“The distinguished editors have secured contributions from the leading experts in nanomedicine law, business, regulation and policy. This handbook represents possibly the most comprehensive and advanced collections of materials on these critical topics. An invaluable standard resource.”

Gregory N. Mandel, JDPeter J. Liacouras Professor of Law and Associate Dean

Temple University Beasley School of Law, USA

“This is an outstanding volume for those looking to become familiar with nanotechnology research and its translation from the bench to market. Way ahead of the competition, a standard reference on any shelf.”

Shaker A. Mousa, PhD, MBAVice Provost and Professor of Pharmacology, Albany College of Pharmacy, USA

“The editors have gathered the distilled experience of leaders addressing the most salient issues confronted in R&D and translation. Knowledge is power, particularly in nanotechnology translation, and this handbook is an essential guide that illustrates and clarifies our way to commercial success.”

Gregory Lanza, MD, PhDProfessor of Medicine and Oliver M. Langenberg Distinguished Professor

Washington University Medical School, USA

“The title of the handbook reflects its broad-ranging contents. The intellectual property chapters alone are worthy of their own handbook. Dr. Bawa and his coeditors should be congratulated for gathering the important writings on nanotech law, business and commercialization.”

Richard J. Apley, JDChief Patent Officer, Litman Law Offices/Becker & Poliakoff, USA

“It is clear that this handbook will serve the interdisciplinary community involved in nanomedicine, pharma and biotech in a highly comprehensive way. It not only covers basic and clinical aspects but the often missing, yet critically important, topics of safety, risk, regulation, IP and licensing. The section titled ‘Perspectives and Editorials’ is superb.”

Yechezkel (Chezy) Barenholz, PhDProfessor Emeritus of Biochemistry and Daniel Miller Professor of Cancer Research

Hebrew University-Hadassah Medical School, Israel

This handbook examines the entire “product life cycle,” from the creation of nanomedical products to their final market introduction. While focusing on critical issues relevant to nanoproduct development and translational activities, it tackles topics such as regulatory science, patent law, FDA law, ethics, personalized medicine, risk analysis, toxicology, nano‐characterization and commercialization activities. A separate section provides fascinating perspectives and editorials from leading experts in this complex interdisciplinary field.

About the Series EditorDr. Raj Bawa is president of Bawa Biotech LLC, a biotech/pharma consultancy and patent law firm based in Ashburn, VA, USA, that he founded in 2002. He is an entrepreneur, professor, researcher, inventor and registered patent agent licensed to practice before the U.S. Patent & Trademark Office. Trained as a biochemist and microbiologist, he is currently an adjunct professor at Rensselaer Polytechnic Institute in Troy, NY, and a scientific advisor to Teva Pharmaceutical Industries, Israel.

edited by

Pan Stanford Series on Nanomedicine Vol. 2

Raj BawaGerald F. AudetteBrian E. Reese

Baw

aA

udetteR

eese

Handbook of

Clinical Nanom

edicine

Vol. 2Pan Stanford Series on Nanomedicine Vol. 2

Handbook of

Clinical NanomedicineLaw, Business, Regulation, Safety,and Risk

ISBN 978-981-4669-22-1V487

Handbook of

Clinical NanomedicineVol. 2

Published

Vol. 1Handbook of Clinical Nanomedicine: Nanoparticles, Imaging, Therapy, and Clinical ApplicationsRaj Bawa, Gerald F. Audette, and Israel Rubinstein, eds.2016978-981-4669-20-7 (Hardcover)978-981-4669-21-4 (eBook)

Vol. 2Handbook of Clinical Nanomedicine: Law, Business, Regulation, Safety, and RiskRaj Bawa, ed., Gerald F. Audette and Brian E. Reese, asst. eds.2016978-981-4669-22-1 (Hardcover)978-981-4669-23-8 (eBook)

Forthcoming

Vol. 3Immune Effects of Biopharmaceuticals and Nanomedicines Raj Bawa, János Szebeni, Thomas J. Webster, and Gerald F. Audette, eds. 2017

Vol. 4Impact of Nanobiotechnology on the Future of Medicine and Personalized MedicineShaker A. Mousa and Raj Bawa, eds.2017

Pan Stanford Series on Nanomedicine

Series Editor

Raj Bawa

Titles in the Series

for the WorldWind PowerThe Rise of Modern Wind Energy

Preben MaegaardAnna KrenzWolfgang Palz

editors

Pan Stanford Series on Nanomedicine Vol. 2

Handbook of

Clinical NanomedicineLaw, Business, Regulation, Safety,and Risk

Editor

Raj Bawa, MS, PhDPatent Agent, Bawa Biotech LLC, Ashburn, Virginia, USAAdjunct Professor, Department of Biological Sciences Rensselaer Polytechnic Institute, Troy, New York, USAScientific Advisor, Teva Pharmaceutical Industries, Ltd., Israel

Assistant Editors

Gerald F. Audette, PhDAssociate Professor, Department of Chemistry Acting Director, Centre for Research on Biomolecular InteractionsYork University, Toronto, Canada

Brian E. Reese, PhD, JD, MBAPatent Attorney and AssociateChoate, Hall & Stewart LLPBoston, Massachusetts, USA

Published by

Pan Stanford Publishing Pte. Ltd.Penthouse Level, Suntec Tower 3 8 Temasek Boulevard Singapore 038988 Email: editorial@panstanford.com Web: www.panstanford.com

Note from the Series Editor and Publisher

It should be noted that knowledge and best practices in the various fields represented in this handbook (such as patent law, FDA law, regulatory science, toxicology, commercialization, pharmaceutical sciences, etc.) are constantly evolving. As new research and experience broaden our knowledge base, changes in research methods, legal and business practices or medical treatments may become necessary. Therefore, the reader is advised to consult the most current information regarding: (i) various products, technologies or companies featured and (ii) legal, business or commercial information provided. It is imperative that researchers, lawyers, policymakers, physicians and business professionals always rely on their own experience and knowledge in evaluating and using any information, procedures, formulations, legal ideas or assays described herein. To the fullest extent of the law, neither the publisher nor the authors or editors, make any representations or warranties, express or implied, with respect to information presented in this handbook. In this regard, they assume no liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any legal opinions, business methods, products, assay techniques, instructions or ideas presented.

A catalogue record for this book is available from the Library of Congress and the British Library.

Handbook of Clinical Nanomedicine: Law, Business, Regulation, Safety, and Risk

Copyright © 2016 Pan Stanford Publishing Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system now known or to be invented, without written permission from the publisher. For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case, permission to photocopy is not required from the publisher.

ISBN 978-981-4669-22-1 (Hardcover)ISBN 978-981-4669-23-8 (eBook)ISBN 978-981-4316-17-0 (Set, Hardcover)ISBN 978-981-4411-66-0 (Set, eBook)

Printed in the USA

This book is dedicated to my wife and parents for their love and support, my students for their inspiration, and my colleagues for their ethical professionalism.

—Raj Bawa

This book is dedicated to my family for their unflagging support, and to my students who continually inspire me with their curiosity.

—Gerald F. Audette

This book is dedicated to my wife and baby boy for making my life rich, to my parents for their unending support, and to the nanotech innovators who strive to make the world a better place.

—Brian E. Reese

About the Editor and Assistant Editors

The Editor

Raj Bawa, MS, PhD, is president of Bawa Biotech LLC, a biotech/pharma consultancy and patent law firm based in Ashburn, Virginia that he founded in 2002. He is an inventor, entrepreneur, professor and registered patent agent licensed to practice before the US Patent & Trademark Office. Trained as a biochemist and microbiologist, he has been an

active researcher for over two decades. He has extensive expertise in the pharmaceutical sciences, biotechnology, nanomedicine, drug delivery, biodefense, FDA regulatory issues, and patent law. Since 1999, he has held various adjunct faculty positions at Rensselaer Polytechnic Institute in Troy, NY, where he is currently an adjunct professor of biological sciences and where he received his doctoral degree in three years (biophysics/biochemistry). Since 2004, he has been an adjunct professor of natural and applied sciences at NVCC in Annandale, VA. He is a scientific advisor to Teva Pharmaceutical Industries, Ltd., Israel. He has served as a principal investigator of National Cancer Institute SBIRs and reviewer for both the National Institutes of Health and the National Science Foundation. In the 1990s, Dr. Bawa held various positions at the US Patent & Trademark Office, including primary examiner for 6 years. He is a life member of Sigma Xi, co-chair of the Nanotech Committee of the American Bar Association and serves on the Global Advisory Council of the World Future Society. He has authored over 100 publications, co-edited four texts and serves on the editorial boards of numerous peer-reviewed journals, including serving as a special associate editor of Nanomedicine (Elsevier) and an editor-in-chief of the Journal of Interdisciplinary Nanomedicine (Wiley). Some of Dr. Bawa’s awards include the Innovations Prize from the Institution of Mechanical Engineers,

viii

London, UK (2008), the Key Award from Rensselaer’s Office of Alumni Relations (2005) and the Lifetime Achievement Award from the American Society for Nanomedicine (2014).

