Filed on behalf of: KVK-Tech, Inc.
`
`By:
`
`Jonathan A. Harris (jharris@axinn.com)
`James T. Evans (jevans@axinn.com)
`Axinn, Veltrop & Harkrider LLP
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`KVK-Tech, Inc.
`Petitioner
`
`v.
`
`Shire PLC
`Patent Owner
`
`____________________
`
`U.S. Patent No. 8,884,100
`
`____________________
`
`DECLARATION OF WILLIAM J. JUSKO, Ph.D.
`
`KVK-TECH EXHIBIT 1006
`
`

`

`
`
`TABLE OF CONTENTS
`Introduction ..................................................................................................... 1 
`I. 
`Qualifications .................................................................................................. 2 
`II. 
`Summary of Opinions ..................................................................................... 5 
`III. 
`IV.  The Pharmacokinetic Parameters and Food Effect Recited in Claims
`5-12 and 21 Are Inherent to the Three Bead Composition of Claim 1 ......... 7 
`A. 
`Pharmacokinetic Parameters ................................................................ 8 
`B. 
`Food Effect ......................................................................................... 10 
`The Delayed Sustained Release Beads of Burnside Example 4 Would
`Prolong the Therapeutic Efficacy of the Adderall XR® Two-Bead
`System ........................................................................................................... 12 
`VI.  The Dosage Range Recited in Claims 22-30 Is Obvious for the
`Composition Recited in Claim 1 .................................................................. 15 
`VII.  Conclusion .................................................................................................... 18 
`
`V. 
`
`
`
`

`

`
`
`I, William J. Jusko, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by KVK-Tech, Inc. as an independent expert
`
`consultant in this proceeding before the United States Patent and Trademark
`
`Office. Although I am being compensated at my normal consulting rate for the
`
`time I spend on this matter, no part of my compensation is dependent on the
`
`outcome of this proceeding, and I have no other interest in this proceeding.
`
`2.
`
`I understand that this proceeding involves U.S. Patent No. 8,884,100
`
`(“the ‘100 patent”), the application for which was filed on May 12, 2006, as U.S.
`
`Patent Application No. 11/383,066 (“the ‘066 application”), and issued on
`
`September 30, 2014. I further understand that the ‘100 patent is assigned on its
`
`face to Shire LLC (“Patent Owner”).
`
`3.
`
`I understand that the claims of the ‘100 patent recite, among other
`
`things, a pharmaceutical composition comprising pharmaceutically active mixed
`
`amphetamine salts in three beads: (1) immediate release beads; (2) delayed pulsed
`
`release beads; and (3) delayed sustained release beads. I refer to this composition
`
`as a three-bead composition.
`
`4.
`
`I have been asked to consider whether, from a pharmacokinetics
`
`perspective, the pharmacokinetic properties recited in claims 5-12 of the ‘100
`
`
`
`

`

`
`patent and the lack of food effect in claim 21 are inherent in the three-bead
`
`composition of claim 1.
`
`5.
`
`I have also been asked to opine on whether any of the beads in
`
`Burnside Examples 1-4 could provide the prolonged drug release needed to
`
`augment Adderall XR®.
`
`6.
`
`Finally, I was also asked to opine on whether the dosages recited in
`
`claims 22-30 of the ‘100 patent are doses a POSA would use in the routine dose
`
`optimization of the composition in claim 1 of the ‘100 patent. My opinions are set
`
`forth below.
`
`II. QUALIFICATIONS
`
`7.
`
`I am a SUNY Distinguished Professor at the State University of New
`
`York at Buffalo in the Department of Pharmaceutical Sciences. I was Chair of the
`
`Department of Pharmaceutical Sciences during 2001 - 2016 and have been
`
`Director of the Center of Excellence in Pharmacokinetics and Pharmacodynamics
`
`since 2005. My primary area of expertise is in pharmaceutical sciences,
`
`particularly pharmacokinetics and pharmacodynamics.
`
`8.
`
`I received a B.S. in Pharmacy from the State University of New York
`
`at Buffalo in 1965. During my undergraduate studies and after receiving my
`
`Bachelor’s degree, I worked as a pharmacist, at Children’s Hospital of Buffalo and
`
`then at Soby’s Pharmacy in Buffalo.
`
`
`
`
`

