UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________________
`
`
`
`Alkermes Pharma Ireland, Ltd.
`and Alkermes, Inc.
`Petitioners,
`
`v.
`
`Otsuka Pharmaceutical Co., Ltd.
`Patent Owner
`Patent No. 9,125,939 B2
`Issued: September 8, 2015
`Filed: August 2, 2006
`Inventors: Tetsuro Kikuchi, Taro Iwamoto, Tsuyoshi Hirose
`
`Title: CARBOSTYRIL DERIVATIVES AND MOOD STABILIZERS FOR
`TREATING MOOD DISORDERS
`___________________
`Inter Partes Review No. IPR2017-00287
`
`DECLARATION OF JESSIE AU, PHARM.D., PH.D., IN SUPPORT OF
`THE PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,125,939
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
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`TABLE OF CONTENTS
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`
`
`INTRODUCTION ........................................................................................... 4
`I.
`BACKGROUND AND QUALIFICATIONS ................................................. 4
`II.
`III. SUMMARY OF OPINION ........................................................................... 12
`IV. LEGAL PRINCIPLES ................................................................................... 13
`V.
`BACKGROUND INFORMATION .............................................................. 14
`A.
`Synergy ................................................................................................ 14
`B.
`Statistical Significance ........................................................................ 14
`C.
`The Methamphetamine-Induced Hyperlocomotion Test .................... 17
`VI. U.S. PATENT NO. 9,125,939 ....................................................................... 19
`A.
`The Claims .......................................................................................... 19
`B.
`Summary of Relevant Portions of the Prosecution History ................ 19
`VII. THE HIROSE DATA IS UNRELIABLE ..................................................... 30
`A.
`The Applicants Did Not Normalize the Hirose Data Against the
`Methamphetamine-induced Hyperlocomotion and Did Not Express
`the Drug Effect in % Suppression ....................................................... 30
`The Hirose Data is Inconsistent and Irreproducible ............................ 31
`Lack of Reproducibility of Known Results ........................................ 38
`The Hirose Data Use Terms That Are Defined Differently From Their
`Accepted Definitions ........................................................................... 40
`The Hirose Declaration Draws Statistically Unsound Conclusions ... 41
`E.
`VIII. THE HIROSE DECLARATION GATHERED AND ANALYZED DATA
`INCORRECTLY FOR A DEMONSTRATION OF SYNERGY ................. 43
`A.
`The Correct Definition of Synergy...................................................... 43
`B.
`The Experimental Design of the Hirose Experiment is Not
`Appropriate for Studying Synergy ...................................................... 45
`a.
`Incorrect Time Points ................................................................ 45
`b.
`Omission of the Time-Dependency of Lithium Effects ........... 47
`c.
`Different Number of Animals ................................................... 47
`
`B.
`C.
`D.
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`C.
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`D.
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`No Dose Response Curve ......................................................... 48
`d.
`The Hirose Experiments Did Not Use a Scientifically Accepted
`Method to Analyze Drug Interactivity ................................................ 49
`Statistical Significance Cannot Be Determined Based on Whether
`Ranges Overlap ................................................................................... 49
`IX. NO SYNERGY AND NO “SIGNIFICANTLY ENHANCED” RESULTS 51
`A.
`The Hirose Data Do Not Illustrate Synergy When Analyzed Using
`Scientifically Accepted Methods with Limiting Assumptions ........... 51
`CONCLUSION .............................................................................................. 55
`
`X.
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`1.
`
`I, Jessie Au, Pharm. D., Ph.D., declare as follows:
`
`INTRODUCTION
`2.
`
`I have been retained by Alkermes, Inc. and Alkermes Pharma Ireland
`
`
`
`I.
`
`Limited (collectively, “Alkermes”) in connection with its petition for inter partes
`
`review of U.S. Patent No. 9,125,939 (“the ’939 patent”). I am being compensated
`
`for the time spent preparing this declaration, at my customary consulting rate of
`
`$750 per hour. My compensation is not contingent on the outcome of any matter
`
`or on any of the opinions provided below. I have no financial interest in the
`
`outcome of this proceeding.
`
`3.
