IPR2018-00293
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`______________________
`
`KVK-TECH, INC.
`
`Petitioner,
`
`v.
`
`SHIRE, LLC
`
`Patent Owner.
`
`______________________
`
`Case IPR2018-00293
`US Patent No. 9,173,857
`
`_______________________
`
`DECLARATION OF JAMES MCCRACKEN, M.D.
`
`KVK-TECH EXHIBIT 1045
`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`______________________
`
`KVK-TECH, INC.
`
`Petitioner,
`
`v.
`
`SHIRE, LLC
`
`Patent Owner.
`
`______________________
`
`Case IPR2018-00293
`US Patent No. 9,173,857
`
`_______________________
`
`DECLARATION OF JAMES MCCRACKEN, M.D.
`
`KVK-TECH EXHIBIT 1045
`
`
`
`IPR2018-00293
`
`TABLE OF CONTENTS
`
`
`I.
`
`OVERVIEW ....................................................................................................................... 1
`
`II.
`
`QUALIFICATIONS ........................................................................................................... 3
`
`III.
`
`SUMMARY OF OPINIONS .............................................................................................. 7
`
`IV.
`
`ACUTE TOLERANCE DOES NOT TEACH AWAY FROM THE USE OF SR
`BEADS IN ADHD FORMULATIONS TO PROLONG CLINICAL EFFICACY ........... 9
`
`A.
`
`B.
`
`C.
`
`Acute Tolerance is not a Clinically Significant Issue with Amphetamine
`Formulations for ADHD ......................................................................................... 9
`
`POSA would not Expect Acute Tolerance to Affect Mixed Pulsatile and
`Sustained Release Amphetamine Formulations.................................................... 36
`
`Burnside Does Not Teach Away from Using SR Beads in Combination with
`Pulsatile Beads Due to Acute Tolerance ............................................................... 42
`
`V.
`
`FOOD EFFECT IS NOT FORMULATION-DEPENDENT ........................................... 46
`
`
`
`i
`
`
`
`IPR2018-00293
`
`DECLARATION OF JAMES MCCRACKEN, M.D.
`
`I, James McCracken, do hereby declare and say as follows:
`
`I.
`
`1.
`
`OVERVIEW
`
`I am over the age of 18 and otherwise competent to make this declaration. I
`
`understand that this declaration is being submitted together with a petition for Inter
`
`Partes Review (“IPR”) of claims 1-31 of U.S.Patent No. 9,173,857 (the “‘857
`
`patent”).
`
`2.
`
`I have been retained as an independent expert on behalf of KVK-Tech, Inc.
`
`(“KVK”), the Petitioner, in this proceeding. I am being compensated for my time
`
`in connection with this IPR at my standard legal consultant rate. I have no personal
`
`or financial interest in KVK or in the outcome of this proceeding.
`
`3.
`
`I understand that this proceeding involves the ‘857 patent, which has an
`
`effective filing date of May 12, 2006, having been filed as U.S. Patent Application
`
`No. 11/383,066 (“the ‘066 application”), and which issued on November 3, 2015. I
`
`understand that the earliest possible filing date of the ‘857 patent is May 12, 2006.
`
`I further understand that the patent is assigned to Shire LLC (“Shire”). I have been
`
`asked to provide my analysis of the ‘857 patent based on prior art and the
`
`knowledge in the art before May 12, 2006.1
`
`
`1 My opinions would be unaffected if Shire established an earlier filing date in 2005 or 2006.
`
`i
`
`
`
`4.
`
`I further understand that the claims of the ‘857 patent recite, among other
`
`things, a method of treating ADHD with a pharmaceutical composition comprising
`
`pharmaceutically active mixed amphetamine salts in three types of beads: (1)
`
`immediate release beads (“IR beads”); (2) delayed pulsed release beads (“DR
`
`beads”); and (3) delayed sustained release beads (“SR beads”). I refer to this
`
`claimed three bead composition as the “Mixed Bead Formulation.”
`
`5.
