Autism Patents and Beyond 9781536104783, 1536104787

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SOCIAL ISSUES, JUSTICE AND STATUS

AUTISM PATENTS AND BEYOND

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SOCIAL ISSUES, JUSTICE AND STATUS

AUTISM PATENTS AND BEYOND

MICHAEL J. DOCHNIAK

New York

Copyright © 2017 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470 E-mail: [email protected]. NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data ISBN: 978-1-53610-478-3

Published by Nova Science Publishers, Inc. † New York

CONTENTS Preface

vii

Acknowledgment

ix

About the Author

xi

Introduction

xiii

Chapter 1

Autism-Related Patents

1

Chapter 2

Universities

5

Chapter 3

Private Companies

31

Chapter 4

Pharmaceutical Companies

47

Chapter 5

Biomedical Companies

59

Chapter 6

Natural Persons

69

Chapter 7

Hospitals

81

Chapter 8

Non-Profits

85

Chapter 9

Medical School

93

Chapter 10

Patent Pending

97

Chapter 11

Year-2016

105

Chapter 12

Year-2015

131

Chapter 13

Year-2014

173

Chapter 14

Year-2013

209

Chapter 15

Year-2012

243

Chapter 16

Year-2011

267

Chapter 17

Years 2010-2006

287

Chapter 18

Years 2005-2003

317

Chapter 19

Years 2002-1987

351

vi

Contents

Chapter 20

Rejected-Applications

375

Chapter 21

Temple Grandin

381

Patent Glossary

383

Conclusion

385

Index of Names

387

PREFACE Humans are social animals. Behaviors that define our greatness include friendship, cooperation, and self-sacrifice for others. Autism spectrum disorders (ASDs) impact these behaviors. In the search for answers, there has been an explosion of ideas on how to alleviate the atypical behaviors in ASDs. Having worked in the field of patent protection for several years, I’ve witnessed many pioneering patents and me-too patents that provide improvements and make a difference. The book Autism Patents and Beyond is a personal attempt to research and disclose such efforts. Most amazing, this research has revealed to me that inventors often succeed because of their friendship, cooperation, and self-sacrifice for others.

ACKNOWLEDGMENT People who invent therapeutic-interventions for autism spectrum disorders. Harmony Dunn, your inner light shines brightly for peace, love, and hope. To my parents, laughter is the love we share together.

ABOUT THE AUTHOR

Michael J. Dochniak Michael J. Dochniak is an inventor in fourteen US patents. Mr. Dochniak was a patent coordinator at a Fortune 500 Company for many years and has co-authored the book Allergies and Autism through Nova Science Publishers.

INTRODUCTION

What we know for sure is that there are many children living with autism who need services and support, now and as they grow into adolescence and adulthood – Stuart K. Shapira, MD PhD chief medical officer for CDC’s National Center on Birth Defects and Developmental Disabilities. Do you have insight into the cause and innovative treatment of disorders that are present in some individual’s on the autism spectrum? Acquiring a United States (US) patent may be the best way to communicate your idea and pursue monetary compensation. Before submitting your idea, although, you’ll need to learn if it has already been disclosed. To better understand the prior art, Michael J. Dochniak has written this book to provide an easy-to-read summary of patents directed at autism spectrum disorders. Since 1987, hundreds of patents have been granted in an effort to help alleviate some of the disabling symptoms present in individuals on the autism spectrum. Furthermore, within the summaries you’ll find InventorProfiles and News Articles that are both informative and enlightening. Impactful inventors include Steven Buyske, Dayan Goodenowe, Michael G. Chez, Sun Joon Min, and Bernd Wellenzohn. Prominent organizations include the University of California, City of Hope, Icahn School of Medicine, Ostuka Pharmaceutical, Prothera Incorporated, and the ScheringPlough Corporation. Furthermore, you’ll discover a sampling of unique pending-applications in Chapter Ten and several disputed rejected-applications in Chapter Twenty. The Autism Patents and Beyond is a quintessential review of creative people who invent - or are trying to invent - therapeutic interventions for autism spectrum disorders.

Chapter 1

AUTISM-RELATED PATENTS

The Centers for Disease Control and Prevention (CDC) is the government agency that monitors the prevalence of autism spectrum disorders in the US. In a communication from the CDC (July 11, 2016) titled, Autism Spectrum Disorder (ASD) Prevalence Data & Statistics, it states that “About 1 in 68 children has been identified with autism spectrum disorder (ASD). ASD is reported to occur in all racial, ethnic, and socioeconomic groups. ASD is about 4.5 times more common among boys (1 in 42) than among girls (1 in 189).”[1] An autism spectrum disorder (ASD) is a neurological and developmental disorder that affects a person’s ability to communicate, form relationships and respond appropriately to the environment. The behavioral symptoms include aggression, agitation, disruptive behavior, and irritability, as well as compulsive-repetitive behavior.. [2] Over the last two decades, there have been hundreds of US patents that explain therapeutic-interventions for autism spectrum disorders. The quote below provides a simple explanation of a patent: A patent, or invention, is any assemblage of technologies or ideas that you can put together that nobody put together that way before. That’s how the patent office defines it. That’s an invention. - Dean Kamen (holds more than 440 US and foreign patents and is the inventor of the Segway, the first drug infusion pump, and many other innovations). The United States Patent and Trademark Office (USPTO) is the federal agency for granting patents. The USPTO fulfills the mandate of Article I, Section 8, Clause 8, of the Constitution. This effort promotes the progress of science by securing for limited times to inventors the exclusive right to their discoveries.

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The world is a better place when ideas are disclosed, patented, and attain financial success. If you have an idea on how to help alleviate symptoms in individuals on the autism spectrum, the USPTO will reward you with patent protection for many years. A well-earned autism-related patent can be part of a strategic business plan that allows you to exclude others from making, using, offering for sale, or selling your invention throughout the US. If you’re the assignee (i.e., owner) of a pioneering patent, you may obtain 20 years of legal protection to acquire exclusive financial-gain. In an article from CBS News (July 30, 2015) titled, Autism costs skyrocket, experts warn, author Ashley Welch writes, “Researchers from the University of California Davis Health System calculated costs for the current calendar year and projected where they’ll be 10 years from now if effective interventions and preventive treatments are not identified and made widely available. They estimated that for medical, non-medical, and productivity losses associated with the disorder, autism will cost $268 billion for 2015 and $461 billion for 2025. But the researchers said these projections are conservative and if prevalence of autism continues to increase at current rates, the costs could reach $1 trillion in the next decade.” [3] The first US patent with the word “autism” in the title was issued on October 18, 1988. Twenty-eight years later (August, 2016), 82 patents have been granted. The graph below shows the number of patents granted per year.

Years (Autism, in Patent Title).

Many countries have been granted autism-related patents in the US. The graph below shows the country of origin of US patents with the word “autism” in the title.

Autism-Related Patents

3

Country of Origin (Autism, in Patent Title).

Organizations and individuals can acquire an ownership interest in a patent by assignment from the inventor(s). The graph below shows assignee designations of US patents wherein the word “autism” is in the title:

Assignee (Autism, in Patent Title).

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Universities have a high number of autism-related patents. In an article from the New York Times (November 20, 2013) titled, Patenting Their Discoveries Does Not Pay Off for Most Universities, a Study Says, author Richard Perez-Pena writes, “Universities are increasingly eager to find new sources of revenue, as they see projections of shrinking student populations, declining government support and growing resistance to tuition increases. Universities make money from patents primarily by licensing them to outside companies, which turn them into commercial products.” [4] In the following chapters, you’ll experience the Herculean effort put forth by inventors to receive an autism-related patent. Most interesting, of the 82 US patents (August, 2016) that have the word “autism” in the title, a gender analysis showed that there were 138 male inventors and 33 female inventors (~ 4:1 ratio). In parallel, the ratio of males to females having an ASD is about 4.5:1.

REFERENCES [1] [2] [3] [4]

Autism Spectrum Disorders, “Data & Statistics” Centers for Disease Control and Prevention, Accessed August 13, 2016. http://www.cdc.gov/ncbddd/autism/data.html. Autism Spectrum Disorder Fact Sheet, “National Institute of Neurological Disorders and Stroke” NIH, Accessed August 13, 2016. http://www.ninds.nih.gov/disorders/ autism/detail_autism.htm. Ashley Welch, 2015. “Autism costs could skyrocket, expert warns” CBS News, Accessed August 13, 2016. http://www.cbsnews.com/news/autism-costs-skyrocket-1trillion-by-2025/. Richard Perez-Pena, 2013. “Patenting Their Discoveries Does Not Pay Off for Most Universities, a Study Says” The New York Times, Accessed on August 13, 2016. http://www.nytimes.com/2013/11/21/education/patenting-their-discoveries-does-notpay-off-for-most-universities-a-study-says.html?_r=0.

Chapter 2

UNIVERSITIES

COMPOUNDS FOR THE TREATMENT OF AUTISM (Ben-Ari et al., Patent number 9,415,028 - August 16, 2016) Abstract - This describes a compound which inhibits the importation of chloride into neurons and a compound which improves the outflow of chloride from neurons for the use in treatment of autism. Claim 1 – A method for treating autism by administering a compound which is a Na--K-Cl co-transporter (NKCC) inhibitor and a loop diuretic, wherein said compound is bumetanide. The inventors explained that an emerging series of studies suggest that chloride accumulates during brain maturation in relation to various developmental malformations. Present observations suggest that a conventional diuretic that reduces this accumulation and acts to reinstate the inhibitory actions of Gamma-Amino butyric acid (GABA) may exert beneficial actions in autism. In the discussion section the inventors state that, “Present results suggest that bumetanide ameliorates behavioral aspects of infantile autistic syndrome (IAS) suggesting that the diuretic has a global action. To the best of our knowledge, this is the first report raising the possibility of chloride alterations in autism.” Yehezkel Ben-Ari (first inventor listed with a co-inventor) received a BSc in biochemistry from the Hebrew University of Jerusalem in Israel and received post-doctoral

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and sabbatical studies at the University of Cambridge, University of Oslo, and McGill University (1973-1980). Dr. Ben-Ari founded Neurobiology Institute of the Mediterranean (INMED) in 1986, and was the director until 2011. Dr. Ben-Ari is the President, acting Chief Executive Officer and co-founder of the Neurochlore, a biotechnology company that aims to understand and treat autism. [1] The National Institute of Health and Medical Research (INSERM), Aix-Marseille University, and Brest University Hospital are the assignees for US patent 9,415,028 (Ben-Ari et al.) In an article from Nature (February 6, 2014) titled, Diuretic drug prevents autism in mice and rats, author Ewen Callaway writes, “A study in mice and rats suggests that an imbalance in chloride ions during a child’s development in the womb could be a factor for autism. A team led by Neuroscientist Yehezkel Ben-Ari at the Mediterranean Institute of Neurobiology in Marseille gave 60 children bumetanide or a placebo daily for three months. Children who had less severe forms of autism showed mild improvements in social behavior after taking the drug, and almost no adverse side effects were observed. Ben-Ari’s team hypothesized that the system malfunctions at around the time of birth, when GABA-releasing neurons in the developing brain switch from activating neurons to inhibiting them. A drop in the concentration of chloride ions in neurons makes this switch. Thus, bumetanide, which reduces the levels of chloride in cells, might restore inhibitory GABA function and improve autism symptoms.” [2]

GENETICALLY ENGINEERED MOUSE MODEL FOR AUTISM SPECTRUM DISORDER HAVING DELETION OF SHANK2 GENE AND USE THEREOF (Lee et al., Patent number 9,232,775 – January 12, 2016) Abstract - This describes a genetically engineered mouse model carrying a deletion of Shank2 gene and having reduced N-Methyl-D-asparate receptor function. Abbreviated Claim 1 – A genetically engineered mouse model having clinical features of ASD. The inventors explained that the genetically engineered mice show clinical features of autism spectrum disorders and can be effectively used to screen candidate therapeutic agents. The inventors write that the mice were bred and maintained according to the Yonsei Medical Center, Korea Advanced Institute of Science and Technology, and Seoul National University Animal Research Requirements, and all procedures were approved by the Committees on Animal Research at Yonsei Medical Center. The invention showed that the mice have partially impaired learning and memory, consistent with exons 6+7 deletion in humans which causes autism spectrum disorders and mild to moderate mental retardation. The results showed that the mice treated with the mGluR5 positive allosteric modulator (i.e., CDPPB) exhibited substantial recoveries in social interaction to an extent greater than D-cycloserine, while having no effect on social novelty recognition.

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Min Goo Lee (first inventor listed with two co-inventors) received an MD and PhD from Yonsei University (1999). Dr. Lee is director at the Pharmacogenomics Research Center for Membrane Transporters in Yonsei University. Korea Advanced Institute of Science, Yonsei University Industry-Academic Cooperation Foundation, and Seoul National University R&D Foundation (current assignee) have protection for US patent 9,232,775 (Lee et al.) to August 28, 2033. In an article from Spectrum (November 14, 2011) titled, Researchers debut SHANK2 mouse, SHANK3 rat, author Virginia Hughes writes, “Mice lacking the autism risk gene SHANK2 show social deficits and are extremely hyperactive. When you watch these animals in the cages, what they’re doing all day long is jumping up and down. Sometimes it’s really hard to make them calm down”, says Tobias Boeckers, professor of anatomy and cell biology at the University of Ulm in Germany. “The mice are called popcorn mice in the lab. The new mice, which lack SHANK2, also have social problems”, collaborator Thomas Bourgeron said. During male-female interactions, male mice lacking SHANK2 sniff a healthy female less often than controls do. The researchers are also analyzing the animals’ ultrasonic vocalizations, which they use to communicate with each other. Researchers sometimes interpret abnormalities in the pattern of these squeaks as akin to language problems in people with autism. “These mice sing less and sing differently”, says Bourgeron, professor of genetics at the Institut Pasteur in Paris.” [3]

AUTISM-ASSOCIATED BIOMARKERS AND USES THEREOF (Lipkin et al., Patent number 9,050,276 – June 9, 2015) Abstract – This describes methods of treating, preventing, and diagnosing autism-related disorders. The inventors explained that molecular studies are lacking that characterize host gene expression or that survey microflora using pyrosequencing methods. The invention showed that intestinal biopsies of children with autism accompanied by gastrointestinal complaints had highly significant elevation of intestinal levels of Sutterella bacteria. These findings can provide insights into the pathogenesis of autism associated with gastrointestinal disorders, enabling new strategies for therapeutic interventions. Ian W. Lipkin (first inventor listed with two co-inventors) is a professor of epidemiology, a professor of neurology and pathology, and director of the Center for Infection and Immunity at Columbia University (original assignee). Dr. Lipkin’s contributions include the first use of subtractive cloning and deep sequencing in pathogen discovery. [4] The Columbia University Department of Psychiatry (current assignee) is one of the largest in the country in terms of faculty size as well as state, federal, and foundation research support. They ranked number one in the nation for psychiatry in the US News and World Report “Best Hospital” as well as number one in psychiatric research funding from the National Institutes of Health. [5] In an article from the Los Angeles Times (September 3, 2001) titled, New York Is Next Stop for Famed UCI Molecular Biologist, author Jeff Gottlieb writes, “Lipkin, who founded the lab at UCI in 1990, is an explorer who, along with fellow researchers, hunts for

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Michael J. Dochniak

unidentified microbes, trying to figure out which illnesses are caused by which viruses. It was Lipkin who, in 1999, identified West Nile virus, previously unknown in the US, as the cause of the encephalitis outbreak that killed seven people in the New York City area. The discovery catapulted the UCI physician and professor of neurobiology into the scientific spotlight and sent him to Japan, Germany, France, Italy and across the US, attending conferences and collaborating with other researchers. The West Nile discovery was the kind of research Lipkin thrives on, delving into the mysterious world of disease and turning up a cause. Working at the frontier of molecular biology, he seeks microbes he believes are responsible for a number of chronic diseases, including multiple sclerosis, autism, Alzheimer’s disease and depression.” [6]

METHODS FOR TREATMENT OF AUTISM SPECTRUM DISORDER (Tierney et al., Patent number 8,987,246 – March 24, 2015) Abstract – This describes methods of treating autism spectrum disorders by administering cholesterol. Abbreviated Claim 4 – The Method of claim 1, wherein the ASD is autism. The inventors explained that a subgroup of children with autism spectrum disorders have low cholesterol and there continues to be a need for treatments. The inventors concluded that children on cholesterol supplementation improve by an average of 7.07 points compared with children not on supplementation. Elaine Tierney (first inventor listed with a co-inventor) received an MD from the University of South Florida in 1989. Dr. Tierney is an associate professor of psychiatry and behavioral sciences at Johns Hopkins Medicine. [7] The Kennedy Krieger Institute Incorporated the US Department of Health and Human Services - National Institutes of Health, and Johns Hopkins University are the assignees for US patent 8,987,246 (Tierney et al.). In a communication from The Kennedy Krieger Institute, Elaine Tierney says, “We know that people can tolerate having low cholesterol, so we suspect that deficiencies in cholesterol combined with mutations to a specific gene may have resulted in autism spectrum disorders in these children. Our next steps are to determine if other abnormalities of cholesterol metabolism can be risk factors for the development of autism.” [8]

METHOD AND KIT FOR DIAGNOSING AUTISM USING GENE EXPRESSION PROFILING (Hu, in Patent number 8,962,307 – February 24, 2015) Abstract – This describes methods and kits for identifying autism spectrum disorders with DNA microarray technology.

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Abbreviated Claim 1 – A composition comprising an ensemble consisting of nucleic acid molecules produced from a sample of peripheral blood cells of an individual having autism, wherein each of the nucleic acid molecules is capable of emitting a detectable signal. The inventor explained that although studies of gene expression in brain tissue may lead to a better understanding of the mechanistic basis for ASD, it is not an appropriate target for diagnostic assays. DNA microarray analysis is used to examine gene expression in lymphoblastoid cell lines derived from peripheral blood lymphocytes. In the conclusion Valerie Hu writes, “While it is unlikely that microarray studies on lymphoblastoid cell lines will identify the etiology(ies) of autism, this global approach to gene expression is expected to highlight molecular or pathway defects related to the pathophysiology of the condition which can be targeted for drug therapies. Moreover, as opposed to fixed autopsy tissues in which RNA may have degraded, a live cell model can be used to examine the functional consequences of the genomic alteration(s) and the efficacy of different pharmacological agents in ameliorating the impaired function.” Valerie W. Hu (inventor) is a professor of biochemistry and molecular medicine at the George Washington University School of Medicine and Health Sciences, and the Chair of the Autism and Neurodevelopmental Disorders Initiative Faculty Committee. A mother of a son with an autism spectrum disorder (ASD), Dr. Hu redirected her research focus towards autism in 2005 and has since published 10 papers on the genes and biological pathways associated with ASD Dr. Hu says, “The long-term goals of my laboratory are personalized diagnosis and treatment of autism spectrum disorders (ASD). We aim to achieve these goals by developing a better understanding of the underlying biology giving rise to different manifestations of autism through the identification of altered genes, pathways, and gene regulatory mechanisms specific to the different subtypes of ASD” [9] George Washington University is the assignee for US patent 8,962,307 (Hu). In an article from Spectrum (January 10, 2012) titled, The value of blood cells in autism research, author Valerie Hu writes, “Employing lymphoblastoid cells from discordant twin and sibling pairs, researchers in a 2010 study demonstrated differences in DNA methylation between cases and controls. Included in these is a gene that regulates the expression of other genes, called retinoic acid-related orphan receptor α, or RORA. There is less RORA protein in the cerebellum and the frontal cortex in postmortem brains from individuals with autism compared with controls, which was found to correlate with the reduction of another protein, aromatase, that controls the levels of male and female hormones in tissues” [10]

DIAGNOSIS OF AUTISM SPECTRUM DISORDERS AND ITS TREATMENT WITH AN ANTAGONIST OR INHIBITOR OF THE 5-HT2C RECEPTOR SIGNALING PATHWAY (Page et al., Patent number 8,940,732 – January 27, 2015) Abstract – This describes methods of diagnosis and treatment of autism spectrum disorders characterized by increased head size (circumference) and deficits in social behavior. Abbreviated Claim 1 – A method for treating an autism spectrum disorder comprising administering an antagonist or inhibitor (e.g., SB242084) of the 5-HT2c receptor signaling

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Michael J. Dochniak

pathway, wherein the subject has a phosphatase and tensin homolog (PTEN) deficiency and/or SLC6A4 gene deficiency and/or increased circulating serotonin. The inventors explained that based on the biochemical interactions of the expression products of PTEN and/or SLC6A4, the applicants have determined that antagonists or inhibitors of the 5-HT2c receptor signaling pathway unexpectedly are viable candidates for human ASD therapeutics. The inventors stated that although the cellular mechanism underlying effect on growth remains to be identified, the data indicates that PTEN and Slc6a4 act cooperatively to influence a brain growth phenotype relevant to ASD. Damon Theron Page (first inventor listed with a co-inventor) received a bachelor degree in biology from Eastern Oregon University and a PhD from the University of Cambridge. Dr. Page was a postdoctoral fellow at the MRC Laboratory of Molecular Biology at the Massachusetts Institute of Technology (MIT) where he worked as a research scientist at MIT. Dr. Page is an associate professor in the Department of Neuroscience at the Scripps Research institute. In a communication from The Scripps Research Institute Dr. Page summarizes his research interests as follows: “My laboratory is focused on understanding how the components necessary for establishing the cellular architecture of the brain (neuronal and glial cell types) are generated and how these assemble into functional circuits that underlie behavior. The mechanisms by which these processes occur are largely unknown, and yet, disruptions can have enormous societal and personal consequences in the form of neurodevelopmental and neuropsychiatric disorders. Such disorders provide a window into the basic genetic and cellular mechanisms involved in building the brain. This insight may be used in turn to benefit those affected by mental illness, pointing to molecular targets for improved diagnostics and therapeutics. Autism spectrum disorder (ASD) is one such disorder. ASD is characterized by a range of phenotypes, including deficits in social behavior, as well as an altered trajectory of brain growth in some cases. Clues to mechanisms come from reports that PTEN-PI3K-mTOR, monoamine, neuropeptide and synaptic signaling pathways have been implicated in ASD pathogenesis. Understanding how these risk factors influence brain and behavior will give us basic insight into how the brain develops and how this process is altered in ASD. Along these lines, my laboratory makes use of transgenic and knockout mice to understand the biology of how risk factors for autism and related neurodevelopmental disorders influence the development of cell types and circuits underlying behavior, and to test efficacy of potential therapeutics. The PTEN-PI3K-mTOR pathway and neural systems relevant for autism and social behavior (e.g., serotonin and oxytocin/vasopressin) are areas of focus for our work. We use a variety of techniques, including transgenic mice, histology, molecular cell biology, genomics, informatics, pharmacology, imaging and behavioral phenotyping.” [11] The Massachusetts Institute of Technology (current assignee) has protection for US patent 8,940,732 (Page et al.) to December 25, 2030. In an article from Scicasts (February 26, 2015) titled, New Study Shows Decreased Aggressive Behaviour Toward Strangers in Autism Spectrum Disorder Model, Scicasts staff write, “While aggression toward caregivers and peers is a challenge faced by many individuals and families dealing with autism, there has been much speculation in the media over the possibility of generally heightened aggression in those diagnosed with autism spectrum disorder. A new study by scientists from the Florida campus of The Scripps Research Institute (TSRI) found no evidence of increased aggressive behaviour toward

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strangers in an animal model of the condition. In fact, the study, published recently online ahead of print in the journal Genes, Brain and Behaviour, found these animals showed decreased aggressive behaviour toward strangers and, instead, engage in more repetitive behaviour than normal mice. ‘These mice show traits relevant to autism, such as an overgrown brain and reduced social interaction’, said Damon Page, a TSRI biologist who conducted the study with Research Associate Amy Clipperton Allen. ‘What we don’t see in this model is a general increase in aggressive behaviour, this is a striking result’, Page said. ‘The mutant mice appear to avoid aggressive encounters with the intruder and instead engage in repetitive behaviour. An analogy might be a stranger entering a house, and the resident rearranging the books on the bookshelf instead of confronting the intruder’. Page plans further studies examining the neurobiological relationship between social deficits and repetitive behaviour, two of the primary symptoms of autism.” [12]

LUTEOLIN AND DIOSMIN/DIOSMETIN AS NOVEL STAT3 INHIBITORS FOR TREATING AUTISM (Tan et al., Patent number 8,778,894 – July 15, 2014) Abstract – This describes methods of treating autoimmune disorders such as autism. Claim 1 – A method of reducing the risk of developing autism due to exposure in utero to elevated levels of maternal IL-6 by inhibiting activation of STAT3 and by administering a flavonoid consisting of luteolin, diosmin, and diosmetin to the mother during pregnancy. The inventors explained that flavonoids were found to inhibit activation/phosphorylation of STAT3 induced by IL-6 in cultured neuronal cells and reduce autistic-phenotype in mice. The main goals of treatment are to lessen associated deficits and family distress, and to increase quality of life and functional independence. No single treatment is best and treatment is typically tailored to the child’s needs. Although there is no cure for autism, clinicians do agree that early detection could significantly improve chances in if not preventing it, then at last reducing its weakening effects. Current treatments were shown efficacious when applied earlier in the child’s life, prior to the full blown onset. Thus the early prognosis is a vital component in the fight against this disease. The invention showed that the STAT3 inhibitor (S31-201) and diosmin reduce proinflammatory cytokines in the brain tissues of IL-6/MIA/newborn mice. It also significantly attenuates the behavioral deficits seen in the adult offspring of IL-6 treated animals. Roland D. Shytle (second inventor listed with two co-inventors) received a PhD in psychology from the University of Wyoming (1994). Dr. Shytle is an associate professor at the center of excellence for aging and brain repair at the University of Southern Florida (original assignee). [13] The University of Southern Florida is the current assignee for US patent 8,778,894 (Tan et al.). In an article from Morsain College of Medicine – Neuroscience and Brain (October 5, 2015) titled, Jun Tan probes the power of flavonoids in fighting Alzheimer’s disease, it is written, “Backed by a diverse research team, Jun Tan, MD and PhD often takes the road less traveled when it comes to searching for new treatments for disorders affecting both the end

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Michael J. Dochniak

and beginning of the lifespan: Alzheimer’s disease and autism. His knack for pursuing new approaches began in 1998, when he started asking if Alzheimer’s disease could be linked with disorders of immunity. This inquiry led Dr. Tan to focus on how amyloid-b (Ab) peptide, which forms the sticky deposits in the brains of patients with Alzheimer’s, affects microglia, the resident immune cells of the brain. He showed that Ab activates microglia by increasing expression of a pro-inflammatory molecule, called CD40. In addition, when microglia and nerve cells (neurons) were combined in a petri dish, treatment with AB caused neuronal injury by activating CD40. It appears that when a switch (CD40) on the surface of microglia is turned ‘on’, these immune cells cease their usual defensive work. They stop cleaning up the Ab protein that kills neurons. Instead, Dr. Tan explained, ‘they begin to produce small proteins called cytokines, which damage neurons’. ‘Alzheimer’s disease is a trickster, able to harm and kill neurons using the brain’s own immune defenders’, Dr. Tan said. Most recently, Dr. Tan has been studying the therapeutic potential of a flavonoid found in the pulp and peel of citrus fruit (diosmin) in helping prevent and reduce Alzheimer’s disease pathology (plaques and tangles) and curbing inflammation in the brains of mice genetically engineered to have the symptoms of the neurodegenerative disease.” [14]