`
`The opinions set forth in this declaration are my own. My opinions
`
`are based on many years of experience in the fields of pharmacology and therapy
`
`development. In forming my opinions, I also relied on the documents cited herein
`
`and in my appendices.
`
`II. BACKGROUND AND QUALIFICATIONS
`4.
`I received my Doctor of Pharmacy (in clinical pharmacy) and Doctor
`
`of Philosophy (in pharmaceutical chemistry) degrees from the University of
`
`California San Francisco, in 1972 and 1980, respectively. I joined the faculty of
`
`The Ohio State University in 1983 as an assistant professor, rose to the rank of Full
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`Professor in 1992, and received the life-time honorific title of Distinguished
`
`University Professor in 1998. I took early retirement from The Ohio State
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`University in 2013 and currently hold the title of Distinguished University
`
`Professor Emeritus.
`
`5.
`
`I am a co-founder and Chief Scientific Officer of Optimum
`
`Therapeutics LLC, a research and development company that has been in operation
`
`since 2003 and is located in Carlsbad, San Diego County, CA.
`
`6.
`
`I have additional appointments at several academic institutions in the
`
`United States and abroad. I am Research Professor and Mosier Endowed Chair in
`
`Pharmaceutical Sciences at the University of Oklahoma Health Sciences Center,
`
`Adjunct Professor of Surgery at Medical University of South Carolina, Chair
`
`Professor in Systems Pharmacology at Taipei Medical University (Taipei, Taiwan,
`
`Republic of China), and Distinguished Scholar at Chinese University of Hong
`
`Kong in Hong Kong (SAR, China).
`
`7.
`
`In April 2016, I co-founded Institute of Quantitative Systems
`
`Pharmacology (QSP). The goal of this institute is to develop a multi-institutional
`
`QSP training program on drug development. This program is designed to (a)
`
`stimulate collaborative QSP research projects among participating faculty
`
`members, (b) provide cross-laboratory training to students (i.e., QSP students are
`
`mandated to work in two or more laboratories for their dissertation research), and
`
`(c) provide internship to QSP students at end-user institutions (e.g., regulatory
`
`agencies, pharmaceutical companies).
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`8.
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`My research interests are in preclinical and clinical pharmacology,
`
`pharmaceutical sciences, cancer therapy development, and identification of
`
`effective combination therapy. My work is typically in the interface between
`
`several disciplines, including biology, pharmacology, engineering, computational
`
`modeling of dynamic biological processes, and computation-based clinical drug
`
`development.
`
`9.
`
`A part of my research is to use mathematics and computational
`
`modeling to solve biological problems. I was a founding member of the Internal
`
`Advisory Board of the first mathematical biosciences institute funded by the
`
`National Science Foundation. I routinely use computation to solve complex
`
`biological problems.
`
`10. During my academic career at The Ohio State University, I held
`
`senior leadership positions in its cancer center. I was Co-director of three research
`
`programs (Developmental Therapeutics, Urologic Oncology, Head and Neck
`
`Oncology), Associate Director of Translational Research, and Deputy Director of
`
`The Ohio State University Comprehensive Cancer Center, one of the then 28
`
`centers in the U.S. that received such designation from the National Cancer
`
`Institute.
`
`11. As a senior faculty member in The Ohio State University, I
`
`participated in committees that made recommendations and/or decisions on
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`university-wide budget and funding priorities and on senior leadership positions
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`such as provost and vice president for research.
`
`12.
`
`I have served on multiple government advisory boards including, inter
`
`alia, US Food and Drug Administration (“FDA”) Advisory Committees, several
`
`research grant review committees of the National Institutes of Health (“NIH”)
`
`(Experimental Therapeutic II Study Section, Pharmacology Study Section,
`
`Developmental Therapeutics Study Section, Biomaterials and Biointerfaces Study
`
`Section), NIH Board of Scientific Counselors, U.S. Army Breast Cancer Program,
`
`Cancer Center Support Grant Review Committee and Manpower Initial Review of
`
`the National Cancer Institute (“NCI”), NCI Clinical Studies Initial Review
`
`Committee, NCI Program Project Initial Review Committee, Review Committees
`
`of the National Institute of Biomedical Imaging and Bioengineering, Review
`
`Committees of the National Institute of Diabetes and Digestive and Kidney
`
`Diseases, Review Committees of the National Center to Advance Translational
`
`Research, Review Committees for NCI Nanotechnology Research
`
`Centers/Projects.