`
`I have been asked to address alleged issues concerning “acute tolerance” and
`
`“food effect” – as raised by Dr. James Polli Ph.D. on pages 74-93 and 100-103 of
`
`his declaration (Polli Decl. EX. 2060) – and what effect, if any, they may have on
`
`the therapeutic efficacy of amphetamine-containing medications. Specifically, Dr.
`
`Polli contends that acute tolerance and food effect are characteristic to
`
`amphetamine formulations, and that these characteristics made the addition of a
`
`third sustained release bead to a formulation containing two pulsed release beads
`
`unlikely to extend therapeutic efficacy of the pulsed beads. I understand that these
`
`questions are relevant to the patentability of the Mixed Bead Formulation claimed
`
`in the ‘857 patent.
`
`6.
`
`First, I have been asked to opine on whether acute tolerance was known to
`
`diminish the therapeutic efficacy of amphetamines, and whether this would have
`
`discouraged the use of the Mixed Bead Formulation for treating ADHD.
`
`2
`
`
`
`7.
`
`Second, I have been asked to opine on whether food effect was a known
`
`issue affecting the absorption and therapeutic efficacy of amphetamines, and
`
`whether the claimed “food effect” recited in claim 19 is an inherent property of the
`
`Mixed Bead Formulation.
`
`II. QUALIFICATIONS
`
`8.
`
`This declaration is based on my personal knowledge as a practicing
`
`physician and expert in the field of psychiatry and the use of amphetamines to treat
`
`attention deficit hyperactivity disorder (“ADHD”).
`
`9.
`
`I am a medical doctor and professor, with significant experience in both
`
`academia and as a practicing physician. I received my B.A. from the University of
`
`Texas in 1976, and attended the Baylor College of Medicine, earning my medical
`
`degree in 1980. I completed my residency in general psychiatry at the Duke
`
`University Medical Center in 1984, and completed a combined child psychiatry
`
`and research fellowship at the UCLA Neuropsychiatric Institute in Los Angeles,
`
`California from 1984 to 1987.
`
`10.
`
`I am board-certified in general and child and adolescent psychiatry, and have
`
`been a full-time faculty member in the Department of Psychiatry and
`
`Biobehavioral Sciences at the David Geffen School of Medicine at UCLA in Los
`
`Angeles, California for 31 years. I am an active clinician, supervising attending
`
`physician, teacher, and researcher with extensive experience in the diagnosis and
`
`3
`
`
`
`treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children and
`
`adults. I have authored or co-authored over 300 professional and scientific
`
`manuscripts including many focused on the treatment of ADHD with medications,
`
`such as my co-authorship of the two highly cited ADHD medication treatment
`
`guidelines, “The Texas Children’s Medication Algorithm Project”, both published
`
`in 2000.
`
`11. One of my primary areas of clinical research, and my specialty for over 30
`
`years as a practicing physician, has been the use of medications in the treatment of
`
`ADHD. I have authored dozens of peer-reviewed papers on this topic, including
`
`several on the use of amphetamines to treat ADHD, and the pharmacokinetics of
`
`amphetamine in children with ADHD. I have prescribed mixed amphetamines for
`
`the management of ADHD since 1996, and I have regularly prescribed Adderall,
`
`Adderall XR, and Mydayis as part of my daily practice.
`
`12. As part of my practice, teaching, and clinical research, I need to thoroughly
`
`understand key biological, pharmacokinetic and pharmacodynamic properties of
`
`drugs – and how these properties affect the absorption and therapeutic efficacy of
`
`drugs in the human body – for the treatment ADHD. I am an author of a chapter
`
`entitled “Principles of pharmacokinetics and pharmacodynamics,” in the Textbook
`
`of Psychopharmacology, and have published multiple peer-reviewed papers on the
`
`4
`
`
`
`pharmacokinetic and pharmacodynamic properties of drugs, including on
`
`amphetamines and how this affects their use in the treatment of ADHD.
`
`13.
`
`I have received numerous professional awards throughout my career. Most
`
`recently, I was recognized as a leading expert in ADHD research as the 2017
`
`recipient of the American Academy of Child and Adolescent Psychiatry, Elaine
`
`Schlosser Lewis Award for Research in Attention Deficit Disorder.