GSTP1 AS TERATOGENIC ALLELE FOR AUTISM AND ASSAYS AND METHODS BASED THEREON (Johnson et al., Patent number 8,722,333 – May 13, 2014) Abstract - This describes a method of identifying individuals who are genetically susceptible to have offspring with autism wherein the genotype of GSTP1, alone or in combination with other genetic markers or other indicators of oxidative stress is determined. The inventors explained that screening for the GSPT1 gene and genotype can be useful in the determination of susceptibility, monitoring, management, diagnosis, and treatment of autism and can also be used in genetic counseling and prenatal diagnosis, management, and care. The invention showed that findings from the combined haplotype and genotype analyses indicated that the GSTP1-313 genotype alone had determined the observed haplotype effect. William G. Johnson (first inventor listed with a co-inventor) received degrees from Columbia University and Princeton University. Dr. Johnson is affiliated with the Robert Wood Johnson University Hospital in New Brunswick, New Jersey. Rutgers State University (current assignee) has protection for US patent 8,722,333 (Johnson et al.) to September 10, 2029. In a paper published in Pediatrics and Adolescent Medicine (April 2007) titled, Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype the inventors concluded that over transmission of the GSTP1 suggests that action in the mother during pregnancy likely increases the likelihood of an autism disorder in her fetus. If this is confirmed and is a result of a gene-environment interaction occurring during pregnancy, these findings could lead to the design of strategies for prevention or treatment. [15]

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IMAGES OF LANGUAGE-SENSITIVE NEUROCIRCUITRY AS A DIAGNOSTIC FOR AUTISM (Hirsch, in Patent number 8,666,475 – March 4, 2014) Abstract - This describes imaging techniques during passive auditory stimulation to objectively provide a diagnostic indicator of ASD. Claim 1 - A method of determining whether a subject suffers from an autism disorder using brain images obtained by a combination of functional MRI and DTI imaging techniques. The inventor explained that despite limitations related to the age of the sample and the lack of a sedated control group, the present finding that fMRI can be employed to differentiate language impaired autistic children from control children at older ages suggests the benefit of larger-scale studies to investigate the use of measures established here as a test for early detection of autism and other developmental disorders. The inventor states that, “The figures also illustrate hypoactivity of the supplementary motor (SM) regions and may also be considered as a diagnostic indicator of autism spectrum disorder.” Joy Hirsch (inventor) is a neuroscientist and professor of psychiatry and neurobiology at Yale University, in New Haven, Connecticut. Dr. Hirsch was professor of neuroscience at Columbia University where she was the director and founded the University-wide Functional MRI Research Center. She has pioneered many breakthroughs in understanding the workings of the human brain, and is one of the early developers of functional magnetic resonance imaging (fMRI), an imaging technique that enables the visualization of individual brain structures and large-scale neural networks that are engaged during specific tasks and cognitive processes. Professor Hirsch has published over 120 peer-reviewed scientific papers and chapters, is a popular world-wide lecturer on the brain, and served as a curator for the 2010-2011 Brain Exhibit at the American Museum of Natural History. She was awarded the prestigious Gamow Science prize in 2009 for her accomplishments in science and was one of the five top women scientists featured in the 2011 World Science Festival. [16] Columbia University is the current assignee for US patent 8,666,475 (Hirsch). In an article from AP Big Story (June 22, 2015) titled, Lasers, magnetism allow glimpses of the human brain at work, author Malcolm Ritter writes, “A brain is like a car motor, says researcher Joy Hirsch. You can study it at rest, but until you start that car up and run it, you don’t really see how all the working parts work together and what the dynamics are. The Yale Brain Function Lab, which she directs, is investigating how our brains let us engage with other people. That’s one of the most basic questions in neuroscience, as well as an ability impaired in autism and schizophrenia, she said: ‘It’s probably one of the most fundamental functions of the human species, and yet we know very little about it.’” [17]

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METHOD FOR DETERMINATION OF DEGREE OF RISK OF ONSET OF HIGH-FUNCTIONING AUTISM (Mori et al., Patent number 8,518,659 – August 27, 2013) Abstract - This describes a method of determining the degree of risk of onset of autism by measuring the triglyceride concentration or the cholesterol concentration in a very lowdensity lipoprotein fraction of plasma or serum. Abbreviated Claim 1 - A method for determining the degree of risk of onset of autism wherein the triglyceride concentration in a very low-density lipoprotein fraction of the plasma or serum is 60 mg /dl or less. The inventors explained that the total amounts of both cholesterol and triglyceride were significantly decreased in underage high-functioning autism compared with the underage healthy controls. The invention can be applied to infants or children, and thus, it enables the establishment of a comprehensive treatment system including prevention of this disease, early treatment, and support of patients for social rehabilitation based on early diagnosis. The invention showed that 8-year old or younger patients with high-functioning autism could be selected at high rates (sensitivity: 83%; specificity: 90%; proper diagnosis rate: 86%) when the triglyceride concentration in the very low-density lipoprotein fraction of patients was lower than 30 mg/dl. Norio Mori (first inventor listed with five co-inventors) received a PhD from Fukushima Medical University. Dr. Mori is professor of psychiatry at the Hamamatsu University School of Medicine. [18] The National University Corporation, Hamamatsu University School of Medicine, and the National University Corporation - Hamamatsu University School of Medicine are the current assignees for US patent 8,518,659 (Mori et al.). Patents also allow the reader to evaluate Patent Examiner documented references that are considered prior art. For example, in 8,518,659 (Mori et al.) the Patent Examiner(s) cite a research paper that suggests the potential hazards of perfumes. Triglycerides are considered the most important part of skin care products (e.g., baby lotion, soap) which may contain perfume. In the prosecution of US patent 8,518,659 (Mori et al.) the foreign search report references O. Bagasra et al., Role of Perfumes in Pathogenesis of Autism. Medical Hypotheses 80 (2013)795-803. In this paper Bagasra et al., state, “We hypothesize and provide scientific evidence that ASD is the result of exposure to perfumes and cosmetics. The highly mutagenic, neurotoxic, and neuro-modulatory chemicals found in perfumes are often overlooked and ignored as a result of a giant loophole in the Federal Fair Packaging and Labeling Act of 1973, which explicitly exempts fragrance producers from having to disclose perfume ingredients on product labels. We hypothesize that perfumes and cosmetics may be important factors in the pathogenesis of ASD Synthetic perfumes have gained global utility not only as perfumes but also as essential chemicals in detergents, cosmetics, soap, and a wide variety of commonly used items, even in food flavoring to enhance product taste. Here we provide evidence that a majority of perfumes are highly mutagenic at femtomolar concentrations, and cause significant neuromodulations in human neuroblastoma cells at

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extremely low levels of concentration, levels that are expected to reach a developing fetal brain if the pregnant mothers are exposed to these chemicals.” [19]

TREATMENT OF AUTISM SPECTRUM DISORDERS WITH AGENTS THAT ACTIVATE THE LOCUS COERULEUS-NORADRENERGIC SYSTEM (Purpura et al., Patent number 8,470,546 – June 25, 2013) Abstract – This describes methods of treating autism spectrum disorders (ASD) using agents that activate the locus coeruleus-noradrenergic (LC-NA) system. Abbreviated Claim 1 - A method for screening for compounds for treating autism spectrum disorders (ASD) by determining whether or not the compound activates the locus coeruleus-noradrenergic (LC-NA) system of the brain, wherein screening is conducted by administering the compound to an animal model that is unable to synthesize norepinephrine and exhibits a motor deficit and/or impaired performance of an active-avoidance task. In inventors explained that the association of febrile episodes and improvement in autistic behaviors provides a basis for the use of α-adrenergic agonists and α-adrenergic re-uptake inhibitors for the treatment of autism. Dominick P. Purpura (first inventor listed with a co-inventor) received a AB degree from Columbia University in 1949 and MD magna cum laude, from Harvard Medical School in 1953. Dr. Purpura is a neuroscientist and the longest-serving Dean of a Medical School in the US. Dr. Purpura was Dean of the Albert Einstein College of Medicine of Yeshiva University from 1984 until 2006 and received the additional title of Vice President for medical affairs. A member of the National Academy of Sciences and its Institute of Medicine, Dr. Purpura is internationally known for studies in mental retardation that demonstrated the primary involvement of certain structural abnormalities of nerve cells in the brain. Also widely recognized for work on the origin of brain waves, developmental neurobiology and the mechanism of epilepsy, he was one of two scientists in the nation to receive the first annual National Medical Research Award of the National Health Council at a White House ceremony in September, 1988. In 1993, he received the Lifetime Achievement Award for Research from the American Epilepsy Society, and in 1996, the Society of Neuroscience presented him with its Presidential Award. In 2001, Dr. Purpura received New York City’s highest scientific honor, the Mayor’s Lifetime Achievement Award for Excellence in the Medical and Biological Sciences. He is a past President of both the (US) Society for Neuroscience and the International Brain Research Organization and served for more than 25 years as chief editor of Brain Research, a major international scientific journal. Dr. Purpura has authored some 200 scientific papers and chapters during a distinguished career. His standing as a scientist as well as a major academic figure has thrust him into leading roles in numerous Educational, Social, Health and Scientific Organizations. [20] The Albert Einstein College of Medicine of Yeshiva University has protection for US patent 8,470,546 (Purpura et al.) to November 11, 2031. In a research paper on febrile episodes from Medical Hypotheses (April, 2013) titled, is fever a predictive factor in the autism spectrum disorders? author AS Megremi writes, “Literature data indicate that probably there are differences in susceptibility to various

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infections between normal and autistic children. In addition, some autistic children show improvement in the characteristics of their autistic behavior during febrile incident and repression of fever (through antipyretics) might be associated with the onset of autistic disorder. Since fever has been associated with mental illness since the time of Hippocrates already and the presence of fever is associated with a favorable outcome in various pathologic conditions, it is assumed that there are probably two subgroups of autistic children: those who have the possibility to develop acute febrile incidents and those who develop acute incidents without fever. If this is the case, it is important to know whether there are differences between the two subgroups in various biological markers (cytokines/chemokines, autoantibodies), neuroimaging findings, personal and family history of these children (use of drugs, vaccinations, history of autoimmunity, etc.) and, if the first subgroup consists of autistic people of higher functionality and better outcome, or not. If such a classification is real, is there a possibility for the fever to be used as a predictor of the autistic disorder outcome and of whether that person will achieve an acceptable level of functionality in the future? If there are positive answers to these questions, are autistic children, who develop fever, at a very critical stage in evolutionary terms, where it is very important not to lose the defense mechanism of fever development and thus mast use the fever repression methods (antipyretic drugs for example) with caution and chariness? If it is confirmed that autistic children with high fevers are of higher functionality, it is possible for preventive intervention programs to be developed where children are exposed to the least possible chemical drugs intervention (antipyretics, antibiotics, etc.) or even selective vaccination. Further experimental, epidemiological and clinical studies are necessary to investigate the above.” [21]

METHODS OF DIAGNOSING AND TREATING AUTISM (Van de Water et al., Patent number 8,383,360 – February 26, 2013) Abstract – This describes methods of determining, preventing, or reducing the risk of developing an autism spectrum disorder in a fetus or child by detecting maternal antibodies that bind to one or more biomarkers. Abbreviated Claim 1 - A method of determining a risk of developing an autism spectrum disorder comprising detecting maternal antibodies in a biological sample selected from blood, serum, plasma, and saliva. The inventors explained that the antibodies that bind to the one or more biomarkers described herein can be removed from the mother anytime during pregnancy. The invention identified fetal brain antigens with apparent molecular weights of 37 kDa, 39 kDa and 73 kDa bound by maternal antibodies. Judy Van de Water (first inventor listed with a co-inventor) received a BSc degree in biologic sciences and a PhD in immunology from the University of California at Davis. Dr. Van de Water is the recipient of the Slifka-Ritvo IMFAR Innovative Basic Science Research Award for her contribution to autism research and the McGovern Research Award for significant impact in the health field. [22] Pediatric Bioscience Incorporated (current assignee) a specialty clinical diagnostic company, discovers, develops, and commercializes products for the diagnosis and treatment

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of children with autism and autism spectrum disorders. The company develops Maternal Antibody Related autism test, a non-invasive blood test, which comprises a set of prognostic markers that identify women who may be at an increased risk of having a child with the MAR form of autism. Pediatric Bioscience Incorporated was founded in 2006 and is based in Sacramento, California. [23] In an article from the University of California Davis Health System (July 9, 2013) titled, UC Davis MIND Institute researchers identify specific fetal antigens attacked by maternal antibodies the authors write, “Researchers have identified the specific antibodies that target fetal brain proteins in the blood of a subset of women whose children are diagnosed with autism. The finding is the first to pinpoint a specific risk factor for a significant subset of autism cases, as well as a biomarker for drug development and early diagnosis. The researchers have named autism related to these antibodies - maternal autoantibody-related. The study titled, Autism-specific maternal autoantibodies recognize critical proteins in developing brain found that the mothers of children with autism were more than 21 times as likely to have the specific maternal autoantibody-related antibodies in their systems that reacted with fetal brain proteins, or antigens, than were the mothers of children who did not have autism. In fact, specific combinations of maternal autoantibody-related antibodies were not found in the blood of mothers whose children were typically developing. The study was led by principal investigator and immunologist Judy Van de Water, a researcher affiliated with the MIND Institute. Earlier studies by Van de Water and her colleagues found that women with certain antibodies in their bloodstreams are at greater risk of having a child with autism and that their children exhibited more severe language delays, irritability and selfinjurious behaviors than did the autistic children of mothers whose blood did not have the antibodies. ‘Now we will be able to better determine the role of each protein in brain development’, said Van de Water, professor of internal medicine. ‘We hope that, one day, we can tell a mother more precisely what her antibody profile means for her child, then target interventions more effectively.’” [24]

AUTISM DIAGNOSIS SUPPORT APPARATUS (Ebisawa, in Patent number 8,371,693 – February 12, 2013) Abstract - This describes a diagnosis support-apparatus that detects a symptom of autism based on the state of a subject looking at a target. Abbreviated Claim 1 – An autism diagnosis support-apparatus comprising a line-ofsight detection unit, a camera, a pupil position detection unit, and a data analysis unit. The inventor explained that when an autistic person is required to communicate with others face-to-face, he/she looks at a body part such as a mouth rather than eyes more frequently than healthy people do. The invention provides a system for diagnosing whether a subject has a symptom of autism from a difference between a time when the subject looks at eyes of an objective person (observed target) and a time when the subject looks at a different point. Yoshinobu Ebisawa (inventor) is professor at the Graduate School of Science and Technology - Department of Nanovision Technology, Shizuoka University. Dr. Ebisawa

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specializes in the development of video-based pupil detection techniques and of pupil detection-based methodology and implementation (e.g., eye-gaze and head pose detection, and drowsiness detection) for human interaction and monitoring are done for the improvement of welfare medical treatment and safe driving. [25] Shizuoka University (current assignee) has protection for US patent 8,371,693 (Ebisawa) to August 8, 2031. In an article from BioSpectrum (March 29, 2013) titled, Japanese develops eye-based autism detector, it is written, “Professor Yoshinobu Ebisawa at Japan’s Shizuoka University developed an Autism-Eye-Gaze Detection System that observes the movements of the infant’s eyes as they focus on an image of the mother’s eyes or mouth. By using cameras and infra-red light sources to track movement of the infant’s pupils, the system can estimate the likelihood of autism. The Autism-Eye-Gaze Detection System is based on the findings of a recent study by The US Department of National Institute of Environmental Health Sciences (NIH), which suggests that fluctuations in eye movement, as small as 25-50 milliseconds, is a symptom of autism in infants as young as seven months old. Previous technologies for eyetracking required minimal head movement and a calibration stage requiring a patient to look at multiple points. Based on the improbability of an infant having that type of focus, Professor Ebisawa developed a system and a software, specialized for screening infants for autism that requires only a one-point calibration measurement. No other system on the market has this simple, rapid one point of gaze format. The system will address the challenges of working with infants for early diagnosis of autism. The current average age of diagnosis for autism is 4.5 years, which is past the age where behavioral therapy would be of the greatest benefit. The Japanese company IP. Shakti has entered into a partnership with Shizuoka University to commercialize the Autism-Eye-Gaze Detection System. Dr. Dipanjan Nag (President/CEO of IP. Shakti LLC) says, ‘Autism is not well understood, so it has not been detected very efficiently. Today millions of kids are affected by the disease, but unfortunately, we have not been able to bring a simple solution to the market. Most of the gene-based detection systems have only provided a partial solution. IP Shakti is committed to the simple yet elegant detection system based on the behavioral aspects of autism.’ Professor Ebisawa say, ‘After more than 10 years of research, I’m truly happy to see my patented technology developed to improve the lives of children.’” [26]

DIAGNOSIS AND TREATMENT OF AUTISM USING CD38 (Higashida, in Patent number 8,222,004 – July 17, 2012) Abstract – This describes a method and kit for diagnosing autism by an abnormality in the oxytocin system based on a mutation in the CD38 gene. Abbreviated Claim 4 – The method according to any one of claims 1 to 3, wherein the disorder is autism. The inventor explained that CD38 gene function-deficient mice exhibit behavior abnormalities (abnormal maternal behaviors and social memory) very similar to autism, and these behavior abnormalities are due to failure of oxytocin release.

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The invention showed that of the 29 autistic individuals, those having the polymorphism at position 4693 in exon-3 region and those having no polymorphism at this position significantly differed in plasma oxytocin levels but did not differ in plasma vasopressin levels. These results suggested that the polymorphism at position 4693 in exon 3 region (R140W) acts in a genetically dominant manner and has some relation to autism since the individuals having this polymorphism have significantly lower serum oxytocin levels. Haruhiro Higashida (inventor) received a PhD in neurophysiology from the Nagoya University Graduate School in Japan. Dr. Higashida is a professor at the Kanazawa University Children’s Heart Research Center in Japan. [27] Tohoku University and Kanazawa University (current assignee) have protection for US patent 8,222,004 (Higashida) to September 9, 2028. In a paper co-authored by Haruhiro Higashida titled, CD38 gene knockout juvenile mice: a model of oxytocin signal defects in autism, it is written, “Oxytocin (OXT) in the hypothalamus is the biological basis of social recognition, trust, and bonding. We showed that CD38, a leukemia cell marker, plays an important role in the hypothalamus in the process of OXT release in adult mice.” [28]

ASSOCIATION OF GSTM1 WITH AUTISM AND ASSAYS AND METHODS BASED THEREON (Buyske et al., Patent number 8,187,806 – May 29, 2012) Abstract - This describes a method and assay for identifying individuals who are genetically susceptible to having offspring with autism wherein the genotype of GSTM1 is determined. Abbreviated Claim 1 - A method for determining the susceptibility of the individual to develop autism by determining whether said participant lacks a functional GSTM1 enzyme. The inventors explained that despite technological advances not all loci in the human genome can readily be fully genotyped using current conventional methods. Incomplete sequence information, unknown splice junction, unknown size of the deletion, and a large amount of homology with nearby sequence can all contribute to such a problem. Improved methods and additional relevant autism genetic markers are needed. The invention showed that the association study of the GSTM1 locus in autism both the traditional case-control analysis and the 1-df likelihood ratio test (utilizing controls) support (at p=0.028 and p=0.046, respectively) the association of the homozygous GSTM1 deletion genotype with an increased risk of autism. Steven Buyske (first inventor listed with two co-inventors) is a research associate professor at the Rutgers University - Department of Statistics and Biostatistics. Dr. Buyske teaches statistical genetics, biostatistics, psychometrics, and experimental design. [29] Rutgers State University of New Jersey (current assignee) has protection for US patent 8,187,806 (Buyske et al.) to March 3, 2028. In a publication from Rutgers University (original assignee) titled, Association of GSTM1 with autism and assays and methods based thereon, it is written, “Researchers at Rutgers have determined that there is a heightened risk of autism for Glutathione-S-transferase m

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genotype GSTM1*0 homozygotes. The genotype is presumably interacting with other genetic and environmental risk factors. The absence of the GSTM1 gene in GSTM1*0 homozygotes, because the variant allele is a complete gene deletion that lacks function of the GSTM1 and enzyme could lead to failure in individuals with autism to detoxify important compounds, including some that could be agents or products of oxidative stress.” [30]

PERIPHERAL GENE EXPRESSION BIOMARKERS FOR AUTISM (Geschwind et al., Patent number 8,173,369 – May 8, 2012) Abstract – This describes methods and materials for screening cells for genetic profiles associated with autism spectrum disorders. Abbreviated Claim 1 - A method of identifying a cell having a gene expression profile observed with autism. The inventors explained that the gene-expression profile of lymphoblastoid cells could be used to subgroup subjects with autism based on their genetic etiologies when the etiologies are due to a single mutation or copy number variation. The invention showed that genes were extremely dysregulated in one of the 15 affected males. Daniel Geschwind (first inventor listed with a co-inventor) received an AB degree in psychology and chemistry at Dartmouth College and an MD and PhD at the Yale School of Medicine prior to completing his internship, residency, and postdoctoral fellowship at UCLA Dr. Geschwind is the Gordon and Virginia MacDonald distinguished professor of human genetics and is a professor of neurology and psychiatry at the UCLA David Geffen School of Medicine. He is director of the Neurogenetics Program and the Center for Autism Research and Treatment and co-director of the Center for Neurobehavioral Genetics at UCLA. [31] The University of California (current assignee) has protection for US patent 8,173,369 (8,173,369) to April 23, 2030. The Geschwind Lab at the University of California communicate that Daniel H. Geschwind and other researchers are currently working on creating in vitro developmental models of autism using primary human neural stem cells. Human neural stem cells appear to effectively model in vivo developmental processes of early fetal stages. Importantly, this epoch of neural development is a crucial time period in autism pathology. We aim to identify core transcriptional programs and neuronal phenotypes shared among different genetic forms of autism that will provide the basis for high-efficiency screening of therapeutic interventions. In this work, we aim to model the effects of highly penetrant duplications or deletions of DNA recently found to occur in autism. We’ve compiled genetic information from many previous studies to determine those copy number variants that are most associated with the presence of the disease. We are manipulating expression of these genes using lentiviral vectors in human neural stem cells. We will infect these cells with the vectors to model the effects of the genetic mutations found in autism. We will study these through 12-weeks of differentiation. At time points throughout the process we will acquire RNA for RNA-seq analysis of the transcriptome and study the morphology of the differentiating neurons. This will allow us to study the effect of autism associated genes throughout development and

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determine if autism associated genes have similar effects on development. After characterization of these lines, we will use computational tools to predict drugs that may reverse the transcriptional signatures caused by the genetic abnormalities. We will test the drugs predicted to have the largest effect on the human neural progenitors. These studies will help us understand the signaling mechanisms associated with autism spectrum disorders from different genetic etiologies and hopefully help us discover potential therapeutic avenues. [32]

COMPOSITIONS AND METHODS FOR DIAGNOSING AUTISM (Millonig et al., Patent number 7,629,123 – December 8, 2009) Abstract – This describes methods of treating autism based upon modulating the level or activity of the homeobox transcription factor engrailed 2. Abbreviated Claim 1 - A method for diagnosing the predisposition for developing an autism spectrum disorder with nucleic acids. The inventors explained detecting the existence of a mutation in the EN2 gene such that the mutation results in the deletion, addition, or substitution of at least one amino acid in the EN2 protein. The invention showed that the data represents the most significant genetic association reported for AS disorders. The over transmission of the A and C alleles of both SNPs indicate risk or these SNPs are in linkage disequilibrium with other polymorphisms that contribute to autism. James H. Millonig, PhD (first inventor listed with two co-inventors) is the Senior Associate Dean at the Rutgers Graduate School of Biomedical Sciences. [33] Rutgers State University of New Jersey (current assignee) has protection for US patent 7,629,123 (Millonig et al.) to May 22, 2025. In a communication from Rutgers - Robert Wood Johnson Medical School (September, 2015) titled, New Research Focuses on Impact of Neurotransmitters in Autism Spectrum Disorder, author Jennifer Forbes writes, “A new study suggests that altered behavior in neuro-developmental disorders may be related to a disruption in the development of neurotransmitters systems that originate in the back of the brain. Research by the laboratory teams of Emanuel DiCicco-Bloom, MD and James Millonig, PhD showed that mice which lacked autism-associated gene Engrailed-2, had a major reduction in the level of norepinephrine (NE) in the forebrain, because the neuronal fibers that carry NE from the back to the front of the brain failed to develop. The reduced NE levels resulted in impaired forebrain growth, as well as behavioral attributes of autism spectrum disorder (ASD). The team found that replacing the NE with pharmaceuticals partially repaired the growth deficiency, suggesting that measuring the levels of NE and transmitter fibers in individuals with ASD could be used to develop personalized therapy.” [34] In an article from Stem Cell Freaks (February 13, 2013) titled, Autism researchers awarded with $2.125 million grant, it is written, “The New Jersey Governor’s Council for Medical Research and Treatment of Autism announced that it will be awarding a team of scientists with a five-year $2.125 million grant for their research on autism spectrum disorders (ASD). The researchers, led by James H. Millonig, intend to use induced pluripotent

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stem cells to develop in vitro human neuron cell lines. Hopefully, by studying these labgrown neurons, they will be able to give new insight on how autism and other ASD conditions develop. Millonig says, ‘We hope to identify the neurobiological, molecular and genetic basis – the biological signature – of autism.’” [35]

BIOMARKERS FOR DIAGNOSING AN AUTISM SPECTRUM DISORDER (Amaral et al., Patent number 7,604,948 – October 20, 2009) and

DIAGNOSTIC METHODS FOR THE DETECTION OF AUTISM SPECTRUM DISORDER (Amaral et al., Patent number 7,452,681 – November 18, 2008) 7,604,948 - Abstract: This describes methods of identifying biomarkers indicative of the presence of an autism spectrum disorder using cytometry and mass spectrometry. 7,604,948 – Abbreviated Claim 1: A method for diagnosing an autism spectrum disorder wherein increased complement factor H-related protein (FHR1) is indicative of an autism spectrum disorder. The inventors explained that because there has been about a 5-fold increase in the diagnosis of new cases of autism spectrum disorder in the last decade in children aged 1.5-6 years, there remains an important need for a reliable diagnostic test to identify susceptibility to the development of an ASD. The invention showed that 29% of the children with autism (HFA and LFA) and only 6% of the typically developing, normal children had relatives with rheumatoid arthritis. The data supports previous reports of abnormalities of various immune-related molecules in the blood of children and adults with autism. University of California (current assignee) has protection for US patent 7,604,948 (Amaral et al.) to August 8, 2027. 7,452,681 - Abstract: This describes methods of identifying antibody- or autoantibodymediated damage of neural tissue indicative of an autism spectrum disorder. 7,452,681 – Abbreviated Claim 1: A method of diagnosing an autism spectrum by determining the presence of antibodies against brain tissue. The inventors explained diagnostic methods for detecting the risk of an individual for developing an autism spectrum disorder by determining the presence of antibodies against brain tissue and identifying the brain regions, cell types and proteins targeted by the antibodies. The invention showed that the treated monkeys in the study did not demonstrate increased stereotypical behavior in their long-term, stable social groups but only in novel environmental or social situations.

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David G. Amaral (first inventor listed with a co-inventor) was the founding research director of the MIND Institute. This Institute was started at UC Davis in collaboration with the parents of children diagnosed with autism spectrum disorders. Amaral’s research team is dedicated to understanding the biological and behavioral features of autism, with the goal or prevention and decreased disability. The partnership between the parents and Amaral’s team of researchers secured $34 million in funding from the California legislature, primarily for research purposes. After raising additional funds and building a state-of-the-art facility in Sacramento, California, the institute has become one the premier autism research centers in the world. The MIND Institute studies all aspects of autism spectrum disorder. Amaral heads a unique longitudinal analysis of young children with autism call the Autism Phenome Project. Started in 2006, this project involves over 400 families as of 2015 and is determining unique features of brain development in children as young as two years of age. [36] The University of California and the National institute of Health have rights to US patent 7,452,681 (Amaral et al.).