`
`13.
`
`I have served on several NCI Task Forces and Working Groups,
`
`including The Cancer Genome Atlas Working Group. The latter working group
`
`has sequenced and published the genome of human bladder tumors. I also serve on
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`the NCI Bladder Cancer Clinical Trial Task Force that has been charged to develop
`
`high priority clinical trials in bladder cancer patients.
`
`14.
`
`I have served on scientific and external advisory boards of academic,
`
`nonprofit and commercial institutions, including University of Pittsburg Cancer
`
`Center, Roswell Park Cancer Institute, State of Oklahoma Biomedical Research
`
`Infrastructure Network (BRIN) Program and IdeA Networks for Biomedical
`
`Research Excellence (INBRE), Attenuon LLC, Ascent Biomedical Ventures,
`
`Actium Biosystems LLC, and Bladder Cancer Advocacy Network. I have been
`
`recently nominated to an American Urologic Association Panel that develops and
`
`recommends the guidelines for Diagnosis and Treatment of Non-Metastatic
`
`Muscle-Invasive Bladder Cancer.
`
`15.
`
`I have been a member of the FDA Pharmaceutical Sciences and
`
`Clinical Pharmacology Advisory Committee since 2006. This committee provides
`
`advice and recommendations to the FDA on policy issues and on product
`
`evaluation and approval, with respect to pharmaceutical sciences and clinical
`
`pharmacology. My appointment was renewed twice and I am on my third term,
`
`ending in 2019.
`
`16.
`
`Throughout my career I received various honors, including a Research
`
`Career Development Award and a Merit Award from NCI. The Merit Award is
`
`given to research projects that rank in the top 5% and have significant impact on
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`human health. In 2004 and 2005, I was selected a semi-finalist for the NIH
`
`Inaugural Pioneer Award.
`
`17.
`
`I received a Distinguished Scholar Award, the Dorothy M. Davis
`
`Chair in Cancer Research and a Distinguished University Professorship from The
`
`Ohio State University. My title of Distinguished University Professor is conferred
`
`only to a total of about 40 faculty members among the 4000+ professors at the
`
`university.
`
`18.
`
`I received the American Association of Pharmaceutical Scientists
`
`(AAPS) Research Achievement Award. This award recognizes outstanding
`
`scientists who have conducted fundamental research that has had significant
`
`impact in the fields of Pharmacokinetics, Pharmacodynamics and Drug
`
`Metabolism. This AAPS Research Award was initiated in 1988 and there are a
`
`total of 14 awardees.
`
`19.
`
`I am Elected Fellow of AAPS, which recognizes a sustained level of
`
`superior and distinguished professional achievement and contributions in a relevant
`
`field in pharmaceutical sciences.
`
`20.
`
`I am Elected Fellow of the American Association for the
`
`Advancement of Science, an honor bestowed in recognition for meritorious efforts
`
`to advance science or its applications.
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`21.
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`In 2014, I was awarded the Mosier Endowed Chair in Pharmaceutical
`
`Sciences by the University of Oklahoma Health Sciences Center, a position I
`
`currently hold.
`
`22.
`
`In August, 2016, I was awarded the Chair Professorship in Systems
`
`Pharmacology by the Taipei Medical University, another position I currently hold.
`
`23.
`
`I have published more than 160 original research articles in peer-
`
`reviewed journals, more than 15 book chapters or review articles, and I have
`
`delivered more than 250 presentations at scientific meetings. I have given more
`
`than 160 invited lectures based on my work at academic institutions and
`
`pharmaceutical companies in the U.S. and other countries. I have received 28
`
`patents for my work in cancer and pharmacology and have additional patent
`
`applications in prosecution, in the U.S. and other countries.
`
`24.
`
`I am among the top 5% best-funded investigators by NIH over a 25-
`
`year period, from 1980 through 2005. I have received a total of about $145 M
`
`USD in research funding from NIH, of which I have been the principal investigator
`
`or co-principal investigator (about $40 M USD) or co-investigator (about $100 M
`
`USD).