`

`
`
`9.
`
`I earned my Ph.D. in pharmaceutical sciences with an emphasis on
`
`pharmacokinetics from the State University of New York at Buffalo in 1970.
`
`Following my doctoral studies, I became Assistant Professor of Pharmacology at
`
`Boston University School of Medicine and served as a Clinical Pharmacologist at
`
`the Boston Veterans Administration Hospital.
`
`10.
`
`In 1972, I returned to the State University of New York at Buffalo as
`
`an Assistant Professor of Pharmaceutics and Director of the Clinical
`
`Pharmacokinetics Laboratory at Millard Fillmore Hospital and have remained a
`
`professor at the University ever since. I have taught a wide variety of courses
`
`during that time, including those that cover the pharmacokinetics and
`
`pharmacodynamics of various types of drugs. For over 20 years, I have given
`
`post-graduate courses in which professionals from the industry and FDA come to
`
`Buffalo for instruction in pharmacokinetics and pharmacodynamics. I also provide
`
`such instruction to industry professionals at their companies as well as other
`
`locations throughout the world.
`
`11.
`
`During my 50-year career as a researcher in the field of
`
`pharmaceutical sciences, I have served as a consultant for the National Institutes of
`
`Health (NIH), United States Food and Drug Administration (FDA), and various
`
`pharmaceutical companies, such as Amgen, Genentech Inc., Pfizer Inc., Roche,
`
`and Wyeth (now Pfizer), among others.
`
`
`
`
`

`

`
`
`12.
`
`I have also served as a consultant on numerous dose-titration studies
`
`for various drugs administered through various routes, such as oral, intravenous
`
`and subcutaneous. I am currently consulting and performing pharmacokinetic data
`
`analyses for a rising-dose titration study for Reveragen, Inc, and have had similar
`
`consulting activities for various pharmaceutical companies in the past such as
`
`Fujisawa and Novartis.
`
`13.
`
`I have authored or co-authored over 600 publications on
`
`pharmacokinetics and pharmacodynamics, which are primarily peer-reviewed
`
`journals and book chapters. I also serve or have served on the editorial board of
`
`several journals, including Clinical Pharmacology and Therapeutics, Journal of
`
`Clinical Pharmacology, and Biopharmaceutics and Drug Disposition. I have also
`
`been the editor-in-chief of The Journal of Pharmacokinetics and
`
`Pharmacodynamics since 2005.
`
`14.
`
`I have received numerous professional awards with the most recent
`
`including the Sheiner-Beal Pharmacometrics Award from the American Society for
`
`Clinical Pharmacology and Therapeutics (2013), The Distinguished Investigator
`
`Award from the American College of Clinical Pharmacology (2012), and a Doctor
`
`Honoris Causae from the University of Paris Descartes (2015). I also received a
`
`Doctor Honoris Causae from Jagiellonian University, Krakow, Poland in 1987, as
`
`
`
`
`

`

`
`well as the MERIT Research Award from the National Institutes of Health (2005-
`
`2015).
`
`15.
`
`A full description of my background, awards, and qualifications can
`
`be found in my curriculum vitae attached as an appendix to this declaration.
`
`III. SUMMARY OF OPINIONS
`16.
`The opinions contained in this declaration are based on the documents
`
`I reviewed and my knowledge and professional judgment. In forming the opinions
`
`expressed in this declaration, I reviewed the following, while drawing on my
`
`experience and knowledge of pharmacokinetics:
`
`Exhibit Reference
`1001
`U.S. Patent No. 8,846,100 (“the ‘100 patent”)
`1002
`U.S. Patent No. 6,605,300 (“Burnside”)
`PHYSICIANS’ DESK REFERENCE® 3144–3146 (58th ed. 2004) (“Adderall
`1003
`XR® PDR®, 2004”)
`Simon J. Tulloch et al., SLI381 (Adderall XR), a Two-Component,
`Extended-Release Formulation of Mixed Amphetamine Salts:
`Bioavailability of Three Test Formulations and Comparison of Fasted,
`Fed, and Sprinkled Administration, 22 PHARMACOTHERAPY 11, 1405–
`1415 (2002)
`FDA Adderall XR® Label, 2004 (Published August 2004)
`FDA Adderall IR® Label, 2005 (Published June 2005)
`Susan B. Clausen et al., Single-and Multiple-Dose Pharmacokinetics of
`an Oral Mixed Amphetamine Salts Extended-Release Formulation in
`Adults, 10 CNS SPECTRUMS 12 (Suppl 20), 6 (2005)
`James T. McCraken et al., Analog Classroom Assessment of a Once-
`Daily Mixed Amphetamine Formulation, SLI381 (ADDERALL XR),
`in Children With ADHD J. AM. ACAD. CHILD ADOLESC.
`PSYCHIATRY, 42:6, June (2003)
`
`1014
`
`1031
`1032
`
`1033
`
`1037
`
`
`
`
`
`
`