METHODS FOR DIAGNOSING AUTISM (Fatemi, in Patent number 7,341,844 – March 11, 2008) Abstract - This describes the use of reelin as a marker for diagnosing autism. Abbreviated Claim 1 - A method for diagnosing autism by determining the level of Reelin. The invention showed that the blood levels of reelin moieties were altered in patients suffering from autism, and in family relatives. S. Hossei Fatemi (inventor) is the associate chair for neuroscience and translational research for the Department of Psychiatry; the Bernstein Endowed Chair in Adult Psychiatry; professor of psychiatry, neuroscience and pharmacology, at the University of Minnesota Medical School. Dr. Fatemi’s research interests include the molecular causes and the biological basis of neurodevelopmental disorders, primarily schizophrenia and autism. [37] The University of Minnesota (current assignee) has protection for US patent 7,341,844 (Fatemi) to October 19, 2024. In an advertisement from the Reagents of the University of Minnesota (original assignee) titled, Reelin Protein Diagnostic Test for Mental Disorders, author Raj Udupa writes, “A Reelin diagnostic blood test aids in the diagnoses and differentiation of autism. The alterations in Reelin levels occur in significantly specific amounts in autistic patients. Study data demonstrates that altered levels of Reelin correlate with the subjective evaluation of patients with suspected disease.” [38]

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MODULATION OF IN VIVO GLUTAMINE AND GLYCINE LEVELS IN THE TREATMENT OF AUTISM (Phillips III et al., Patent number 6,362,226 – March 26, 2002) Abstract and Abbreviated Claim 1 – These describe a method of treating autism comprising administering a glutamine level reducing agent (phenylbutyrate), a glycine level reducing agent (Sodium Benzoate) or combinations thereof. The inventors explained that phenylbutyrate conjugates to glutamine in vivo. The lowering of glutamine is contemplated to decrease the stimulation of the EAA receptors that is contemplated to occur in autistic patients with high levels of glutamine. The invention showed that both patients’ special education and classroom explainers and speech and occupational therapists, who were blinded to treatment, reported significant improvement in the patients’ expressive and receptive language skills, attention span and focus, motor planning and socialization with peers. Susan G. McGrew (second inventor listed with a co-inventor) graduated from Northwestern University, Chicago. Dr. McGrew is board certified in pediatrics with special expertise in autistic disorders. [39] Vanderbilt University (original assignee) has allowed Patent 6,362,226 to expire on March 26, 2014 due to failure to pay the maintenance fee. In an article from the Los Angeles Times (December 7, 2009) titled, Four autism treatments that worry physicians, it is written, “Phenylbutyrate is used in the treatment of rare diseases and is FDA approved for urea cycle disorders. Risks include Rectal bleeding, vomiting, peptic ulcer disease, irregular heartbeat, depression and experts at the Kennedy Krieger Institute say no research on phenylbutyrate has been conducted its use for autism.” [40]

GENETIC POLYMORPHISMS WHICH ARE ASSOCIATED WITH AUTISM SPECTRUM DISORDERS (Rodier et al., Patent number 6,228,582 – May 8, 2001) Abstract - This describes a method of screening polymorphisms of the nucleic acids encoding HoxA1 and HoxB1 in autism spectrum disorders. Abbreviated Claim 1 – A method of screening genetic markers associated with autism by testing a biological sample or genetic material for a polymorphism in a Hox A1 or B1 coding sequence. The inventors explained that there is a need for a blood test for polymorphisms causing autism spectrum disorders. Families with affected members need to know whether they carry a mutation which could affect future pregnancies. Clinicians need a test as an aid in diagnosis, and researchers would use the test to classify subjects according to the etiology of their disease.

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The invention demonstrated that both the HoxA1 and HoxB1 polymorphisms are significantly associated with autism as judged by the Transmission Disequilibrium Test for Association (Spielman and Ewens, 1996), which compares the rate of transmission “into the disease” to the 50% rate one would expect in offspring of parents with the allele of interest. In a Memorial for Patricia Rodier (first inventor listed with four co-inventors) from the University of Rochester Medical Center (May 7, 2012) titled, Scientist Patricia Rodier, Trailblazer in Early Origins of Autism, dies, author Emily Boynton writes, “Patricia Rodier, PhD the first scientist to formulate and study the idea that autism can originate long before a child is born, died May 3 at Strong Memorial Hospital. She was 68. An embryologist specializing in the nervous system, Dr. Rodier completely changed the way we think about the development of autism. While many believed that the disorder arose very late in pregnancy or in the early part of an infant’s life, Dr. Rodier’s research turned that widely held, but unproven, belief upside down. Her work established that genetic and environmental factors can also spur the development of the disorder as early as three weeks into a pregnancy, when the first cells of the nervous system start to develop. Building on this work, Dr. Rodier went on to identify one of the first genes linked to autism. The gene – HOXA1 – plays a crucial role in early brain development and likely underlies the development of the disorder in some cases. A professor in the Department of Obstetrics and Gynecology at the University of Rochester Medical Center, Dr. Rodier was also a world expert on mercury toxicity, studying how single exposures to the chemical during pregnancy influence a baby’s brain development. To this day, much of the research being done on mercury exposure and birth defects is based on Dr. Rodier’s early findings. A testament to her extraordinary expertise in both areas, Dr. Rodier was called to serve as a key government witness for the highly publicized court cases regarding vaccines containing thimerosal, a mercury-containing preservative, playing a key role showing that the preservative and vaccines have no link whatsoever to autism. While many will recall Dr. Rodier’s fiery red hair and distinct sense of style, those closest to her say it was her sweet, warm and gentle personality that made her stand out. ‘Even when she was critiquing something you did, it was like she was giving you a compliment because she did it so nicely; it would take you a minute to realize what she was actually saying’, said Christopher J. Stodgell, PhD an associate professor in the Department of Obstetrics and Gynecology who came to the Medical Center to work with Dr. Rodier 16 years ago. James R. Woods, MD the Henry A. Thiede professor and chair of the Department of Obstetrics and Gynecology, said, ‘Patty was the quintessential researcher and a talented writer with an inquisitive mind. Her death is a great loss to the academic world. Our hearts go out to her family.’ Dr. Rodier began her career at the Medical Center in 1980. Though her PhD was in psychology, she learned anatomy and embryology as a post-doctoral fellow and went on to explain anatomy at the medical school from the time she arrived through the early 1990’s. ‘Dr. Rodier taught anatomy to half the physicians in Rochester and was a very accomplished basic scientist whose landmark work in the neurotoxicology of mercury, in addition to the effects of genetics and environment on early brain development in autism, significantly impacted scientific understanding of these disorders’, said Susan Hyman, MD an autism expert at the Medical Center who worked closely with Dr. Rodier. ‘Dr. Rodier was the recipient of many NIH grants that not only supported her basic science but fostered visionary translational investigations here at the Medical Center and around the world.’ Dr. Rodier’s research, coupled with advanced clinical work conducted at the Medical Center, brought the autism program national recognition. The program was designated by the National Institutes

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of Health as one of 10 Collaborative Programs for Excellence in Autism in the US from 1998 to 2008. Elaine Francis, PhD the former national program director for the Environmental Protection Agency and incoming President-elect for the Teratology Society, the major organization focused on birth defects research, education and prevention, added, ‘When I first joined the Teratology Society, Patty was incredibly nice and always willing to provide advice on my career path. I looked to her as a scientific ‘big sister.’ While at EPA, I often cited the research products that came out of an EPA grant to Patty’s lab as a model of how our funding could have a significant impact. She was a great scientist, with incredible composure, and exquisite style.’ Following many years studying the effects of mercury and other chemicals on the nervous system, Dr. Rodier turned her focus to autism in 1994 after learning that researchers had discovered a high rate of autism in people who had been exposed to thalidomide in the 1960s; they had been exposed in the first month of gestation, before the time when thalidomide causes limb defects. Some of the autistic children born to mothers who took thalidomide also had misshapen ears, as well as abnormalities in the nerves of the head and face. Dr. Rodier knew from her work in embryology that facial nerves develop during this time period, sometime between the 20th and the 24th day after conception, thus she wondered if autism might have something to do with the damage to the facial nerves. She then assembled a multidisciplinary team of scientists ranging from molecular biologists, psychologists, geneticists, pharmacologists and pediatricians to tackle the problem by investigating the genetics of autism and developing an animal model of the disorder.” [41] The University of Rochester is the current assignee for US patent 6,228,582 (Rodier et al.).

METHOD OF TREATING SCHIZOPHRENIA, TOURETTE’S SYNDROME, MANIA, AUTISM, AND OBSESSIVE COMPULSIVE DISORDER WITH INHIBITORS OF BRAIN NITRIC OXIDE SYNTHASE (Karson et al., Patent number 5,527,825 – June 18, 1996) Abstract – This describes a pharmaceutical composition and method for the treatment of brain diseases characterized by excessive activity of brain dopamine systems and/or nitric oxide systems. Abbreviated Claim 5 – The method of claim 1, wherein said brain disease is autism. The inventors explained that the prior art is deficient in treating dopamine and nitric oxide dysfunctional states. The invention showed that nitroglycerin causes an increase in dopamine-related activity. This was illustrated by the greater rearing, grooming and walking in male amphetamine animals given nitroglycerin, as compared to both control and undernourished controls. In an obituary for Melvin Lyon (second inventor listed with two co-inventors) titled, A Life Dedicated to Scientific Inquiry, it is written, “Dr. Melvin Lyon, born May 17, 1930 in Gardner, Massachusetts, died May 4, 2014. He attended Colby College in Waterville Maine and was a lifelong supporter of Colby. He received a master degree in psychology and a PhD in experimental psychology from Boston University, and completed a postdoctoral degree at University of Pennsylvania. Following that he began a long research and explaining career

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which spanned two continents, beginning at Stonybrook University, New York, moving to the University of Copenhagen, Denmark, the University of Arkansas Medical School, and finally retiring from the University of Southern California. Throughout his career he tackled difficult questions of experimental neuroscience, attempting to expand the understanding of challenging brain conditions such as autism and schizophrenia.” [42] The University of Arkansas (current assignee) has allowed US patent 5,527,825 (Karson et al.) to expire on June 18, 2004 due to failure to pay the maintenance fee.

METHOD OF TREATING AUTISM (Gruber, in Patent number 5,008,251 – April 16, 1991) Abstract – This describes methods for the treatment of autism by administering purine nucleoside and purine nucleoside-related analogs which increase extracellular adenosine concentrations. Abbreviated Claim 1 - A method for the treatment of autism which comprises administration of at least about 1 mg /kg/day of a drug selected from the group consisting of AICA riboside, AICA ribotide, ribavirin and ribavirin monophosphate. AICA-riboside (e.g., Acadesine) is an AMP-activated protein kinase activator and ribavirin is an anti-viral drug. In 2008, researchers at the Salk Institute discovered that AICAriboside (i.e., acadesine) injected in mice significantly improved their performance in endurance-type exercise, apparently by converting fast-twitch muscle fibers to the more energy-efficient, fat-burning, slow-twitch type. AICA-riboside is on the World Anti-Doping Agency prohibited list. The inventor explained that autism patients with chronic low adenosine, and illnesses relating to mast cell degranulation, will benefit from the compounds of the invention. The invention showed that two months later following the six-week interruption of AICA riboside treatment, both patients were described as “more pleasantly active and more easy to handle during therapy” by the father, thereby prompting a request for resumption of the trial. Harry E. Gruber (inventor) received a BA and an MD from the University of Pennsylvania and trained in Internal Medicine, Biochemical Genetics and Rheumatology/Immunology at the University of California, San Diego. Dr. Gruber is recognized as one of the pioneers in gene therapy and is co-founded/director of Tocagen, a company dedicated to the development and commercialization of breakthrough treatments for cancer using advanced gene transfer technology. He is the author of over 100 original scientific articles and an inventor on over 33 issued and numerous pending patents. [43] The University of California was the original assignee for US patent 5,008,251 (Gruber).

REFERENCES [1]

Yehezkel Ben-Ari at Neurochlore, “Company Website,” Accessed on September 2, 2016. HTTP://WWW.NEUROCHLORE.FR/.

28 [2] [3] [4] [5] [6] [7] [8]

[9] [10] [11] [12]

[13] [14]

[15] [16]

Michael J. Dochniak Ewen Callaway, 2014. “Diuretic drug prevents autism in mice and rats” Nature, Accessed on September 1, 2016. http://www.nature.com/news/diuretic-drug-prevents-autism-in-mice-andrats-1.14683. Virginia Hughs, 2011. “Researchers debut SHANK2 mouse, SHANK3 rat” Spectrum, Accessed August 13, 2016. https://spectrumnews.org/news/researchers-debut-shank2mouse-shank3-rat/. W. Ian Lipkin, “John Snow Professor of Epidemiology, Columbia University” SFARI, Accessed on August 13, 2016. https://sfari.org/author/%3Fauthor%3Dhttps%253A// id.simonsfoundation.org/ianlipkin. Columbia Psychiatry, “About Us,” Accessed August 13, 2016. http://columbia psychiatry.org/about-us. Jeff Gottlieb, 2001. “New York Is Next Stop for Famed UCI Molecular Biologist” Los Angeles Times, Accessed August 13, 2016. http://articles.latimes.com/2001/ sep/03/local/me-41677. Elaine Tierney, “Profile”, Accessed on October 14, 2016, https://www.kennedykrieger.org/patient-care/faculty-staff/elaine-tierney. Kennedy Krieger Institute, 2006. “Autism: New Study Discovers Statistically Significant Link Between Abnormally Low Cholesterol Levels and Autism Spectrum Disorders,” Accessed August 13, 2016. https://www.kennedykrieger.org/overview/ news/autism-new-study-discovers-statistically-significant-link-between-abnormallylow-chole. Valerie Hu, “Professor, Biochemistry and Molecular Medicine” The George Washington University, Accessed on August 13, 2016. https://andinitiative. gwu.edu/ valerie-hu. Valerie Hu, “The value of blood cells in autism research” Spectrum, Accessed on August 13, 2016.https://spectrumnews.org/opinion/viewpoint/the-value-of-blood-cellsin-autism-research/. Damon Page, “Lab Members” Scripts Florida – The Page Laboratory, Accessed on August 13, 2016. http://www.scripps.edu/page/members.html. Scicasts Staff, 2015. “New Study Shows Decreased Aggressive Behavior Toward Strangers in Autism Spectrum Disorder Model” Scicasts, Accessed August 13, 2016. https://scicasts.com/neuroscience/2066-neuropsychology/9035-new-study-showsdecreased-aggressive-behaviour-toward-strangers-in-autism-spectrum-disorder-model/. Roland Shytle, “Associate Professor, Center of Excellence for Aging & Brain Repair” USF Health, Accessed on August 13, 2016. http://health.usf.edu/medicine/ neuro surgery/profiles/10527/Ronald-Shytle.aspx. Admin, 2015. “Jun Tan probes the power of flavonoids in fighting Alzheimer’s disease” USF Heath News Blog, October 5, Accessed August 13, 2016. https://hscweb3.hsc.usf.edu/blog/2015/10/05/juan-tan-probes-the-power-of-flavonoidsin-fighting-alzheimers-disease/. Williams TA et al., 2007. “Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype” Arch Pediatr. Adolesc. Med. Apr;161(4):356-61. DOI:10.1001/archpedi.161.4.356. Joy Hirsch, “Professor of Psychiatry and Neurobiology,” Yale School of Medicine” GoldLab, Accessed on August 13, 2016. http://goldlabfoundation.org/presenters/joyhirsch/.

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[17] Malcolm Ritter, 2015. “Lasers, magnetism allow glimpses of the human brain at work” AP – The Big Story, Accessed August 13, 2016. http://bigstory.ap.org/article/3038 1f2e2d8d4f31a534e0ea1c5d067c/lasers-magnetism-allow-glimpses-human-brain-work. [18] Norio Mori, “Research Center for Child Mental Development” RCCMD, Accessed August 13, 2016. https://translate.google.com/translate?hl=en&sl=ja&u=http://rcc M.D..org/modules/staff/index.php%3Fcontent_id%3D2&prev=search. [19] Bagasra O. et al., 2013. “Role of perfumes in pathogenesis of autism” Med Hypotheses, Jun;80(6):795-803. doi: 10.1016/j.mehy.2013.03.014. [20] Dominick P. Purpura, “Dominick P. Purpura Department of Neuroscience” Albert Einstein College of Medicine, Accessed August 13, 2016. https://www.einstein.yu.edu/ departments/neuroscience/dominick-purpura.aspx. [21] Megremi AS, 2013. “Is fever a predictive factor in the autism spectrum disorders?” Med Hypotheses. Apr;80(4):391-8. doi: 10.1016/j.mehy.2013.01.007. [22] Judy Van de Water, “Professor, Department of Internal Medicine, UC Davis School of Medicine” UC Davis Mind Institute, Accessed August 13, 2016. http://www.ucdmc. ucdavis.edu/mindinstitute/ourteam/faculty/vandewater.html. [23] Bloomberg, “Company Overview of Pediatric Bioscience Inc.” Accessed August 13, 2016. http://www.bloomberg.com/research/stocks/private/snapshot.asp?privcapId=3318 2338. [24] Newsroom, 2013, “UC Davis MIND Institute researchers identify specific fetal antigens attacked by maternal antibodies” UC Davis Health System, Accessed August 13, 2016. https://www.ucdmc.ucdavis.edu/publish/news/newsroom/7439. [25] Yoshinobu Ebisawa, “Professor/Hamamatsu” Shizuoka University, Accessed August 13, 2016. http://gsst.shizuoka.ac.jp/en/kyoiku/senkonanov. [26] BioSpectrum Bureau, 2013. “Japanese develops eye-based autism detector” BioSpectrum, Accessed August 13, 2016. http://www.biospectrumasia.com/ biospectrum/news/186092/japanese-develops-eye-autism-detector. [27] Haruhiro Higashida, “In Haruhiro’s profile” LinkedIn, Accessed on August 14, 2016. https://translate.google.com/translate?hl=en&sl=ja&u=https://jp.linkedin.com/in/haruhi ro-higashida-406a9247&prev=search. [28] Higashida H. et al., 2011. “CD38 gene knockout juvenile mice: a model of oxytocin signal defects in autism” Biol Pharm Bull. 2011;34(9):1369-72. [29] Steven Buyske, Rutgers Education, Accessed August 14, 2016. http://www.stat.rutgers. edu/home/buyske/Home.html. [30] Invention Summary, “Association of GSTM1 with autism and assays and methods based thereon” Rutgers Office of Research Commercialization, Accessed August 14, 2016. http://techfinder.rutgers.edu/tech/Association_of_GSTM1_with_autism_and_ assays_and_methods_based_thereon. [31] Daniel H. Geschwind, “The Geschwind Lab” Geffen School of Medicine, Accessed August 14, 2016. http://geschwindlab.neurology.ucla.edu/people/daniel-h-geschwind. [32] Geschwind Lab, Accessed August 14, 2016. http://geschwindlab.neurology. ucla.edu/node/211 [33] James Millonig, “Associate Professor” Rutgers – Graduate Program in Molecular Biosciences, Accessed August 14, 2016. http://molbiosci.rutgers.edu/faculty/ millonig.html.

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[34] Jennifer Forbes, 2015. “New Research Focuses on Impact of Neurotransmitters in Autism Spectrum Disorder” Rutgers Robert Wood Johnson Medical School, Accessed on August 14, 2016. http://google.rbhs.rutgers.edu/search?q=cache:XM2e8 hlYwDAJ: rwjms.rutgers.edu/news_publications/news_release/2013_releases/DiCiccoBloomMillo nig.htm+autism++(site:rwjms.rutgers.edu+)&output=xml_no_dtd&client=rwjms&ie=U TF-8&proxystylesheet=rwjms&access=p&oe=UTF-8. [35] 2013. “Autism researchers awarded with $2.125 million grant” Stem Cell Freak, Accessed on August 14, 2016. http://www.stemcellsfreak.com/2013/02/fund-researchstem-cells-autism.html. [36] “David Amaral’ Wikipedia, the fee encyclopedia, Accessed on August 14, 2016. https://en.wikipedia.org/wiki/. [37] S. Hossein Fatemi, “Professor, Department of Psychiatry” University of Minnesota, Accessed August 14, 2016. http://www.psychiatry.umn.edu/bio/psychiatry/s-fatemi. [38] Raj Udupa, 2016. “Reelin Protein Diagnostic Test for Mental Disorders” University of Minnesota Office for Technology Commercialization, Accessed on August 14, 2016. http://license.umn.edu/technologies/z02081_reelin-protein-diagnostic-test-for-mentaldisorders. [39] Dr. Susan G McGrew, “Vitals,” Browse Health, Accessed August 14, 2016. http://www.vitals.com/doctors/Dr_Susan_Mcgrew.html#ixzz4GzELhgYA. [40] Articles, 2009. “Four autism treatments that worry physicians” Los Angeles Times, Accessed on August 14, 2016. http://articles.latimes.com/2009/dec/07/health/la-heautism-side7-2009dec07. [41] URMC Newsroom, 2012, “Scientist Patricia Rodier, Trailblazer in Early Origins of Autism, dies” University of Rochester Medical Center, Accessed on August 14, 2016. https://www.urmc.rochester.edu/news/story/3490/scientist-patricia-rodier-trailblazer-inearly-origins-of-autism-dies.aspx. [42] Dignity Memorial, 2014, “In Memory of Melvin Lyon” Joseph Gawler’s Sons, LLC. Accessed on August 14, 2016. http://obits.dignitymemorial.com/dignity-memorial/ obituary.aspx?n=Melvin-Lyon&lc=2216&pid=170956304&mid=5960902. [43] Harry E. Gruber, “President and Chief Executive Officer” Tocagen, Accessed on August 14, 2016. http://tocagen.com/management-member/harry-e-gruber-M.D./.

Chapter 3

PRIVATE COMPANIES

BIOMARKER AND USES THEREOF IN DIAGNOSIS, TREATMENT OF AUTISM (Momeni et al., Patent number 9,347,956 -May 24, 2016) Abstract - This describes a treatment of autism comprising administering a complement Factor-I inhibitor. Abbreviated Claim 1 - A method of diagnosis for an autism spectrum disorder based on the concentration of a peptide. The inventors explained the treatment of autism by administering a serine-protease inhibitor (e.g., Suramin, FUT-175, and Elafin). The invention showed that administration of the Complement Factor-I Inhibitors provided significant improvements in functioning during the course of the treatment compared to baseline. Naghi Momeni (first inventor listed with a co-inventor) received an education from Linnaeus University in Kalmar Sweden and was a director for Biomedical Sciences at the Brain Feedback Center in Malmo, Sweden. [1] Autism Biotech Ltd (original assignee) is advertising a diagnostic test for autism and states, “ASDtect® will make early detection of autism possible. It can diagnose autism from a tiny drop of blood. ASDtect® uses patented biomarkers. In a first clinical study these

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biomarkers have shown remarkably high accuracy. Autism Biotech is currently conducting further trials and aims to make ASDtect® available in 2017.” [1] Autism Biotech Ltd (current assignee) has protection for US patent 9,347,956 (Momeni et al.) to February 3, 2033. In an article from the guardian (July 29, 2015) titled, Light across the spectrum: the challenges of autism in Iran, author Denise Hassanzade Ajiri writes, “some parents say they want to leave Iran for countries with nursing homes for autistic people. But it’s not a viable option for many: it’s expensive and chances of acquiring foreign residency with an Iranian passport are slim. Others say they are willing to work together and help establish a nursing home in Iran. Naghi Momeni is among them. He is a biomedical scientist in Sweden who researches the origins of autism spectrum disorders. Momeni says the main issue in Iran is the lack of resources for families. He and his team are planning to establish centres for autism in Iran and working with authorities to ensure the services they want to provide are affordable to those who need it. ‘We are planning on establishing special schools, daycares and nursing homes, all run by autism specialists’, he says. ‘Our centres will be able to network nationwide and globally, updating ourselves with the world’s latest scientific developments and share them with families and our staff.’ Momeni says these centres will be established soon. ‘We haven’t determined a specific time yet, but it will be in the near future.’” [2]

USE OF LACTULOSE IN THE TREATMENT OF AUTISM (Fallon et al., Patent number 9,345,721 - May 24, 2016) and

USE OF LACTULOSE IN THE TREATMENT OF AUTISM (Fallon et al., Patent number 8,673,877 – March 18, 2014) 9,345,721 – Abstract: This describes a treatment for autism by administering lactulose to bind excess ammonia in the gastrointestinal tract, the bloodstream, and the nervous system in order to prevent or reverse ammonia poisoning caused by the administration of certain antibiotics. 9,345,721 – Abbreviated Claim 1: Method for treating an autistic disorder comprising administering lactulose and mannitol, wherein lactulose follows administration of an antibiotic and lactulose increases the number of lactobacilli and bifidobacteria in a gut flora. 8,673,877 – Abstract: This describes a treatment for autism by administering lactulose which lowers the serum ammonia levels and reduces neurotoxicity. 8,673,877 – Abbreviated Claim 1: A method for decreasing levels of ammonia in an individual diagnosed with autism, comprising administering lactulose and about 0.1 g./kg. mannitol per dose, wherein administration of the lactulose follows administration of an

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antibiotic, and wherein administration of lactulose increases the number of lactobacilli and bifidobacteria in a gut flora. The inventor explained that increased levels of ear infections in children with autism combined with the use of Augmentin to treat these infections has the potential to make these children vulnerable to the buildup of ammonia in the gastrointestinal tract, the bloodstream, and the nervous system, leading to a neurotoxic state. By administering lactulose after getting antibiotics, the potential for developing autism is reduced. Joan M. Fallon (first inventor listed with a co-inventor) received a DC degree from Palmer University and has completed her work for the M.Sc. in clinical investigation from Harvard University’s joint program with Massachusetts General Hospital. Dr. Fallon also received a BA degree from Franklin and Marshall College. Dr. Fallon is the founder and Chief Executive Officer of CureMark LLC. She brings to CureMark visionary science and its application to multiple disease targets. Dr. Fallon’s discovery of the biomarker for autism and ADHD and her vast array of the intellectual property in the area of gastrointestinal secretory deficiencies, forms the basis of CureMark. She worked as a pediatric chiropractor for 25 years specializing in pediatric development. As a pediatric specialist she was one of the first physicians of any type to enter Romania and to help determine the state of the Romanian orphanages. She served as an Advisor to the New York Yankees for disability services at Yankee Stadium. Dr. Fallon taught anatomy, physiology and developmental biology as an assistant professor of natural science and mathematics at Yeshiva University, in addition to lecturing about pediatric development around the world. Dr. Fallon has both clinical and academic experience. She serves as a director of CureMark LLC. Dr. Fallon served on the Advisory Board for Oxford Health Plans, as well as on the boards of numerous not for profits. [3] CureMark LLC is the current assignee for US patent 9,345,721 (Fallon et al.) and US patent 8,673,877 (Fallon et al.). In an article published in the Journal of Medical Hypotheses titled, Could one of the most widely prescribed antibiotics amoxicillin/clavulanate “augmentin™” be a risk factor for autism, author Joan Fallon writes, “Since the introduction of clavulanate/amoxicillin in the 1980s there has been the increase in numbers of cases of autism. In this study 206 children under the age of three years with autism were screened by means of a detailed case history. A significant commonality was discerned and that being the level of chronic otitis media. These children were found to have a mean number 9.96 bouts of otitis media (with a standard error of the mean of ±1.83). This represents a sum total for all 206 children of 2052 bouts of otitis media. These children received a mean number of 12.04 courses of antibiotics (standard error of the mean of ±.125). The sum total number of courses of antibiotics given to all 206 children was 2480. Of those 893 courses were Augmentin® with 362 of these Augmentin courses administered under the age of one year. A proposed mechanism whereby the production of clavulanate may yield high levels of urea/ammonia in the child is presented. Further an examination of this mechanism needs to be undertaken to determine if a subset of children is at risk for neurotoxicity from the use of clavulanic acid in pharmaceutical preparations.” [4]