The Assistant Editors

Gerald F. Audette, PhD, has been a faculty member at York University in Toronto, Canada, since 2006. Currently, he is an associate professor in the Department of Chemistry and acting director of the Centre for Research on Biomolecular Interactions at York University. He received his doctorate in 2002 from the Department of Biochemistry at the

University of Saskatchewan in Saskatoon, Canada. Working with Drs. Louis T. J. Delbaere and J. Wilson Quail (1995–2001), Dr. Audette’s research focused on the elucidation of the protein–carbohydrate interactions that occur during blood-group recognition (in particular during the recognition of O blood type) using high-resolution X-ray crystallography. Dr. Audette conducted his postdoctoral research at the University of Alberta (2001–2006) in Edmonton, Canada. Working with Drs. Bart Hazes and Laura Frost; his research again utilized high-resolution protein crystallography to examine the correlation between protein structure and biological activity of type IV pilins that are assembled into pili used by bacteria for multiple purposes, including cellular adhesion during infection. It was during these studies that Dr. Audette identified the generation of protein nanotubes from engineered pilin monomers. Dr. Audette also studied the process of bacterial conjugation (or lateral gene transfer) using the F-plasmid conjugative system of Escherichia coli. Current research directions include: structure/function studies of proteins involved in bacterial conjugation systems, the structural and functional characterization of several type IV pilins (the monomeric subunit of the pilus), their assembly systems, and adapting these unique protein systems for applications in bionanotechnology. Dr. Audette has previously served as co-editor- in-chief of the Journal of Bionanoscience (2007–2010), and is currently a subject editor of structural chemistry and crystallography for the journal FACETS.

About the Editor and Assistant Editors

ix

Brian E. Reese, PhD, JD, MBA, is an associate at the law firm of Choate, Hall, and Stewart in Boston, Massachusetts since 2012. Dr. Reese has extensive experience in intellectual property law, particularly patenting and trademark issues in the life sciences, and brings a practical knowledge of business strategy to his practice. As a former

stock analyst, Dr. Reese has a strong appreciation for the business realities his clients face and how intellectual property can help them achieve their objectives. Dr. Reese graduated with a BS in cellular biochemistry from the State University of New York at Plattsburgh, where he received the Chancellor’s Award for academic excellence. He subsequently obtained his PhD from Pennsylvania State University for his research in the areas of neuroscience, molecular biology and toxicology. He also completed his MBA at Pennsylvania State University. Dr. Reese attended Albany Law School in Albany, NY, where he graduated magna cum laude. As a trained neuroscientist, Dr. Reese has authored several scientific and legal research papers in peer- reviewed journals. Each year, he moderates the American Bar Association’s panel on science and technology law at the Current Issues in Medicine and Pharma conference held at Rensselaer Polytechnic Institute in Troy, NY. Dr. Reese is active in providing pro bono services in intellectual property for several entities in the Boston area and currently serves as co-chair of the Nanotech Committee of the American Bar Association.

About the Editor and Assistant Editors

Contents

List of Corresponding Authors xxixForeword xxxiiiRacing Ahead: Nanomedicine under the Microscope xxxviiAcknowledgements liii

Section I: Law, Business, and Commercialization

1. An Intellectual Property Primer for Nanomedical Researchers and Engineers 3

Brian E. Reese, JD, PhD, MBA

1.1 Introduction 3 1.2 What Is Intellectual Property? 6 1.3 Closing Comments 34

2. Strategic Intellectual Property Management: Building IP Portfolios 43

Jeffery P. Langer, PhD, JD

2.1 Introduction 43 2.2 Comprehensive Intellectual Property Portfolios 44 2.3 IP Portfolio Strategies 45 2.4 Building the Portfolio 54 2.5 Conclusions 56

3. Extending Patent Term for Nanomedical Inventions: A Nexus between the FDA and the Patent System 61

Susanne M. Hopkins, JD, and Ari G. Zytcer, JD

3.1 Introduction 61 3.2 Medical Nanotechnology: The Beginning 62 3.3 PTE for Medical Devices Utilizing Nanotechnology 64

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3.4 Prophetic Example 67 3.5 Conclusion 68

4. When Patented Technologies Get Put to Experimental Use: Practical Considerations for Nanotech R&D 73

Victor H. Polk, Jr, JD, and Roman Fayerberg, JD

4.1 Introduction 73 4.2 Experimental Use Exception 74 4.3 Available Remedies 76 4.4 Laches Defense 80 4.5 Conclusion 81

5. Bridging Diagnostics Research, Development and Commercialization 85

Rosanna W. Peeling, PhD

5.1 Lack of Access to Diagnostics as a Contributor to the Burden of Infectious Diseases 85

5.2 Role of Diagnostic Tests 86 5.3 Diagnostic Landscape in the Developing World 86 5.4 Lack of International and National Regulatory

Standards for Approval of Diagnostics 88 5.5 The Ideal Diagnostic Tool 88 5.6 Development of Diagnostic Tests 89 5.7 Challenges in the Availability of Quality-Assured

Diagnostic Tests in the Developing World 90 5.8 Opportunities for a Better Future 94 5.9 Bridging Research, Product Development, and

Commercialization 98

6. What the Supreme Court’s Myriad Decision Means for Nanotechnology Patents 103

Andrew S. Baluch, JD, Stephen B. Maebius, JD, and Harold C. Wegner, JD

6.1 Introduction 103 6.2 Background on Patent Eligibility 104 6.3 Patent Office 2001 Policy on Isolated DNA 105 6.4 The Myriad Case 106

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6.5 The Second Trip to the Supreme Court 107 6.6 Impact on Nanotech Patents 108 6.7 Conclusion 109

7. Managing the Expense of Patent Litigation in Nanotechnology 115

Todd G. Vare, JD

8. Technology Transfer: An Overview 123

Bruce D. Goldstein, JD, MS

8.1 Introduction 123 8.2 Agreements to Protect Data 125 8.3 Agreements to Share Materials 127 8.4 Agreements Establishing Collaborations 129 8.5 Agreements to Conduct Clinical Research 130 8.6 License Agreements 131 8.7 Conclusions 135

9. Licensing Issues in Nanotechnology 141

Joanna T. Brougher, JD, MPh

9.1 Introduction 141 9.2 Reasons for Entering into License Agreements 142 9.3 Overview of Intellectual Property Licensing 143 9.4 Best Practices When Entering into a License

Agreement 145 9.5 Potential Issues in Nanotechnology Licensing 148 9.6 International Issues Surrounding Nanotechnology

Licensing 159 9.7 Conclusions 163

10. Commercializing Your Intellectual Property: Steps to Take and Pitfalls to Avoid 167

Inna Dahlin, PhD, JD, and Michael J. Pomianek, PhD, JD

10.1 Introduction 167 10.2 Steps to Take 168 10.3 Pitfalls to Avoid 178 10.4 Takeaways 182

xiv Contents

11. Overcoming Nanotechnology Commercialisation Challenges: Case Studies of Nanotechnology Ventures 187

Elicia Maine, PhD

11.1 Introduction 187 11.2 Case Studies 188 11.3 Analysis of Case Study Commercialisation

Challenges 206 11.4 Approaches to Nanotech Commercialisation

Critical Success Factors 209 11.5 Conclusion 217

12. The Commercialisation of Nanotechnology: The Five Critical Success Factors to a Nanotech-Enabled Whole Product 223

Craig Belcher, MBA, PhD, Richard Marshall, MBA, Grant Edwards, PhD, and Darren Martin, PhD