`

`
`
`17.
`
`I understand from communication with Dr. Burgess that she has
`
`opined that at the time of the alleged invention, a person of ordinary skill in the art
`
`would have at least a Bachelor of Science Degree in Pharmacy, Chemistry, or
`
`Chemical Engineering, or similar field, and experience in the field of
`
`pharmaceutics (including pharmaceutical formulation or pharmacokinetics or a
`
`similar technical field of study) and that the person of ordinary skill may consult
`
`with a pharmacologist with experience in the field of pharmacokinetics and/or an
`
`M.D. with clinical experience with ADHD and pharmacological treatments for
`
`ADHD. I provide my opinions from the perspective of a person with ordinary skill
`
`in the art of pharmacokinetics of drugs as of the time of the alleged invention,
`
`which I have been asked to initially assume is May 12, 2006.1
`
`18.
`
`Based on my experience and expertise, it is my opinion that the
`
`pharmacokinetic parameters recited in claims 5-12 and the lack of food effect
`
`recited in claim 21 of the ‘100 patent are necessarily present when the
`
`amphetamine salt composition recited in claim 1 is administered. I understand that
`
`Dr. Burgess has opined that this composition is anticipated or obvious based on the
`
`prior art.
`
`
`
`1 My opinions would not be affected by an earlier invention date.
`
`
`
`
`

`

`
`
`19.
`
`It is also my opinion that the delayed sustained release beads in
`
`Burnside Example 4 would provide the prolonged active release required to extend
`
`the duration of therapeutic efficacy of the type of two-bead system found in
`
`Adderall XR® and Burnside Example 5.
`
`20.
`
`It is also my opinion that the doses recited in claims 22-30 simply
`
`recite the obvious range a person of ordinary skill in the art would try in routine
`
`optimization of the composition recited in claim 1 of the ‘100 patent.
`
`IV. THE PHARMACOKINETIC PARAMETERS AND FOOD
` EFFECT RECITED IN CLAIMS 5-12 AND 21 ARE
`INHERENT TO THE THREE BEAD COMPOSITION OF CLAIM 1
`21.
`I understand from reading the ‘100 patent that the values for the
`
`pharmacokinetic parameters as recited in claims 5-12 are actually ranges due to the
`
`modifier “about” in claims 5-12. The ‘100 patent states that the term “about”
`
`means “within an acceptable error range for the particular value as determined by
`
`one of ordinary skill in the art, which will depend in part on how the value is
`
`measured or determined” and can mean “a range up to 20%” of a given value.
`
`(See Ex. 1001 at 11:65-12:11.)
`
`22.
`
`In defining “about” in relation to the pharmacokinetic parameters in
`
`claims 5-12 a person of ordinary skill in the art would consider the numeric ranges
`
`recited by the patentee and reported herein to be within an acceptable error range.
`
`(See, e.g., Ex. 1001 at 25:36-26:6 (Table 10); see also Ex. 1014 at 8 (Table 2))
`
`
`
`
`