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METHODS AND SYSTEMS FOR DETERMINING AUTISM SPECTRUM DISORDER RISK (Geigenmuller et al., Patent number 9,176,113 – November 3, 2015) Abstract – This describes an analysis of metabolite levels in blood to predict autism spectrum disorders (ASD). The inventors explained that twenty-one metabolites have been identified that are highly informative individually and collectively for predicting ASD, particularly in male subjects. The invention showed that a positive odds ratio indicates that a tail effect of the metabolite is predictive of ASD. Ute Geigenmuller (first inventor listed with three co-inventors) was educated at the University of California – Santa Cruz. Dr. Geigenmuller has been director of R&D of biology at Covaris and director/VP of assay development at SynapDX Corporation. SynapDX (current assignee) is a laboratory services company developing a blood-based test for the early detection of autism spectrum disorder (ASD). Today, ASD is diagnosed using a variety of assessments that combine direct patient observation and medical history. The addition of a clinically meaningful blood test could hasten the diagnostic process and help children at risk for ASD get access to the right evaluations earlier – and end up with better outcomes as they grow. SynapDX approach measures a variety of biomarkers with the goal of developing the most informative test possible. SynapDX has just finished enrolling one of the largest prospective multi-site clinical studies to validate its approach. In an article from Techcrunch (July 22, 2013) titled, SynapDx Raises $15.4M in Quest to Create a Blood Test for Autism, author Kim-Mai Culter writes, “Autism, the disorder that affects social skills and communication and that is seeing a rising number of diagnoses, has a myriad number of causes from genetic to environmental factors. Because it’s largely behavioral, it may not be formally diagnosed until a child is a few years old, preventing much-needed early intervention and care. But a Massachusetts-based startup SynapDx is hoping to change that by combining advanced bioinformatics, genome sequencing and blood tests in a way that may help parents diagnose their children at a much earlier age. The company just closed a $15.4 million round led by Google Ventures to develop a blood test for the disorder, by studying the genetic make-up of children who are clinically diagnosed with the condition. The more the company can understand about different genetic mutations that are associated with autism, the more accurate a blood test they can create to signal for the disorder. ‘We don’t know what the root causes of autism are, but we can correlate what we see in the blood with clinical diagnoses’, said Theresa Tribble, the Vice President of commercial strategy for the company. ‘We hope to collaborate with researchers to give us additional insight to what those causes are.’ The end goal isn’t to create a bulletproof blood test for autism, but to create an early-stage test that can help parents refer their children for a full medical diagnosis earlier on. ‘This is more of a risk assessment’, she said. ‘The goal is to help pediatricians identify children who should be referred for a full clinical evaluation earlier than they do today.’ She added that the average age of diagnosis is around four and a half years, but parents often become worried at around 18 months.” [5]

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METHODS OF TREATING AUTISM (Roberts et al., Patent number 9,044,443 – June 2, 2015) Abstract - This describes subjects having autism that are treated with baclofen to improve motivation, calmness, class participation, ability to tolerate stress, and sleep patterns. Abbreviated Claim 1 - A method of improving an autism spectrum disorder by administering a GABA(B) agonist. The invention describes that a 23-year-old female with autism spectrum disorder (height 61'', weight 170 lbs.) was hospitalized and being prepared for port-a-catheter placement to begin TPN for an undetermined period of time to allow total gut rest. Baclofen was prescribed 5-mg tid (three times daily) to improve bowel motility. Within about 24-hours, abdominal pain appeared to be resolved and GI motility became functional, allowing oral feeding. Over the next several days and weeks improvements were noted in cognitive and behavioral domains that had been unchanged for over 10 years. Mark A. DePristo (fourth inventor listed with three co-inventors) received a PhD in biochemistry from Cambridge University and a Bachelor of Arts in computer science and mathematics from Northwestern University. Dr. DePristo has served as Vice President of Informatics at SynapDx Corporation. At SynapDx, Mr. DePristo assisted in the design and implementation of the bioinformatics strategy supporting the company’s test for the early detection of autism spectrum disorders. He joined SynapDx from the Broad Institute of Harvard and MIT, where he served as the co-director of Medical and Population Genetics. Prior to joining SynapDx, Mr. DePristo led the Genome Sequencing and Analysis Group within the Broad Institute’s Program in Medical and Population Genetics. There, his team created the Genome Analysis Toolkit, a software package used by researchers and clinicians from academic institutions and commercial companies for the analysis of next-generation DNA sequencing data. These tools are used worldwide by researchers involved in large-scale, prominent projects, including the 1000 Genomes Project and The Cancer Genome Atlas. He served as a Damon Runyon Cancer research fellow at Harvard University. He is a US National Science Foundation graduate research fellow and a marshall scholar. [6] Clinical Research Associates LLC (current assignee) is an independent research company located in Northwest Oklahoma City. We contract with pharmaceutical companies and CRO’s to run phase II, III, and IV trials on Investigational New Drugs and already approved drugs for post marketing safety. [7] In an article from Time (December 1, 2010) titled, New Version of an Old Drug Could Treat Autism (and Addiction Too), author Maia Szalauitz writes, “One night in 2006, Kathy Roberts rushed her autistic daughter, Jenny, to the hospital. Nothing had been able to stop the young woman, then in her mid-20s, from vomiting. Jenny had recently suffered several major seizures and her entire gastrointestinal system was going haywire. To try to calm Jenny’s GI tract, doctors at Massachusetts General Hospital prescribed baclofen, an antispasmodic drug that is also being studied as a potential treatment for alcoholism and other addictions. The drug relieved Jenny’s vomiting, but it did something else too — a completely unexpected and welcome side effect. ‘Within 24 hours, I saw a change’, says Roberts. ‘Right away, I saw that it was globally calming. In September, Seaside announced positive results from a phase II clinical trial of STX209, an experimental drug that is chemically related to baclofen. In the

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trial, which was not blinded or placebo controlled, STX209 led to a reduction in agitation and related emotional outbursts in autistic people. Such behavior is common in people with autism - often, a result of anxiety caused by extreme sensory oversensitivity or frustration over being unable to communicate their needs. To cope, autistic people often develop behavioral mechanisms, include tantrums, social withdrawal or repetitive behaviors like rocking or hand flapping. STX209, while not a cure, appeared to ease anxiety. ‘We’re seeing reductions in a lot of types of outbursts and irritable behavior, along with increased communication and social behavior’, says Dr. Randall Carpenter, co-founder, President and CEO of Seaside, Addiction.”[8]

COMPOSITION OF A LIQUID DIETARY SUPPLEMENT TO TREAT SYMPTOMS OF AUTISM SPECTRUM DISORDERS IN CHILDREN (Nieuwenhuijsen, in Patent number 8,652,545 – February 18, 2014) Abstract - This describes an all-natural dietary supplement formulation for management of behavioral and neurological symptoms associated with autism spectrum disorders. Abbreviated Claim 1 - Formulation for treating autism comprising a water-soluble extract of mastic gum, L-Theanine, Passionflower extract, Feverfew extract, and Vitamin B6. The inventor explained that the formulation may be beneficial in treating and alleviating the symptoms of neurological disorders, where a relationship exists between improper intestinal functioning and (brain) neuropathy. Bart Nieuwenhuijsen (inventor) was educated at Drexel University in the LeBow College of Business. He is CEO and founded Reverta Health Solutions LLC (original assignee). In a LinkedIn profile for Bart Nieuwenhuijsen it says, “We are about to enter the age of word of mouth, and that, paradoxically, all of the sophistication and wizardry and limitless access to information of the New Economy is going to lead us to rely more and more on very primitive kinds of social contacts. Classically trained in molecular biology, seven years ago, I made the jump from pharmaceutical R&D to pursue my passion of bringing natural products to the public. Suffering from a skin condition myself and being frustrated with the effectiveness and toxicity of so many skincare products on the market, I decided to develop my own line of unique, natural skincare products centered around active ingredients that are also safe to eat. I like simple, innovative solutions to complex problems. Can I save on resources, can it be safer, more effective? While a problem may not have an obvious solution, in the end all problems can be solved. I see my strengths as finding simple, innovative solutions to complex problems. In the last five years, I received 2 patents for an innovative sunscreen formulation that is free of any toxic ingredients and 1 patent for a dietary supplement aimed to decrease the symptoms common in children on the autistic spectrum. While my career has been multidisciplinary, I see my career as identifying and serving the needs of my customers by offering positive, unique solutions to their problems, whether they are direct customers or teams/collaborators within a company.” [9] In a communication from Reverta Health Solutions LLC (current assignee), it is written, “Since autism is a multi-factorial condition, the best results are achieved by using a combination of various therapies. It is important to note however, that the sooner therapy

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begins, the better the outcome. Treatment plans will vary greatly from child to child, since every child is unique and has its own special needs. Treatments may include occupational therapy, behavioral therapy, speech therapy, art therapy and music therapy. Since dietary intervention has been so beneficial for many children on the spectrum, it has been suggested that autistic symptoms could be the result of mal-absorption of or intolerance to certain food ingredients. Many parents have seen great improvements after following a special diet, in which gluten, casein and food colorings were eliminated. It is important to consult a nutritionist about this to ensure that your child’s diet contains the proper balance of nutrients that can compensate for the elimination of certain food ingredients. Natural treatments can be very effective and can be integrated very well into an overall treatment plan. If your child is taking prescription medications, it is recommended to consult your child’s doctor before starting a natural treatment.” [10] Reverta Health Solutions LLC (current assignee) has protection for US patent 8,652,545 (Nieuwenhuijsen) to April 25, 2031.

NEUROAUDIOLOGICAL CENTRAL AUDITORY TEST APPARATUS AND METHOD OF DIFFERENTIATION OF THE NEURAL CORRELATES IN PTS, TBI, AUTISM, ADHD ET AL. (Dalton, in Patent number 8,313,441 – November 20, 2012) Abstract - This describes reducing the perception of tinnitus (auditory ringing or buzzing) in autism. The inventor explained that psychoacoustics technique can totally cancel tinnitus or replaces it with a barely discernable external noise of lesser volume with no pitch characteristics. The invention showed that of the 33-subjects only three reported no tone decay or residual inhibition. Leslie Dalton, Jr. (inventor) is a professor at West Texas A&M University. Dichonics Corporation (current assignee) has protection for US patent 8,313,441 (Dalton) to June 14, 2031. In an article from West Texas A&M University News (June 2, 2014) titled, WTAMU Tinnitus Research Needs Volunteers for Study, author Rana McDonald writes, “Dalton has been delving into the problem of tinnitus or ringing in the ears for many years. He came to West Texas in 2008 as a professor in the communications disorders department and brought his brain research with him as well as a prototype tinnitus cancellation program. His current efforts in advanced studies in tinnitus, hearing disorders and other neurological disorders such as autism and post-traumatic stress disorder (PTSD) are joint projects with Dr. Gary Byrd, professor of psychology, and Dr. Timothy Atchison, assistant professor of psychology, on the WTAMU Department of Psychology, Sociology and Social Work. In 2010 Dalton joined forces with Headsets Incorporated a long-time Amarillo manufacturer of military and aviation earphones and headsets, in obtaining a grant from the Amarillo EnterPrize Challenge, a program of the West Texas A&M Enterprise Center. The grant was used to develop the tinnitus patent Dalton brought with him to WTAMU into a marketable product. The patent

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was granted but Dalton is quick to point out that ‘I’ve have been working with that dang procedure for neigh on 20 years now, and I’m ready to do something else’ Headsets Incorporated under the name Dichonics, markets the Dalton invention as a revolutionary, high tech, on-line tinnitus diagnosis and treatment program available to anyone, anywhere, anytime who has an internet link.” [11]

METHODS FOR THE DIAGNOSIS, RISK ASSESSMENT, AND MONITORING OF AUTISM SPECTRUM DISORDERS (Goodenowe, in Patent number 8,273,575 – September 25, 2012) Abstract – This describes methods of diagnosis, risk assessment, and monitoring of autism spectrum disorder (ASD). More specifically to the measurement of small molecules (metabolites) in plasma that are found to have different abundances between persons with a clinical manifestation of ASD and subjects not expressing symptoms of ASD Further, it relates to the monitoring of putative therapeutic strategies designed to ameliorate the biochemical abnormalities associated with ASD. Abbreviated Claim 1 - A method for diagnosing an autism spectrum disorder (ASD) comprising: analyzing a blood sample using a mass spectrometer; comparing the metabolite marker to a reference blood sample to identify an increase or decrease in the metabolite marker; and diagnose the health state. The inventor explained that the metabolite marker is selected from the group consisting of ethanolamine phospholipids; docosahexaenoic acid (DHA)-containing phospholipids; DHA precursor-containing phospholipids; catabolic products of DHA β-oxidation-containing phospholipids; polyunsaturated very long chain fatty acids (VLCFA) containing phospholipids; and combinations thereof, and wherein the human subject is diagnosed with ASD based on having: elevated levels of ethanolamine phospholipids containing saturated or monounsaturated VLCFA, docosahexaenoic acid (22:6, DHA), VLCFA DHA precursor (24:5, 24:6), catabolic products of DHA β-oxidation (20:6), or polyunsaturated VLCFA; decreased levels of ethanolamine phospholipids containing 18:3, 20:3, 22:3, 24:3 fatty acids; or combinations thereof. The invention showed that in 8/8 families in which a non-ASD sibling was available for comparative analysis the ASD child had a more pronounced biochemical phenotype than the non-ASD sibling. Dayan Goodenowe (inventor) has over 20 years of advanced laboratory, biochemistry and mass spectrometry discovery and development experience. With an undergraduate degree in chemistry, a PhD in medicine, and 16 patents covering analytical technology, bioinformatics, disease biomarkers and targets, and novel therapeutic drug compositions, Dr. Goodenowe has the breadth of knowledge across all areas related to the biochemical understanding of disease and the practical implementation of diagnostic and therapeutic solutions to disease management. He is founder, President, and CEO of Phenomenome Discoveries Incorporated. Phenomenome Discoveries Incorporated (original assignee) is a health research company with a novel and patented metabolomics technology. We use this technology to investigate how diseases arise, determine who is most likely to develop a

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disease, and to design mechanism-based restorative therapies that treat the causes of disease rather than the symptoms. Through this integrated approach, our ultimate goal is to prevent diseases from developing. PDI is based in Saskatoon, Saskatchewan, Canada. Through collaborations and partnerships with researchers and companies worldwide, PDI is a global health research company. Dr. Goodenowe writes in his LinkedIn profile, “I do not believe that disease is either random or unpredictable. However, medicine, as it is currently practiced, is based upon this passive acceptance model. Passive, in that we primarily wait for disease to happen to us, and accepting in that we assume that we are powerless, in any specific way, to predict or prevent a specific disease prior to its occurrence. The practice of medicine will not change from its current acute-care focus to a preventative-care focus by simply wishing it so. Our acute-care system, despite its faults, is practiced well and has systematically improved year after year. Each improvement must be targeted to an unmet need, actionable, and measurable. Only after these requirements are met will a change become accepted. This is the correct way to advance changes to any system. My primary professional interest is the advancement of prevention-based medicine into mainstream medical practice. The achievement of this goal involves the integration and translation of various scientific and technological fields such as basic biochemistry, biomarker discovery, diagnostic technology, biostatistics, clinical trial design and execution, targeted therapeutic development, epidemiology, and healthcare economics.” [12] Phenomenome Discoveries Incorporated (current assignee) has protection for US patent 8,273,575 (Goodenowe) to September 18, 2028.

DIAGNOSIS OF AUTISM (Grubb et al., Patent number 8,268,576 – September 18, 2012) Abstract - This describes a method of diagnosing autism by determining the presence and concentration of specific peptides in body fluid. Abbreviated Claim 1 - A method for diagnosing autism comprising: analyzing a blood sample to detect peptides; comparing the peptides with individuals not afflicted with autism; and diagnosing autism when the peptide concentration is more than ten times greater. The inventor explained that autism is the presence of an abnormal peptide pattern in the brain and/or the fluids penetrating or surrounding the brain, i.e., blood and cerebrospinal fluid, and that some of these peptides might disturb the signals (e.g., carried neuropeptides), used by the brain for communication. Anders Grubb (second inventor listed with a co-inventor) is a senior professor in the Department of Clinical Chemistry and Pharmacology at Lund University. In Dr. Grubb’s LinkedIn profile his background summary States, “Curious guy, Father of 5, Husband of 1, and Author of 315 articles.” [13] Autism Biotech Ltd (original assignee) is a biotechnology company that develops test for autism spectrum disorders. The company uses a product called ASDtect which uses dried blood spots for diagnosing ASD. The company was incorporated in 2011 and is based in Reading, United Kingdom. In the Autism Biodiagnostic Ltd (current assignee) LinkedIn profile it is written, “Autism Biodiagnostic Ltd. (ABD) is a new established company that

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independently funds a scientific breakthrough research on autism. To help diagnosing autism the company has set up a research laboratory in Linnaeus University in Kalmar. Researchers from various universities in Sweden have been brought together by this UK based company to exclusively work on this research. This research has been undertaken as a part of the ACE’s (Asbestos Consultants to the Environment Ltd) Corporate Social Responsibility. The owner of both companies, Mr. Siamak Shahnooshi, says that this research is aligned with his personal mission – ‘to improve quality of lives’. So, since 2007 he has been dedicating his time towards this ground-breaking research. Unlike other genetic disorders, the scientists have yet to find out a reliable test to confirm autism spectrum disorder (ASD). ABD’s aim is to establish a blood test which could reveal neurological disorders such as ASD. The company anticipates that with the development of this research, early diagnosing of ASD and its related disorders would be possible. This in return would help to improve the conditions of thousands of children.” [14]

TREATMENT OF AUTISM USING PROBIOTIC COMPOSITION (Cobb et al., Patent number 7,749,509 – July 6, 2010) Abstract - This describes a method of treating autism using a probiotic composition. Abbreviated Claim 1 - A method of treating autism by administering a probiotic composition comprising Bacillus subtilis, Bacillus coagulans and Enterococcus faecium. The inventors (e.g., Mark L. Cobb) explained that probiotic microorganisms can be employed to protect the body against pathogens, maintain vital chemical and micro-flora balance in the gastrointestinal tract, produce essential vitamins and hormones, and assist in stimulating the immune response. The invention describes a seven-and-a-half-year-old male patient with autism for at least four years had substantial difficulties learning to speak, read, write and process language. The patient was orally administered approximately 4 g of Composition-A per day with water. Within three weeks with such daily treatment, the patient learned to ride a two-wheel bicycle for the first time. After six weeks of such daily treatment, the patient’s speech and his ability to read, write and process language improved substantially and his self-stimulating behaviors decreased. In an article from Autism Speaks (December 6, 2013) titled, What’s Next in Probiotics for Autism? author Jessica Sachs writes, “The bottom line is that science can’t yet provide us with solid guidance on whether probiotics will ease autism symptoms in children or adults with autism. Anecdotally, it’s looking like the right probiotics can help some individuals. But we don’t yet know which probiotics or how to identify those who will benefit. And probiotics are certainly not a full answer for anyone. While this lack of clear-cut guidance is no doubt frustrating, it’s exciting to see research in this field accelerating at an exponential rate. While we’re waiting for the results to come in, we do know that probiotic foods such as yogurt are widely recognized as safe. As for probiotic supplements, a small but growing number have shown themselves safe and effective for relieving other medical conditions. For now, autism experts including Dr. Fasano caution against their long-term use in children with ASD – until we understand more about their effects in this population.” [15]

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In an article from Science Daily (June 16, 2016) titled, a single species of gut bacteria can reverse autism-related social behavior in mice, it is written, “We cultured a strain of Lactobacillus (L.) reuteri originally isolated from human breast milk and introduced it into the water of the high-fat-diet offspring. We found that treatment with this single bacterial strain was able to rescue their social behavior, Buffington says. Other ASD-related behaviors, such as anxiety, were not restored by the reconstitution of the bacteria. Interestingly, the authors found that L. reuteri also promoted the production of the ’bonding hormone’ oxytocin, which is known to play a crucial role in social behavior and has been associated with autism in humans.” [16]

COMPOSITIONS AND METHODS RELATING TO REDUCTION OF SYMPTOMS OF AUTISM (Houston, in Patent number 6,899,876 – May 31, 2005) and (Houston, in Patent number 6,821,514 - November 23, 2004) and (Houston, in Patent number 6,808,708 – October 26, 2004) and (Houston, in Patent number 6,447,772 – September 10, 2002) 6,899,876 – Abstract: This describes a composition for reducing the symptoms of autism comprising a purified casomorphin inhibitor and a purified gluteomorphin inhibitor. The inventor explained that there is a need for improved methods of treating patients with autism who exhibit the effects of exorphins such as gluteomorphin and casomorphin without requiring the patient to adhere to difficult dietary restrictions. Similarly, there is a need to protect autistic patients from inadvertent exposure to gluten and casein, typically in the form of dairy products and wheat products. The invention showed that a substantial number of the participants noted significant improvement of their symptoms. The inventor states that, “The results also demonstrated that the composition of Example 2 was generally very well tolerated and quite safe. Except for two cases it was noted that adverse responses were generally transient and did not continue throughout the full four weeks. In evaluating the two who experienced these responses, there may have been other factors that could have contributed to some of the symptoms.” Devin B. Houston (inventor) received a BA degree in biology from Hendrix College in 1979. He then was awarded a BSc degree in medical science in 1980, and a PhD in biochemistry from the University of South Alabama College of Medicine in 1987. Dr. Houston’s graduate work focused on how the aging process affected certain enzyme systems. Following the defense of his thesis work, Dr. Houston accepted a post-doctoral position at the University of Virginia where he became involved in several fields of research, including ligand-receptor interactions of the adenosine receptor, diabetes, and mechanisms of how cells respond to environmental signals. Dr. Houston’s work was funded by the American Heart Association. In 1990, Dr. Houston received a position at Saint Louis University School of Medicine. While there, he received the position as assistant professor in the Department of Pharmacology and Physiology. His research focus was on characterizing the cannabinoid (marihuana) receptor as a possible model for Alzheimer’s research. Dr. Houston’s work was

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funded by several grants from the National Institutes of Health. He published several peerreviewed papers, as well as presenting his finding at several symposia. In 1997, Dr. Houston left academia for industry, and accepted a position as Manager of Research and Development at National Enzyme Company. While there, he upgraded the existing lab and instituted more advanced methods of analysis. Instrumental in new product development, he developed the first enzyme product targeted to the autism community in 1999. In March of 2000, Dr. Houston left National Enzyme and became a scientific consultant to the dietary supplement industry prior to founding Houston Nutraceutical Incorporated. [17] In an advertisement from Prothera Incorporated (original assignee) it is written, “VitalZymes™ Complete is a favorite of healthcare practitioners for children with ASD because it provides potent, broad-spectrum enzymatic support in easy-to-swallow capsules that are free from most common allergens.” [18] ProThera Incorporated (current assignee) has protection for US patent 6,899,876 (Houston) to January 20, 2020.

METHOD OF USING SECRETIN AND COMPOSITIONS MADE THEREFROM FOR THE TREATMENT OF AUTISM AND OTHER NEUROLOGICAL, BEHAVIORAL AND IMMUNOLOGICAL DISORDERS (Beck et al., Patent number 6,790,825 – September 14, 2004) and (Beck et al., Patent number 6,197,746 – March 6, 2001) 6,790,825 - Abstract: This describes secretin and secretin compositions that are used for the treatment of autism. 6,790,825 - Claim 1: A method for treating an autistic disorder by stimulating secretion of pancreatic juices. The inventors explained that the hormone secretin stimulates the pancreatic acinar cells to release bicarbonate and water, which are excreted into the duodenum and change the pH in the gut from acid too alkaline, thereby facilitating the action of digestive enzymes. Secretin is always used and indeed is intended only to be used in diagnostic tests given to patients with gastrointestinal disorders to stimulate the release of pancreatic juices for testing purposes. Prior to the discovery of the present invention however secretin has never before been linked to autistic spectrum disorders, either as a possible cause or treatment, nor has it been used in the treatment of other neurological and/or immunological disorders. The inventors concluded that a secretin deficiency can therefore account for the gastrointestinal disorders as well as the behavioral symptoms found in many individuals with autistic spectrum disorder. In an obituary from The New York Times (November 28, 2006) titled, Bernard Rimland, 78, Scientist Who Revised View of Autism, dies, author Benedict Carey writes, “Bernard Rimland overturned conventional theories about the origin of autism in the 1960s and later forced scientists and policymakers to consider alternative causes and treatments. Dr. Rimland’s interest in autism, the puzzling social-skills disorder, and his work on behalf of families touched by it grew out of his intuition as an experimental psychologist and his

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experience as a father. When his young son Mark received a diagnosis of autism, doctors generally blamed the disorder on cold, distant mothering. In his book ‘Infantile Autism: The Syndrome and Its Implications for a Neural Theory of Behavior’, Dr. Rimland demolished the cold-mother theory by presenting lucid evidence that the disorder was rooted in biology. ‘He was tremendously important to the field, in that he reoriented research from a focus on the parents to a focus on the brain’, Dr. Fred R. Volkmar, director of the Child Study Center at Yale, said. ‘He also developed the first checklist for diagnosing autism. He was a pathfinder and tireless advocate for families dealing with autism.’ Early on, his judgment was prescient. He was among the first scientists to recognize that a brand of systematic rewards and punishments, pioneered the University of California psychologist O. Ivar Lovaas, could lead to significant improvements in autistic children. The treatment is widely used today. Dr. Rimland also quickly saw through the spurious claims of a therapy called ‘facilitated communication’, in which therapists claimed to help channel the thoughts of autistic children and heal them. He wrote articles, pushed for more research and founded advocacy organizations, including what is now the Autism Society of America, in Bethesda, MD and the Autism Research Institute in San Diego, where he was director. In 1985, after retiring from his day job as a Navy researcher, Dr. Rimland’s research and ideas made him perhaps more prominent and took him outside the scientific mainstream. He published papers on the effects of high doses of vitamin-B6 for autistic children. Tens of thousands of parents have said the vitamins helped their children, but most academic researchers have been skeptical. They have been equally unmoved by Dr. Rimland’s argument that childhood vaccines with trace amounts of mercury are a major cause of autism. Yet parents, journalists and patients’ advocates have rallied against the vaccines and forced changes in legislation in some states, altering the shots. ‘He was an iconoclast, and people like that are willing to buck the tide’, said Dr. Robert L. Hendren, executive director of the MIND Institute at the University of California, Davis. Even if people in traditional medicine say Dr. Rimland did not stick to the evidence, Dr. Hendren added, ‘he was the kind of person who opened up new ideas and challenged people’s thinking, and the field needs people like that.’” [19] Repligen Corporation is an American company devoted to the development and production of materials used in the manufacture of biological drugs. Repligen’s company headquarters are housed together with its manufacturing facility in Waltham, Massachusetts. A decision was made in 2012 to focus on the bioprocessing business and reduce research and development expenditures. [20] Repligen Corporation (current assignee) has protection for US patent 6,790,825 (Beck et al.) to August 26, 2018.

COMPOSITION AND METHOD FOR INCREASING EXORPHIN CATABOLISM TO TREAT AUTISM (Brudnak, in Patent number 6,783,757 – August 31, 2004) Abstract - This describes a composition for treating autism spectrum disorders by increasing the expression and/or activity of exorphin cleaving gene products.