`
`14. As a recognized expert in the diagnosis, treatment, and pharmacology of
`
`ADHD, I am the primary lecturer responsible for developing and presenting the
`
`ADHD “module,” a series of 4 to 5 lectures concerning ADHD, as part of the 1st
`
`year core seminar for child psychiatry trainees at UCLA. This is provided in their
`
`“Basic Child Psychopathology and Treatment” course, and includes the treatment
`
`of ADHD with stimulants such as amphetamine, and amphetamine pharmacology.
`
`15.
`
`I currently hold multiple leadership roles and am recognized by my peers as
`
`a leader in the field of psychiatric medicine. Since 2007, I have served as the Vice
`
`Chair for Junior Faculty Development in the Department of Psychiatry and
`
`Biobehavioral Sciences, David Geffen School of Medicine at UCLA. Since 1994, I
`
`have served as the Director of the Division of Child and Adolescent Psychiatry,
`
`within the Department of Psychiatry and Biobehavioral Sciences at the UCLA
`
`Neuropsychiatric Institute and Hospital. I have also served as Medical Director at
`
`5
`
`
`
`the UCLA Child Anxiety, OCD, and Tic Program since 1995, and as Director of
`
`the UCLA Child and Adult Neurodevelopment Clinic since 2013.
`
`16. Within my institution, I hold membership in multiple committees and
`
`leadership groups which provide oversight for training and clinical care including,
`
`for example, the: Intellectual and Developmental Disabilities Research Center, at
`
`UCLA (since 1992); Child Psychiatry Training Advisory Committee (since 1992);
`
`Neuropsychiatric Hospital Professional Staff Executive Committee (since 1995);
`
`Neuropsychiatric Hospital Clinical Coordinating Committee (since 1995);
`
`Neuropsychiatric Hospital Research Residency Track Committee (since 1995);
`
`Departmental Steering Committee (since 2000); and the Neuropsychiatric Institute
`
`(Semel Institute) Directors Forum (since 2000).
`
`17.
`
`I am currently a member of multiple professional and scientific
`
`organizations including, the American Academy of Child and Adolescent
`
`Psychiatry (Distinguished Fellow), the American Psychiatric Association
`
`(Distinguished Life Fellow), and elected memberships in the American College of
`
`Psychiatrists, and the American College of Neuropsychopharmacology.
`
`18. Accordingly, I submit that I am an expert in the field of ADHD, the
`
`treatment and management of ADHD, biological, pharmacokinetic and
`
`pharmacodynamic considerations of drugs used in the treatment of ADHD, and the
`
`use and required dosage amounts of amphetamine-containing drugs to achieve
`
`6
`
`
`
`therapeutic efficacy in the treatment of patients with ADHD. Included in Appendix
`
`II is a copy of my curriculum vitae that includes a more detailed description of my
`
`education and professional experience, as well as a list of my publications.
`
`III. SUMMARY OF OPINIONS
`
`19.
`
`I understand that Dr. Burgess 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 who has consulted with an
`
`M.D. with clinical experience with ADHD and pharmacological treatments for
`
`ADHD as of the time of the alleged invention, which I have been asked to initially
`
`assume is May 12, 2006.
`
`20. First, it is my opinion that it was well-known prior to 2006 that acute
`
`tolerance had little to no effect on the therapeutic efficacy of amphetamine-
`
`containing drug products like Adderall® and Adderall XR®. As such, it would be
`
`obvious to add the SR bead – which was disclosed in Example 4 of Shire’s ‘300
`
`7
`
`
`
`patent (referred to herein as “Burnside” or the “Burnside patent” (Burnside EX.
`
`1002) covering Adderall XR® – to extend the duration of therapeutic efficacy of
`
`the two-bead system of Adderall XR®, as first disclosed in Example 5 of the same
`
`patent. Multiple other publications taught combining different release forms of
`
`amphetamine to achieve optimized symptom control. Indeed, applying that very
`
`tactic has been a part of my clinical teaching content to trainees since the
`
`availability of multiple amphetamine release preparations, including different
`
`combinations of immediate release d-amphetamine, mixed amphetamine salts
`
`(“MAS”) immediate release beads, MAS delayed release beads, and sustained
`
`release beads containing d-amphetamine spansules.