`
`25.
`
`I have participated in over 10 phase I/II/III clinical trials, in the role of
`
`principal investigator, co-principal investigator, or investigator.
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`26.
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`In addition to my academic pursuits, I am Chief Scientific Officer of
`
`Optimum Therapeutic LLC (“Optimum”), a biotech company I co-founded in
`
`2000. Optimum is engaged in research and development of anticancer drugs. One
`
`of the two main product pipelines is the development of new agents that produce
`
`synergy with existing or established drugs that have been successfully used in
`
`patients with cancers. Optimum has received continuous funding from NIH for its
`
`R&D effort. The current NIH funding for active projects exceeds $10 M USD. In
`
`2012, Optimum received one of the three NIH Bridging Interventional
`
`Development Gaps (BRIDGS) awards given in that fiscal year.
`
`27.
`
`The most advanced project of Optimum is the development of a
`
`nontoxic drug to improve the activity of standard-of-care cancer
`
`chemotherapeutics. This project is derived from our work in combination therapy.
`
`My group made the observation that the compound suramin, when it is given in
`
`noncytotoxic doses, produces synergy with multiple commonly used standard-of-
`
`care cytotoxics in multiple types of human xenograft tumors grown in animals, but
`
`that this synergy is lost at the higher, cytotoxic suramin doses.
`
`28. Another area of my research focus is rational development of drug
`
`combinations that produce additive or synergistic effects. My earlier research in
`
`the 1990s evaluated combinations of anti-HIV drugs. More recent research is on
`
`combinations of anticancer drugs. The field of analysis of drug interactivity began
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`more than 140 years ago, and there are several methods that are available to
`
`researchers. As discussed in Appendix A, Background on Synergy, the most
`
`widely used mathematical model is the Loewe Additivity model. At present, there
`
`are a total of five methods derived from the Loewe Additivity model. The oldest
`
`method was first described in 1872. Three methods were developed between
`
`1970s and 1990s. The fifth and most recent method was developed by my group
`
`and published in 2004.
`
`29. A copy of my curriculum vitae (which includes a list of the
`
`publications and presentations I have authored) is Exhibit 1005.
`
`III. SUMMARY OF OPINION
`30.
`It is my opinion that the data presented during the prosecution of the
`
`application that issued as the ’939 patent do not demonstrate any synergy between
`
`aripiprazole and lithium with respect to the ability of that combination therapy to
`
`suppress manic behavior. Further, the data do not demonstrate any unexpected
`
`results with respect to the degree to which that combination therapy suppresses
`
`manic behavior because the effect of the (aripiprazole + lithium) combination is
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`not statistically significantly different from the arithmetic sum of the effect of these
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`two individual agents when given alone, i.e., the measured effect is not statistically
`
`significantly different from the expected effect.
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`31.
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`The data presented during prosecution are unreliable in a variety of
`
`ways, including, for example, the finding of different or opposite outcomes in the
`
`same control groups that received identical treatments; the inconsistent results for
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`the effect of lithium on manic behavior; and the applicants’ inability to reproduce
`
`the well-established lithium effect on suppressing the methamphetamine-induced
`
`hyperlocomotion in rodents as repeatedly reported by multiple independent groups
`
`of investigators in the field over the last 40+ years. Furthermore, the data
`
`presented during prosecution were not gathered or analyzed in a way that may be
`
`used to demonstrate synergy or any statistically significant differences between the
`
`therapies. To the extent that the data may be analyzed using scientifically accepted
`
`methods, the analysis of the results do not illustrate synergy or any statistically
`
`significant differences between the therapies.
`
`IV. LEGAL PRINCIPLES
`32.
`I am not an attorney. For purposes of this declaration, I have been
`
`informed about certain aspects of the law that are relevant to my analysis and
`
`opinions as set forth below.
`
`33.
`
`I understand that a patent claim is obvious if the differences between
`
`what is set forth in the claims and what is disclosed in the prior art would have
`
`been obvious to a person of ordinary skill at the time that the patent application
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`was filed.
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`34.