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The inventor explained that there exists for a more effective manner of breaking down exorphins in the stomach and the intestinal tract of an autistic individual. A need also exists to increase expression of dipepital peptidase-4 (DPPIV) and DPPIV-like compounds from within an autistic individual’s own body, i.e., overcoming the apparent down regulation of these or related genes. Mark A. Brudnak (inventor) has authored more than 40 peer-reviewed scientific and trade journals while an undergrad (University of Southern California) and a graduate student (University of Tulsa). He is often quoted in the health food industry, cited in the scientific literature, and sought out worldwide as a leading expert and speaker in the areas of probiotics, enzymes and functional carbohydrates. Mark is the originator of the term genomeceuticals, which denotes the natural ingredients that beneficially affect gene expression. He is a member of many academic honors societies and has been the recipient of grants and scholarships throughout his career. A board certified Naturopath, Mark has also worked with numerous companies and universities to develop novel products, many of which are available in local health food stores. [21] In an advertisement from Kirkman Group Incorporated (current assignee) it is written, “EnZymAid™ Multi-Enzyme Complex is a plant-based enzyme formulation that specifically targets the breakdown (cleaving) of casein, gluten and gliadin and facilitates the breakdown of wheat (gluten) and milk (casein) proteins. This proprietary enzyme also enhances the absorption and utilization of important minerals. (This is accomplished by the addition of the enzyme phytase, which breaks down phytic acid found in grains, beans, soybean, etc. Phytic acid is known to interfere with the absorption of crucial minerals including calcium, magnesium and zinc) D-galactose and peptidase enzymes are included to exert DPP-IV activity to support casein and gluten digestion.” [22] In a paper published in Medical Hypotheses (May 2002) titled, Enzyme-based therapy for autism spectrum disorders -- is it worth another look? author Mark Brudnak writes, “Of the treatment options available, a number of them have been nutritionally based in an attempt to address one or more of the theories regarding the etiology of the disease. An example would be enzyme therapy for the digestion of purported offending neuroactive peptides collectively known as exorphins. This paper discusses the exorphin theory of autism and subsequent treatment with dietary enzyme therapy. Novel data are presented in support of the theory that enzymes play a critical role in autism. Forty-six patients between the ages of 5 and 31 were selected for inclusion in the study based on a diagnosis placing them in the category of the autism spectrum disorders (ASD). The diets were supplemented with a novel dietary enzyme formulation, Enzymaid, for a period of 12 weeks. Progress was tracked according to the Symptom Outcome Survey (SOS) (1) form method of symptom charting and presented in a table for further analysis. The novel enzyme formula, Enzymaid, beneficially and safely affected all 13 of the parameters measured. Improvements ranged from 50-90%, depending on the parameter measured. Enzyme therapy to treat ASD may indeed a viable option in treatment protocols. These results indicate that further controlled studies are warranted.” [23]

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REFERENCES [1] [2]

[3] [4]

[5] [6]

[7] [8] [9] [10] [11] [12] [13] [14] [15]

Naghi Momeni, “Dr. in Biomedical Sciences” LinkedIn, Accessed on August 14, 2016. https://www.linkedin.com/in/naghi-momeni-2177417b. Denise Hassanzade Ajiri, 2015. “Light across the spectrum: the challenges of autism in Iran” Iran Tehran Bureau, Accessed on August 14, 2016. https://www.theguardian. com/world/iran-blog/2015/jul/29/light-across-the-spectrum-the-challenges-of-autismin-iran. Joan Fallon, 2016. “Executive Profile” Bloomberg, Accessed on August 14, 2016. http://www.bloomberg.com/research/stocks/private/person.asp?personId=39593734&pr ivcapId=30242823. Joan Fallon, 2005. “Could one of the most widely prescribed antibiotics amoxicillin/clavulanate ‘augmentin™’ be a risk factor for autism?” Medical Hypotheses, 2005, Volume 64, Issue 2, Pages 312–315. DOI: http://dx.doi.org/ 10.1016/j.mehy.2004.06.023. Kim-Mai Cutler, 2013. “SynapDx Raises $15.4M in Quest to Create a Blood Test for Autism” Techcrunch, Accessed on August 14, 2016. http://techcrunch.com/ 2013/07/22/synapdx/. Mark De Pristo, 2016. “Executive Profile” Bloomberg, Accessed on August 14, 2016. http://www.bloomberg.com/research/stocks/private/person.asp?personId=247223397& privcapId=106838494&previousCapId=106838494&previousTitle=SynapDx%20Corp oration. Clinical Research Associates LLC. “Funding” SFARI, Accessed on August 14, 2016. https://sfari.org/funding/clinical-research-associates. Maia Szalavitz, 2010. “New Version of an Old Drug Could Treat Autism (and Addiction Too)” Time, Accessed on August 14, 2016. http://healthland.time.com/2010/12/01/how-anew-version-of-an-old-drug-may-someday-help-treat-autism-and-addiction-too/. Bart Nieuwenhuijsen, LinkedIn Profile, Accessed on August 14, 2016. https://www.linkedin.com/in/bartnieuwenhuijsen. Reverta Health Solutions, Accessed on August 14, 2016. https://www.reverta.com/. West Texas A&M University, 2015. “WTAMU Professor Focuses Research on Tinnitus” Accessed on August 14, 2016. http://wtamu.edu/news/wtamu-tinnitusresearch-needs-volunteers-for-study.aspx. Dayan Goodenowe, “President/CEO at Phenomenome Discoveries Inc. “LinkedIn Profile, Accessed on August 14, 2016. https://www.linkedin.com/in/dayangoodenowe. Anders Grubb, LinkedIn, Accessed on August 14, 2016. https://www.linkedin.com/in/ anders-anders-grubb-45722481. Autism Biotech Ltd, 2016. “Company Overview of Autism Biotech Limited” Bloomberg, Accessed on August 14, 2016. http://www.bloomberg.com/research/stocks/ private/snapshot.asp?privcapId=288637525. Jessica Sach, 2013. “What’s Next in Probiotics for Autism?” AutismSpeaks® Point of View, Accessed on August 14, 2016. https://www.autismspeaks.org/science/sciencenews/whats-next-probiotics-autism.

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[16] Science Daily, 2016. “A single species of gut bacteria can reverse autism-related social behavior in mice” Cell Press, Accessed on August 14, 2016. https://www.sciencedaily. com/releases/2016/06/160616140723.htm. [17] About Dr. Houston, “The Authority on Enzymes” Houston Enzymes, Accessed on August 14, 2016. http://www.houston-enzymes.com/drhouston/about.php. [18] Prothera, 2008. “Vital-Zymes™ Complete: Enzyme Support for Children on the Autism Spectrum,” Accessed on August 14, 2016. https://www.protherainc.com/ images/prod/UpdateArticles/2008_08_vitalzymes.asp. [19] Benedict Carey, 2006. “Bernard Rimland, 78, Scientist Who Revised View of Autism, dies” The New York Times, Accessed on August 14, 2016. http://www.nytimes.com/ 2006/11/28/obituaries/28rimland.html. [20] Repligen, Wikipedia, the free encyclopedia, Accessed on August 14, 2016. https://en.wikipedia.org/wiki/Repligen. [21] Healthy Living Naturally, “Mark A. Brudnak” Accessed on August 14, 2016. http://markbrudnak.com/about.htm. [22] Kirkman, “EnZymAid™ Multi-Enzyme Complex,” Accessed on August 14, 2016. http://www.kirkmangroup.com/index.php/enzymaid-180ct.html. [23] Brudnak MA et al., 2002. “Enzyme-based therapy for autism spectrum disorders -- is it worth another look?” Med Hypotheses. 2002 May;58(5):422-8, DOI:10.1054/ mehy.2001.1513.

Chapter 4

PHARMACEUTICAL COMPANIES

The cost of filing a high quality US patent application with the intent of obtaining meaningful, strong patent protection is about $20,000. For pharmaceutical companies, the process of developing a drug is incredibly expensive and costs have skyrocketed over the past few decades. According to the Pharmaceutical Research and Manufacturers of America, the cost for developing a single new drug, including money spent on researching unsuccessful drugs which don’t pass the US Food and Drug Administration (FDA) screening, was $1.2 billion in the early 2000s. Estimates released in August 2013 by Forbes indicate that the price of developing a single new drug is about $5 billion per medicine accepted by the US Food and Drug Administration (FDA). Robert Jarvik, the American scientist, researcher and entrepreneur known for his role in developing the Jarvik-7 artificial heart says, “The US has an active pharmaceutical industry that has brought huge benefits to the US public. Most Americans, who benefit from these advances, have little understanding of how difficult it is to create an important new medical therapy and make it available to improve public health.” In an article from Spectrum (June 29, 2010) titled, Pharma companies set their sights on autism, author Virginia Hughs writes, “A decade of research on the biology of autism, combined with a steady rise in diagnosis, has finally piqued the pharmaceutical industry’s interest in developing drugs for the disorder.” [1]

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INTRANASAL CARBETOCIN FORMULATIONS AND METHODS FOR THE TREATMENT OF AUTISM (Leonard et al., Patent number 9,023,793 – May 5, 2015) Abstract – This describes methods and compositions containing oxytocin or analogs for the prevention and treatment of autism spectrum disorders. Abbreviated Claim 5 - The method for treating autism comprising administering the formulation of claim 1. The inventors explained that current treatments for autism spectrum disorders are mainly symptomatic and have proven unsuccessful in allowing such children and adults to become symptom, or disorder, free. The invention showed that the time spent in open arm exploration and percent time spent in open arm exploration showed that ICV administration of carbetocin reduced anxiety in rats compared to oxytocin using the elevated plus-maze assay. Steven C. Quay (ninth inventor listed with eight co-inventors) is a physician scientist and biotechnology entrepreneur who has founded six companies and rebranded a seventh over a 25+ year career. He has received 84 US patents and has five drugs and one medical device FDA approved that he invented. Dr. Quay has authored more than 130 papers in RNA interference, diagnostic imaging, oncology and biochemistry and is a member of the Association for Molecular Pathology. He received an MD and PhD from the University of Michigan and postgraduate training at MIT and Harvard Medical School. He is board certified in Anatomic Pathology. Before entering biotechnology, he was a faculty member at Stanford University. He was an adjunct professor at National Yang-Ming University, Taipei, Taiwan, in the Institute of Microbiology and Immunology and is on the External Advisory Board, the Institute of Aging, University of Pennsylvania. [2] Retrophin (current assignee) is a pharmaceutical company focused on the development, acquisition and commercialization of drugs for the treatment of serious, catastrophic or rare diseases for which there are currently no viable options for patients. The company intends to initiate clinical trials for intranasal oxytocin as a potential treatment for schizophrenia and autism. [3] In an article from BuisnessWire (December 12, 2013) titled, Retrophin Signs U.S. License Agreement for Syntocinon™ Nasal Spray (Oxytocin), author Marc Panoff writes, “Martin Shkreli, founder and Chief Executive Officer of Retrophin says ‘We believe that Syntocinon™ is an underutilized drug. Compelling data from studies that show positive results in patients with schizophrenia and autism lead us to believe that this drug may have significant utility in treating these conditions. We look forward to initiating a clinical program in order to develop the drug for these indications.’” [4]

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METHOD OF TREATING AUTISM (Jordan et al., Patent number 8,642,600 – February 4, 2014) Abstract - This describes a method of treating a patient with a carbostyril derivative, wherein the patient is suffering from a disorder of the central nervous system associated with 5-HT.sub.1A receptor subtype. Abbreviated Claim 1 - A method of treating a patient suffering from autism by administering a carbostyril compound of formula (1). The inventors explained that the compounds have not been previously reported as having agonistic activity at the 5-HT.sub.1A receptor subtype. The invention showed high affinity binding to 5-HT.sub.1A in Chinese Hamster ovary (CHO) cell membranes. Shaun Jordan (first inventor listed with four co-inventors) is a neurology medical liaison (Southeast Region) for Bayer pharmaceuticals. Mr. Jordan studied Neuroscience Pharmacology at Aston University. He was also director of CNS Drug Discovery and Development at Otsuka Pharmaceutical Companies (US). [5] Otsuka Pharmaceutical Company Ltd (current assignee) is a pharmaceutical company headquartered in Tokyo, Osaka and Naruto, Japan. The company was established August 10, 1964. As of 2012, OPC employed 40,000 people worldwide. Abilify (Aripiprazole) was developed by Otsuka in Japan. In the US, Otsuka America markets it jointly with BristolMyers Squibb. [6] In an article from the Wall Street Journal (May 3, 2016) titled, FDA Warns of Rare Impulse Reactions to Abilify Medication, author Thomas M. Burton writes, “The Food and Drug Administration on Tuesday warned of rare cases in which patients taking the antipsychotic medication Abilify have experienced uncontrollable urges to gamble, binge eat, shop and engage in sex. The drug is also sold under the generic name aripiprazole and the brand names Abilify, Maintena, and Aristada. The FDA noted that such cases, while rare, can in theory affect anyone taking the medication. The medicine is sold as a generic and also by Otsuka Pharmaceutical Company. Such cases of impulse control have been reported to the FDA or in medical literature 184 times over the 15 years since the medicine was approved in the US in November 2002, the FDA said. Approximately 1.6 million patients got a prescription for the drug from US outpatient retail pharmacies during 2015. The drug is prescribed for a range of mental disorders, including schizophrenia, bipolar disease, Tourette Syndrome and irritability linked to autism. The medicine also can be used to treat depression, when taken in combination with antidepressant medicines. The agency said the uncontrollable urges were reported to have stopped when the drug was stopped, or when the dose was lowered. While pathological gambling is listed as a side effect on current aripiprazole drug labels, the agency said the labels don’t adequately describe the risk that it noted. The FDA said it also has become aware of other behaviors such as compulsive eating, shopping and sexual actions. The agency said patients and caregivers need to be aware of these possibilities and to talk to a health care professional right away if a family member shows such tendencies.” [7]

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METHOD FOR TREATING AUTISM (Chez, in Patent number 7,456,224 – November 25, 2008) Abstract - This describes a method of treating autism by administering an NMDAreceptor antagonist (e.g., memantine) or salt thereof. Abbreviated Claim 1 - A method of treating autism comprising administering 1-amino3,5-dimethyladamantane in a dosage ranging from approximately 1 mg to approximately 100 mg per day. The inventor explained that memantine appears to substantially improve frontal executive functions associated with autistic symptoms including speech expression and decreased perseveration. In the Experiment Section, the invention showed that after thirty patients were treated for more than 2-months with Memantine, parents reported improvements in 26 of the 30 patients in one or more categories: attention, motor planning, language function (both receptively and expressively), and self-stimulatory behaviors. Moderate to significant improvement occurred in 16 of the 26, with milder improvement in 10 of the 26. No side effects were reported. Michael G. Chez (inventor) principle investigator at Sutter Neuroscience Institute has been in practice and an active investigator in pediatric neurological conditions for more than 18 years. He is an international resource in the diagnosis and treatment of epilepsy and autism in children. Some of his significant breakthroughs include using Alzheimer’s medications like memantine to treat autism and frontal lobe damage in children. He has also explored the use of natural supplements with neuro-protective properties like carnosine and turmeric to improve communication and behavior in autistic children. Dr. Chez has also been collaborating with leading researchers in the US on immunological and neurotransmitter abnormalities in various types of autistic patients. [8] Forest Laboratories Holdings Limited (original assignee) is a subsidiary of the pharmaceutical company Allergan Plc. The company discovers, develops, and researches therapeutics and pharmaceutical drugs. It was incorporated in 1992 and is based in Dublin, Ireland. Forest Laboratories Holdings Ltd (current assignee) has protection for US patent 7,456,224 (Chez) to April 21, 2025. In an article from PR Newswire (June 14, 2016) titled, Ajanta Pharma Announces the Launch of Memantine Hydrochloride Tablets, it is written, “Ajanta Pharma Ltd announces the launch of Memantine Hydrochloride Tablets (5mg, 10mg), a bioequivalent generic version of Namenda, into the US market. Namenda is a registered trademark of Forest Laboratories, Incorporated.” [9]

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LIPID-SOLUBLE THIAMINE DERIVATIVES IN THE TREATMENT OF AUTISM (Lonsdale et al., Patent number 6,585,996 – July 1, 2003) Abstract – This describes a treatment for autism by administering a lipid-soluble thiamine derivative. Abbreviated Claim 1 - A method of treating autism comprising administering a lipidsoluble thiamine derivative to a person in need of such treatment. The inventors explained that the preferred thiamine derivative is thiamine tetrahydrofurfuryl disulfide (TTFD) which is the disulfide derivative of vitamin B. Furthermore, it is proposed that the use of TTFD causes an increase in the activation of rhodanese in the liver, which rids the body of the accumulation of cyanide ions, thus producing a treatment for autism. The invention showed that 8 of the 10 subjects in the pilot study showed clinical improvement in their autistic disorder while being treated with TTFD. James Frackelton (second inventor listed with a co-inventor) changed the direction of his medical practice in 1976 to focus his growing interest in and clinical research for preventive and alternative medicine, forming the Preventive Medicine Group. After many years of studying biochemistry, he began explaining nutrient and detoxification therapies to alternative-oriented physicians throughout North America. A founding member, Dr. Frackelton was elected President of the American College for Advancement in Medicine from 1985-87 and continued to serve as an Advisor to its board until several years before his death. [10] Westlake Laboratories Incorporated (current assignee) is a pharmaceutical company located in Cleveland, Ohio. The vitamin B1 derivative (TTFA) based products are sold under the expired tradename Authia. Patent 6,585,996 (Lonsdale et al.,) expired on July 1, 2015 due to failure to pay the maintenance fee. In an article from Medical Science Monitor (September 10, 2004) titled, Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent, author Derrick Lonsdale writes, “Thiamine tetrahydrofurfuryl disulfide (TTFD) is the synthetic counterpart of allithiamine, occurring naturally in garlic. Allithiamine was discovered in Japan in 1951. Its extensive research was reported by a group known as the Vitamin B Research Committee of Japan, and given this name because of its existence in the bulbs of many of the allium species of plants. It was found to be a disulfide derivative of thiamine, produced as a result of enzymatic action on the thiamine molecule in garlic bulbs when the bulb is cut or crushed. Subsequent experimental work in both animals and human subjects revealed that its metabolic effect was much more powerful than the thiamine from which it was derived. Japanese investigators created a number of synthetic forms and investigated their use in a number of human disease conditions. Although some derivatives have been synthesized without a disulfide bond in the molecule, these investigators emphasized that the disulfide was an extremely important part of its biologic action and TTFD is the most modern of the disulfide derivatives. Because at least part of its beneficial effects are the same as water soluble thiamine salts, this review deals first with the clinical uses of thiamine (vitamin B1) in medicine.” [11]

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ANTICONVULSANT DERIVATIVES USEFUL IN TREATING AUTISM (Van Kammen, in Patent number 6,552,000 – April 22, 2003) Abstract – This describes treating autism with a topiramate-based composition. Abbreviated Claim 1 - A method for treating autism by administering a sulfamate compound of Formula (I). The inventor explained a daily dosage in the range of about 50 to 600 mg, usually in two divided doses, for an average adult human is preferred. A unit dose would contain about 25 to 200 mg of the active ingredient. Daniel P. Van Kammen (inventor) received an MD and PhD in pharmacology at the University of Utrecht – The Netherlands. He began his career at the National Institute of Mental Health in Bethesda where he headed the Biomarker and Small Trial Research Program in schizophrenia for 10 years. Subsequently, he moved to the University of Pittsburgh, where he built a similarly internationally recognized Biomarker and Small Trial Research Program in schizophrenia with a biochemistry laboratory and a sleep lab. Dr. Van Kammen’s experience led him to overseeing clinical development programs among others in schizophrenia, multiple sclerosis, Parkinson’s psychosis, sleep maintenance insomnia, bipolar disorder and major depression. Most recently he has focused on neurodegenerative disorders, including Alzheimer’s, Huntington’s, Parkinson’s and FTLD with strong translational aspects working closely with Biotech’s and midsize companies. [12] Ortho-McNeil Pharmaceutical (original assignee) produced topiramate (i.e., sulfamatesubstituted monosaccharide), an anticonvulsant. Patent 6,552,000 (Van Kammen) expired on April 21, 2011 due to failure to pay the maintenance fee. In an article from the Journal of Child and Adolescent Psychopharmacology (March 17, 2015) titled, Topiramate for Weight Loss in Two Young Adult Women with Autism Spectrum Disorder, the researchers conclude, “Topiramate can be highly effective for weight loss in this patient population with minimal side effects.” [13]

METHOD OF TREATING OBSESSIVE COMPULSIVE DISORDERS, SOMATOFORM DISORDERS, DISSOCIATIVE DISORDERS, EATING DISORDERS, IMPULSE CONTROL DISORDERS, AND AUTISM (Coffin, in Patent number 6,410,527 – June 25, 2002) Abstract - This describes a method of treating autism by administering a D1/D5 antagonist. Abbreviated Claim 1 - A method for treating autism by administering (-)-trans6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5-H-benzo [d] naphtho{2,1-b} azepine HCl. The inventor explained that the “D1/D5 antagonist” is a compound that selectively binds to the D1 receptors and/or the D5 receptors in the brain, thereby decreasing or preventing dopamine access to these sites.

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The inventors recommend administering the treatment (containing 25.0 mg of SCH 39166) once a day, for six months to a patient diagnosed as having autism, thereby reducing or eliminating the observable symptoms of the disorder. Vicki L. Coffin (inventor) received a BSc degree in biology from The Pennsylvania State University in State College, Pennsylvania and a PhD in pharmacology from the University of Oklahoma Health Sciences Center, Oklahoma City, OK. She did her postdoctoral training at Wayne State University School of Medicine and at Harvard Medical School in Southborough Massachusetts. She continued her research career at Schering Plough Research Institute and focused on the pharmacological actions of dopamine, acetylcholine, glycine and neurokinins. Besides experience with drug development she also was a sr. director for Business Licensing with Schering Corporation and active in licensing with VC Pharma Consulting. She is a member of the American Society of Neuro-therapeutics and the Movement Disorder Society. In addition, she is a member in the Licensing Executive Society International and active in their educational program and was a board member of the Healthcare Business Association and director of Volunteers for 5 years and actively supported the mentoring program. She has helped develop neuro-psychopharmacology curricula for lecture and materials for problembased learning approaches for small groups. [14] Schering-Plough Corporation (original assignee) was a pharmaceutical company based in the US. It was founded in 1851 by Ernst Christian Friedrich Schering as Schering AG in Germany. In 1971, the Schering Corporation merged with Plough (founded by Memphis area entrepreneur Abe Plough in 1908) to form Schering-Plough. On November 4, 2009 Merck and Company merged with Schering-Plough with the new company taking the name of Merck and Company. Schering-Plough manufactured several pharmaceutical drugs, the most well-known of which were the allergy drugs Claritin and Clarinex, an anti-cholesterol drug Vytorin, and a brain tumor drug Temodar. These are now available from Merck and Company. [15] Merck Sharp and Dohme Corporation (current assignee) allowed US patent 6,410,527 (Coffin) to expire on June 6, 2006 due to failure to pay the maintenance fee. Psyadon Pharmaceuticals Incorporated markets a D1/D5 antagonist under the tradename Ecopipam which is being researched for the treatment of Tourette’s Syndrome. [16] An article from Research News and Vanderbilt (January 9, 2015) titled, Altered dopamine signaling may offer a clue to autism, author Bill Snyder writes, “Altered dopamine signaling may offer a clue to autism. ‘We’re looking at a network of (endogenous) molecules that disrupt dopamine neurotransmission in different ways, but they converge sometimes with the same mechanism’, Galli said. ‘We’ve never seen anything like that before.’” [17]

5-HT.SUB.3 RECEPTOR ANTAGONISTS FOR THE TREATMENT OF AUTISM (Oakley et al., Patent number 5,225,407 – July 6, 1993) Abstract - This describes a treatment for autism in which there is mental retardation.

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Abbreviated Claim 1 - A method for the treatment of autism originating in childhood in which there is mental retardation by administering an antagonist of 5-hydroxytryptamine (5HT) at 5-HT.sub.3 receptors. The inventors explained that 5-HT.sub.3 receptor antagonists have been shown to promote gastric emptying, and are thus useful in the treatment of conditions which may be relieved by the promotion of gastric emptying. A condition in which 5-HT.sub.3 antagonists may be effective includes irritable bowel syndrome. Nigel Oakley (first inventor listed with three co-inventors) worked at the Hammersmith Hospital in London England. He then became a Nuffield fellow in Pittsburgh, before returning to the Middlesex Hospital where he was appointed as deputy director of the Metabolic Unit at St. Mary’s. It was during this time that he carried out research on diabetic pregnancy and oral contraceptives. Dr. Oakley’s final NHS post was as consultant physician and service delivery leader in diabetes and endocrinology at St. George’s Hospital – where he set up a new diabetes unit. His unit pioneered the use of computers in clinical care. [18] In a communication from Prometheus Laboratories Incorporated (current assignee) titled, Neurological Disorders, it is written, “A broad category of conditions caused by multiple factors affect a child’s growing brain. We are concerned with these and many other childhood conditions, and are actively developing nutritional therapies for the needs of young patients to improve their quality of life while growing up.” [19]

PHARMACEUTICAL COMPOSITION AND METHOD FOR THE TREATMENT OF INFANTILE AUTISM (Naruse et al., Patent number 4,920,122 – April 24, 1990) and (Naruse et al., Patent number 4,778,794 – October 18, 1988) 4,920,122 – Abstract: This describes a composition for the treatment of infantile autism which contains tetrahydrobiopterin and 5-hydroxytryptophan and/or L-DOPA as an optional auxiliary effective ingredient. 4,920,122 – Abbreviated Claim 1: A method for ameliorating infantile autism by administering tetrahydrobiopterin or a derivative thereof and hydroxytryptophan and/or LDOPA at a ratio of 1:0.1 - 10 by weight. The inventors explained that tetrahydrobiopterin turned out be surprisingly effective in the treatment of autism and that no etiotropic drug for the treatment of autism has been found and there exists a strong need to develop such a drug. The inventors postulate that insufficiency of serotonin and catecholamines in the brain could cause autism and therefore use tetrahydrobiopterin which is a coenzyme for the hydroxylase of aromatic acids which is a rate-limiting factor for the synthesis of serotonin and catecholamines. The invention showed that remarkable effects were attained even when BPH.sub.4 was administered alone, but the two case studies demonstrate that satisfactory results could also be obtained by using BPH.sub.4 in combination with 5-HTP and/or with L-DOPA capable of increasing the levels of catecholamines in the brain. In a communication from Daiichi Sankyo Company Limited (November 2, 2013) titled, Daiichi Sankyo Launches Natural Tetrahydrobiopterin Agent Biopten® Granules 10%, it is

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written, “Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced that today it launched natural tetrahydrobiopterin agent Biopten® Granules 10% (generic name: sapropterin hydrochloride; approved for manufacture and marketing in Japan: August 20, 2013; Listing in the National Health Insurance drug price list: November 29, 2013). Biopten® is a highly pure, chemically synthesized form of natural tetrahydrobiopterin (hereafter, BH4) that occurs naturally in the human body. It is used to treat patients with atypical hyperphenylalaninemia (hereafter, HPA; approved in March, 1992) and those with BH4responsive HPA (approved in July, 2008) by maintaining an appropriate phenylalanine level. As Biopten® Granules 2.5% was administered to infants based on their body weight, or one sachet per kilogram, to treat BH4-responsive HPA, it became evident that an extremely large amount of sachets would be necessary each day for growing infants; consequently, an improved formulation was badly needed. In order to meet this need while improving patient adherence and lessening the physical burden, Daiichi Sankyo developed high content Biopten® Granules 10% containing 100 mg of sapropterin hydrochloride per sachet (1g). Today’s launch of the new formulation follows approval by the Japanese authorities in August 2013.” [20] In a paper presented by Frye et al. (2012) titled, Metabolic Effects of Tetrahydrobiopterin Treatment, it is written, “Several clinical trials have suggested that treatment with BH4 improves ASD symptomatology in some individuals. Specifically, Tetrahydrobiopterin (BH4), produced in the US as Kuvan for the treatment of BH4-responsive phenylketonuria, has been shown in several open-label and two double-blind placebo-controlled studies conducted in Japan and Scandinavia to have efficacy in the treatment of core autism spectrum disorder (ASD) symptoms. Given the dearth of available treatments for core ASD symptoms, interest has grown for the use of Kuvan for the treatment of ASD A double-blind placebocontrolled study examining the efficacy of Kuvan for the treatment of core ASD symptoms has recently been completed by the Children’s Health Council (Palo Alto, CA). BH4 is known to influence neurotransmitter, nitric oxide and oxidative stress metabolism. The current study was designed to complement the Children’s Health Council study by examining the metabolic effect of Kuvan treatment using a similar treatment protocol. The author concluded that Kuvan was associated with significant improvement in the transmethylation, redox and nitric oxide pathways as well as the reduced-to-oxidized pterin ratio. Greater improvements were seen in patients with more favorable improvements in biomarkers of nitric oxide and reduced-to-oxidized pterins. These data suggest that behavioral improvement associated with Kuvan® treatment may be associated with improvements in nitric oxide metabolism.” [21]

REFERENCES [1] [2]

Virginia Hughes, 2012. “Pharma companies set their sights on autism” Spectrum, Accessed on August 14, 2016. http://sfari.org/news-and-opinion/news/2010/pharmacompanies-set-their-sights-on-autism/. Steven Quay, LinkedIn Profile, Accessed on August 14, 2016. https://www.linkedin. com/in/stevenquay.