`
`21. Second, it is my opinion that it was well-known prior to 2006 that
`
`amphetamine drug formulations could be taken with food because food does not
`
`affect the extent of absorption of amphetamine. The lack of food effect recited in
`
`claim 19 of the ‘857 patent is inherently present when the Mixed Bead Formulation
`
`of the amphetamine salts recited in claim 1 is administered.
`
`22. 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 have reviewed the materials identified in Appendix
`
`I, while drawing on my clinical experience and knowledge of treating ADHD with
`
`diverse amphetamine drug formulations.
`
`8
`
`
`
`IV. ACUTE TOLERANCE DOES NOT TEACH AWAY FROM THE USE
`OF SR BEADS IN ADHD FORMULATIONS TO PROLONG
`CLINICAL EFFICACY
`
`23. Dr. Polli claims that acute tolerance issues with amphetamine formulations
`
`made it impossible to have any reasonable expectation of success in using the
`
`MAS-containing SR bead of Burnside to treat ADHD. Dr. Polli even suggests that
`
`the ‘300 patent – which explicitly teaches the use of the SR beads in combination
`
`with other beads in amphetamine formulations – somehow teaches away from the
`
`use SR beads in amphetamine formulations. Dr. Polli’s declaration reveals a
`
`fundamental misunderstanding of acute tolerance and of the claimed amphetamine
`
`formulation of the ‘857 patent, which I will help remedy below.
`
`A. Acute Tolerance is not a Clinically Significant Issue with
`Amphetamine Formulations for ADHD
`
`24. Acute tolerance, also known as tachyphylaxis, is a medical term describing
`
`an acute (or sudden) and clinically meaningful decrease in the therapeutic effect of
`
`a drug shortly after administration, generally occurring when drug plasma
`
`concentrations are no longer rising. (See, e.g., Spencer 2046 at 578; Kratochvil EX.
`
`1010 at p. 2; Swanson EX. 2045 at p. 2). Classic examples of acute tolerance
`
`include the response to repeated nicotine or nitroglycerin exposure (See, e.g.
`
`Burnside EX. 1002 at col. 1:31-35), wherein repeated doses providing similar
`
`maximum plasma concentrations (“Cmax”) fail to produce equivalent physiologic
`
`and behavioral effects, but doses increasing drug plasma levels can achieve
`
`9
`
`
`
`continued efficacy. (See Polli Decl. EX. 2060 at ¶ 155; ¶ 164). Dr. Polli and I
`
`agree that the significant loss of therapeutic effect due to acute tolerance must be
`
`rapid. (see Polli Decl. EX. 2060 at ¶ 156).
`
`25.
`
`If acute tolerance affected amphetamines, it would not associate with “level
`
`plasma concentrations” of sustained release formulations only, as Dr. Polli
`
`includes in his definition. Rather, acute tolerance would cause a rapid and
`
`clinically obvious decrease in therapeutic effect when amphetamine plasma levels
`
`are decreasing – even if gradually decreasing – regardless of the formulation type.
`
`Dr. Polli should agree given that he believes increasing plasma concentrations are
`
`necessary to avoid tolerance: “prior art taught that the increasing (not sustained)
`
`plasma concentrations were necessary for continued therapeutic amphetamine
`
`effect throughout the day (See Polli Decl. EX. 2060 at ¶ 155; see also ¶ 164 “acute
`
`tolerance . . . could be overcome by an increasing or ascending serum
`
`concentration.”) (citations omitted).
`
`26. No amphetamine formulations for treating ADHD – especially those
`
`incorporating pulsatile delivery elements as claimed in the ‘857 patent – have been
`
`experimentally proven to show a rapid decrease in therapeutic efficacy suggestive
`
`of significant acute tolerance issues. Instead, loss of therapeutic efficacy in
`
`amphetamines is generally more gradual in nature, and additive with regards to
`
`circadian fluctuations in arousal. In my publication (EX. 1037) which I discuss
`
`10
`
`
`
`herein, the gradual reduction in amphetamine efficacy most closely resembles a
`
`zero-order correlation, which is a linear relationship of drug level to clinical
`
`response; this is far from the rapid and clinically observable loss of efficacy
`
`observed in drugs with acute tolerance.