12.1 Introduction 224 12.2 Nanotechnology Commercialisation Critical

Success Factors 228 12.3 Conclusions 252

13. Overcoming the Odds: How to Incubate Fledging Bioscience Companies 261

Patti Breedlove, MS

13.1 Introduction 261 13.2 The Climate 263 13.3 Learning from Missteps 267

14. Market Opportunity for Molecular Diagnostics in Personalized Cancer Therapy 273

Elemer Piros, PhD, Istvan Petak, MD, PhD, Attila Erdos, MD, John Hautman, JD, and Julianna Lisziewicz, PhD

14.1 Introduction 273 14.2 Targeted Drug Revolution 276 14.3 The $1000 Genome Is Here 276 14.4 Molecular Diagnostics for Targeted Drugs 279

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14.5 Molecular Diagnostics for Targeted Immunotherapy 283

14.6 Conclusions 290

15. Nanotechnology Implications for Labor 303

Noela Invernizzi, PhD, and Guillermo Foladori, PhD

15.1 Nanotechnology and Employment 304 15.2 Analyzing Nanotechnology Impacts on Labor 306 15.3 Conclusions 312

16. Insurance Market Perception of Nanotechnology and Nanomaterials Risks 323

Lijana Baublyte, PhD, Martin Mullins, PhD, Finbarr Murphy, PhD, and Syed A.M. Tofail, PhD

16.1 Introduction 323 16.2 Nanotechnology and Insurance 324 16.3 Research Design 325 16.4 Results 326 16.5 Discussion and Conclusion 330

Section II: Regulatory Issues and Nanogovernance

17. FDA and Nano: Baby Steps, Regulatory Uncertainty and the Bumpy Road Ahead 339

Raj Bawa, MS, PhD

17.1 Introduction 340 17.2 Defining Nanotechnology in the Context of

Medicine: Does Size Matter? 343 17.3 FDA Confronts Nano 348 17.4 Nanoproducts as Combination Products? 368 17.5 Recommendations, Conclusions and Future

Prospects 370

18. EU Regulation of Nanobiotechnology 385

John Quinn, LLM

18.1 Introduction 385 18.2 The European Union Approach 387 18.3 Nanobiotechnology Regulations 389

xvi Contents

18.4 Regulating Nanobiotechnology and the Precautionary Principle 391

18.5 Conclusion 395

Regulating Nanomedicine 401 Shannon G. Fischer, MS

19.1 Introduction 401 19.2 What’s the Problem? 402 19.3 Caution Is Advised 403 19.4 What We Don’t Know Can Hurt Us 404 19.5 Future Tense 406

20. Nanomedicines: Addressing the Scientific and Regulatory Gap 413

Sally Tinkle, PhD, Scott E. McNeil, PhD, Stefan Mühlebach, PhD, Raj Bawa, MS, PhD, Gerrit Borchard, PhD, Yechezkel Barenholz, PhD,

Lawrence Tamarkin, PhD, and Neil Desai, MS, PhD

20.1 Nanomedicine: The Nexus of Medical Research and Nanotechnology 414

20.2 Keynote Address: The Current State of Nanomedicine 415

20.3 Characterization and Safety of Nanomedicines: Lessons Learned from the Nanotechnology Characterization Laboratory 418

20.4 Nanosimilars and Follow-On Nanosized Therapeutics 420

20.5 The FDA’s Approach to the Regulation of Nanotechnology Products 433

20.6 Nanopharmaceuticals in the Post-Blockbuster World: Critical Patent Issues 437

20.7 Addressing the Regulatory Gap of Nanosimilars 440 20.8 Doxil®, the First FDA-approved Nano-Drug:

Experience Gained and Lessons Learned 443 20.9 Using Nanotechnology to Change Cancer Care 447 20.10 Lessons Learned From Albumin-Bound

Nanoparticles 450 20.11 Conclusions and Future Perspectives 453

1

xviiContents

21. Regulation of Combination Products in the United States 471

John Barlow Weiner, JD, and Thinh X. Nguyen

21.1 Introduction 471 21.2 What Products Are Considered Combination

Products 472 21.3 The Standards for Determining If a Product Is a

Combination Product 472 21.4 The Standards for Determining Which FDA

Component Has Primary Responsibility for Regulating a Combination Product 473

21.5 Requests for Designation 476 21.6 Premarket Review Considerations 476 21.7 Post-Market Regulatory Considerations 478 21.8 Role of Office of Combination Products 480 21.9 Near-Term Developments That May

Arise in the US 480 21.10 International Harmonization and Coordination

Activities with Foreign Counterparts 481 21.11 FDA Resources for Obtaining Additional

Information 481

22. Regulation of Combination Products in the European Union 485

Janine Jamieson, PhD, and Elizabeth Baker

22.1 Introduction: Legal Basis 485 22.2 Combination Products Regulated as Medicinal

Products 490 22.3 Drug-Delivery Products Regulated as Medical

Devices 491 22.4 Combination Products Regulated as Devices

Incorporating, as an Integral Part, an Ancillary Medicinal Substance 492

22.5 The Consultation Process 493 22.6 Information to Be Provided on the Ancillary

Medicinal Substance 494 22.7 Other Combination Products 496

xviii Contents

23. Brief Overview of Current Developments in Nanotechnology EHS Regulation in the U.S. 499

Theodore Voorhees, Jr., JD

23.1 Introduction 499 23.2 Standard-Setting 501 23.3 The Role of Standards Compliance in the

Determination of Product Safety 503 23.4 Regulation of Existing and New Nanoscale

Substances by the EPA 504 23.5 Regulation by Category or by Case 507 23.6 The Role of Regulatory Compliance in the

Determination of Product Safety 508 23.7 Conclusion: No Meaningful Judicial Guidance

Yet on Nanotechnology ESH 508

24. EPA Targets Nanotechnology: Hi-Ho, Nanosilver, Away? 515

David L. Wallace, JD, and Justin A. Schenck, JD

24.1 Introduction 515 24.2 The Case of the Accidental Pesticide Retailer 516 24.3 Nanotechnology and FIFRA: Nomenclature Over

Matter? 517 24.4 EPA’s About-Face on FIFRA Registration 518 24.5 A Fork in the Road 520 24.6 Is Nanosilver Really Something New Under the

Sun? 521 24.7 A Cautionary Tale: The Pathway Saga 522 24.8 The Silver Lining in Pathway’s Cloud 523 24.9 Conclusions 526

25. Graphene: Regulatory Considerations for the “Wonder Material” 535

Matthew Kaplan, JD, and Jennifer Woloschyn, JD

25.1 Graphene: What Is It? 535 25.2 How Is Graphene Regulated? 536 25.3 Regulation Under the Toxic Substances

Control Act 537 25.4 Future Regulation of Graphene? 539

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26. The Enduring Embrace: The Regulatory Ancien Régime and Governance of Nanomaterials in the U.S. 545

Christopher Bosso, PhD

26.1 The Story of a Technology 545 26.2 The Pesticides Revolution 547 26.3 The “Problem” of Nano 550 26.4 Path Dependence in U.S. Environmental Policy 554 26.5 A Path Ahead? 559

Section III: Health, Safety, Risk, and Biological Interactions

27. Safety of Engineered Nanomaterials and Occupational Health and Safety Issues for Commercial-Scale Production 569

Paul F. A. Wright, PhD, and Neale R. C. Jackson, PhD

27.1 Introduction 569 27.2 Overview of Nanotoxicology 571 27.3 Overview of Occupational Health and Safety

Issues and Workplace Controls 593

28. Engineered Nanoparticle Release, Exposure Pathway and Dose, Measures and Measuring Techniques for Nanoparticle Exposure in Air 621

Heinz Fißan, PhD, and Hans-Georg Horn, PhD

28.1 Introduction 621 28.2 ENP Release into Air 624 28.3 ENP Exposure Pathway in Air and Dose 631 28.4 Relevant Measures 635 28.5 Concentration Measurement Techniques 638 28.6 Exposure Measurements 646 28.7 Conclusions and Outlook 649

29. Managing Environmental and Health Risks in the Nanotechnology Industry 659

Joseph Luke Huan, LLB (Hons), MPhil

29.1 Introduction 659 29.2 What Is Nanotechnology and What Are the

Opportunities? 660

xx Contents

29.3 The Environmental Health Risks 663 29.4 The Drivers of Environmental Protection and

Sustainability 664 29.5 Risks to Business and Industry 668 29.6 Corporate Sustainability Strategies to Achieve