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[5] [6] [7]

[8] [9]

[10] [11] [12] [13] [14] [15] [16] [17]

[18] [19]

Michael J. Dochniak Retrophin Announcement, 2013. “Retrophin Announces Agreement to Acquire Kyalin Biosciences” Retrophin, Accessed on August 14, 2016. http://ir.retrophin.com/ releasedetail.cfm?releaseid=813546. Business Wire, 2013. “Retrophin Signs U.S. License Agreement for Syntocinon™ Nasal Spray (Oxytocin)” Accessed on August 14, 2016. http://www.businesswire. com/news/home/20131212005564/en/Retrophin-Signs-U.S.-License-AgreementSyntocinon%E2%84%A2-Nasal. Shaun Jordan, LinkedIn Profile, Accessed on August 14, 2016. https://www.linkedin. com/in/shaunjordan44. Otsuka Pharmaceutical, Wikipedia, the free encyclopedia, Accessed on August 14, 2016. https://en.wikipedia.org/wiki/Otsuka_Pharmaceutical. Thomads M. Burton, 2016. “FDA Warns of Rare Impulse Reactions to Abilify Medication” The Wall Street Journal, Accessed on August 14, 2016. http://www.wsj.com/articles/fda-warns-of-rare-impulse-reactions-to-abilify-medication1462315510. Michael G. Chez, “Research” Sutter Neuroscience Institute, Accessed on August 14, 2016. http://www.checksutterfirst.org/neuro/autism/research.html. Ajanta Pharma USA Inc, 2016. “Ajanta Pharma Announces the Launch of Memantine Hydrochloride Tablets” PR Newswire, Accessed on August 14, 2016. http://www.prnewswire.com/news-releases/ajanta-pharma-announces-the-launch-ofmemantine-hydrochloride-tablets-300284337.html. Dr. James Frackelton, 2012. “Memorial,” Jenkins Funeral Chapel, Accessed on August 14, 2016. http://www.jenkinsfuneralchapel.com/memorials/607. Lonsdale D., 2004, “Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent” Med Sci Monit. 2004 Sep;10(9): RA199-203. Daniel P. Van Kammen, LinkedIn Profile, Accessed on August 27, 2016. https://www.linkedin.com/in/dpvankammen. Crowley Brittany, Howe Yamini J., and McDougle Christopher J. Journal of Child and Adolescent Psychopharmacology. March 2015, 25(2): 183-185. doi:10.1089/ cap.2014.0140. Vicki Coffin, “Professor Pharmacology” Ross University School of Medicine, Accessed on August 14, 2016. http://medical.rossu.edu/medical-school/faculty/faculty.cfm? faculty_id=604. Schering-Plough, Wikipedia, The Free encyclopedia, https://en.wikipedia.org/wiki/ Schering-Plough. Psyadon Pharmaceuticals Inc, “Ecopipam” Accessed on August 14, 2016. http://www.psyadonrx.com/ecopipam.html. Research News @Vanderbilt, 2015. “Altered dopamine signaling may offer a clue to autism” Vanderbilt University, Accessed on August 14, 2016. http://news.vanderbilt.edu/2015/01/altered-dopamine-signaling-may-offer-a-clue-toautism/. Dr. Nigel Oakley, “About” London Medical, Accessed on August 14, 2016. http://www.londonmedical.co.uk/consultants/dr-nigel-oakley/. Neurological Disorders, “Infants and Children Can Suffer from a Variety of Neurological Disorders” Nestle Health Science, Accessed on August 14, 2016.

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https://www.nestlehealthscience.com/health-management/pediatrics/neurologicaldisorders. [20] Biopten Granules 10%, 2013. “Daiichi Sankyo Launches Natural Tetrahydrobiopterin Agent Biopten® Granules 10%” Daiichi-Sankyo, Accessed on August 14, 2016. http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/0 06042.html. [21] R.E. Frye et al., 2012. “Metabolic Effects of Tetrahydrobiopterin Treatment” INSAR, Accessed on August 14, 2016. https://imfar.confex.com/imfar/2012/webprogram/ Paper11063.html.

Chapter 5

BIOMEDICAL COMPANIES

METHODS OF TREATING AUTISM SPECTRUM DISORDERS AND COMPOSITIONS FOR SAME (Theoharides, in Patent number 9,176,146 – November 3, 2015) and (Theoharides, in Patent number 9,050,275 - June 9, 2015) 9,176,146 - Abstract: This describes treating autism spectrum disorders with compositions that inhibit brain blood vessel leakage. 9,176,146 - Abbreviated Claim 1: A method for preventing brain blood vessel leakage in susceptible children who have already developed an autism spectrum disorder by administering the flavonoid luteolin. In Example 4 of the invention, a 5-year old girl with atypical autism (PDD-NOS) would not allow the health provider to even come close to her. She would hide under the table and would scream if addressed more than once. She was put on 2 capsules of NeuroProtek™/20 kg body weight per day. Six months later, her ability to interact with others and learn simple words improved significantly. She would allow the health provider to hold her and help her make simple drawings. 9,050,275 - Abstract: This describes a method of preventing brain blood vessel leakage in susceptible children who have already developed an autism spectrum disorder by

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administering a composition comprising the flavonoids and olive kernel extract, wherein the flavonoids comprise luteolin, quercetin, and rutin. 9,050,275 - Abbreviated Claim 1: A method of treating an autism spectrum disorder by administering a composition comprising flavonoids and olive kernel extract, wherein the composition inhibits brain blood vessel leakage. In Example 4 of the invention (Patient D), a 4-year-old girl with autism had been taking NeuroProtek for one month. Health care providers observed that her feces were no longer typical autism spectrum feces, but solid, clean and not difficult for her. They also noticed an improvement in her focus and speech. Her family observed that was noticeably more social. The girl has also hugged a neighbor and hugged her mother and father without prompting. Theoharis C. Theoharides (inventor) received degrees from Yale University and was awarded the Winternitz Price in Pathology. He has a Certificate in Global Leadership and Management from the Fletcher School of Law and Diplomacy at Tufts University. Dr. Theoharides served on the Research Faculty of Allergy and Immunology at Yale before training in internal medicine at New England Medical Center (NEMC) in Boston. He joined Tufts University in 1983 and became tenured, full professor in 1995. He helped develop the Department and graduate studies in Pharmacology and Experimental Therapeutics, and was the director of Medical Pharmacology (1986-1993). He has served on 10 different NIH Study Sections. Based on his discoveries, Dr. Theoharides developed the novel foundation that mast cells play a critical role, in addition to allergies, in inflammatory diseases such as autism, atopic dermatitis, cardiovascular disease, migraines, multiple sclerosis and psoriasis. He has been placed in the top 1% of authors most cited in pharmacological journals. He is a member of 4 Academies and 17 scientific societies and has published over 300 research papers, with more than 10,000 citations, and 2 textbooks. Dr. Theoharides has served as consultant to the Ministry of Health, the Ministry of Labor and the Institute of Pharmacology Research and Technology in Greece, and to many pharmaceutical companies. He was instrumental in the preclinical work that led to the development of Zyrtec (UCB) and Niacin (Kos), and is now developing a unique anti-allergic skin cream (Galenica). He is the scientific director of Algonot LLC and has developed a number of nutraceuticals and medicinal foods for inflammatory conditions (www.algonot.com). He is also the President of Theta Biomedical Consulting and Development Company Incorporated and has received numerous US and International patents, as well as Trade Marks (www.thetabiomed.com). [1] The Theta Biomedical Consulting and Development Company Incorporated (original assignee) writes that all profits will be dedicated to research. US patent 9,176,146 (Theoharides) expires on March 25, 2030. [2] In an article from Translational Psychiatry (2015) titled, Children with autism spectrum disorders, who improved with a luteolin-containing formulation, show reduced serum levels of TNF and IL-6 g, the authors write, “Here we report that serum IL-6 and TNF levels that were elevated in the children with an ASD in that study before treatment were significantly reduced at the end of the treatment period; moreover, this reduction strongly correlated with those children who improved by this luteolin dietary supplement.” [3]

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METHODS AND SYSTEMS FOR TREATING AUTISM BY DECREASING NEURAL ACTIVITY WITHIN THE BRAIN (Foster et al., Patent number 9,095,713 – August 4, 2015) Abstract – This describes methods of treating autism by applying stimulation within the brain of a patient wherein the implanted stimulator is configured to decrease neural activity. Abbreviated Claim 1 - A method of treating autism by applying a stimulus to the brain. The inventors explained that applying an appropriate stimulus to selectively reduce or interrupt some brain activity in one or more areas within the brain may be useful in treating autism. The stimulus may be configured to decrease neural activity within the brain of autistic patients, thereby ameliorating or eliminating an autistic patient’s hypersensitivity to external stimuli. Consequently, a stimulator may be implanted in an autistic patient and configured to deliver a stimulus to one or more stimulation sites within the brain to treat the autism. The stimulus may include an electrical stimulation current, one or more drugs, gene infusion, chemical stimulation, thermal stimulation, electromagnetic stimulation, mechanical stimulation, and/or any other suitable stimulation. Allison M. Foster (first inventor listed with three co-inventors) received a PhD in neuroscience and psychology from University of Indiana, Bloomington (2004). Dr. Foster was a Clinical Trials Manager at Boston Scientific (2008-2009). Dr. Foster is at ABI Rehabilitation Auckland, New Zealand and is freelance consulting in medical writing, data analysis, health reporting, research, and science. [4] Boston Scientific Neuromodulation Corporation (current assignee) has protection for US patent 9,095,713 (Foster et al.) to July 3, 2033.

USE OF EPOTHILONES IN THE TREATMENT OF NEURONAL CONNECTIVITY DEFECTS SUCH AS SCHIZOPHRENIA AND AUTISM (Andrieux et al., Patent number 8,513,280 – August 20, 2013) and (Andrieux et al., Patent number 7,816,370 – October 19, 2010) 8,513,280 – Abstract: This describes epothilones for use in the treatment of disease(s) involving a neuronal connectivity defect. 8,513,280 - Abbreviated Claim 1: A method of treating autism by administering an epothilone. The inventors explained that the beneficial effect of epothilones has now been demonstrated in STOP deficient mice which display neuronal connectivity defects not associated with any detectable anatomical, degenerative or proliferative anomalies. Epothilones were originally identified as metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. The invention showed that epothilone treatment can alleviate behavioral disorders in an animal model of psychiatric disease involving connectivity disorders while unaffecting wild type mice.

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Gerhard Höfle (fourth inventor listed with three co-inventors) is a German natural product chemist and former university lecturer. He is especially known for the isolation of epothilones from the Myxobacterium Sorangium cellulosum. [5] The Helmholtz Centre for Infection Research, the Commission for Atomic Energy and Alternative Energy, and the French National Institute of Health and Medical Research (INSERM) are the current assignees for US patent 8,513,280 (Andrieux et al.) and US patent 7,816,370 (Andrieux et al.). In an article from Neuroscience News (March 12, 2015) titled, Regeneration of Damaged Neurons Promoted by Cancer Drug, it is written, “Epothilones, a cancer drug, appears to be effective in reducing scar tissue formation in spinal cord injuries and neuroregeneration.” [6]

SYSTEMS AND METHODS FOR TREATING AUTISM SPECTRUM DISORDERS (ASD) AND RELATED DYSFUNCTIONS (Fowler et al., Patent number 8,135,472 – March 13, 2012) Abstract - This describes a method of implanting an electrode within the patient’s skull and external to a cortical surface of the patient’s brain, and treating the autistic disorder by applying electrical signals to the implanted electrode. Abbreviated Claim 1 - A method for treating an autism spectrum disorder by applying electromagnetic signals to the target neural population; and administering a training program to the patient to train the patient to recognize expressions of facial emotion thereby promoting cortical organization of the patient’s brain by administering a behavioral adjunctive therapy in conjunction with delivering electromagnetic signals. The inventors explained implanting an electrode within the skull, and external to a cortical surface of the brain, then treating the autistic disorder by applying electrical signals. Dominic W. Massaro (second inventor listed with a co-inventor) is a research professor at the University of California, Santa Cruz. He has an extensive record of innovative language research with preschool and school children as well as adults. His research has advanced the field empirically, theoretically, and technologically. Dr. Massaro was one of the first researchers to apply Bayesian principles to language understanding. He is also well-known for the development of Baldi, a computer-animated face that produces accurate visible speech. Dr. Massaro is currently President of Psyentific Mind. He has applied technology and behavioral science to real-world problems. He invented the Kid Klok, an educational, easy-toread analog clock, and developed successful products for language learning for languagechallenged children such as those with hearing loss and autism. Dr. Massaro received a BA in psychology from the University of California, Los Angeles in 1965, and completed a PhD in mathematical psychology at the University of Massachusetts Amherst in 1968. After his postdoctoral work at the University of California, San Diego, he was professor of psychology at the University of Wisconsin, Madison from 1970 to 1979. [7] Advance Neuromodulation Systems (ANS) was founded in 1979 and has developed into a technology leader for implantable neuromodulation. They specialize in Spinal Cord Stimulation (SCS), which can be used for chronic pain treatments. ANS received patents for

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techniques to modulate neural activity via stimulation of various kinds. Since 2005 ANS has operated as a subsidiary of St. Jude Medical. [8] Advanced Neuromodulation Systems Incorporated (current assignee) has protection for US patent 8,135,472 (Fowler et al.) to January 20, 2030.

METHOD FOR TREATMENT OF ALZHEIMER’S DISEASE AND AUTISM SPECTRUM DISORDERS (DeLack, in Patent number 8,314,136 – November 20, 2012) Abstract - This describes a method of treating autism spectrum disorder (ASD) by administering at least one alky ester of imidazolecarboxylc acid. Abbreviated Claim 1 - A method for treatment of an autism spectrum disorder by administering methyl 4-imidazolecarboxylate. The inventor explained that the treatment counters AD/ASD by maintaining the intracellular/extracellular osmolyte gradient in the central nervous system (CNS) within a substantially normal range. The methyl ester group (--COCH3) in the Methyl 4imidazolecarboxylate molecule is responsible for creating the high-density water networking necessary to maintain the intracellular/extracellular osmolyte gradient. It is further speculated that in this functional group, the oxygen atoms are in closer proximity than what normally occurs in bulk water. This creates a higher-density water clustering around these groups. (Water molecules hydrogen-bonded to these oxygens are closer together than they would be in bulk water.) In Example 2 of the invention, a subject was developing normally until age two, and had started developing language, 4-word vocabulary. Then at 2-1/2 years of age he suddenly regressed and lost all verbal and nonverbal communication, lost receptive language, developed skin hypersensitivity to touch and would not wear clothes. He would not interact with his environment and would not interact with others. The transdermal application of 0.2 mcg of methyl 4-imidazolecarboxylate was applied at night since the subject would remove it during the waking hours. The first day following the first night of application, the aid at school said that the subject had increased concentration and focus at school and good eye contact. After one week of applying the 0.2 mcg of methyl 4-imidazolecarboxylate transdermally every night, the subject verbalized the words, “I’m hungry” at school and his mother reports hearing many new speech sounds. The subject continues to make progress wearing the transdermal application of 0.2 mcg of methyl 4-imidazolecarboxylate every night. The subject now seeks out his mother and gives her a hug. He is happy and smiling frequently and playing with his brother. He is keeping his clothes on without requiring constant supervision to do so. Elaine DeLack, RN (inventor) is the founder and CEO of MedDEV, Incorporated (original assignee). The mission of the biomedical company MedDEV Incorporated is to create new treatments that address the needs of individuals with central nervous system (CNS) and neurological conditions, specifically those related to mitochondrial dysfunction. [9]

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MedDev Incorporated (current assignee) has protection for US patent 8,314,136 (DeLack) to May 23, 2028.

METHODS OF TREATING FRAGILE X SYNDROME AND AUTISM (Roberts et al., Patent number 8,278,276 – October 2, 2012) and (Roberts et al., Patent number 8,143,311 – March 27, 2012) 8,278,276 - Abstract: This describes subjects having autism that are treated with a composition that includes gamma-aminobutyric acid agonists (e.g., baclofen). 8,278,276 - Abbreviated Claim 1: A method of improving a social domain in a human having autism spectrum disorder, comprising administering a composition that includes a gamma-aminobutyric acid agonist. In Example 1 of the invention, a 23-year-old female with autism spectrum disorder (height 61'', weight 170 lbs.) was hospitalized and being preparing for port-a-catheter placement to begin T.P.N. for an undetermined period of time to allow total gut rest. Baclofen was prescribed 5 mg tid (three times daily) to improve bowel motility. Within about 24-hours abdominal pain appeared to be resolved and GI motility became functional, allowing oral feeding. Over the next several days and weeks improvements were noted in cognitive and behavioral domains that had been unchanged for over 10 years. Mark F. Bear (Third inventor listed with two co-inventors) is an investigator at the Howard Hughes Medical Institute, and Picower professor of neuroscience at the Massachusetts Institute of Technology. After receiving a BSc degree from Duke University, he received a PhD in neurobiology at Brown. His laboratory is interested in how the brain is modified by experience. He uses a variety of methods (electrophysiological, biochemical, molecular, behavioral, and anatomical) to examine the synaptic modifications that form the neurobiological basis of learning and memory. His work is particularly focused on understanding developmental plasticity in the visual cortex, as well as other forms of experience-dependent synaptic modification in visual cortex and hippocampus. In recent years Dr. Bear has described novel forms of procedural learning in the visual system, and investigated synaptic function in models of fragile x syndrome and other autism spectrum disorders. [10] Seaside Therapeutics Incorporated (original assignee) was the first to identify GABA-B as a drug target in treating fragile x syndrome and autism. Recent studies show that there is deficient inhibitory neurotransmission in fragile x syndrome and autism, and that STX209, a GABA-B agonist, has the potential to normalize this deficiency. Furthermore, modulation of the GABA-B pathway may provide additional therapeutic benefits by indirectly reducing activation of the mGluR5 pathway. [11] Clinical Research Associates LLC (current assignee) is an affiliate of the Simons Foundation (SFARI). Clinical Research Associates’ at SFARI have a goal to better understand the causes of autism, accelerate translational and clinical research, and improve the lives of individuals with autism. [12]

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NUTRIENT SUPPLEMENTS AND METHODS FOR TREATING AUTISM AND FOR PREVENTING THE ONSET OF AUTISM (Walsh et al., Patent number 7,534,450 – May 19, 2009) and (Walsh et al., Patent number 7,232,575 – June 19, 2007) 7,534,450 – Abstract: This describes a method of promoting metallothioneins by administering a copper-free nutrient supplement comprising zinc, vitamin B6, pyridoxal-5'phosphate, vitamin E, vitamin A, vitamin C, selenium, glutathione, taurine and a mixture of amino acids consisting essentially of cysteine, serine, lysine, alanine, glycine, threonine, proline, aspartic acid, asparagine, glutamic acid, methionine, glutamine, isoleucine, and valine. The invention showed since the metallothionein promotion supplement was the notable component that had changed in Matthew’s treatment prior to the improvements, the improvements appear to be a consequence of the Metallothionein Promotion Supplement therapy. Health Research Institute (original assignee) abandoned patent 7,534,450 (Walsh et al.) on May 19, 2013 due to failure to pay the maintenance fee. 7,232,575 –Abstract: This describes a method of treating autism by administering a copper-free nutrient supplement comprising zinc, vitamin B6, pyridoxal-5’-phosphate, vitamin E, vitamin A, vitamin C, selenium, glutathione, taurine, and a mixture of amino acids in amounts effective to promote metallothioneins in said person. The invention showed since the metallothionein promotion supplement was the notable component that had changed in Miles’ treatment prior to the improvements, the improvements appear to be a consequence of the metallothionein promotion supplement therapy. Health Research Institute (original assignee) abandoned Patent 7,232,575 (Walsh et al.) on June 19, 2015 due to failure to pay the maintenance fee. William J. Walsh (first inventor listed with a co-inventor) is founder and President of the Walsh Research Institute. Dr. Walsh authored a book titled, Nutrient Power: Heal Your Biochemistry and Heal Your Brain wherein he writes about healing the brain with nutrient supplements. [13] In an article from CAN latitudes (August 14, 2014) titled, Dr. William Walsh on Autism, OCD, PANDAS, Depression, and Methylation, author William Walsh writes, “Autism is very treatable and complete recovery is possible in young persons whose brains have not completed the early development process. I’ve worked with thousands of patients with an autism spectrum disorder and seen hundreds who achieved full recovery after biochemical therapy and a special diet. Early intervention is essential. We can make more progress in a month with a two-year-old than in six months with an eight-year old. It’s becoming increasingly clear that autism is an epigenetic gene-regulation disorder in which environmental insults alter DNA methylation. Treatment success requires powerful antioxidant therapy, a toxic-free environment, and coping with GI tract problems. I believe the greatest progress can be made with brain-directed therapies that promote development of

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brain neurons and synapses to enable improved cognition, speech, and socialization. My personal favorite is metallothionein-promotion therapy.” [14] In an article from Medical Press (August 31, 2016) titled, Zinc found to reverse brain cell changes in autism, it is written, “Cellular changes in the brain caused by genetic mutations that occur in autism can be reversed by zinc, according to research at the University of Auckland. Too much zinc can be toxic, so it is important to determine the optimum level for preventing and treating autism and also whether zinc is beneficial for all or a subset of genetic changes that occur in Autism patients. This latest work - a joint collaborative effort lead by neuroscientist collaborators in Auckland, America and Germany - was published today in the high impact journal, the Journal of Neuroscience.” [15]

IDENTIFICATION OF ETIOLOGY OF AUTISM (Vojdani, in Patent number 7,252,957 – August 7, 2007) Abstract - This describes a method of detecting antibodies against infectious agents, toxic chemicals, self-tissue or peptide, or dietary proteins. Claim 1 – A method wherein the autistic spectrum disorder is autism. Aristo Vojdani (inventor) is Chief Executive Officer and technical director of Immunosciences Lab Incorporated. An owner of 15 US patents for laboratory assessments, professor Vojdani has published more than 140 articles in scientific journals. He is the CEO and technical director of Immunosciences Lab Incorporated in Los Angeles, CA, and sits on the editorial board of five Scientific Journals. In 2006, he was given the prestigious Herbert J. Rinkel Award by the American Academy of Environmental Medicine (AAEM) for excellence in explaining the techniques of environmental medicine. On November 7, 2009, he was given the Linus Pauling, PhD Award by the American College for Advancement in Medicine. And in October of 2012 he was given the F. R. Carrick Research Institute’s extremely distinguished Lifetime Achievement Award. [16] Immunosciences Lab (original assignee) foundation menu includes vital markers for autoimmunity, Lyme disease, and viral infection. Tailored autoimmune assessments include: The autoimmune profile (basic), the autoimmune profile (comprehensive), and the autoimmune liver disease panel. Viruses, in particular, HHV-6, are some of the major contributing factors in autoimmunity, thus, the addition of HHV-6 IgG and IgM to EBV, CMV, HSV, VZV and measles makes ISL’s viral assessments unique. Borrelia burgdorferi, the infectious agent of Lyme disease, is another known factor associated with autoimmune diseases such as Lyme arthritis and neuroborreliosis. ISL’s patented Lyme Panel A and Panel B, the most sensitive assessment for Lyme disease and other tick-borne infections, is once again available for your clinical practice. The simultaneous detection of biomarkers of autoimmunity along with viral or Borrelia antibodies may assist the practitioner in pinpointing the cause and effect relationship of a disease, which can help to design an effective treatment. [17] Immunosciences Lab Incorporated (current assignee) has protection for US patent 7,252,957 (Vojdani) to January 15, 2025.

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REFERENCES [1] [2] [3] [4] [5]

[6] [7] [8]

[9] [10] [11] [12] [13] [14] [15] [16] [17]

Theoharis Theoharides, LinkedIn Profile, Accessed on August 14, 2016. https://www.linkedin.com/in/theoharis-theoharides-ms-PhD-M.D.-faaaai-67123735. Theta Biomedical Consulting & Development Company Inc., “Home” Accessed August 14, 2016. http://www.thetabiomed.com/default.htm. I. Tsilioni et al., 2015. “Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6” Translational Psychiatry 5, e647; doi:10.1038/tp.2015.142. Allison Foster, LinkedIn Profile, Accessed on August 14, 2016. https://www.linkedin. com/in/allison-foster-5b48207. Gerhard Hofle, Wikipedia, The free encyclopedia, Accessed on August 14, 2016. https://translate.google.com/translate?hl=en&sl=de&u=https://de.wikipedia.org/wiki/Gerhar d_H%25C3%25B6fle&prev=search

Epothilone, “Regeneration of Damaged Neurons Promoted by Cancer Drug” NeuroscieceNews.com, Accessed on August 14, 2016. http://neurosciencenews.com/ neuroscience-terms/epothilone/. Dr. Dominic William Massaro, “Research Professor of psychology” University of California, Santa Cruz, Accessed on August 14, 2016. https://www.coursera.org/ instructor/~337. SharpBrains, 2015. “Advanced Neuromodulation Systems: #2 Holder of Pervasive Neurotech Intellectual Property*“St. Jude Medical Company, Accessed on August 14, 2016. http://sharpbrains.com/blog/2015/05/19/advanced-neuromodulation-systems-stjude-medical-2-holder-of-pervasive-neurotech-intellectual-property/. MedDev Inc, “Home” Accessed on August 14, 2016. http://meddevinc.com/home/. Mark F. Bear, “Principal Investigator” Bear Lab, Accessed on August 14, 2016. http://bearlab-s1.mit.edu/BearLab/people/bear.html. Seaside Therapeutics, “GABA-B pathway” Accessed on August 14, 2016. http://www.seasidetherapeutics.com/gaba-b-pathway/. Clinical Research Associates LLC. SFARI, Accessed on August 14, 2016. https://sfari.org/funding/clinical-research-associates. William J. Walsh, “Better Health Through Biochemistry” Walsh research Institute, Accessed on August 14, 2016. http://www.walshinstitute.org/. Sheila Rogers DeMare, “Dr. William Walsh on Autism, OCD, PANDAS, Depression and Methylation “, ACN latitudes, Accessed on August 14, 2016. http://latitudes.org/drwilliam-walsh-autism-ocd-pandas-depression-methylation/. Medical Press, 2016. “Zinc found to reverse brain cell changes in autism” Accessed on September 1, 2016. http://medicalxpress.com/news/2016-08-zinc-reverse-brain-cellautism.html. Immunosciences Lab Inc, “Aristo Vojdani, PhD, MSc, CEO.” Accessed on August 14, 2016. http://www.immunoscienceslab.com/aboutus.html. Immunosciences Lab Inc, Accessed on August 14, 2016. http://www.immuno scienceslab.com/index.html.