`
`27. For example, Adderall XR® shows no therapeutically significant acute
`
`tolerance issues after reaching Cmax. The label for Adderall XR® reports the time
`
`to reach Cmax (“Tmax”) to be about 7 hours in adults (expected to be less in
`
`children) as shown in the figure from the Adderall XR® label comparing a single
`
`XR dose to 2 IR doses. (See EX. 1031 at p. 1). Actual PK data from the largest PK
`
`study of Adderall XR® in children 6-12 years of age in fact identified Tmax values
`
`of 6.4, 5.8, and 5.5 hours respectively for Adderall XR ® doses of 10, 20 and 30
`
`mg. (McGough EX. 1057 at Table 3 p. 688 - 689). Provided below is a figure from
`
`the Adderall XR® label showing the PK profile of Adderall XR®; two lines drawn
`
`over this figure represent (i) the point at which amphetamine plasma concentration
`
`begin to plateau and (ii) reach Cmax (i.e. stop increasing), These lines also roughly
`
`coincide with the ranges for Tmax provided in McGough and the label. (See EX.
`
`1031 at p. 1; McGough EX. 1057 at Table 3 p. 688 - 689).
`
`11
`
`
`
`
`
`28. As I explain further below, clinical benefits are observable at least 12 hours
`
`after ingestion of Adderall XR® (IR + DR) which is well-after plasma
`
`amphetamine levels stop increasing. This period of prolonged clinical efficacy
`
`includes time points 5 to 7 hours after Tmax, corresponding to the portion of the
`
`PK curve reflecting plasma concentrations that plateau and slowly descend. (See
`
`McCracken EX. 1037 at 676). This prolonged efficacy stands in stark contrast to
`
`what a presumption of “acute tolerance” for XR® would predict.
`
`29.
`
`If acute tolerance were a clinically significant issue, you would expect to see
`
`a significant, rapid, and clinically obvious decline in therapeutic efficacy after
`
`Tmax – between 5 and 7 hours after administration – when plasma levels are no
`
`longer increasing, and where restoration of efficacy could only be achieved by
`
`rapidly increasing drug level to exceed the prior Cmax. Thus, if significant
`
`tolerance issues were at play, another dose of amphetamine sufficient to exceed the
`
`prior Cmax would be necessary at this time to maintain therapeutic efficacy.
`
`12
`
`
`
`30. However, Adderall XR provides therapeutic efficacy that persists for at least
`
`12-hours – 5 to 7 hours after plasma concentrations level off – which is not
`
`indicative of a “rapid dissipation of the clinical effects of amphetamines after . . .
`
`its initial effects.” (see, e.g., ‘857 patent EX. 1001 at col.3:39-42; Polli Decl. EX.
`
`2060 at ¶156). Rather, Adderall XR®, similar to other amphetamine formulations
`
`including sustained release formulations, presents a more gradual decline in
`
`therapeutic efficacy generally correlated with the observed gradual fall in plasma
`
`levels. (See Adderall XR® Product Label EX. 1031 at p. 1) To the extent acute
`
`tolerance in amphetamines exists at all, it has a negligible, clinically insignificant
`
`effect on clinical efficacy and real-world use of amphetamines. This is
`
`demonstrated in several rigorous time-action (pharmacodynamic) studies,
`
`including my own.
`
`31.
`
`In 2003, I published a paper on the “Analog Classroom Assessment of a
`
`Once-Daily Mixed Amphetamine Formulation, SLI381 (Adderall XR®), in
`
`Children with ADHD” (See McCracken EX. 1037) that assessed clinical
`
`implications of Adderall XR®. In this paper I discussed the therapeutic affect of
`
`Adderall XR® directly observed and assessed by raters without knowledge of
`
`treatment received over the course of 12 hours, the final tested timepoint in the
`
`study. As of 2003, this study was the largest single direct observational study of
`
`the effects of an amphetamine-containing ADHD drug in children. (See
`
`13
`
`
`
`McCracken EX. 1037 at p. 681). I understand that both Dr. Jusko and Dr. Polli
`
`discussed my paper during the course of these proceedings. (see Jusko Dep. EX.