Win-Win Outcomes 671 29.7 Conclusions 676

30. Risk Perception and Risk Communication on the Issue of Nanotechnology 683

Gaby-Fleur Böl, PhD, Guido Correia Carreira, PhD, Astrid Epp, PhD, Eva Häffner, PhD, and Mark Lohmann, PhD

30.1 Introduction 683 30.2 Risk Perception of Nanotechnology: Differences

between Experts and Laypeople 686 30.3 The Role of the Media in the Perception of

Nanotechnology Risks 690 30.4 Citizen Involvement and Participation 694 30.5 Risk Communication on New Technologies: Best

Practice 703

31. In vitro Risk Assessment of Nanoparticles 719

Birgit K. Gaiser, Julia Susewind, Nadia Ucciferri, Eva-Maria Collnot, Arti Ahluwalia, and Vicki Stone

31.1 Introduction 719 31.2 Materials 723 31.3 Methods 728 31.4 Notes 738

32. Biological Responses to Nanoparticles 745

Reinhard Zellner, PhD, Julia Blechinger, PhD, Cristoph Bräuchle, PhD, I. Hilger, Andreas Janshoff, PhD, Juergen Lademann, PhD, Volker Mailänder, PhD, Martina C. Meinke, PhD, G. U. Nienhaus, PhD, A. Patzelt, MD, F. Rancan, Barbara Rothen-Rutishauser, PhD, Roland H. Stauber, PhD, A. A. Torrano, PhD, Lennart Treuel, PhD, and A. Vogt

32.1 Introduction 746 32.2 Interactions of Nanoparticles with Proteins 749

xxiContents

32.3 Transfer of Nanoparticles Across Membranes and Cellular Uptake Mechanisms 755

32.4 Trafficking and Intracellular Distribution of Nanoparticles 763

32.5 Impact of Nanoparticles on Biological Functions 769 32.6 Uptake of Nanoparticles by the Lung 775 32.7 Interaction of Nanoparticles with the Skin 781 32.8 Conclusions 789

33. Cell and Protein Interactions with Diamond 809

Roger J. Narayan, MD, PhD, R. D. Boehm, BS, and Nancy A. Monteiro-Riviere, PhD

33.1 Introduction 809 33.2 Interactions with Cells 810 33.3 Interaction with Proteins and Blood Components 815 33.4 Conclusions 817

34. Intracellular Transport and Unpacking of Polyplex Nanoparticles 823

Andrey A. Rosenkranz, PhD, Yuri V. Khramtsov, PhD, Alexey V. Ulasov, PhD, Nikita Rodichenko, and Alexander S. Sobolev, DSci, PhD

34.1 Introduction 823 34.2 Optimization of Polyplexes to Increase Their

Transfection Efficacies 825 34.3 Kinetics of Polyplex Intracellular Transport and

Unpacking 826 34.4 Models of Polyplex Intracellular Transport and

Unpacking 829 34.5 Conclusions 836

35. Complement Activation: A Capricious Immune Barrier to the Clinical Use of Nanomedicines 845

János Szebeni, MD, PhD, DSc

35.1 Introduction 845 35.2 Complement Surveillance with Multivision

Camera and Machine Gun 846 35.3 Complement on Attack against Nanomedicines 849

xxii Contents

35.4 Mechanism of CARPA 853 35.5 Tolerization against CARPA 861 35.6 Summary and Outlook 862

36. Nanotoxicology: Focus on Nanomedicine 873

Helinor Johnston, PhD, Ali Kermanizadeh, PhD, and Vicki Stone, PhD

36.1 Introduction 873 36.2 Nanomedicine and Nanotoxicology 874 36.3 Nanomaterial Physicochemical Properties 877 36.4 Assessment of Nanomaterial Toxicity 885 36.5 Nanomaterial Physicochemical Characterization 888 36.6 Relationship Between Exposure Route and Toxicity 889 36.7 Conclusions 891

37. Toxicity and Genotoxicity of Metal and Metal Oxide Nanomaterials: A General Introduction 901

Mercedes Rey, David Sanz, and Sergio E. Moya

37.1 Introduction 901 37.2 Effect of Different Metal and Metal Oxide

Nanoparticles on the Immune Response 904 37.3 Metallic Nanoparticles and Their Interactions

with Plasma Proteins 914 37.4 Intracellular Signaling Pathways Activated by

Metallic Nanoparticles 915 37.5 Genotoxic Studies on NMs 917 37.6 Conclusions 922

38. Toxicity of Silicon Dioxide Nanoparticles in Mammalian Neural Cells 931

James C. K. Lai, PhD, Ashvin R. Jaiswal, MS, Maria B. Lai, MS, Sirisha Jandhyam, MS, Solomon W. Leung, PhD, and Alok Bhushan, PhD

38.1 Introduction 931 38.2 Nanoparticles Can Cross the Blood–Brain Barrier 932 38.3 Toxicity of Silicon Dioxide Nanoparticles in

Mammalian Neural Cells 933

xxiiiContents

38.4 PathophysiologicalImplicationsofToxicityofSiliconDioxideNanoparticlesinMammalianNeuralCells 946

38.5 ConclusionsandProspectsforFutureResearch 948

Section IV: Future Implications, Ethics, Perspectives, and

Editorials

39. Future Concepts in Nanomedicine 961

Rob Burgess, PhD

39.1 Introduction 961 39.2 NanoroboticsandMedicine 962 39.3 PersonalizedNanomedicine 982 39.4 Nanonephrology 986 39.5 NanoneuralInterfaces 988 39.6 OpticalImagingattheNanoscale 989 39.7 ArtificialIntelligenceand“TheSingularity” 991

40. Is Translational Medicine the Future of Therapy? 997

Christopher-Paul Milne, PhD, and James Mittra, PhD

40.1 WhatDoestheFutureHoldforTranslationalMedicine? 997

40.2 FixingtheR&DParadigm 998 40.3 Patient-CenteredHealthcare 1000 40.4 TheGeographyofChange 1004 40.5 TheFutureofTherapy 1005

41. Nanomedical Cognitive Enhancement: Challenges and Future Possibilities 1013

Melanie Swan, MBA

41.1 Introduction 1013 41.2 Nanopharmaceuticals 1015 41.3 NeuralElectrodes 1017 41.4 Brain–MachineOrganic–InorganicInterfacing 1019 41.5 NeuralCellGrowthPromotion 1020 41.6 NanoroboticRemovalofNeuralLipofuscin 1021 41.7 Conclusion 1024

xxiv Contents

42. Nanomedicine: Ethical Considerations 1031

Todd Kuiken, PhD

42.1 Introduction 1031 42.2 Personalized Medicine 1035 42.3 Ethical and Policy Implications Surrounding

Nanomedicine 1038 42.4 Ethical Dilemma: Is Anything New or Unique to

Nanomedicine? 1044 42.5 Conclusions 1048

43. Clinical Nanobioethical Problems: A Value Approach 1057

Jorge Alberto Álvarez-Díaz, MD, PhD

43.1 From Nanoethics and Bioethics to Clinical Nanobioethics 1057

43.2 What Is (and What Is Not) an Ethical Problem? 1060 43.3 A Foundation for Ethics: The Experience of

Obligation 1061 43.4 A Methodology to Propose Solutions for

Ethical Problems: Deliberation 1068

44. Nanomedicine: Shadow and Substance 1081

Z. Shadi Farhangrazi, PhD, and S. Moein Moghimi, PhD

44.1 Perspective: A View from Outside the Box 1081 44.2 Creative Yet Realistic Path 1085

45. The Tower of Babel: Miscommunication within and about Nanomedicine 1091

Rudolph L. Juliano, PhD

45.1 Introduction 1091 45.2 Nanomedicine and the Communication Issue 1093 45.3 Conclusions 1097

46. Is Nanotechnology Toxic? Was Prince Charles Correct? 1101

Pelagie M. Favi, PhD, and Thomas J. Webster, PhD

46.1 Introduction 1101 46.2 Toxicity: Impact of Nanotechnology on Health

and Environment 1103

xxvContents

46.3 Social Impact of Nanotechnology 1106 46.4 The Challenge: Translation of Academic and

Industrial Discoveries into Commercialized Products 1107

46.5 Conclusions 1108

47. The Audience Is the Message: Nanomedicine as Apotheosis or Damnatio Memoriae 1117

David M. Berube, PhD

47.1 Introduction 1117 47.2 Development of Nanomedicine 1119 47.3 The Mediated Status Quo 1120 47.4 Public Understanding of Nanomedicine 1122 47.5 Establishing Risk Signatures 1123 47.6 Choice and Nanomedicine 1125 47.7 Choosing to Choose 1126 47.8 Nanomedicine Engagement 1127 47.9 Apotheosis 1130 47.10 Damnatio Memoriae 1131 47.11 Conclusions 1133