Chapter 6

NATURAL PERSONS

CLENBUTEROL FOR USE IN TREATMENT OF AUTISM (Kobel-Buys, in Patent number 9,364,450 - June 14, 2016) Abstract – This describes clenbuterol for use in the treatment of pediatric autism. Abbreviated Claim 1 - A method of alleviation of symptoms of autism by administering clenbuterol or its salt. The inventor explained that the aim is to provide an efficacious and safe method of alleviation and treatment of autistic symptoms, free of adverse effects. Clenbuterol is a β2-agonist that stimulates adrenergic receptors in muscles and increases metabolism of carbohydrates and fats as well as metabolism and synthesis of proteins in striated muscles. Apart from its known (and applied in treatment) activity on smooth muscles of the bronchial tree and blood vessels, clenbuterol increases the mass and strength of muscles. In Example 1 of the invention, a 4-year old patient with autistic symptoms in the form of disorders of social integration, verbal and non-verbal communication, play disorders and concomitant anxiety, especially when changing environment, was administered clenbuterol at a dose of 1/4 tablet containing 20 mug of clenbuterol once daily for a period of 3-months. After application of the therapy the increased interest in the environment was observed; the child’s contact with surroundings improved and the anxiety symptoms decreased.

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Krystyna Kobel-Buys (inventor) writes, “It has been assumed that clenbuterol, modulating the brain neurotransmitter systems, affects also the endocrine and immunological system. As a result, alleviation of communication disorders and improved contact with surroundings is observed in autistic children. Improved contact with surroundings, better concentration, improved ability to plan a specific task, improved understanding, calming, and reduced psychomotor anxiety were observed during administration of clenbuterol at very small doses to autistic children.” In an article from Health Guidance (2016) titled, What is Clenbuterol, author Dr. Janice Rachael Mae writes “Clenbuterol is a performance enhancing drug that is not a steroid like Dianabol or Anavar. Rather, this is a drug that is commonly used by performance athletes and particularly long-distance runners. Increasingly however, it is being used as a weight loss aid, owing to its ability to increase the metabolism for rapid lipogenesis. Essentially, Clenbuterol is similar to an amphetamine such as speed and can have similar impacts on training regime. The most alarming danger of Clenbuterol though is that it can lead to cardiac hypertrophy. This is the abnormal growth of the heart, which can potentially lead to heart attack and eventually death.” [1] Stowarzyszenie SW Celestyna and Krystyna Kobel-Buys (current assignee) have protection for US patent 9,364,450 (Kobel-Buys) to July 6, 2032.

SPECTRAL LIGHT THERAPY FOR AUTISM SPECTRUM DISORDERS (Davis, in Patent number 9,352,170 - May 31, 2016) Abstract - This describes a spectral color and light therapy system that treats and/or ameliorates the symptoms of autism. The visible colored lights are blue, green, rose pink, and peach. These four colors are provided in a therapy room having light fixtures that can be viewed at the same time. Abbreviated Claim 1 – A Color therapy room comprising four walls which are pale gold in color, an entrance, and a spectral color and light therapy system useful in treating and/or ameliorating the symptoms of an autism spectrum disorder. The inventor (Christine Davis) explained that results have been found to be independent of age, health, or disability and include: improved communication and eye contact; increased appetite and sleep; mental calmness and focus. The inventor further writes, “When using the method of the invention, the changes in behavior and focus are felt within the first fifteen minutes. Without wishing to be bound by theory, it is believed this is due to the light penetration from the optical nerved to the frontal lobes. Color light travels so swiftly that absorption changes the brainwaves, e.g., to one of calm and alert focus. Results have been observed that on two occasions non-verbal individuals have said their first work, and reclusive tendencies developed into socializing within thirty minutes.” The inventor concluded that the assimilation of four colored frequencies mimics natural sunrise and sunset, and has been proven to be indispensable to these individuals and the entire family, resulting in manageability of their challenges. In a communication from The Peace Valley Holistic Center, it is written, “Dr. Davis, focuses on helping adults and children with special needs achieve maximum, lasting wellness

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by giving them the tools to heal their bodies and spirits. She uses many modalities, utilizing over 45 years of research and study in the field of traditional Vitamin Therapy, natural herbal and homeopathic remedies, natural nutrition (w/o pesticides), Color and Light Therapy, Neuro-linguistic-programming, Music Therapy, Shiatsu Collage, and SEF, (Scientific Efficacy of Prayer), QiGong Massage, (a needless form of acupuncture), any or the entire above are incorporated on a case by case basis. Dr. Davis has a rich background in vitamin and herbal therapy dating back to her own youth when she could not digest food properly, until her father started to research her allergies to foods, and began a regiment of these therapies. Although she graduated from Philadelphia Business College, while an executive for Tel Ra Productions, she continued her studies in the holistic field, defying the odds that these studies may never be accepted traditionally in 1965. She graduated Magna Cum Laude from the School of Ethical Hypnotherapy, Naples, Fla., received a doctorate in Natural Medicine, from the International School of Holistic Practices, Virginia Beach, Va., doctorate in World Shamanistic Practice, Christ Light Institute, Theological and Ministerial degree, Christ Light Church, Fairfax, W. VA. She has taught for these schools until starting her own practice in 1985. After years of research on the effects of QiGong, color healing, light therapy and mental health, she began explaining her protocol to the Medical community, at Jefferson Hospital, Temple University, Holy Redeemer Hospital, Gwynedd Mercy, Arcadia University, various clinics in the tristate area, and is accredited by the University of Penna. Today Dr. Davis remains focused on her research and therapies in her on-going work to defeat autism, helping all children with special needs, and their families.” [2]

STEM CELL ADMINISTRATION TO REDUCE TNF-Α LEVEL IN CSF OF AN AUTISM SPECTRUM DISORDER OR PERVASIVE DEVELOPMENT DISORDER PATIENT (Chez, in Patent number 9,265,755 – February 23, 2016) Abstract - This describes a method of treating an autism spectrum condition by administering corticosteroid and stem cell preparations to reduce inflammatory markers. Abbreviated Claim 1 - A method for treating an autism spectrum disorder comprising administering a corticosteroid and a stem cell preparation, thereby lowering the elevated ratio of TNF-α in the cerebrospinal fluid. The inventor explained that the treatments have been shown to lower levels of tumor necrosis factor alpha (THF-α) and affect clinical responses in core areas of autism dysfunction including social and language areas. Michael G. Chez (inventor and assignee) is a research pediatric neurologist for the Sutter Institute for Medical Research. In an article from CBR Systems, Incorporated titled, Autism Trial, it is written, “Sutter Neuroscience Institute in Sacramento, California, and Cord Blood Registry have launched the first FDA-regulated clinical trial to assess the use of a child’s own cord blood stem cells to treat select patients with autism. This first-of-its-kind placebocontrolled study is important because 1 in 88 children in the US are diagnosed with autism spectrum disorders each year. The clinical trial will evaluate the ability of an infusion of cord blood stem cells to help improve language and behavior in children with autism. ‘This study

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goes beyond treating symptoms to understanding how stem cells may initiate repair or healing in chronic conditions like cerebral palsy or autism’, stated Dr. Chez, director of pediatric neurology at Sutter Medical Center and principal study investigator. ‘We have evidence to suggest that certain children with autism have dysfunctional immune systems that may be damaging or delaying the development of the nervous system’, continued Dr. Chez. ‘Cord blood stem cells may offer ways to modulate or repair the immune systems of these patients, which would also improve language and some behavior in children who have no obvious reason to have become autistic.’” [3]

METHODS FOR TREATING GASTROINTESTINAL DISORDERS ASSOCIATED WITH PARKINSON’S DISEASE, AUTISM, DIABETIC GASTROPARESIS (Borody, in Patent number 9,095,545 – August 4, 2015) Abstract - This describes a method of treating or substantially ameliorating a gastrointestinal disorder, wherein the gastrointestinal disorder is alternating constipation and diarrhea in an autism spectrum disorder. Abbreviated Claim 9 - The method of treating or substantially ameliorating a gastrointestinal disorder comprising administering an anti-Clostridial agent, wherein the gastrointestinal disorder is constipation alternating at times with a diarrhea in an autism spectrum disorder. In Example 4 of the invention, an 8-year-old male with constipation alternating at times with diarrhea with autism spectrum disorder was commenced on Vancomycin 250 mg twice daily together with Naloxone hydrochloride 10 mg twice daily. After 3-weeks of treatment the constipation was completely resolved but in addition his behavior and lethargy changed. He became affectionate and relatively calm, achieving toilet retraining which he had never previously achieved. His vocabulary began to increase quite rapidly, his on task performance, compliance with parental requests and awareness of surroundings improved quite quickly and he was engaging in positive activities. Repetitive and self-stimulatory behaviors were reduced. Thomas Julius Borody (inventor and assignee) received degrees in science and medicine from the University of New South Wales in the mid-1970s and then worked for nine years at St Vincent’s Hospital in Sydney before undertaking postgraduate research at Sydney’s Garvan Institute of Medical Research and at the Mayo Clinic. He received a PhD in medicine in 1984. [4] In a communication from The Probiotic Therapy Research Centre (PTRC), it is written, “PTRC was established by Prof. Thomas Borody, gastroenterologist and director of the Centre for Digestive Diseases (CDD). Professor Borody originally conceived the idea for creating such a centre in the year 2000. He wanted to provide new alternative treatments for patients who suffer from gastrointestinal problems using faecal microbiota transplantation.” [5]

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HERBAL-BASED COMPOSITIONS FOR ALLEVIATING SYMPTOMS ASSOCIATED WITH AUTISM (Hatipoglu et al., Patent number 8,828,453, September 9, 2014) Abstract - This describes a compositions comprising passiflora extracts that may improve neurological and behavioral symptoms associated with pervasive developmental disorders. Abbreviated Claim 13 - The method of claim 10, wherein the pervasive developmental disorder is autism. The inventors explained that the herbal-based compositions have an endocannabinoid agonist-antagonist effect. In Example 2 of the invention, patients with autism were treated with a formulation comprising passion flower extract. The formulation (capsule) included a combination of 500 mg blend of purified of Passiflora Incarnata extract (400 mg); Passiflora Coerulea extract (90 mg) and Passiflora Edulis extract (10 mg). A parent or caregiver evaluated the child’s behavior and symptoms during the course of treatment. In both cases, parents reported improvements in personality, mood, self-control, empathy, and social functioning, reduced sensitivity to sound, better sleep patterns, decreased aggressiveness, improved attention span and eye contact, lessened hyperactivity. Betul Hatipoglu (first inventor listed with a co-inventor) is a staff member in the Department of Endocrinology, Diabetes and Metabolism at Cleveland Clinic’s main campus, having accepted that appointment in 2008. Prior to that appointment, she was an assistant professor of medicine and medical director for pancreas and islet cell transplant program at the University of Illinois at Chicago for nearly eight years. Her clinical interests include diabetes, thyroid disease in woman and pituitary and adrenal disorders and alternative medicine. Dr. Hatipoglu received her medical degree from Istanbul Medical School. She completed an internal medicine residency and chief residency at Michael Reese-University of Illinois at Chicago and an endocrinology fellowship at the University of Illinois at Chicago. For four consecutive years 2004, 2005, 2006 and 2007 she received the Excellence in explaining award from University of Illinois at Chicago Department of Medicine. Dr. Hatipoglu speaks three languages -- English, Turkish and French -- and is board certified in Internal Medicine as well as Endocrinology, Diabetes and Metabolism. She is a member of the Endocrine Society, American Diabetes Association, American College of Medicine and the American Association of Clinical Endocrinologists. [6] In an article from Mother Earth Foods (2014) titled, your source for healthy eating, it is written, “Dr. Hatipoglu has a son with severe autism. Her desire was a simple one; Find help for her son without side effects or personality altering medications. Her quest for a natural and effective solution led her on a journey of discovery that she shared with Pharmacist Randy Margrave. His background in research motivated Randy to dig deeper into the discoveries that Dr. Hatipoglu had made. He quickly saw the benefit of Passiflora and began encapsulating an herbal blend based on the information Dr. Hatipoglu had given him. The results were even better than expected. That herbal composition became known as Anandanol and was granted US patent 8,828,453 in September 2014.” [7]

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Betul Hatipoglu and Randolph Margrave (assignee) have protection for US patent 8,828,453 (Hatipoglu et al.) to September 28, 2031.

HARMONIC AND OVERTONE AUDIO THERAPY FOR AUTISM SPECTRUM DISORDER (ASD) AND REGULATED EMOTIONAL AND PSYCHOLOGICAL DISORDERS (Zimmerman in 8,343,030 – January 1, 2013) Abstract - This describes a therapeutic method and sound recording. Claim 1 - A method for treating autism spectrum disorder (ASD) and related disorders in a patient, comprising the steps of: playing a first harmonic interval for a first duration of at least approximately one minute, wherein the patient having ASD or a related disorder listens to the first harmonic interval on a sound generation device; and playing a second harmonic interval for a second, consecutive duration of at least approximately one minute, wherein the patient having ASD or a related disorder listens to the second harmonic interval on a sound generation device; wherein listening to the first and second harmonic intervals treats the patient’s ASD or related disorder by at least one selected from the group consisting of: increasing the speed of brain synapses; enhancing the communication of the patient’s neural networks; improving motor coordination; speeding up pattern recognition; and a combination thereof. Clifford N. Zimmerman (inventor and assignee) writes,” I have spent the last eight years developing a breakthrough technology in the treatment of autism spectrum disorder. A NeuroVibrational Processor, the US Patented Sound Therapy CD is the first – and only – technology to apply Deep Brain Stimulation via Prolonged Sympathetic Resonance Vibration. Utilizing the center’s own calibrated medical equipment, in 2008, I conducted an extremely successful clinical trial (non IRB approved), for Hypertension, at Emory Johns Creek Hospital. Every single test-subject’s blood pressure was lowered, some by as much as 49 points. The compelling factor was that, when the systolic number needed adjusting – whether an increase or decrease – but the diastolic number did not, that is exactly what happened, the same for the reverse. This is because of the direct cause-and-effect on the NTS (Nucleus Tractus Solitarius). Data and details form this trial are available upon request. Please be assured that this is not any type of ‘new age’ nonsense, it is a completely unique and totally science-based, the only technology that has ever utilized specific frequencies that are purposely all mathematically divisible by each other, resulting in the only technology ever to receive a US Patent which employs ‘Prolonged Sympathetic Resonance Vibration.’ The US Patent is titled, ‘Harmonic and Overtone Audio Therapy for autism spectrum disorder (ASD) And Regulated Emotional and Psychological Disorders.’ The result is the most optimum form of Neuro-Plasticity, the brain’s ability to literally heal itself. This has never been tested on the human brain before. By employing ‘The Scientific Method’, (double-blind studies, placebo, control-group studies, etc.), and utilizing fMRIs, PET scans, blood and chemical analysis, etc., the goal is to prove its scientific and medical efficacy. Some of these benefits will include – but are not in any way necessarily limited to – increases in endorphin levels, such as Serotonin, Dopamine and Norepinephrine, as well as decreases in Cortisol and ACTH levels.

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The ultimate goal, ‘The Holy Grail’, so to speak, is to stimulate and thereby generate tremendous improvement in the Autistic brain’s limbic system, enough to process the electrical currents between the brain’s synapses properly, resulting in a dramatic improvement in alleviating symptomatic autism spectrum disorder. This is because of the effect that it has on the brain’s Neuro-Transmitters, on a sub-atomic level, because all matter is composed of quarks, strings, and ultimately, vibration, thus making this technology the vibration equivalent of Higgs Boson, otherwise known as ‘The God Particle.’ Please understand, on so many technical levels, the magnitude and significance of this historic recording, the first and only one of its kind in existence. Since 1857 (155 years), when Edouard-Léon Scott de Martinville invented the phonautograph – the first device that could record sound waves as they passed through the air – there has never been a recording as ‘technically pure’ as The Sound Therapy CD. The frequencies are accurate to within five decimal places. I have US Trademarked the phrase: ‘The Perfect Recording of the Perfect Sound’, because that is, in fact, exactly what has transpired. Second, the pure frequencies from absolutely pitch-perfect tuning forks are incorporated into a tuning known as “’justified’ or ‘Justification’ tuning, which, for the very first time in audio and recording history, enables a pure Perfect 5th (P5), also known as an ‘Open 5th’, in the exact and precise ratio that Pythagoras formulated: [3 to 2] or [1.5 to 1]. This is uncommon and rare in Western Music and Western Civilization, which utilizes ‘Tempered’ Tuning, in which the polar opposite is true, the frequencies are specifically not mathematically divisible. Therefore, the concept and process which I have the US Patent for, which utilizes Sympathetic Resonance Vibration, is not technically, mathematically or scientifically possible. Third, the correct terminology is actually ‘Prolonged Sympathetic Resonance Vibration.’ This is because normally, when a tuning fork vibrates, the frequencies will continue to vibrate for 2-3 minutes. It has taken over eight years, and 15,000 hours, in order to technically, scientifically and mathematically, stretch those frequencies into an entire 60-minute (two 30-minute tracks), recording. In this process, the ‘integrity’ of the harmonics and the overtones – wherein lies the therapeutically medical value – has been maintained. Again, this has never even been attempted before, let alone successfully accomplished, in the entire history of recording and audio-engineering. This is a monumental technical achievement, and these are the specific resulting patented scientific and technical reasons for the many therapeutic benefits consequently derived upon the human brain. This is the only recording which, through this patented process, achieves maximum Neuro-Plasticity, for the very first time. The resulting benefits for maximum Neuro Health are nothing short of astonishing for the Autistic brain.” [8] Clifford Neil Zimmerman has protection for US patent 8,343,030 (Zimmerman) to October 14, 2030.

METHOD OF TREATING AUTISM USING BRAIN JOGGING SYSTEM (Pennebaker, in Patent number 7,901,211 – March 8, 2011) Abstract - This describes performing mental exercises with computers to treat autism. Claim 1 - A method for the treatment of autism, comprising: providing a first eye movement activity to a user with autism wherein the user with autism responds to a display of

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visual flash stimuli by verbalizing at least a portion of the visual flash stimuli during the first eye movement activity, the first eye movement activity comprising: providing a letter flash activity to the user, wherein a display of letters is presented to the user in lower case and the user is instructed to input the letters displayed in upper case into a computer system; providing a word flash activity to the user comprising a display of words, wherein the user is instructed to respond to the display of words by inputting the words into the computer system if the user achieves a predetermined success threshold for the letter flash activity; and providing a second eye movement activity comprising at least one of: displaying a first word and a definition for the word; and displaying a first word and one or more rhyming words that rhyme with the first word. The inventor discloses that the preferred use of the brain jogging system with an autistic student includes using questions and answers in the eye movement exercises. For example, the question “Is Mary happy today?” is displayed on the left-hand side of the screen and the answer “Mary is happy today.” is displayed on the right-hand side of the screen. In addition, content that reflects a topic of interest to the student, such as cars or trains, is used in the brain jogging exercises. The recommended frequency of use for a student with autism is a maximum of three times a day. Shirley Pennebaker (inventor and assignee) writes in her LinkedIn profile that Brainjogging is a web-based, multisensory (seeing, speaking, hearing) program to help children with learning challenges. The two areas where most children struggle are brain processing speed and working memory. Brainjogging strengthens these areas with exercises that are customized to the child and result in academic, social, and behavioral improvement. Brainjogging was first developed in the 1980’s as a new theory and practice for children with learning disabilities after a visit to Yerkee’s Primary Center! There, Dr. Sue Savage Rumbaugh utilized computer technology to facilitate language in a Bonobo named Kanzi. Based on these findings, Shirley Pennebaker, MEd developed a theory for cognitive processing enhancement to use with children with severe learning disabilities. She began employing the theory and developed Brainjogging, a patented software program utilized to assist individuals in overcoming their learning difficulties. Students utilize this program in their schools and at home. Before it became web-based, students would travel from locations all over the US and several foreign countries as far away as New Zealand, to experience the incredible change that comes from using the Brainjogging application. [9] Shirley M. Pennebaker (current assignee) has protection for US patent 7, 901,211 (Pennebaker) to February 14, 2024.

BED FOR CHILDREN WITH AUTISM OR OTHER SLEEPING DISORDERS (Volk et al., Patent number D554,871 – November 13, 2007) An ornamental design for a bed for children with autism or other sleeping disorders. The inventors (e.g., Mathew A. Volk) market and sell the patented bed at Noah’s World LLC and state, “The patented design of the Noah’s World Autism Sleep Bed is amazing. The wooden construction is finely crafted out of solid wood by co-founder Chris Stupp, who has more than 20 years’ experience as a craftsman and successful business owner. The cushioned

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inside padding is soft to touch and the zippers are strong and resistant to breakage. The exterior of the Noah’s Bed is individually sewn and we use only the strongest materials to maximize the strength and durability of the bed. We have made the best bed we could mostly because we knew our child was going into it. Each bed is individually inspected for quality before it is shipped to you. We’re confident you will get the best bed on the market for autistic children. If you are not completely satisfied with your purchase, please contact us immediately so we can help make it right for you. If we cannot solve your issues or objections, we will gladly refund 100% of your purchase price.” [10] In Noah’s World LLC website titled, Beds that Keep Children Safe - Reimbursement for Your Noah’s World Bed, it is written, “We understand that having a child with autism can be very difficult at times. We truly believe that this bed will change your life by giving you peace of mind knowing that your child is safe during the night. One of the biggest obstacles that prevents families from owning a bed like this is money. Even though we have tried to reduce the cost to make it affordable for everyone, cost may still be an issue. To help get a bed in your home, we have been working with families to get the Noah’s World Bed paid for by Medicaid. How to Apply for Reimbursement for Your Noah’s World Bed; 1. Speak with your child’s Pediatrician regarding your concern for their safety. Explain that they may be awake and active during ‘sleep hours’. If possible, give specific examples of situations where their safety may have been compromised. (i.e., They got out of the house, climbed on furniture, fell down the stairs, etc.); 2. Have your child’s Physician write a letter of medical necessity and/or a prescription for the Noah’s World Bed; 3. Contact your Medicaid/Insurance case manager and request payment for a Noah’s World Bed; 4. As parents or guardian, write a letter to your Medicaid/Insurance Provider describing; o What your life is like now and why you need the bed? o How the bed will solve the concerns listed? o How your child will be safe with the Noah’s World Bed? 5. Ask your child’s therapists and explainers to write a letter as well; 6. In some areas it may be necessary to have your local fire and police departments endorse this bed as safe in case of emergency (With a Noah’s World Bed you will always know where your child is at night); and 7. You may also contact a local Durable Medical Equipment Dealer to help you with this process.” [10]

TREATING AUTISM AND OTHER DEVELOPMENTAL DISORDERS IN CHILDREN WITH NMDA RECEPTOR ANTAGONISTS (Zimmerman, in Patent number 4,994,467 – February 19, 1991) Abstract - This describes a method of treating autism in children by the administration of an N-Methyl-D-aspartate (NMDA) receptor antagonist.

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Abbreviated Claim 1 - A method of treating autism in children comprising the administration of an N-Methyl-D-aspartate receptor antagonist chosen from the group consisting of ketamine, dextromethorphan and pharmaceutically acceptable salts thereof. The inventor explained that ketamine may be increasing (or disinhibiting) activity in the limbic system pathways in the brain of children with autism. The invention showed that the continuous dosage of about 20 mg /12 hr of NMDA receptor antagonist produced improvements in the behavior of the children treated and those improvements remained stable over a period of weeks. Andrew W. Zimmerman (inventor and assignee) received an AB from Princeton and attended medical school at Columbia University, where he received a medical degree in 1970. While at Columbia, he was awarded the E.J. Noble Foundation International Fellowship and the Medical Student Research Award. After training in pediatrics at the University of Michigan, Dr. Zimmerman served as a clinical associate in the developmental and metabolic neurology branch of NINDS at NIH He came to Johns Hopkins in 1974 as a fellow in pediatric neurology, and received a Certificate of Excellence in Explaining from Johns Hopkins University School of Medicine in 1977. He was on the faculty of the University of Connecticut School of Medicine until 1983, and in private practice with Knoxville (TN) Neurology Clinic until 1994. Dr. Zimmerman is a pediatric neurologist at the Kennedy Krieger Institute, with a special interest in behavioral neurology and autism. Dr. Zimmerman is a diplomate of the American Board of Pediatrics, the American Board of Psychiatry and Neurology (special competence in child neurology), and has a continuing education recognition certificate from the American Board of Psychiatry and Neurology. He also received memberships in the American Academy of Pediatrics, the American Academy of Neurology, the Child Neurology Society, the American Medical Association, and the Society for Neuroscience. In 1991, Dr. Zimmerman received an Award for Distinguished Service from the East Tennessee Chapter of the Autism Society of America. Dr. Zimmerman carries out medical evaluations of children and adults with symptoms of autism and other behavioral problems that are neurologically based. Dr. Zimmerman says, “The objective is to understand each child with respect to known neurological and genetic disorders, and to outline other necessary referrals and a treatment plan.” [11] In a communication from the Kennedy Krieger Institute it is written, “Dr. Zimmerman has been interested in research into possible relationships between nervous system disorders and the immune system. A variety of studies have shown that from 30 to 70 percent of children with autism (in different studies) have distinct abnormalities in their immune systems, including decreased immunoglobulins and T cells, as well as altered lymphocyte and natural killer cell functions. However, there is no evidence, as yet, that children with autism have increased susceptibility to infections, or that specific therapies for the immune system can alter their symptoms. Dr. Zimmerman and colleagues recently found that rheumatoid arthritis and other autoimmune disorders are more common than expected in the families of children with autism. This leads to speculation that autoimmune disorders might be a sign of genetic susceptibility to autism. Such a predisposition may act through genes associated with the human lymphocyte antigens, which commonly have specific associations with autoimmune disorders. These genetic effects most likely begin before birth and might be modified by the mother’s, as well as the father’s, genes. This may lead to disruption in normal development of the immune, as well as the nervous, systems in the fetus. It is hoped that a

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better understanding of the links between the developing immune and nervous systems will eventually improve the treatment of persons with autism.” US patent 4,994,467 (Zimmerman) expired on February 19, 2003 due to failure to pay the maintenance fee.