`
`2070 at pp. 26:23 to 36:25; 65:5-8 and Polli Decl. EX. 2060 at ¶¶ 157 to 159).
`
`32. One of the issues that motivated my study was the “surprising paucity of
`
`studies on the pharmacokinetic (PK) and behavioral time course of effects of low-
`
`dose amphetamine administration for ADHD (Brown et al., 1979, 1980; Pelham et
`
`al., 1999; Swanson et al., 1998).” (EX. 1037 at p. 674).” These prior studies,
`
`including Brown (EX. 2065), which was underpowered and included significant
`
`methodologic flaws, were not indicative of amphetamines having acute tolerance
`
`issues.
`
`33.
`
`In my study, 51 children (mean age 9.5 years) with ADHD were treated with
`
`Adderall XR® (10, 20 and 30 mg). (McCracken EX. 1037 at p. 674-675). The
`
`children were assessed using the Analog Classroom Protocol which is a standard
`
`assessment protocol used for evaluating the time-efficacy effects of ADHD drugs
`
`by measuring changes in the “SKAMP” rating scale’s Attention and Deportment
`
`variables, and the “PERMP,” a 10-minute math test repeated at multiple intervals
`
`measuring the number of math problems attempted, and the number of correct
`
`answers. (Id. at 675). These measures have been shown to be sensitive to both
`
`dosage and time effects in prior stimulant research. Id.
`
`14
`
`
`
`34.
`
` In relevant part, the results of this study showed that Adderall XR®
`
`exhibited robust, dose-dependent and statistically significant therapeutic efficacy in
`
`SKAMP and PERMP ratings that extended for at least 12 hours (the final
`
`measurement time) for the Adderall XR® 20 and 30 mg doses when compared to
`
`placebo, which represent typical clinical doses for children, adolescents, and many
`
`adults. (See McCracken EX. 1037 Tables 3 and 4, pp. 677 to 679). “SLI381
`
`(Adderall XR®) 20- and 30-mg doses were associated with statistically significant
`
`increases in number attempted and number solved for all postdose time points
`
`through 12 hours.” (See McCracken EX. 1037 at 676).
`
`35. These data confirmed robust 12-hour clinical efficacy lasting at least 5 to 7
`
`hours beyond the point at which amphetamine plasma levels reach Cmax, plateau,
`
`and then decline, which is indicative of a gradual – not rapid – accompanying
`
`decline in clinical efficacy. This gradual decline in efficacy is easily seen in the
`
`following graphs that plot the mean data for SKAMP and PERMP scores from
`
`Tables 3 and 4:
`
`Figure 1: Lower SKAMP scores (lower scores reflect better therapeutic efficacy)
`
`show significant improvement in efficacy up to 12 hours for three dosage amounts
`
`of Adderall XR® relative to placebo, with improved therapeutic efficacy at the
`
`higher dosages. (McCracken EX. 1037 at p. 677).
`
`15
`
`
`
`Figure 2: Higher PERMP math scores show significant improvement in efficacy
`
`up to 12 hours for three dosage amounts of Adderall XR® relative to placebo, with
`
`improved therapeutic efficacy at the higher dosages.
`
`
`
`
`
`16
`
`
`
`36. Dr. Jusko stated in his deposition that the above figures show good clinical
`
`effect that “wears off in tandem with the pharmacokinetics” with no evidence of
`
`acute tolerance or, if there is, “it is very modest [such that] children are still getting
`
`an excellent benefit with the drug” (See Jusko Dep. EX. 2070 at 28:5-24). I agree
`
`that these data show that clinical effect lasts late into the day and wears off in
`
`tandem with the decrease in plasma concentrations of drug. I also agree that these
`
`data provide no clinically significant evidence of acute tolerance. Indeed, a POSA
`
`could reasonably infer that therapeutic efficacy is simply dependent on
`
`maintenance of a suitable amphetamine plasma PK level, rather than an “ascending
`
`PK profile.”