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`I understand that as part of the analysis of whether a given patent
`
`claim is obvious, one should consider: (i) the scope and content of the prior art; (ii)
`
`the level of ordinary skill in the art; (iii) the differences between what is claimed
`
`and the prior art; and (iv) any secondary considerations that may indicate that the
`
`claims are not obvious.
`
`35.
`
`I understand that one of the secondary considerations which bear on
`
`the obviousness of a patent claim is unexpected results that arise from the
`
`purported invention that is claimed.
`
`V. BACKGROUND INFORMATION
`A.
`Synergy
`36.
`
`“Synergy” is defined as an interaction between two drugs in which the
`
`pharmacological effect when the drugs are given together, “the Combined Effect,”
`
`is greater than the expected sum of the effects of the individual drugs when given
`
`alone, “the Additive Effect.”
`
`37. Appendix A to this declaration includes a more complete explanation
`
`of synergy and outlines the methods for analyzing drug interactivity.
`
`B.
`38.
`
`Statistical Significance
`
`In scientific investigations, statistics is routinely used to determine the
`
`probability that a difference associated with an event is caused by the event and is
`
`not due to chance alone. A “statistically significant” cause-and-effect is concluded
`
`if the probability for the observed difference due to chance (e.g., due to the data
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`variability inherent in every experiment) is lower than a predefined value. A
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`probability (P) of 5% (0.05) or less is the customary cut-off for statistical
`
`significance: less than 5% means that the data is statistically significant and greater
`
`than 5% means that the data is not statistically significant. See, e.g., Appendix D,
`
`listing seven research articles by separate investigator groups relevant to the
`
`opinions expressed in this declaration, each of which defines “statistical
`
`significance” as occurring when P < 0.05, regardless of the statistical test used to
`
`compute the P value.
`
`39.
`
`The statistical significance or the P value of, e.g., a difference
`
`between two treatment groups, is calculated based on three values: (i) magnitude of
`
`the difference between the mean values of two treatment groups, (ii) magnitude of
`
`data variability within each treatment group, and (iii) degrees of freedom, which is
`
`related to the number of replicates or samples within each treatment group.
`
`40.
`
`In general, experimental results with greater between-replicates1 data
`
`variability have lower statistical power or significance compared to experimental
`
`results with less between-replicates data variability. Variability may be measured
`
`or expressed in a variety of statistical terms, including the range, standard
`
`
`1 The term “replicates” is used to describe samples run with the same experimental
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`conditions.
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`deviation, variance, and standard error of the mean (S.E.M.). 2 Larger values for
`
`any of these measurements indicates larger variability between replicates. See,
`
`e.g., Zar, Measures of Dispersion and Variability, in Biostatistical Analysis,
`
`Prentice Hall (1974) (Ex. 1030).
`
`41.
`
`In addition, experimental results obtained using a larger number of
`
`replicates or a larger sample size generally have smaller between-replicates S.E.M.
`
`and therefore have the effect of increasing the statistical power or significance
`
`compared to results obtained using fewer replicates or a smaller sample size.
`
`42.
`
`For statistical analysis, a Student’s t-test is often used to determine
`
`whether the mean data for two groups are significantly different from each other. 3
`
`
`2 For example, a test that is run with five replicates or samples may have its results
`
`denoted as follows: 6 ± 2. The “6” in this statement is generally the arithmetic
`
`mean or average of the five measured samples. The “2” in this statement will need
`
`to be defined in the legend accompanying the results. If, for example, the “2” is
`
`the range, then the five samples have values that vary from (6 minus 2) to (6 plus
`
`2) or from 4 to 8.
`
`3 Comparisons of multiple groups typically use ANOVA (analysis of variance),
`
`which is designed to identify if any of the group means is significantly different
`
`from at least one of the other group means, regardless of the number of groups
`
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`The results of a statistical test is a P value. According to the general principles
`
`discussed above, a P value greater than 5% (0.05) means that the data for the two
`
`groups are not significantly different from each other and a P value less than 5%
`
`(0.05) means that the two groups are significantly different from each other.