METHOD FOR THE TREATMENT OF AUTISM (Han et al., Patent number 9,138,581 – September 22, 2015) Abstract - This describes a method of acupuncture therapy using transcutaneous acupoint electrical stimulation and electro-acupuncture stimulation with low and high frequency waveforms. Abbreviated Claim 1 - A method of treating autism comprising: step 1, applying a first electrical current stimulation of 30-minutes in the vicinity of the Hegu acupuncture point and the Nei guan acupuncture point, wherein the first electrical current stimulation has a first slow-quick waveform, and the maximum current of the first electrical current stimulation is 310 mA; and step 2, applying a second electrical current stimulation of 30 minutes in the vicinity of the Zusanli acupuncture point, and the Sanyinjiao acupuncture point at opposite side of the patient, wherein the second electrical current stimulation has a second slow-quick waveform, and the maximum current of the second electrical current stimulation is 4-15 mA, wherein the step 1 and step 2 are executed synchronously, wherein a slow-quick waveform is a waveform including alternating low frequency waveforms and high frequency waveforms with the frequency of the low frequency waveforms being lower than the frequency of the high frequency waveforms. The inventors explained the method may actually aim at the etiology in the biological and medical aspects, and results in actual therapeutic significance. In the course of treatment, the method is not found to have any side effects, so it can be used for a long time. The method is non-invasive and painless, and it is acceptable for children, and suitable for family use. The method can obviously improve the symptoms of autism. The clinical manifestations are an increase of passive and active language, an improvement of social interaction-ability, emotion becoming stable, a better sleep (sleep quickly, a long time). In addition, the method is simple and do not need an acupuncturist. Ji-Sheng Han (first inventor listed with five co-inventors) graduated from Shanghai Medical College (1947-1953). He served as professor and head, dept. of physiology, Beijing Medical University (1983-1993). He was director of the Neuroscience Research Institute at Peking University (1993-2003) and was Vice President of the Chinese Society for Neuroscience (1994-1999). [12] In an advertisement from BioBalance LLC (2012) titled, HANS® Places your health in your hands it is written, “It combines the ancient healing technique of acupuncture with modern science and technology. Through adhesive skin electrodes placed on acupoints, gentle electrical stimulation at certain frequencies mobilizes the body’s own natural healing processes to restore biological balance.” A recently published clinical trial (Zhang et al. 2012) indicates that after a 12-week treatment with HANS®, autistic children of certain types (i.e., passive and aloof behavior)

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showed significant improvement over the control group. The changes observed in these children include improved communication, lowered anxiety and better control of emotions. Certain biochemical change was also detected in the HANS® treated group. Most interestingly, such biological change paralleled with behavioral improvements. Treatment with regular 30-minute sessions per day for 2-3 months seems necessary to gain efficacy. Younger patients seem to respond to the HANS® treatment better than the older patients. During the clinical study, most children accepted the treatment. In fact, after the treatment routine was established, some even asked their caregivers for it. The side effects of HANS® therapy for autism are yet to be identified. [13] US patent 9,138,581 (Han et al.) expires on September 24, 2031.

REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

Janice Rachael Mae, “What is Clenbuterol?” Health Guidance, Accessed on August 14, 2016. www.healthguidance.org/entry/17508/1/What-Is-Clenbuterol.html. Christina Davis, “Meet Our Staff” Peace Valley Holistic Center, Accessed on August 14, 2016. http://www.peacevalleyholisticcenter.org/pages/meet_our_staff.html. Autism Trial, Cbr Cord Blood Registry, Accessed On August 14, 2016. http://www.cordblood.com/stem-cell-research/cord-blood-research/autism. Thomas Borody, Wikipedia, the free encyclopedia, Accessed on August 14, 2016. https://en.wikipedia.org/wiki/Thomas_Borody. Probiotic Therapy Research Centre, Probiotic Therapy, Accessed August 14, 2016. http://www.probiotictherapy.com.au/. Betul Hatipoglu, Cleveland Clinic, Accessed on August 14, 2016. http://my.clevelandclinic.org/staff_directory/staff_display?doctorid=9240. Mother earth Foods, Accessed on August 14, 2016. http://shop.motherearthworks. com/daves-top-picks/neural-balance/. The thinking Mom’s Revolution, 2013, Accessed on August 14, 2016. http://thinkingmomsrevolution.com/autism-diagnostic-observation-schedule-ados/. Brainjogging, LinkedIn, Accessed on August 14, 2016. https://www.linkedin.com/ in/brainjogging. Noah’s World LLC. “The Noah’s World Bed is Changing Lives!” Accessed on August 14, 2016. http://noahsworldllc.com/. Andrew Zimmerman, “BIOGRAPHICAL SKETCH” Kennedy Krieger Institute, Accessed on August 14, 2016. https://www.kennedykrieger.org/patient-care/facultystaff/andrew-zimmerman. Ji-Sheng Han, LinkedIn Profile, Accessed on August 14, 2016. https://www.linkedin.com/in/ji-sheng-han-0b83a476. HANS® places your health in your hands, Accessed on August 14, 2016. http://thehanssite.com/#treatment-autism.

Chapter 7

HOSPITALS

METHOD FOR DIAGNOSING AUTISM SPECTRUM DISORDER (Wu et al., Patent number 8,003,326 – August 23, 2011) Abstract - This describes diagnosing and/or predicting an autism spectrum disorder by determining the presence of microdeletions and micro-duplications on chromosomes 15 and 16. Abbreviated Claim 1 - A method for diagnosing a predisposition to an autism spectrum disorder comprising: (a) detecting in nucleic acids the presence of a microdeletion of about 500 kb that is flanked by a micro-duplication of about 100kb to about 147 kb on the chromosome region 16p11.2 between positions 29.5Mb and 30.1 Mb. The inventors explained that there is no single test for ASD and/or autism. In evaluating a child, clinicians rely on behavioral characteristics to make a diagnosis. The present discoveries are useful for making a diagnosis as well as a prediction of the probability and/or likelihood of developing ASD. The invention showed that regions of rare copy-number variation have been identified in families with autism. In addition, there is an association between a microdeletion on chromosome 16 (and the inherited reciprocal duplication) and autism. Both the deletion and the duplication are likely to be mediated by the 147-kb segmental duplication flanking the deleted or duplicated sequence.

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Bai-Lin Wu (first inventor listed with three co-inventors) received the master-ofmedicine degree in medical genetics at Shanghai Medical University, China. Dr. Wu received clinical genetics fellowship training in the Harvard Genetics Training Program. He is a Diplomate of the American Board of Medical Genetics and assistant professor in pathology at Harvard Medical School and Boston Children’s Hospital. [1] Boston Children’s Hospital (original assignee) is located in the Longwood Medical and Academic Area of Boston, Massachusetts. Children’s was ranked number one in eight out of ten clinical specialties by the US News & World Report, and as the nation’s number one pediatric hospital for 2014–15. [2] In a communication from Boston Children’s Hospital titled, Autism: Finding the genes behind the disease, author Michelle Pflumm writes, “In the early 1960s, when karyotyping became available, researchers inspected the chromosomes of people with autism, seeking deleted or duplicated regions that might contain the critical genes. They largely came up empty-handed. Some experts, however, suspected that deletions and duplications were there, but were simply too small to be detected by this technique. With the introduction of chromosomal microarray analysis in 2005, however, researchers could detect deleted or duplicated regions at roughly 100-fold greater resolution. Using chromosomal microarray analysis, the Genetics Diagnostic Laboratory of Boston Children’s Hospital, led by director Bai-Lin Wu, PhD noticed that several patients with a diagnosis of autism spectrum disorders had missing or extra sections of chromosomes 15 and 16. Deletions or duplications of these chromosome regions-15q on chromosome 15 and 16p on chromosome 16-occur in about 1 percent of autistic children. These regions are now under active investigation to zero in on possible causative genes within them. ‘I don’t think we’re going to find one genetic cause that explains 50 percent of autism’, says David T. Miller, MD PhD of the Division of Genetics and the Department of Laboratory Medicine, a coauthor on these studies. ‘It’s going to be an incremental process. Even if it’s 1 percent at a time, that’s still progress.’” [3]

DIAGNOSIS OF AUTISM AND TREATMENT THEREFOR (Shaw, in Patent number 5,686,311 – November 11, 1997) Abstract - This describes a method of detecting autism-related compounds and correlating the quantity of the compound with an autism condition. Abbreviated Claim 1 - A method of detecting autism-related compounds in a patient comprising: obtaining a sample of a body fluid selected from the group consisting of urine, blood, saliva and cerebral spinal fluid; analyzing the sample to determine the quantity therein of at least one compound selected from the group consisting of citramalic acid, 5-hydroxymethyl-2-furoic acid, 3-oxo-glutaric acid, furan-2,5-dicarboxylic acid, tartaric acid, furancarbonylglycine, arabinose, dihydroxyphenylpropionic acid, carboxycitric acid and phenyl carboxylic acid; and correlating the quantity of the compound with an autism condition or lack thereof. The invention also explained treating autistic patients with antifungal drugs in order to ameliorate the clinical symptoms of autism.

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In Example 3 of the invention, the parents of the autistic patients also reported some amelioration of the symptoms of autism in the treated patients including decreased hyperactivity, better sleep patterns, less stereotypical behavior, better eye contact, increased socialization, more and better vocalization, and increased concentration and focus. William Shaw (inventor) is an American chemist, autism researcher and founded the Great Plains Laboratory based in Lenexa, Kansas. Shaw began studying autism in 1993, and has contended that acetaminophen may be a major cause of autism, a hypothesis which he advanced in a paper published in 2013 in the Journal of Restorative Medicine. Shaw has also contended that yeast infections may also cause autism, and has also endorsed chelation therapy as an autism treatment. Another topic Shaw has researched has been the excretion of certain metabolites of clostridia bacteria, such as 3-(3-hydroxyphenyl)-3-hydroxypropionic acid. This research has concluded that autistic children excrete higher levels of this compound, and that antibiotics may therefore be useful as an autism treatment. Shaw is the author of “Biological Treatments for Autism and PD.” [4] Children’s Mercy Hospital (original assignee) is a comprehensive pediatric medical center in Kansas City, Missouri that integrates clinical care, research and medical education to provide care for patients ages birth to 21. The Great Plains Laboratory Incorporated (current assignee) is a world leader in providing testing for metabolic, genetic, mitochondrial, and environmental factors in chronic illnesses. We offer a variety of state-of-the-art metabolic and genetic tests such as the Organic Acids Test, GPL-TOX (Toxic Organic Chemical Profile), IgG Food Allergies Test, and GPLSNP1000, our DNA Sequencing Profile. Our ultimate goal is to help you provide your patients with the most personalized medicine possible and improve their quality of life. [5] In a communication from Great Plains Laboratory (December 6, 2015) titled, Laboratory Testing for Autism: A Parent’s Perspective, author Terri Hirning writes, “Lab testing can be a critical piece to understanding and treating the underlying biomedical issues related to autism. As a parent, you have many things to consider when evaluating lab testing, including cost, method of testing (whether it is blood, urine, hair, or saliva), usefulness, and the possible benefits of it. Understanding these aspects of testing is important for parents to make informed decisions about whether to test and what to test.” [6]

TOURETTE SYNDROME, AUTISM AND ASSOCIATED BEHAVIORS (Comings, in Patent number 5,405,943 – April 11, 1995) Abstract – This describes a genetic test for autism by identification of deletions, duplications and other defective alleles of the human tryptophan oxygenase (TO) gene. The inventor explained that tryptophan 2,3 dioxygenase (i.e., tryptophan oxygenase) is the rate-limiting enzyme in the catabolism of tryptophan, the precursor of serotonin. A mutation that results in decreased activity of the TDO2 can decrease catabolism of tryptophan and increase the level of whole body serotonin. David E. Comings (inventor) was the director of the Department of Medical Genetics at the City of Hope National Medical Center for 37 years before retiring in 2002. Dr. Comings was past editor of the American Journal of Human Genetics and past President of the

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American Society of Human Genetics. He is an internationally known scientist-physician who has written over 470 scientific articles and four books. [7] City of Hope (current assignee) is a private, not for profit clinical research center, hospital, and graduate medical school located in Duarte, California. [8] In the book titled, The Gene Bomb (1996), author Dr. Comings writes, “Higher education and advanced technology may unintentionally favor the selection of genes that increase the likelihood of ADHD, autism, drug addiction, learning disorders, and behavior problems.” [9]

REFERENCES [1] [2] [3]

[4] [5] [6]

[7] [8] [9]

Bai-Lin Wu, “Co-Founder and Medical Director” Claritas Genomics, Accessed on August 15, 2016. http://claritasgenomics.com/leadership/bai-lin-wu-PhD-facmg. Boston Children’s Hospital, Wikipedia, the free encyclopedia, Accessed on August 15, 2016. https://en.wikipedia.org/wiki/Boston_Children%27s_Hospital. Michelle Pflumm, “Research + Innovation, Autism: Finding the genes behind the disease” Boston Children’s Hospital, Accessed on August 15, 2016. http://www.childrenshospital.org/research-and-innovation/research/divisions/geneticsand-genomics/genetics-and-genomics-stories/autism. William Shaw, Wikipedia, the free encyclopedia, Accessed on August 15, 2016. https://en.wikipedia.org/wiki/William_Shaw_(autism_researcher). Great Plains Laboratory Inc, “Website,” Accessed on August 15, 2016. http://www.greatplainslaboratory.com/. Great Plains Laboratory Inc, “LABORATORY TESTING FOR AUTISM: A PARENT’S PERPECTIVE,” Accessed on August 15, 2016. http://www.great plainslaboratory.com/upcoming-webinars/2015/12/16/laboratory-testing-for-autism-aparents-perpective. David E. Comings, “Carlsbad Science Foundation,” Wikigenes, Accessed on August 15, 2016. https://www.wikigenes.org/e/author/e/253088.html. City of Hope, “Homepage,” Accessed on August 15, 2016. http://www.city ofhope.org/homepage. The Gene Bomb, Wikipedia, the free encyclopedia, Accessed on August 15, 2016. https://en.wikipedia.org/wiki/The_Gene_Bomb.

Chapter 8

NON-PROFITS

DETERMINATION OF DECREASED METABOLISM OF TRYPTOPHAN IN DIAGNOSIS OF AUTISM SPECTRUM DISORDERS (Schwartz et al., Patent number 9,164,106 – October 20, 2015) Abstract - This describes a method of diagnosis for autism spectrum disorders by the ability of the cells to properly metabolize tryptophan. Abbreviated Claim 1 - A method for diagnosing an autism spectrum disorder comprising: deriving lymphoblastoids or leukocytes; culturing the cell sample wherein the only energy source comprises tryptophan; and determining the presence or quantity of a nicotinamide adenine dinucleotide. The inventors explained that a decrease in the quantity of nicotinamide adenine dinucleotide (NADH) is an indication of an autism spectrum disorder. The invention confirmed the lower production of NADH in the patients as compared to controls. Charles E. Schwartz (first inventor listed with a co-inventor) research interests have focused on the causes of intellectual disabilities and birth defects. Most recently, we utilized a metabolic platform developed by Biolog, Incorporated (Hayward, CA) to determine cells from patients with ASD fail to utilize tryptophan as efficiently as controls. In 2003, Dr. Schwartz received the Robert Guthrie Award for advances in biochemical and molecular genetics. [1]

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Greenwood Genetic Center Incorporated (current assignee) has protection for US patent 9,164,106 (Schwartz et al.) to July 29, 2033. In a communication (June 5, 2013) from The Greenwood Genetic Center Incorporated, it is written, “Researchers at the JC Self Research Institute of the Greenwood Genetic Center (GGC), along with collaborators from Biolog Incorporated in California, have reported an important discovery in the understanding of autism which was published this week in Molecular Autism. The study, led by GGC’s director of research, Charles Schwartz, PhD and staff scientist, Luigi Boccuto, MD found that individuals with an ASD showed significantly decreased metabolism of the amino acid L-tryptophan when compared to both typical controls and individuals with other neurodevelopmental disorders. Cells from individuals with autism metabolized L-tryptophan at a decreased rate whereas cells from individuals without autism did not show this change. Researchers also measured the expression of genes that are known to be involved in L-tryptophan metabolism in a small subset of patients with autism and found they also expressed some of the genes at lower levels than those without autism. ‘The important and immediate implication of this work is the development of a simple, early blood screening test for autism by measuring the metabolism of L-tryptophan using Biolog’s technology’, shared Dr. Boccuto. Biolog’s assay method, called Phenotype MicroArray technology, allows researchers to measure the ability of cells to generate energy from various biochemical nutrients, including L-tryptophan. Currently there are no laboratory tests that can accurately diagnose an ASD, which are estimated to affect 1 in 50 school-aged children in the US Current diagnosis depends upon a developmental evaluation and parent interviews and can often not be made prior to 2-3 years of age. ‘A screening, and eventually, a diagnostic blood test for autism would be of immense value to families’, explained Dr. Schwartz. ‘An early, accurate diagnosis is key to providing effective and timely therapies for these patients and their families.’ Dr. Boccuto added, ‘We also see tremendous potential that these findings will aid in our understanding of the molecular and metabolic bases of autism. Once we have a clear vision of what has gone awry within the tryptophan metabolism pathways, we can develop therapies to target and correct those problems at the biochemical level.’ L-tryptophan is one of twenty amino acids used by cells to make protein. It is one of eight amino acids that cannot be made by the body, so it must be obtained from the diet. More importantly, Ltryptophan plays an important role in brain development and function as it is the precursor of key neurochemicals such as serotonin and melatonin which have already been linked to behavioural and neurodevelopmental problems. ‘This discovery leads us toward a possible unifying biochemical mechanism for ASD which could ultimately lead to a treatment’, shared Dr. Schwartz. ‘Now that we have additional evidence that the features of ASD may be related to the metabolic pathways involving L-tryptophan, we can focus further studies on determining at what point along those pathways the disruption occurs, which may vary from one patient to another. With treatments that target various points along the pathway, a modality that works for one patient may not work for another.’” [2] In a paper from Molecular Autism (June 3, 2013) titled, Decreased tryptophan metabolism in patients with autism spectrum disorders, it is written, “Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural precursor of NAD+, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity of the immune system.

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Therefore, decreased tryptophan metabolism may alter brain development, neuro-immune activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying biochemical basis for ASD and perhaps an initial step in the development of a diagnostic assay for ASD.” [3]

METHODS AND COMPOSITIONS FOR TREATMENT OF AUTISM (Talalay et al., Patent number 8,937,050 – January 20, 2015) Abstract – This describes methods and compositions for treating an autism spectrum disorder. Abbreviated Claim 1 - A method of treating an autism spectrum disorder by administering a composition comprising a sulforaphane, a sulforaphane dithiocarbamate, or combination thereof. The inventors explained that what is needed is a mechanism-based strategy that targets the intrinsic cellular stress response and modulates the metabolic defects that contribute to the symptomatology of autism spectrum disorders. Paul Talalay (first inventor listed with two co-inventors) is the John Jacob Abel distinguished service professor of pharmacology and director of the Laboratory for molecular sciences at Johns Hopkins School of Medicine in Baltimore, Maryland. [4] The Kennedy Krieger Institute Incorporated is a nonprofit, 501(c)(3) tax-exempt, Johns Hopkins affiliate located in Baltimore, Maryland that provides inpatient and outpatient medical care, community services, and school based programs for children and adolescents with learning disabilities. The Kennedy Krieger Institute Incorporated (current assignee) has protection for US patent 8,937,050 (Talalay et al.) to April 12, 2033. [5] In a paper from the Proceedings of the National Academy of Sciences (October 28, 2014) titled, Sulforaphane treatment of autism spectrum disorder (ASD), it is written, “In a placebocontrolled, randomized, double-blind clinical trial, daily oral administration for 18-weeks of the phytochemical sulforaphane (derived from broccoli sprouts) to 29 young men with an autism spectrum disorder (ASD) substantially (and reversibly) improved behavior compared with 15 placebo recipients. Behavior was quantified by both parents/caregivers and physicians by three widely accepted measures. Sulforaphane, which showed negligible toxicity, was selected because it upregulates genes that protect aerobic cells against oxidative stress, inflammation, and DNA-damage, all of which are prominent and possibly mechanistic characteristics of ASD.” [6] In a communication from Johns Hopkins Medicine (October 13, 2014) titled, Chemical Derived from Broccoli Sprouts Shows Promise in Treating Autism, it is written, “Researchers say that many of those who received a daily dose of the chemical sulforaphane experienced substantial improvements in their social interaction and verbal communication, along with decreases in repetitive, ritualistic behaviors, compared to those who received a placebo. ‘We believe that this may be preliminary evidence for the first treatment for autism that improves symptoms by apparently correcting some of the underlying cellular problems’, says Paul Talalay, MD professor of pharmacology and molecular sciences, who has researched these vegetable compounds for the past 25 years.” [7]

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DETERMINING A PROBABILISTIC DIAGNOSIS OF AUTISM BY ANALYSIS OF GENOMIC COPY NUMBER VARIATIONS (Wigler et al., Patent number 8,554,488 – October 8, 2013) Abstract - This describes a method of determining whether a patient is autistic by a segmented genomic profile using representational oligonucleotide microarray analysis (ROMA). The inventors explained that identifying one or more specific genomic segments and their relative copy number can correlate with a clinical outcome. The invention showed that a deletion of a region in the chromosome band 2q37.3 was observed in an autism patient. Jonathan Sebat (third inventor listed with two co-inventors) is chief, Beyster Center for Molecular Genomics of Neuropsychiatric Diseases and an associate professor of psychiatry and cellular and molecular medicine, UCSD. The Sebat laboratory is interested in understanding the molecular basis of neuropsychiatric disorders including schizophrenia, bipolar disorder and autism. We are interested the role of copy number variants (CNVs) in disease. Our approach is to apply advanced mutation-detection methods, including microarray and Next Generation Sequencing technologies, to identify mutations that confer high risk of disease. Further, we are investigating the functional impact of CNVs on genes and corresponding cellular pathways. [8] Cold Spring Harbor Laboratories (original assignee) is a private, non-profit institution with research programs focusing on cancer, neuroscience, plant genetics, genomics and quantitative biology. Cold Spring Harbor Laboratories (current assignee) has protection for US patent 8,554,488 (Wigler et al.) to January 12, 2028. [9] In an article from the Proceedings of the National Academy of Science (June 20, 2007) titled, A Unified Genetic Theory for Sporadic and Inherited Autism, author Michael H. Wigler writes, “Autism is among the most clearly genetically determined of all cognitivedevelopmental disorders, with males affected more often than females. We have analyzed autism risk in multiplex families from the Autism Genetic Resource Exchange (AGRE) and find strong evidence for dominant transmission to male offspring. By incorporating generally accepted rates of autism and sibling recurrence, we find good fit for a simple genetic model in which most families fall into two types: A small minority for whom the risk of autism in male offspring is near 50%, and the vast majority for whom male offspring have a low risk. We propose an explanation that links these two types of families: sporadic autism in the low-risk families is mainly caused by spontaneous mutation with high penetrance in males and relatively poor penetrance in females; and high-risk families are from those offspring, most often females, who carry a new causative mutation but are unaffected and in turn transmit the mutation in dominant fashion to their offspring.” [10]

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METHODS FOR DETERMINING DYSREGULATION OF METHYLATION OF BRAIN EXPRESSED GENES ON THE X CHROMOSOME TO DIAGNOSE AUTISM SPECTRUM DISORDERS (Stevenson et al., Patent number 8,367,417 – February 5, 2013) and (Stevenson et al., Patent number 7,998,744 – August 16, 2011) 8,367,417 – Abstract: This describes alterations in methylation, which can cause one or more genes on the single X chromosome in males to be partially silenced or overexpressed, constitute a predisposition to autism spectrum disorders. 8,367,417 – Abbreviated Claim 1: A method for the diagnosis of an autism spectrum disorder by the cytosine methylation level of corresponding genes. The inventors explained that the various chromosomal alterations and gene mutations currently reported in association with autism indicate the genetically heterogeneous nature of autism and taken together account for only a minority (less than 20%) of cases. Therefore, because of the absence of consistent physical findings in autism and the uncertainty of the diagnosis in the first couple of years of life, a laboratory test that helps diagnose autism at an early age would be desirable. The invention showed that the autistic males were hyper-methylated at a CpG within the promoter region of AVPR2, the gene adjacent to L1CAM, when compared to the control group. 7,998,744 - Abstract: This describes alterations in methylation, which can cause one or more genes on the single X chromosome in males to be partially silenced or overexpressed, constitute a predisposition to autism spectrum disorders. 7,998,744 - Abbreviated Claim 1: A method for determining predisposition of an autism spectrum disorder wherein the finding that three or more of the test X-chromosome genes are either overexpressed or underexpresed determine that the individual is predisposed to or affected with an autism spectrum disorder. The inventors explained that because of the absence of consistent physical findings in autism and the uncertainty of the diagnosis in the first couple of years of life, a laboratory test that helps diagnose autism at an early age would be desirable. Alterations in methylation on the X chromosome, which can cause one or more genes on the single X chromosome in males to be partially or totally silenced or overexpressed, can constitute a predisposition to autism spectrum disorders. The present disclosure is directed to methods for determining whether one or more brain expressed genes located on the X chromosome are hypo-methylated or hyper-methylated and the subsequent predisposition for or diagnosis of ASD. The invention showed that three of the five samples from autistic individuals showed a significant reduction in global DNA methylation along the entire length of the X chromosome compared to normal male controls. Julie R. Jones (second inventor listed with three co-inventors) came to the Greenwood Genetic Center (GGC) as a clinical molecular fellow in 2003. After completing her fellowship, she became assistant director of the Molecular Diagnostic Laboratory and in 2008 assumed the position of director. She has recently taken a new position as director of the

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Clinical Genomic Sequencing Program. In this new role, Dr. Jones’s primary responsibilities include the clinical validation of whole exome sequencing (WES) and the analysis of next generation sequencing data including WES, the Syndromic Autism Panel, and the 2nd Tier Rett/Angelman Syndrome Panel. Her primary research focuses on the dysregulation of methylation of X-linked, brain-expressed genes in males with autism. Dr. Jones is board certified by the American Board of Medical Genetics. She is a member of the American Society of Human Genetics and the American College of Medical Genetics. [11] The Greenwood Genetic Center (original assignee) communicates that although considerable progress has been made in recent decades, the understanding of birth defects and intellectual disabilities is surprisingly limited. In only about half of patients who have intellectual disabilities or significant birth defects can the cause be identified - a necessary first step if prevention strategies are to be developed. Roger E. Stevenson (first inventor listed with three co-inventors) is a senior clinical geneticist/research scientist who has been devoted to the study of birth defects and developmental impairments. He has contributed broadly to the literature on the cytogenetic, metabolic, molecular and environmental causes of these disabilities, authored two editions of the textbook The Fetus and Newly Born Infant, Influences of the Prenatal Environment, and with Dr. Judith Hall produced two editions of Human Malformations and Related Anomalies. He and his colleagues, Charles Schwartz, PhD and Curtis Rogers, MD, authored Atlas of XLinked Intellectual Disability Syndromes (Oxford University Press, 2012). [12] In a related article on DNA methylation from Medical Hypotheses (December, 2015) titled, An epigenetic basis for autism spectrum disorder risk and oral contraceptive use, author Kim Strifert writes, “Oral contraceptives, synthetic hormones created to imitate natural human hormones and disrupt endogenous endocrine function to inhibit pregnancy, may be causing the harmful neurodevelopmental effects that result in the increased prevalence of ASD It is conceivable that the synthetic hormones repeatedly assault the oocyte causing persistent changes in expression of the estrogen receptor β-gene. Ethinylestradiol, a known endocrine disruptor, may trigger DNA methylation of the estrogen receptor β- gene causing decreased mRNA resulting in impaired brain estrogen signaling in progeny. In addition, it is possible the deleterious effects are transgenerational as the estrogen receptor gene and many of its targets may be imprinted and the methylation marks protected from global demethylation and preserved through fertilization and beyond to progeny generations. This article will delineate the hypothesis that ethinylestradiol activates DNA methylation of the estrogen receptor β-gene causing decreased mRNA resulting in diminished brain estrogen signaling in offspring of mothers exposed to oral contraceptives. Considering the detrimental epigenetic and transgenerational effects proposed, it calls for further study.” [13]

HIGH FREQUENCY OF NEUREXIN 1 Β SIGNAL PEPTIDE STRUCTURAL VARIANTS IN PATIENTS WITH AUTISM (Sommer et al., Patent number 7,871,820 – January 18, 2011) Abstract – This describes methods of diagnosing or predicting susceptibility to developing autism by determining the genetic variants of a neurexin-1 gene.

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Abbreviated Claim 1 - A method for predicting susceptibility to autism comprising detecting the presence of a nucleic acid sequence variant of a neurexin 1 β gene and predicting that the individual is susceptible to developing autism by DSM-IV criteria. The inventors explained that mutations located within the gene encoding neurexin-1 have been identified as molecular markers associated with autism and autism-related disorders. The estimated attributable risk is 2 percent. The invention shows that neurexin-1 β missense variants are associated with autism in a case-control study (p