`

`
`
`A.
`23.
`
`Pharmacokinetic Parameters
`It is my opinion that the pharmaceutical parameters recited in claims
`
`5-12 of the ‘100 patent are necessarily present in the three-bead composition of
`
`claim 1, which I understand Dr. Burgess opines is anticipated or obvious based on
`
`the prior art. Given Dr. Burgess opinion that the composition of claim 1 of the
`
`‘100 patent was known in the prior art, it is my opinion that the composition would
`
`necessarily produce the pharmacokinetic parameters of claims 5-12.
`
`24.
`
`If two chemical compositions are physically the same, they must have
`
`the same properties, which are inherent to the composition. Stated differently, a
`
`chemical composition and its properties are inseparable. I understand that claims
`
`to a chemical composition are therefore not rendered patentable by mere recitation
`
`of properties when the prior art teaches that same chemical composition.
`
`25.
`
`In this case, Examples 1-4 of the ‘100 patent, which are nearly
`
`identical to Examples 1-4 in Burnside, serve as the basis for the pharmacokinetic
`
`parameters recited by claims 5-12. (Ex. 1001 at 18:50-20:67 compared to Ex.
`
`1002 at 10:30-12:26.)
`
`26.
`
`The claimed pharmacokinetic data appears in Table 10 of the ‘100
`
`patent, which is based upon Examples 1, 3 and 4 of the ‘100 patent. I understand
`
`from communication with Dr. Burgess that these Examples correspond to
`
`Examples 1, 2, and 4 of Burnside. (Ex. 1002 at 10:30-11:24; 11:58-12:26.)
`
`
`
`
`

`

`
`
`‘100 Patent Claims
`
`Immediate Release Bead
`
`‘100 Patent
`Examples
`Example 1
`
`Delayed Pulsed Release Bead2
`
`Example 3
`
`Delayed Sustained Release
`Bead
`27.
`
`Example 4
`
`Burnside Examples
`
`Example 1
`
`Example 2
`
`Example 4
`
`I further understand from Dr. Burgess that the slight variations in
`
`ingredient concentrations in Burnside Examples compared to the ‘100 patent
`
`Examples and addition of 2% Opadry in Example 2 of the ‘100 patent compared to
`
`Example 3 of Burnside are inconsequential to the performance and properties of
`
`the composition.
`
`28.
`
`Table 10 of the ‘100 patent compares pharmacokinetic data after
`
`administration of 37.5 mg of the obvious three-bead composition to 25 mg
`
`Adderall XR® followed by 12.5 mg Adderall IR® 8 hours later. (See Ex. 1001 at
`
`25:36-26:6 (Table 10).) The pharmacokinetic ranges recited in claims 5-12
`
`encompass the values in Table 10, which is what a POSA would have expected or
`
`predicted because the claimed pharmacokinetic data is comparable to the
`
`
`
`2 Example 2 of the ‘100 patent corresponds to Example 3 of Burnside and reflects
`
`another version of the delayed pulsed release bead. (See Ex. 1001 at 19:15-51
`
`compared to Ex. 1002 at 11:25-57.)
`
`
`
`
`

`

`
`pharmacokinetic data after administration of 25 mg Adderall XR® followed by
`
`12.5 mg Adderall IR® 8 hours later.
`
`29.
`
`Thus, the three-bead composition characterized by Dr. Burgess as
`
`anticipated or obvious based on the prior art would necessarily exhibit the
`
`pharmacokinetic values recited by claims 5-12 of the ‘100 patent “after
`
`administration of a 37.5 mg dose of the pharmaceutical composition” of claim 1.
`
`B.
`30.
`
`Food Effect
`The food effect, like the pharmacokinetic parameters, is inherent to
`
`the three-bead composition covered by claim 1 of the ‘100 patent and anticipated
`
`and obvious based on the prior art. (See ¶20 above.)
`
`31.
`
`The ‘100 patent defines food effect as follows: food effect “means a
`
`significant difference in the bioavailability of a drug in a patient when the drug is
`
`administered in a fasted state compared to a fed state.” (Ex. 1001 at 11:59-61.) No
`
`food effect is defined as “there is no significant difference in the bioavailability of
`
`a drug in a patient when the drug is administered in a fasted state compared to a fed
`
`state.” (Id. at 11:61-64.) I use the ‘100 patent’s definition of “no food effect” in
`
`my analysis. Based on this definition, the absence of a food effect recited by claim
`
`21 means that there is no significant difference in the bioavailability (or
`
`absorption) of a drug in a patient when the drug is administered in a fasted state
`
`
`
`
`