`
`43. A Student’s t-test is computed using the values of mean, standard
`
`deviation and degrees of freedom. The exact calculation of the P value using the
`
`Student’s t-test is beyond the scope of this Declaration. However, multiple
`
`statistical computer software packages have a pre-programmed function that could
`
`be used to calculate the P value under the Student’s t-test when the user inputs the
`
`observed results of the experiment. The Microsoft Excel program was used to
`
`calculate the P values in Appendix C of this Declaration.
`
`C. The Methamphetamine-Induced Hyperlocomotion Test
`44. During prosecution of the application that led to the ’939 patent, one
`
`of the named inventors submitted a declaration in which he said that the
`
`methamphetamine-induced hyperlocomotion test is “considered to be one of the
`
`
`being compared. While comparisons between multiple groups can be performed
`
`by applying the Student’s t-test to each of the pairs-of-interest, the multiple
`
`comparisons used to compare all possible pairs increase the probability of finding a
`
`statistically significant difference even when the difference is due to chance alone.
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`models of manic conditions of bipolar disorder, which model is widely used in
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`pharmacological tests.” (Hirose Declaration, June 29, 2011, at 2 (Ex. 1076 at
`
`1161).) In my work as a pharmacologist and in my role as a consultant or advisor
`
`on FDA and NIH committees, I am routinely called upon to offer my opinions on
`
`biological or pharmacological systems with which I am not familiar. In such cases,
`
`I perform literature research on the subject matter and apply known
`
`pharmacological principles to address the questions being posed. In the current
`
`case, I researched the methamphetamine-induced hyperlocomotion test that is often
`
`used as a model for manic behavior, such as the behavior observed in bipolar
`
`disease. See Appendix D for a sampling of literature over the past 40+ years
`
`illustrating that the methamphetamine-induced hyperlocomotion test has been used
`
`as a model for manic behavior.
`
`45.
`
`In the methamphetamine-induced hyperlocomotion test, a rodent is
`
`administered methamphetamine to induce a “manic” state. The manic behavior
`
`may be quantified by counting the amount of movements that the rodent does in a
`
`given amount of time. A higher number of movements indicates a more manic
`
`state. The rodent may also be given another drug to suppress the manic behavior.
`
`For example, it is known that the movement counts for a rodent treated with
`
`methamphetamine are higher than the movement counts in a rodent that has not
`
`been treated with methamphetamine; the increase in the movement or locomotion
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`is the methamphetamine-induced hyperlocomotion. The effectiveness of a test
`
`drug in treating manic behavior is indicated by the drug’s ability to suppress the
`
`methamphetamine-induced hyperlocomotion. The suppression is measured by
`
`comparing the movement counts in two groups of methamphetamine-treated
`
`rodents, one receiving the additional treatment of the test drug and one without this
`
`additional treatment. The amount of suppression is considered to be a surrogate
`
`for how well a drug, such as lithium, treats manic behavior.
`
`VI. U.S. PATENT NO. 9,125,939
`A. The Claims
`46.
`I have reviewed the challenged claims 2, 6, 7, and 9 of the ’939
`
`patent. In general, these claims are directed to a method of treating bipolar
`
`disorder comprising administering to a patient a therapy comprising two drugs, i.e.,
`
`aripiprazole and lithium. I have been asked to evaluate the claim of unexpected
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`synergy made during the prosecution of the ’939 patent and, thus, I address that
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`question but offer no opinion as to the ultimate obviousness of the claims.
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`B.
`Summary of Relevant Portions of the Prosecution History
`47. During prosecution, the examiner repeatedly rejected the claims based
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`on the obviousness of the combination of aripiprazole and lithium over prior art
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`references. The applicants were not able to overcome these rejections based on
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`arguments directed to the prior art alone over the course of several cycles of
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`arguments. The applicants then asserted that the combination of aripiprazole and
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`lithium produced “significantly enhanced” results as compared to either lithium or
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`aripiprazole alone. The applicants further asserted that the combination resulted in
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`synergy. According to the applicants, this “synergy” was unexpected because the
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`prior art combination of lithium and olanzapine did not result in synergy.
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`(Response to Office Action dated July 1, 2011, at 10 (Ex. 1076 at 1158).)
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`48.