`
`37. Dr. Jusko also recognized the importance of including placebo data in
`
`ADHD studies when he noted during his deposition that “[clinical effect] also
`
`wears off in tandem with the behavior of the children in the placebo group.” (See
`
`Jusko Dep. EX. 2070 at 28:8-9). Indeed, the placebo data in my paper showed
`
`placebo-treated (untreated) patients displaying natural circadian fluctuations in
`
`their behavior and cognitive performance scoring with worse scores – i.e. higher
`
`SKAMP and lower PERMF scores – occurring from about 6 hours to 10 hours
`
`after time of administration. The significance of this correlation can be seen by
`
`looking more closely at an exemplary section of the Fig. 2 graph isolating PERMP
`
`score data for the placebo and the 10mg dose of Adderall XR®:
`
`17
`
`
`
`
`
`
`
`38. This magnified section of Fig. 2 shows that both the placebo group and the
`
`group receiving the 10 mg dose Adderall XR® showed marked decrease in math
`
`scores from approximately the 6 hour to 10.5 hour timepoints (bracketed for
`
`visualization in above figure). This correlation between the placebo and the
`
`different Adderall XR® doses can be seen throughout Figures 1 and 2; the
`
`respective slopes (i.e. rates) of declining SKAMP and PERMP scores from 6 hours
`
`to 10.5 hours are similar in the placebo and drug curves. Acute tolerance, by
`
`definition, would predict loss of efficacy at a much faster rate than the placebo
`
`responses. Yet this was clearly not the case for the 20 and 30 mg conditions until at
`
`least 12 hours after administration:
`
`18
`
`
`
`[W]e
`
`have
`
`documented
`
`statistically
`
`significant
`
`differences between SLI381 [Adderall XR®] 20 mg and
`
`30 mg versus placebo on both behavioral and academic
`
`measures at 12 hours after administration. As these
`
`differences calculate to dimensionless effect sizes of
`
`between approximately 0.3 and 0.5, we would argue that
`
`they represent at least suggestive evidence of “clinically
`
`significant” (Kraemer, 1992) remaining treatment benefit
`
`from this extended-release preparation for ADHD as long
`
`as 12 hours after administration.
`
`(McCracken EX. 1037 at 681).
`
`39. Analysis of clinical efficacy data for the single morning dose of Adderall®
`
`IR provides additional support that amphetamines do not display acute tolerance.
`
`Adderall® IR has “peak plasma concentrations [of] about 3 hours for both d-
`
`amphetamine and l-amphetamine.” (See, e.g. Adderall XR® Product Label EX.
`
`1031 at p. 1) In my paper, I report significant positive academic and behavioral
`
`effects for children receiving a single 10 mg morning dose of Adderall® IR that
`
`remained significant for up to 9.0 hrs for academic testing (PERMP scores) and
`
`10.5 hrs for improved SKAMP Deportment scores, versus placebo. This is well
`
`beyond an expected Cmax of 3 hours. (McCracken EX. 1037 at pp. 677 to 679).
`
`Again, any suggestion of a clinically significant “acute tolerance” effect for
`
`amphetamine is simply not present during the 6 – 7.5 hours after predicted Cmax,
`
`19
`
`
`
`given the maintenance of benefits observed. Such rigorous data from the largest
`
`pharmacodynamic study of amphetamines is a powerful rebuttal of the poorly
`
`substantiated and largely outdated (since well before 2006) claims of Dr. Polli.
`
`40. Clinically, this is consistent with my hundreds of observations in patients
`
`taking Adderall XR® who require a “booster” or later day dose of drug in order to
`
`sustain adequate clinical benefit beyond 12 hours. For those minority of patients,
`
`any significant decline in efficacy can usually be managed by increasing plasma
`
`levels with a later-day dose of immediate release amphetamine.
`
`41. Data provided by Swanson (EX. 2045) in a 1998 methylphenidate ADHD
`
`study also supported the pattern of deterioration of placebo in that drug: “[i]t is
`
`interesting that the Swanson ct al. (1998) report also demonstrated the pattern of
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`deterioration on placebo in performance across morning into afternoon
`
`assessments, highlighting the importance of providing appropriate control groups
`
`for time-response studies.” (See McCracken EX. 1037 at 674).
