 Patent at 3:49-50;
`
`5:16-19; see also, e.g., id. at 25:59-60 (claim 1, “lurasidone is included in the
`
`15
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`Par Pharm., Inc.
`Exhibit 1002
`Page 019
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`preparation in an amount of from 20 to 45% (wt/wt)”). The ’027 Patent presents
`
`no data or disclosure concerning any alleged importance of this particular range
`
`(which, as I describe later, overlaps with the prior art).
`
`35.
`
`Against this backdrop, the ’027 Patent purports to improve on prior
`
`art formulations of lurasidone chiefly by adding pregelatinized starch and by
`
`increasing the amount of lurasidone per dosage form, while maintaining equivalent
`
`dissolution between varying strengths:
`
`the present invention which comprises a
`The preparation of
`pregelatinized starch can provide an oral preparation with higher
`contents of lurasidone which imposes less of burdens [sic] on a
`patient. Additionally, the present invention can provide an oral
`preparation with high contents of lurasidone, and a preparation for
`oral administration which has an equivalent dissolution profile even
`though contents of lurasidone therein are varied.
`
`Ex. 1001, ’027 Patent at 4:50-58.
`
`36.
`
`The ’027 Patent compares the performance of its disclosed oral
`
`preparations containing pregelatinized starch with comparative examples lacking
`
`pregelatinized starch. See Ex. 1001, ’027 Patent at 9:40-52 (Table 1). The
`
`specification reports that the preparations with pregelatinized starch
`
`showed similarities of dissolution profiles without depending on
`contents in tablets (unit strength) even in preparations wi