`

`
`compared to a fed state. This is an inherent property of the three-bead composition
`
`of claim 1.
`
`32.
`
`In fact, the Adderall XR® PDR®, 2004 states: “Food does not affect
`
`the extent of absorption of ADDERALL XR® capsules, but prolongs Tmax by 2.5
`
`hours . . . .” (Ex. 1003 at 5.) Further, the Tulloch Study reported that a 30 mg dose
`
`of Adderal XR® “administered in applesauce is bioequivalent for both d- and l-
`
`amphetamine with the same dose administered as an intact capsule in either high-
`
`fat fed or fasting state . . . .” (Ex. 1014 at 4.) It is therefore expected that the three-
`
`bead composition of claim 1 would likewise not exhibit a food effect.
`
`33.
`
`The absence of a food effect is an inherent property of the mixed
`
`amphetamine salts in Adderall® that were previously reported to have no food
`
`effect, as that is defined in the ‘100 patent. Therefore, a POSA would have
`
`predicted that the absence of food effect would be present in a controlled release or
`
`immediate release formulations of the salts. These same mixed amphetamine salts
`
`are encompassed in Examples 1-4 and all claims of Burnside and are also claimed
`
`in the ‘100 patent. (See Ex. 1003 at 4-5; Ex. 1002 at 3:13-18, 8:2-9, claims 1 and
`
`12; Ex. 1001 at claims 19 and 20.) It is necessarily the case, and a POSA would
`
`have expected, that the claimed amphetamine salt composition containing
`
`immediate release and delayed release beads, like Adderall XR® and Burnside
`
`
`
`
`

`

`
`Example 5, along with the sustained release beads of Burnside Example 4, exhibits
`
`no food effect.
`
`V. THE DELAYED SUSTAINED RELEASE BEADS OF
`BURNSIDE EXAMPLE 4 WOULD PROLONG THE THERAPEUTIC
`EFFICACY OF THE ADDERALL XR® TWO-BEAD SYSTEM
`34.
`A person of ordinary skill in the art would have understood that the
`
`period of efficacy provided by the Adderall XR® “two-bead” system could be
`
`safely prolonged by the addition of a third bead providing additional amphetamine
`
`salts that are released and absorbed into the plasma at a later time than provided
`
`with the Adderall XR® system alone. (See Ex. 1003 at 4-5.) The person of
`
`ordinary skill in the art would reasonably have expected the delayed sustained
`
`release beads of Burnside Example 4 to prolong the Adderall XR® two-bead
`
`system.
`
`35.
`
`The delayed sustained release beads taught in Example 4 of Burnside
`
`is the only formulation taught in the Burnside Examples that, if added to the two-
`
`bead system, could provide such additional and later release of the active drug.
`
`36.
`
`Specifically, Burnside Figure 3 illustrates that the immediate release
`
`beads taught in Example 1 release 100% of the amphetamine active immediately
`
`(within 15 minutes) after administration. (See Ex. 1002 at Fig. 3.) Figures 4 and 5
`
`illustrate that the delayed pulsed release beads taught in Examples 2 and 3 begin to
`
`release the amphetamine active at 2 and 3 hours after administration, respectively,
`
`
`
`
`

`

`
`and reach 100% release within 3 and 3.5 hours. (See Ex. 1002 at Figs. 4 and 5.) I
`
`understand that the person of ordinary skill in the art would have known that
`
`Example 5 of Burnside, which is combination of the beads of Example 1 and 2 and
`
`Examples 1 and 3, is essentially the formulation of Adderall XR®
`
`37. The delayed sustained release beads of Burnside Example 4 also begin
`
`to release the amphetamine active at 2 hours after administration but, in contrast to
`
`the delayed pulsed release beads of Example 2 and 3, release only about 30%
`
`within 3.5 hours. (Ex. 1002 at Fig. 6.) The beads then continue to release active
`
`for at least another 4.5 hours when about 80% release is reached. (Id.)
`
`Consequently, the person of ordinary skill in the art would understand that adding
`
`the delayed sustained release beads of Example 4 to Adderall XR®, or to Example
`
`5 of Burnside, would release significant additional amphetamine active after all the
`
`active in the immediate and delayed pulsed beads has been released.
`
`38. The general relationship between the timing of the release of the
`
`active amphetamine and its absorption into the blood plasma can be seen from the
`
`Figures in Burnside. Figures 3, 4 and 5 show the drug release from Examples 1, 2
`
`and 3, respectively, and Figures 7 and 8 show the amphetamine plasma
`
`concentrations resulting from administration of a two-bead composition containing
`
`beads from either Examples 1 and 2 or Examples 1 and 3. It is evident that the
`
`immediate release beads and delayed pulsed release beads are associated with
`
`
`
`
`