48. A Sample of Religious Thought on Nanotechnology 1141

Chris Toumey, PhD

48.1 Introduction 1141 48.2 Synoptic Statements on Religion and

Nanotechnology 1145 48.3 Conclusions 1156

49. Iron Oxide Nanoparticles for Treatment of Anemia of Chronic Kidney Disease: Too Much of a Good Thing? 1163

Amy Barton Pai, PharmD

49.1 Introduction 1163 49.2 Structure and Biodistribution of Intravenous

Iron Formulations 1164 49.3 Adverse Safety Signals from in vitro, Animal,

and Human Studies 1166

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50. Perspectives on Legal Challenges in the Development and Commercialization of Nanotechnology 1175

Annette I. Kahler, JD

50.1 Introduction 1175 50.2 Definitional Challenges 1176 50.3 The National Nanotechnology Initiative 1177 50.4 Background on Federal Nanotechnology

Legislation 1178 50.5 Health, Safety, and Environmental Concerns

about Nanotechnology 1178 50.6 Challenges for Patent Protection of

Nanotechnology 1181 50.7 Conclusions and Future Implications 1184

51. Nanomedicine and the Fight against HIV/AIDS: Expert Perspectives 1191

André Nel, MBChB, PhD, Susan Swindells, MD, Tatiana Bronich, PhD, and Howard E. Gendelman, MD

52. Interdisciplinary Nanomedicine Publications through Interdisciplinary Peer-Review 1223

Andrew Owen, PhD, Steve P. Rannard, DPhil, Raj Bawa, MS, PhD, and Si-Shen Feng, PhD

53. Nanopharmaceutics Innovations in Gene Therapy: Moving towards Non-Viral and Non-Invasive Delivery Methods 1239

Marianna Foldvari, PhD, DPharmSci

54. Recent Developments in Ocular Nanotherapy: An Editorial 1245

Kislay Roy, PhD, and Jagat R. Kanwar, MSc, PhD

55. The Promise of Nanoneuromedicine: An Editorial 1253

Howard E. Gendelman, MD, R. Lee Mosley, PhD, Michael D. Boska, PhD, and JoEllyn McMillan, PhD

55.1 Defining Nanoneuromedicine 1254 55.2 Nanoneuromedicine and Bioimaging 1255

xxviiContents

55.3 Targeted Therapy and Toxicology of Nanoneuromedicines 1257

55.4 Diseases of the Nervous System: New Opportunities for Nanoneuromedicine 1258

56. Principles of Nanoethics: Theoretical Models and Clinical Practice 1269

Mario Ganau, MD, PhD, Lara Prisco, MD, Nikolaos Syrmos, MD, and Laura Ganau

56.1 Principles of Nanoethics 1269 56.2 The Evolving Art of Nanomedicine 1270 56.3 Risk Assessment and Nanoethics 1271 56.4 Developing a Nanoethical Framework 1272 56.5 Human Enhancement 1274 56.6 Conclusion 1275

57. The Tree and the Forest: A Need for Dialogue and a Collaborative Approach in the Safety of Nanomedicines 1281

Hassan A. N. El-Fawal, MSc, PhD

57.1 Introduction 1281 57.2 Tree Huggers 1282 57.3 Embracing the Forest 1284

58. The Translational Challenge in Medicine at the Nanoscale 1291

Raj Bawa, MS, PhD, S. R. Bawa, MSc, PhD, and Ratnesh N. Mehra, DO

58.1 Nano Frontiers: Dreams and Reality 1292 58.2 Basic Science in the Era of Clinical Translation 1299 58.3 Chaos in Academia: Irreproducible Preclinical

Research 1307 58.4 Overcoming the Valley of Death in Drug

Commercialization 1317 58.5 Scientific Innovation in a Culture of Conformity 1326 58.6 Patents and Translational Research 1327 58.7 Lost in Translation: The Issue of Nomenclature 1329

xxviii Contents

58.8 RegulatoryGuidance:CriticalforTranslation 1334 58.9 FinalThoughts:StreamliningTranslational

MedicineattheNanoscale 1338

59.NanotechnologytowardAdvancingPersonalizedMedicine 1347

JasonH.Sakamoto,PhD,BianaGodin,PhD,YeHu,PhD,ElvinBlanco,PhD,AnneL.vandeVen,PhD,AdaikkalamVellaichamy,PhD,MatthewB.Murphy,PhD,SaverioLaFrancesca,MD,TerrySchuenemeyer,RN,MS,BruceGiven,MD,AnneMeyn,andMauroFerrari,PhD

59.1 Introduction 1347 59.2 ConventionalCancerChemotherapeutics 1350 59.3 ConceptofPersonalizedMedicine 1353 59.4 NanotechnologyinMedicine 1354 59.5 InjectableTherapeutics 1354 59.6 MolecularImaging 1361 59.7 EarlyDetection 1363 59.8 RegenerativeMedicineandTissueEngineering 1371 59.9 TheRoleofNanotechnologyandPersonalized

Medicine 1375 59.10VantagePoints:NanomedicineAdvancing

PersonalizedMedicine 1376 59.11Summary 1389

60.Science,Business,andImpactofNanomedicine:FinalThoughts 1413

MichaelHehenberger,PhD,DrSc

Index 1417

List of Corresponding Authors

Jorge Alberto Álvarez-Díaz Universidad Autónoma Metropolitana Unidad Xochimilco, Edificio A, 2o Piso. Área de Postgrados en Ciencias Biológicas y de la Salud, Calzada del hueso 1100, Colonia Villa Quietud, Delegación Coyoacán, CP 04960 México DF, Email: jalvarez@correo.xoc.uam.mx

Elizabeth Baker Licensing Division, Medicines and Healthcare Products Regulatory Agency, London SW1W 9SZ, United Kingdom, Email: elizabeth.baker@mhra.gsi.gov.uk

Raj Bawa Bawa Biotech LLC, 21005 Starflower Way, Ashburn, VA 21047, USA, Email: bawa@bawabiotech.com

Craig Belcher UniQuest Pty Ltd, Level 7, General Purpose South Building, Staff House Road, St Lucia, Queensland 4072, Australia, Email: c.belcher@uniquest.com.au

David M. Berube Department of Communication, North Carolina State University, Campus Box 8104, Raleigh, NC 27695-8104, USA, Email: dmberube@ncsu.edu

Alok Bhushan Department of Pharmaceutical Sciences, School of Pharmacy, Thomas Jefferson University, 901 Walnut Street, Suite 915, Philadelphia, PA 19107, USA, Email: alok.bhushan@jefferson.edu

Gaby-Fleur Böl Department of Risk Communication, Federal Institute for Risk Assessment, Postfach 12 69 42D-10609 Berlin, Germany, Email: Gaby-Fleur.Boel@bfr.bund.de

Christopher Bosso School of Public Policy and Urban Affairs, 310 Renaissance Park, Northeastern University, Boston, MA 02115, USA, Email: c.bosso@neu.edu

Patti Breedlove University of Florida’s Sid Martin Biotechnology Incubator, 12085 Research Drive, Alachua, FL 32615, USA, Email: pbreedlove@sidmartinbio.org

Joanna T. Brougher Harvard T. H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA, Email: jbrough@hsph.harvard.edu; joannabrougher@gmail.com

Rob Burgess RayBiotech, Inc., 3607 Parkway Lane, Suite 100, Norcross, GA 30092, USA, Email: paraxis1@yahoo.com

Inna Dahlin Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, PC, One Financial Center, Boston, MA 02111, USA, Email: idahlin@mintz.com