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`In support of their argument that the combination of lithium and
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`aripiprazole results in unexpectedly “significantly enhanced” results or synergy,
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`the applicants submitted a declaration by one of the named inventors (“the Hirose
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`Declaration”). The Hirose Declaration describes a series of methamphetamine-
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`induced hyperlocomotion tests, and concludes based on the data presented (“the
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`Hirose Data”) that the combination of aripiprazole and lithium results in synergy.
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`(Hirose Declaration at 4 (Ex. 1076 at 1163).) The applicants explained their
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`understanding of “synergy” as follows: “the inventive combination of the present
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`invention (aripiprazole and lithium) significantly enhanced the locomotion
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`suppressing function achieved by either of aripiprazole or lithium alone, which
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`means that the inventive combination achieves a synergistic effect.” (Response to
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`Office Action dated July 1, 2011, at 10 (Ex. 1076 at 1158).)
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`49.
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`In two later responses, the applicants gave a different definition of
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`synergy:
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`[I]n general, two test paradigms for investigating a synergistic effect of
`two drugs, which are:
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`(i) Investigating whether the drugs co-used at a dose where each of
`said drugs renders little (medium) response in the objected test regime
`when used alone would enhance the objected response to an
`unpredictable degree; or
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`(ii) Investigating whether the drugs co-used at a dose where each of
`said drugs renders no effect on the parameter for response in the
`objected test regime when used alone would generate the objected
`response.
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`(Response to Office Action dated August 20, 2014, at 9-10 (Ex. 1076 at 1207-
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`1208); Response to Office Action dated April 24, 2015, at 8-9 (Ex. 1076 at 1265-
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`66).)
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`50.
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`The Hirose Declaration describes the “Hirose Experiments” which
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`included two separate experimental arms. One arm compared the effect of the
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`(aripiprazole + lithium) combination with the effect of either lithium alone or
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`aripiprazole alone (“the Aripiprazole Arm”). The other arm compared the effect of
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`the (olanzapine + lithium) combination with the effect of either lithium alone or
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`olanzapine alone (“the Olanzapine Arm”). In addition, both arms included three
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`identical control groups. For each experimental arm, the applicants tested five
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`conditions: condition 1 – Vehicles with no methamphetamine and no locomotor
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`suppressing agent; condition 2 – Vehicles with methamphetamine but no
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`locomotor suppressing agent; condition 3 – Vehicle with methamphetamine and a
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`test drug (i.e., either aripiprazole or olanzapine); condition 4 – Vehicle with
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`methamphetamine and lithium; condition 5 – methamphetamine with lithium and
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`the test drug. (Hirose Declaration at 3 (Ex. 1076 at 1162).)
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`51.
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`In this study design, condition 1 provides the baseline movement
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`counts; comparison of condition 2 to condition 1 provides the measurement of
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`methamphetamine-induced hyperlocomotion; comparison of condition 3 to
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`condition 2 provides a measurement of the effect of the test drug on suppressing
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`the methamphetamine-induced hyperlocomotion; comparison of condition 4 to
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`condition 2 provides a measurement of the effect of lithium on suppressing the
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`methamphetamine-induced hyperlocomotion; and comparison of condition 5 to
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`condition 2 provides a measurement of the effect of the (test drug + lithium)
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`combination on suppressing the methamphetamine-induced hyperlocomotion.
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`Eight animals were used for each treatment condition in the Aripiprazole Arm, and
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`six or seven animals were used for each condition in the Olanzapine Arm. The
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`applicants described the experimental conditions as follows:
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`As the animals, five to six-week-old Male ddY mice were used.
`Aripiprazole (0.15 mg/kg) or olanzapine (0.1 mg/kg) as well as the
`solvent were orally administered to the mice one hour before the start
`of the locomotion measurement; after forty minutes of acclimatization
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`to the environment of the acryl cylinder, lithium chloride (25 mg/kg)
`or the solvent was intraperitoneally administered, which is 20 minutes
`before the start of the measurement.
` Twenty minutes later,
`Methamphetamine (3 mg/kg) was subcutaneously injected in the
`dorsal neck, the locomotion of the mice for 1 hour right after the
`injection was measured with Supermex.
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`Aripiprazole and olanzapine were suspended in a 5% gum Arabic-
`