`

`
`separate plasma concentration high-points occurring a few hours after all the active
`
`is released from the beads. This time between drug release and plasma
`
`concentration levels reflects the absorption rate for the mixed amphetamine salts.
`
`The same general absorption rate is reflected in the plasma concentration figure
`
`provided in the Adderall XR® PDR® and label. (Ex. 1003 at 5, 7 (Figure 1); Ex.
`
`1031 at 2 (Figure 1.)
`
`39.
`
`In view of the general absorption rate of the mixed amphetamine salts
`
`from the immediate and delayed pulsed release beads, the person of ordinary skill
`
`in the art would understand that absorption of amphetamine active released from
`
`the delayed sustained release beads of Example 4 would initially overlap with
`
`absorption of amphetamine active from the delayed pulsed release beads and
`
`continue on for at least 5 to 6 hours thereafter.
`
`40. Furthermore, the person of ordinary skill in the art would be familiar
`
`with the basic principle of pharmacokinetics called the “superposition principle.”
`
`The superposition principle provides that, under linear conditions (i.e., a constant
`
`rate of clearance of drug from the body), the total concentration of drug in the body
`
`is the sum of the remaining concentrations from each administered dose at the time
`
`of measurement plus newly absorbed drug. Pursuant to this principle, the person
`
`of ordinary skill would understand that the later release and absorption of drug
`
`from the delayed sustained release beads taught in Burnside Example 4 would be
`
`
`
`
`

`

`
`additive to the residual drug in the system from release of the two-bead
`
`composition. This, in turn, would lead the person of ordinary skill to expect that
`
`adding the delayed sustained release beads of Burnside Example 4 to the two-bead
`
`system exemplified by Adderall XR® would provide a plasma concentration profile
`
`with both a higher maximum concentration and sustained higher concentrations for
`
`at least 5 to 6 hours thereafter as compared to Adderall XR®.
`
`41. Finally, therapeutic efficacy is generally related to the concentration
`
`of active amphetamine in the blood plasma. The person of ordinary skill in the art
`
`would therefore reasonably expect that the elevated plasma concentration profile
`
`provided by the addition of the delayed sustained release beads of Example 4 of
`
`Burnside would result in hours of additional therapeutic efficacy as compared to
`
`Adderall XR®.
`
`VI. THE DOSAGE RANGE RECITED IN CLAIMS 22-30
`IS OBVIOUS FOR THE COMPOSITION RECITED IN CLAIM 1
`42. As discussed in Section II(A), the three-bead composition recited in
`
`claim 1 is simply a combination of the limited number of beads taught in Burnside
`
`Examples 1-4. The obvious three-bead composition recited in claim 1 was made in
`
`response to a population of patients who needed a longer duration of efficacy than
`
`provided by one administration of Adderall XR®.
`
`43.
`
`It was known in the art that “Adderall XR® demonstrates linear
`
`pharmacokinetics over the dose range of 20 to 60 mg in adults and 5 or 10 to 30
`
`
`
`
`

`

`
`mg in children aged 6 to 12 years.” (See Ex. 1003 at 5 (reporting linear
`
`pharmacokinetics over the dose range of 10 to 30 mg); See Ex. 1033 at 11
`
`(reporting linear pharmacokinetics over the dose range of 10 to 30 mg for children
`
`and from 20 mg to 60 mg for adults).) I note that the FDA Adderall XR® Label,
`
`2004 reports linear kinetics over the dosage range from 20 to 60 mg for adults and
`
`over a dosage range of 5 to 30 mg for children aged 6 to 12 years. (See Ex. 1031
`
`at 2.) Together, this information teaches linear pharmacokinetics for patients
`
`(pediatric and adult combined) at a dosage range of 5 mg to 60 mg for Adderall
`
`XR®. It was also well known that Adderall IR® was available in doses ranging
`
`from 5 mg to 30 mg (See Ex. 1009; Ex. 1032.)
`
`44.
`
`In designing a dose-titration study for augmented Adderall XR® or the
`
`composition in Burnside claim 1, an obvious titration range would be based on the
`
`prior art range taught to be safe and to provide linear pharmacokinetics for
`
`Adderall XR® plus the concentration of Adderall IR® clinicians prescribed to
`
`augment Adderall XR®. That combination provides a range with a low end greater
`
`than 10 mg (lowest does of Adderall XR® for children(5 mg) plus lowest dose of
`
`Adderall IR® (5 mg)) (See Ex. 1031 at 2.) and a high end at or below 90 mg
`
`(highest dosage of Adderall XR® for adults (60 mg) plus the highest dose of
`
`Adderall IR® (30 mg)).
`
`
`
`
`