Hassan A. N. El-Fawal Neurotoxicology Laboratory, Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue, Albany, NY 12208, USA, Email: hassan.el-fawal@acphs.edu

xxx

Roman Fayerberg Greenberg Tauring, LLP, One International Place, Boston, MA 02110, USA, Email: fayerbergr@gtlaw.com

Si-Shen Feng Xi’an Jiaotong-Liverpool University, 111 Ren Ai Road, Dushu Lake Higher Education Town, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China, Email: chefss@nus.edu.sg

Heinz Fißan Institute of Energy and Environmental Technology, Bliersheimer Str. 60, 47229 Duisburg, Germany, Email: heinz.fissan@uni-due.de

Shannon Fischer Boston, MA, USAGuillermo Foladori Universidad Autónoma de Zacatecas, Unidad de

Estudios en Desarrollo, Av. Preparatoria s/n, Col. Hidráulica, Zacatecas, ZAC, México, Email: fola@estudiosdeldesarrollo.net

Marianna Foldvari School of Pharmacy, University of Waterloo, 200 University Avenue West, Waterloo, ON, Canada N2L 3G1, Email: foldvari@uwaterloo.ca

Birgit K. Gaiser Heriot-Watt University, School of Life Sciences, John Muir building, Edinburgh, EH14 4AS United Kingdom, Email: b.gaiser@hw.ac.uk

Mario Ganau Department of Surgical Science, Asse Didattico di Medicina, Cittadella Universitaria, S.S. 554. 09042 Monserrato (CA), Italy, Email: mario.ganau@singularityu.org

Howard E. Gendelman Department of Pharmacology and Experimental Neuroscience, Durham Research Center, 985880 Nebraska Medical Center, Omaha, NE 68198, USA, Email: hegendel@unmc.edu

Bruce D. Goldstein NIH Office of Technology Transfer, 6011 Executive Boulevard, Suite 325, Rockville, MD 20852, USA, Email: goldsteb@mail.nih.gov

Susanne M. Hopkins Vorys, Sater, Seymour and Pease LLP, 1909 K Street NW, Suite 900, Washington, DC 20006, USA, Email: smhopkins@vorys.com

Joseph Luke Huan ANU College of Law, Australian National University, 5 Fellows Road, Canberra, Australian Capital Territory 0200, Australia, Email: joseph.huan@anu.edu.au

Rudolph L. Juliano UNC Eshelman School of Pharmacy, CB # 7362, University of North Carolina, Chapel Hill, NC 27599, USA, Email: arjay@med.unc.edu

Annette I. Kahler Heslin Rothenberg Farley & Mesiti PC, 5 Columbia Circle, Albany, NY 12203, USA, Email: aik@hrfmlaw.com

Jagat R. Kanwar Laboratory of Immunology and Molecular Biomedical Research, Deakin University, Waurn Ponds, Victoria 3217, Australia, Email: jagat.kanwar@deakin.edu.au

Matthew Kaplan Tucker Ellis LLP, 515 South Flower Street, Forty-Second Floor, Los Angeles, CA 90071, USA, Email: matthew.kaplan@tuckerellis.com

Todd Kuiken Science and Technology Innovation Program, Woodrow Wilson International Center for Scholars, 1300 Pennsylvania Avenue, NW, Washington, DC 20004, USA, Email: todd.kuiken@wilsoncenter.org

List of Corresponding Authors

xxxi

Jeffery P. Langer Osha Liang LLP, 1800 Diagonal Road, Suite 600, Alexandria, VA 22314, USA, Email: langer@oshaliang.com

Julianna Lisziewicz eMMUNITY Inc., 4400 East West Highway, Suite 1126, Bethesda, MD 20814, USA, Email: julianna.lisziewicz@emmunityinc.com

Stephen Maebius Foley Lardner, Washington Harbour, 3000 K Street, NW, Suite 600, Washington, DC 20007, USA, Email: SMaebius@foley.com

Elicia Maine Beedie School of Business, Simon Fraser University, 500 Granville Street, Vancouver, BC, V6C 1W6, Canada, Email: emaine@sfu.ca

James Mittra Science Technology and Innovation Studies, School of Social and Political Science, University of Edinburgh, Room G.03, Old Surgeons’ Hall, High School Yards, Edinburgh, United Kingdom EH1 1LZ, Email: James.Mittra@ed.ac.uk

S. M. Moghimi Department of Pharmacy, and Centre for Pharmaceutical Nanotechnology and Nanotoxicology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark, Email: moein.moghimi@gmail.com

Sergio E. Moya CIC biomaGUNE, Paseo Miramón, San Sebastian, Spain, Email: smoya@cicbiomagune.es

Martin Mullins Department of Accounting and Finance, Kemmy Business School, University of Limerick, Limerick, Ireland, Email: martin.mullins@ul.ie

Roger J. Narayan UNC/NCSU Joint Department of Biomedical Engineering, Box 7115, Raleigh, NC 27695-7115, USA, Email: rjnaraya@ncsu.edu

Andrew Owen Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, United Kingdom, Email: aowen@liverpool.ac.uk

Amy Barton Pai Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue, O’Brien 232, Albany, NY 12208, USA, Email: amy.bartonpai@acphs.edu

Rosanna W. Peeling Department of Clinical Research, ITD, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom, Email: rosanna.peeling@lshtm.ac.uk

John Quinn Dublin City University, Glasnevin, Dublin 9, IrelandSteve Rannard Department of Chemistry, University of Liverpool, Liverpool

L697ZD, United Kingdom, Email: S.P.Rannard@liverpool.ac.ukBrian Reese Choate Hall & Stewart LLP, 2 International Place, Boston, MA

02110, USA, Email: breese@choate.comJason H. Sakamoto The Houston Methodist Research Institute, 6670 Bertner

Street, Houston, TX 77030, USA, Email: jhsakamoto@houstonmethodist.org

Alexander S. Sobolev Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, Moscow 119334, Russia, Email: sobolev@igb.ac.ru

Vicki Stone Room F17, John Muir Building, School of Life Sciences, Heriot-

List of Corresponding Authors

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Watt University, Edinburgh, Scotland, United Kingdom EH14 4AS, Email: v.stone@hw.ac.uk

Melanie Swan Contemporary Philosophy, 242 East 60th Street #4-D, New York, NY 10022, USA, Email: m@melanieswan.com

János Szebeni Nanomedicine Research and Education Center, Semmelweis University, Nagyvárad tér 4, Budapest 1089, Hungary, Email: jszebeni2@gmail.com

Chris Toumey Center for Environmental Nanoscience & Risk, Department of Environmental Health Sciences, Discovery Building, 915 Greene Street, University of South Carolina, Columbia, SC 29208, USA, Email: Toumey@mailbox.sc.edu

Todd G. Vare Intellectual Property Department, Barnes & Thornburg LLP, 11 South Meridian Street, Indianapolis, IN 46204, USA, Email: todd.vare@btlaw.com

Theodore Voorhees, Jr. Covington & Burling LLP, 1201 Pennsylvania Avenue NW, Washington, DC 20004, USA, Email: tvoorhees@cov.com

David L. Wallace Herbert Smith Freehills New York LLP, 450 Lexington Avenue, New York, NY 10017, USA, Email: david.wallace@hsf.com

Thomas J. Webster Department of Chemical Engineering, 313 Snell Engineering Center, Northeastern University, 360 Huntington Avenue, Boston, MA 02115-5000, USA, Email: th.webster@neu.edu

John Barlow Weiner Office of Combination Products, Food and Drug Administration, WO32, Hub/Mail Room #5129, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA, Email: John.Weiner@fda.hhs.gov

Paul F. A. Wright Department of Medical Sciences, Nanosafe Australia & School of Medical Sciences, RMIT University, Bundoora, VIC 3083, Australia, Email: paul.wright@rmit.edu.au

Reinhard Zellner Institute of Physical Chemistry, University of Duisburg-Essen, 45117 Essen, Germany, Email: reinhard.zellner@uni-due.de