`
`42. This repeated deterioration in placebo performance scores demonstrates the
`
`lack of clinically significant acute tolerance issues in amphetamines, instead
`
`confirming that any late day deterioration in therapeutic efficacy is likely
`
`attributable to normal common fatigue and decreased afternoon arousal, which
`
`occurs regardless of the presence of amphetamine plasma concentrations and
`
`ADHD.
`
`20
`
`
`
`43. Despite this clear evidence, Dr. Polli disagrees that my paper “supports a
`
`conclusion of no acute tolerance for amphetamine” because “Adderall XR is a
`
`formulation that successfully overcame acute tolerance.” To the extent that I
`
`understand this argument, I disagree with the assumption that this formulation
`
`overcame something that does not exist. Benefits of the dual bead formulation
`
`were consistent across the 12-hour testing period for the two highest and most
`
`clinically relevant dose conditions, sufficient for the FDA to approve its “once-
`
`daily” clinical description.
`
`44. Even if there was evidence of tolerance issues – which there is not – the
`
`overall efficacy of the drug is substantial as the drug treatment profiles differ
`
`appreciably from the placebo profiles, both for measures of concentration and
`
`behavior, and for the proxy measure of academic productivity. Moreover, the data
`
`from my study showed that higher doses of amphetamine improved therapeutic
`
`efficacy on behavior and testing performance up to 12 hours relative to placebo
`
`and lower doses. This is most apparent when comparing the 20 mg and 30 mg
`
`doses of Adderall XR® to placebo. Thus, even if there were evidence for some
`
`minor level of acute tolerance present in amphetamine formulations, it could easily
`
`be remedied by introducing higher doses of amphetamine later in the day when
`
`plasma levels are decreasing. This is precisely what Shire did when it combined
`
`21
`
`
`
`the SR bead disclosed in Example 4 of Burnside to the IR plus DR formulation
`
`disclosed in Example 5.
`
`45. Dr. Polli cites multiple references in the acute tolerance section of his
`
`declaration (see Polli Decl. EX. 2060 at pp. 74 to 93), many of which are irrelevant
`
`because they do not specifically relate to the issue of acute tolerance in
`
`amphetamines. See, e.g., Swanson EX. 2045 (discusses acute tolerance to
`
`methylphenidate); Patrick EX. 2019 (discusses IR versus SR methylphenidate);
`
`Porter EX. 2013 (discusses coating of pharmaceutical dosage forms in general);
`
`Limmer EX. 1027 (discusses the tolerance of nitroglycerin); Chiao EX. 2026
`
`(generally discusses sustained release drug delivery systems but not specific to
`
`amphetamines or acute tolerance); Chasseaud EX. 2043 (generally discusses the
`
`bioavailability of drugs from formulations after oral administration); Gupta EX.
`
`2034 (is a treatise on controlled drug delivery).
`
`46.
`
`It is noteworthy that most literature concerning acute tolerance issues in
`
`ADHD medications involved the drug methylphenidate. Acute tolerance in
`
`methylphenidate drugs was a more widely studied topic, and many of the
`
`references that Dr. Polli cites in his declaration concern this drug. However,
`
`methylphenidate is a different drug substance than amphetamine with a different
`
`underlying biological mechanism, and thus has little relevance to this analysis. It is
`
`well known that methylphenidate differs pharmacokinetically on multiple
`
`22
`
`
`
`parameters, with a shorter behavioral effect, more rapid clearance, lack of
`
`significant hepatic metabolism, and a differing neurochemical effect relating to
`
`therapeutic efficacy. (Swanson EX. 2061 at p. 5). “Whereas methylphenidate
`
`specifically blocks the dopamine transporter protein, amphetamines also release
`
`dopamine stores and cytoplasmic dopamine directly into the synaptic cleft.” (See
`
`e.g., Spencer EX. 2046 at p. 578; Tulloch EX. 1014 at 1406). Therefore, it is
`
`scientifically inappropriate to extrapolate from studies of methylphenidate to reach
`
`conclusions regarding amphetamine’s clinical actions and characteristics.
`
`47.
`
`Indeed,
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