`

`
`
`45.
`
`In designing a dose-titration study for augmented Adderall XR® or the
`
`composition in Burnside claim 1, an obvious titration range would be based on the
`
`prior art range taught to be safe and to provide linear pharmacokinetics for
`
`Adderall XR® plus the concentration of Adderall IR® clinicians prescribed to
`
`augment Adderall XR®. That combination provides a range with a low end of 10
`
`mg (lowest does of Adderall XR® for children(5 mg) plus lowest dose of Adderall
`
`IR® (5 mg)) (See Ex. 1031 at 2.) and a high end at 90 mg (highest dosage of
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`Adderall XR® for adults (60 mg) plus the highest dose of Adderall IR® (30 mg)).
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`The range of 12.5 mg to 75 mg in claims 22-30 of the ‘100 patent is within the
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`range a of 10 mg to 90 mg that a person of ordinary skill in the art would try in
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`routine dose optimization of the three-bead composition in claim 1 of the ‘100
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`patent.
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`46.
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`Further, I understand that as with the pharmacokinetic parameters
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`discussed in Section II(A), that the values for the doses recited in claims 22-30 are
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`actually ranges due to the modifier “about” in claims 22-30, and that “about” can
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`mean “a range up to 20%” of a given value. (See Ex. 1001 at 11:65-12:11.) In
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`defining “about” in relation to the doses in claims 22-30 a person of ordinary skill
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`in the art would consider the numeric ranges recited by the patentee and reported
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`herein to be within an acceptable error range. Such variance when applied to the
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`claimed dosages provides for the total dosage range from 10 mg to 90 mg, which is
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`the exact range a person of ordinary skill in the art would try in routine
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`optimization of the composition recited in claim 1 of the ‘100 patent.
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`VII. CONCLUSION
`47.
`It is my expert opinion, as a clinical pharmacologist, that the
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`pharmaceutical parameters recited in claims 5-12 and the lack of food effect recited
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`in claim 21 are inherent in the-three bead composition of claim 1 and are results a
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`POSA would have expected or predicted as claimed.
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`48.
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`It is also my opinion that a person of ordinary skill in the art would
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`have understood that of the beads recited in Burnside Examples 1-4, only the beads
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`in Example 4 would have provided the prolonged release of active required to
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`augment Adderall XR®. A person of ordinary skill in the art would have had a
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`reasonable likelihood of success in achieving “longer day” efficacy by adding the
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`beads from Example 4 to the Adderall XR® two-bead composition.
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`49.
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`It is also my expert opinion that the doses recited in claims 22-30
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`simply recite the obvious range a person of ordinary skill in the art would try in the
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`routine optimization of the composition recited in claim 1 of the ‘100 patent.
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`I hereby declare that all statements made herein ofmy knowledge are true,
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`and that all statements made on information and belief are believed to be true, and
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`further that these statements were made with the knowledge that willful false
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`statements and the like so made are punishable by fine or imprisonment, or both,
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`under Section 1001 of Title 18 of the United States Code.
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`Dated: November 16, 2017
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`By: 'Y\ � 1r-�
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`William J. Jusko, Ph.D.
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`APPENDIX A
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`APPENDIX A
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`CURRICULUM VITAE: WILLIAM J. JUSKO
` November 2017
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` E-MAIL: wjjusko@buffalo.edu
` ORCID No. 000-0003-4027-0550
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`http://www.webofknowledge.com/ Jusko, W
`http://pharmacy.buffalo.edu/departments-offices/pharmaceutical-sciences.html
`http://www.researcherid.com/rid/G-4885-2015
`https://www.linkedin.com/pub/william-jusko/33/aa7/825
`https://www.facebook.com/william.jusko
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`Salamanca High School, NY
`State University of New York at Buffalo
`State University of New York at Buffalo
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` 1956-1960 Secondary Education