List of Corresponding Authors

Foreword

With the recent passing of Maureen O’Hara (one of my favorite actresses) I recalled her role in the classic movie Miracle on 34th Street. At the trial to “prove” that the defendant Kris Kringle was the one and only Santa Claus on the basis of some competent authority, the defendant received 21 full mailbags with letters addressed to Santa Claus. Based upon that evidence, New York Supreme Court Judge Henry X. Harper ruled that “if the U.S. Post Office (and therefore by extension the Federal Government) acknowledged that the defendant was ‘The Santa Claus’ then he would acquiesce in their decision.” In a similar vein of acquiescence, the US Patent and Trademark Office (USPTO) established Class 977 on nanotechnology with a definition of the term “nanostructure” to mean an atomic, molecular, or macromolecular structure that has at least one physical dimension in the nanoscale and possesses a special property, provides a special function, or produces a special effect that is uniquely attributable to the structure’s nanoscale physical size. As Judge Harper realized in ruling on the real Santa Claus, I too realized that if the USPTO defined nanostructure I may as well acquiesce. I had a 36-year career at the USPTO mainly in the medical arts and spent at least ten of those years working with Dr. Raj Bawa, the editor of this remarkable series on clinical nanomedicine. Together, we worked on various aspects of patent examination, issuance of nanotech-related patents and teaching new patent examiners on the nuances of patent law at the Patent Academy. Since my retirement from the USPTO I have helped many inventors obtain patents claiming nanostructures, especially in the medical disciplines. I have frequently collaborated with Dr. Bawa and will continue to do so until I retire again. Volume 2 of this outstanding series, aptly titled The Handbook of Clinical Nanomedicine: Law, Business, Regulation, Safety, and Risk, provides a well-edited, reader-friendly, multidisciplinary assemblage in this complex field. It clearly communicates essential information on the entire “product life cycle,” from the creation of nanomedical products to their final market introduction. The style

xxxiv Foreword

and content of this handbook is attractive for both the novice and the expert. The “bench to commercialization” approach of this handbook is relevant not only to nanomedicine but also to a multitude of other disciplines ranging from biotechnology, medical devices, bioengineering, pharmaceutical sciences, the insurance industry, future studies, business and law. While focusing on critical issues relevant to product development and translational activities, it also tackles related topics such as regulatory science, patent law, FDA law, ethics, personalized medicine, risk analysis, toxicology and nano-characterization. A separate section provides fascinating perspectives and editorials. The co-editors have masterfully organized highly relevant contributions from an array of experts into 60 chapters. The four sections that constitute the book successfully bridge communication and terminology issues often encountered in such multi-disciplinary efforts. In fact, this unique handbook remains loyal to its title theme: Section I—law, business and commercialization; Section II—regulatory issues and nanogovernance; Section III—health, safety, risk and biological interactions; and Section IV—future implications, ethics, perspectives and editorials. The wide range of topics covered as well as the multidisciplinary approach of all volumes in this series has been impressive. Similarly, this second volume should serve as an essential reference asset that should be invaluable to all who are interested in the explosive growth and future promise of this emerging area. It will undoubtedly help bridge the gap between basic nanomedical R&D and translation. In this respect, it will be of interest to all stakeholders from big pharma, academia and government— scientists, physicians, engineers, chemists, biotechnologists, drug formulators, pharmacologists, policy-makers regulators, toxicologists, business lawyers, patent attorneys, patent agents, the venture community and the consumer-patient. Volume 1 has been a major hit, attracting a global audience. I am confident that The Handbook of Clinical Nanomedicine: Law, Business, Regulation, Safety, and Risk will follow the same path to success.

Richard J. Apley, JDPatent Agent and Chief Patent Officer

Litman Law Offices/Becker & PoliakoffManassas, Virginia, USA

February 2016

xxxvForeword

Richard J. Apley serves as the Chief Patent Officer in the intellectual property and emerging technologies practice group of the commercial law firm, Becker & Poliakoff in their Virginia office. The firm, founded in 1973, has more than one hundred seventy attorneys, lobbyists and other professionals in Florida, New York,

New Jersey, Washington, DC, Virginia and Prague (Czech Republic). Mr. Apley is a registered patent agent licensed to practice before the United States Patent and Trademark Office (USPTO). At the firm, he is responsible for training on patent practice and procedures and supervising patent practitioners and staff. He handles patent prosecution matters, particularly applications participating in the “Interview Before First Action” program. Mr. Apley retired from the USPTO in 2002 after a distinguished 36-year career. He became a Supervisory Patent Examiner at the USPTO in 1982 and supervised various art units, including mechanical and chemical engineering, computer-controlled teaching apparatus and simulators, and biomedical and surgical devices. In the late 1990s, he served as Director of the Office of Independent Inventor Programs. Mr. Apley also represented the USPTO in the media, on the board of directors of the National Inventor Hall of Fame, and on the Consumer Protection Initiatives Committee (part of the US Attorney General’s Council on White Collar Crime). He instructed new patent examiners in their initial training and was responsible for rewriting and updating various training manuals used by patent examiners and their instructors. Mr. Apley obtained his bachelor’s degree in civil engineering from Rensselaer Polytechnic Institute in Troy, New York, and his law degree (magna cum laude) from the University of Baltimore in Baltimore, Maryland. In 2012, he coauthored Business Method and Software Patents—A Practical Guide, published by Oxford University Press.

Racing Ahead: Nanomedicine under the Microscope

Small has always been beautiful although smallness has often been overlooked and unappreciated. But now, nanoscale constructs are transforming our world. Small is big. For me, what a long strange trip it’s been regarding nano.1 Back in 2002, I presented on nanomedicine at the Canadian Space Agency to an audience primarily composed of materials scientists and engineers. After a few excellent questions, I realized that physical scientists and pharmaceutical scientists view the nanoworld quite differently and that there is tension between the two camps. This was back then, but the state of affairs is the same today, maybe even more profound. Since then, nano has become more sectorized, with nanomedicine2 and nanoelectronics leading the way. There are hundreds of nanomedical products on the market and the potential is vast. The race is on. In spite of this, nanomedicine is still under the microscope. Optimists tout nanotechnology as an enabling technology, a sort of next industrial revolution that could enhance the wealth and health of nations. They promise that many areas within nanomedicine (nanoscale drug delivery systems, theranostics, imaging, etc.) will soon be a healthcare game-changer by offering patients access to personalized or precision medicine. Pessimists, on the other hand, take a cautionary position, preaching instead a go-slow approach and pointing to a lack of sufficient scientific data on health risks, general failure on the part of regulatory agencies to provide clearer guidelines and issuance of patents of dubious scope by patent offices. As usual, the reality is somewhere between such extremes. Whatever your stance, nanomedicine has already 1What a Long Strange Trip It’s Been, subtitled The Best of the Grateful Dead, is a 1977 Warner Brothers Records compilation album by the Grateful Dead, the iconic rock band formed in 1965 in Palo Alto, California.

2There is no standard definition for nanomedicine. I define it as the science and technology of diagnosing, treating and preventing disease and improving human health via nanoscale tools, devices, interventions and procedures. It is driven by collaborative research, patenting, commercialization, business development and technology transfer within diverse areas such as biomedical sciences, chemical engineering, biotechnology, physical sciences, and information technology.

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permeated virtually every sector of the global economy. It continues to evolve and play a pivotal role in various industry segments, spurring new directions in research, product development and translational efforts.3 In our publish-or-perish culture, is scientific innovation being smothered by a culture of conformity? There is evidence that research is becoming more conservative and risk-averse.4 Risk is essential for ground breaking work and creativity to fully flourish. I firmly believe that we must also broaden our horizons beyond boundaries between disciplines, embrace global scientific collaborations and leverage interconnected global networks to address grand challenges in biomedicine. In my view, to drive science, innovation and the economy, we need doctorates and physician-scientists trained in a variety of fields. And, yes, we need risk- takers in biomedicine. Furthermore, the expensive and time-consuming training of graduate students needs to be accomplished via carefully monitored baby steps, keeping in mind Friedrich Nietzsche’s advice: “He who would learn to fly one day must first learn to stand and walk and run and climb and dance; one cannot fly into flying.” The number of science doctorates is rising, but graduate training has deviated little over the decades. Graduate programs should be revamped to incorporate workplace skills and courses in management, communication, commercialization and business. In this regard, nano has an edge over other 3The prefix “nano” in the SI measurement system denotes 10−9 or one-billionth. There is no firm consensus over whether the prefix “nano” is Greek or Latin. While the term “nano” is often linked to the Greek word for “dwarf,” the ancient Greek word for “dwarf” is actually spelled “nanno” (with a double “n”) while the Latin word for dwarf is “nanus” (with a single “n”). While a nanometer refers to one-billionth of a meter in size (10−9 m = 1 nm), a nanosecond refers to one billionth of a second (10−9 s = 1 ns), a nanoliter refers to one billionth of a liter (10−9 l = 1 nl) and a na-nogram refers to one billionth of a gram (10−9 g = 1 ng). The diameter of an atom ranges from about 0.1-0.5 nm, a DNA molecule about 2-3 nm, and a gold atom about 1/3rd of a nm. Some other interesting comparisons: fingernails grow around a nanometer/second; in the time it takes to pick a razor up and bring it to your face, the beard will have grown a nanometer; a single nanometer is how much the Himalayas rise in every 6.3 seconds; a sheet of newspaper is about 100,000 nanometers thick; it takes 20,000,000 nanoseconds (50 times per second) for a hummingbird to flap its wings once; a single drop of water is ~50,000 nanoliters; a grain of table salt weighs ~50,000 nanograms.