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` 1960-1965 B.S. Pharmacy
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`1966-1969 Ph.D. 1970
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`Address:
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`Department of Pharmaceutical Sciences, Kapoor 404
`School of Pharmacy and Pharmaceutical Sciences
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`State University of NY at Buffalo, Buffalo, NY 14214-8033
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`Phone (716) 645-2855; FAX (716) 829-6569
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`Weblinks:
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`Education:
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`Appointments:
`State University of New York at Buffalo, School of Pharmacy and Pharmaceutical Sciences,
` Department of Pharmaceutical Sciences
`SUNY Distinguished Professor
` Nov 2008 - present
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`UB Distinguished Professor
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` April 2007-Nov 2008
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` April 1977 – Apr 2007
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`Professor
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`Chair, Department of Pharmaceutical Sciences
` Jan 2001 – May 2016
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`Director, Center of Excellence in Pharmacokinetics and Pharmacodynamics
` Dec 2005 -present
`Vice-Chairman, Department of Pharmacy
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`April 1984 - Oct. 1986
`Director, Doctor of Pharmacy Program
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` Sept. 1981 - Aug. 1986
`Associate Professor of Pharmaceutics
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` March 1974 - April 1977
`Assistant Professor of Pharmaceutics
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` Aug.1972 - March 1974
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`Millard Fillmore Hospital, Buffalo, NY
`Director, Clinical Pharmacokinetics Laboratory
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`Mario Negri Institute for Pharmacological
`Research, Milan, Italy, Visiting Scientist
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`Veterans Administration Hospital, Boston, MA
`Clinical Pharmacology Section, Research Pharmacologist
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`Boston University School of Medicine
`Department of Pharmacology, Assistant Professor of Pharmacology
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`Boston Collaborative Drug Surveillance Program
`Boston University Medical Center, Research Associate
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` Aug. 1972 - Sept. 1981
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`Sept. 1978 - June 1979
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`Sept. 1969 - July 1972
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`June 1970 - July 1972
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`Sept. 1969 - July 1972
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` Sept. 1962 - Aug. 1969
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` March 1966 - June 1968
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`Sept. 1962 - Feb. 1966
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`Council for International Exchange of Scholars (Fulbright Scholar Program)
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`Medical Sciences Award Committee, 1980-84
`National Institutes of Health, Pharmacology Study Section, 1980-84, 1997-01
`Food and Drug Administration, CDER, Clinical Pharmacology Advisory Committee, 1999-2007
`Various pharmaceutical companies, 1978-present
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`Soby's Pharmacy, Buffalo, NY, Pharmacist
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`2
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`Children's Hospital of Buffalo, NY, Hospital Pharmacist
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`State University of New York at Buffalo
`Dept. of Pharmaceutics, Research Assistant
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`Consultant:
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`Awards and Honors:
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`NIH Predoctoral Research Fellowship, 1966-1969.
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`Fulbright-Hays Award to Mario Negri Institute, Milan, Italy, 1978-1979.
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`Fellow, Academy of Pharmaceutical Sciences, 1980.
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`Rorer Award, Second Best paper in: Am. J. Gastroent., 1980, (Ref. 116).
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`Fellow, American Association for the Advancement of Science, 1985.
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`Fellow, American Association of Pharmaceutical Scientists, 1986.
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`Rawls-Palmer Award, Am. Soc. Clinical Pharmacology & Therapeutics, 1987.
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`Doctor Honoris Causae, Jagiellonian University, Krakow, Poland, 1987.
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`Russell R. Miller Award, Am. College of Clinical Pharmacy, 1988.
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`Citizen of the Year (Health/Medicine), Am-Pol Eagle, Buffalo, NY, 1987
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`Distinguished Service Award, Am. College Clinical Pharmacology, 1989.
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`Fellow, American College of Clinical Pharmacology, 1989.
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`Faculty Exchange Scholar, State University of New York, 1990
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`Kosciusko Award, General Pulaski Assn. of Niagara Frontier, 1996
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`Research Achievement Award in PPDM, AAPS, 1998
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`John G. Wagn