4Rzhetsky, A., Foster, J. B., Foster, I. T., Evans, J. A. (2015). Choosing experiments to accelerate collective discovery. PNAS, 112(47), 14569–14574.

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fields: interdisciplinarity and international collaboration are the hallmarks of nano. Maybe all science students at some stage in their undergraduate or graduate careers should be required to take a basic course in nanoscience or nanomedicine. This will be beneficial because nanomedicine’s interdisciplinary nature necessitates a breadth of knowledge and appreciation of a multitude of disciplines. However, even with nano, there is a clear need for “true” interdisciplinarity and collaboration given the different approaches of physical scientists versus pharmaceutical scientists with respect to generation, examination, analysis and discussion of data. I have been extremely cognizant of this fact in developing this handbook series. I believe, everyone will find the volumes relevant and useful. Each stand-alone volume in this series is focused on salient aspects of nanomedicine, pharma and various branches of medicine. It is essential reading for both the novice and the expert in medicine, pharmaceutical sciences, biotechnology, immunology, engineering, FDA law, intellectual property, policy, future studies, ethics, licensing, commercialization, risk analysis and toxicology. Each volume is not only intended to serve as a useful reference resource for professionals but also to provide supplementary readings for courses for graduate students and medical fellows. Diversity within the broad and evolving arena of nanomedicine is reflected in the expertise of the distinguished contributing authors. All chapters contain key words, figures in full-color and an extensive list of references. As compared to other books on the market, each volume in the series is comprehensive, truly multidisciplinary—all presented in an easily accessible, user-friendly format. The editors have skillfully curated each chapter to reflect the most relevant and current information. Unlike other books in this evolving field that quickly go out-of-date, this series contains excellent reviews that can not only provide the most current information on advances now but also serve as the basis or starting point to explore future advances on a particular topic. My purpose in constructing each volume is to provide chapters that give the reader a better understanding of the subject matter while provoking reflection, discussion and catalyzing collaborations between diverse stakeholders. Each volume is essentially a guided tour of critical topics and issues that should arouse the reader’s curiosity so that they will engage more profoundly with the broader theme reflected.

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Ever since the Canadian Space Agency talk in 2002, I have been involved in almost all aspects of nanoscience, nanomedicine and nanotechnology—patent prosecution, teaching, research, FDA regulatory filings, conference organizer and speaker. I have intimately seen the evolution of nanomedicine. I have cheered on the cutting-edge discoveries and inventions but also stood up to criticize inept governmental regulatory policies, spotty patent examination at patent offices, hyped-up press releases from eminent university labs and inaccurate depiction of nano by the media and politicians.55Too often, start-ups, academia and companies exaggerate basic research developments as potentially revolutionary advances and claim these early-stage discoveries as confirmation of downstream novel products and applications to come. In fact, nanotechnology’s potential benefits are frequently overstated or inferred to be very close to application when clear bottlenecks to commercial translation persist. Many have desperately tagged or thrown around the “nano” prefix to suit their purpose, whether it is for federal research funding, patent approval of supposedly novel inventions, raising venture capital funds, running for office or seeking publication of a journal article. The Office of Science and Technology Policy (OSTP) in 2015 issued a “Request for Information (RFI)” to seek suggestions for nanotechnology-inspired “Grand Challenges” for the next decade. See: Wackler, T. (2015). Nanotechnology-inspired grand challenges for the next decade. Federal Register, 80(116), 34713–34715. This RFI was characterized as “ambitious but achievable goals that harness nanoscience, nanotechnology, and innovation to solve important national or global problems and have the potential to capture the public’s imagination. This RFI is intended to gather information from external stakeholders about potential grand challenges that will help guide the science and technology priorities of Federal agencies, catalyze new research activities, foster the commercialization of nanotechnologies, and inspire different sectors to invest in achieving the goals. Input is sought from nanotechnology stakeholders including researchers in academia and industry, non-governmental organizations, scientific and professional societies, and all other interested members of the public.” The RIF provided examples of potential nanotechnology-inspired grand challenges for the next decade: (i) increase the five-year survival rates by 50 percent for the most difficult to treat cancers; (ii) create devices no bigger than a grain of rice that can sense, compute, and communicate without wires or maintenance for 10 years, enabling an ‘‘internet of things’’ revolution; (iii) create computer chips that are 100 times faster yet consume less power; (iv) manufacture atomically-precise materials with fifty times the strength of aluminum at half the weight and the same cost; (v) reduce the cost of turning sea water into drinkable water by a factor of four; and (vi) determine the environmental, health, and safety characteristics of a nanomaterial in a month. Let us see if these ambitious goals are achieved by 2035 or if they turn out to be mere rhetoric and politics as usual on the part of federal agencies like the OSTP, National Nanotechnology Initiative (NNI) and the National Nanotechnology Coordination Office (NNCO). Echoing governmental “grand challenge projects” some scientists and organizations are proposing similar action. For example, see: Parak, W. J., Nel, A. E., Weiss, P. S. (2015). Grand challenges for nanoscience and nanotechnology. ACS Nano, 9, 6637–6640. In the end, achieving such

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While the nano die was cast long ago, it is well entrenched now and there is no turning back. Although the air may be thick with news of nano-breakthroughs and a hot topic for discussion in industry, pharma, patent offices and regulatory agencies, the average citizen knows very little about what constitutes a nanoproduct, a nanomaterial or a nanodrug. This was apparent to me early on when the CBS TV station in Albany, NY, while interviewing me for a story on nanotechnology, approached people on the street and asked them to define nano. To my amazement, not a single person could come up with even a functional description of the term. At the time, there were close to two thousand marketed products that incorporated nano in some form. This problem persists. These interviews were taking place a few blocks from the massive, world-class education and research complex comprising Albany Nanotech (now SUNY Polytechnic Institute’s Colleges of Nanoscale Science and Engineering), where billions have been invested since the early 1990s. Recognizing that the so-called “nanorevolution” will have limited impact unless all stakeholders, especially the public, are fully on board, I immediately organized an annual nano-conference that continues to this day. The conference is free to all attendees and for the first dozen years was held at Rensselaer Polytechnic Institute in Troy, NY. Since 2015 it has been held at the Albany College of Pharmacy and Health Sciences in Albany, NY. Louis Pasteur famously said: “Science knows no country, because knowledge belongs to humanity, and is the torch which illuminates the world. Science is the highest personification of the nation because that nation will remain the first which carries the furthest the works of thought and intelligence.” Perhaps, nothing is truer in this regard than nanoscience, nanotechnology and nanomedicine. However, we are in a rapidly changing, yet interconnected and globalized world—politically, economically, societally, environmentally and technologically.6 At the present time in our history, many national boundaries are rendered artificial, there are few true leaders on the global stage, the world power dynamics are shifting and the outdated bureaucratic structures firmly in place are unable to deal effectively with the emerging knowledge economy. While grand challenges will require the right mix of funding, vision, political will, scientific expertise, analytical tools, regulatory clarity, patent laws, etc.

6See: Jackson, S. A. New vantage points. Available at: http://www.rpi.edu/president/speeches/ps102915-falltownmeeting.html (accessed on March 6, 2016).

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economic woes, wars, disease and turbulence are shaking our world, these changes are also causing a certain degree of chaos in the world of biomedicine. By extension, this may be considered one of the most exciting times for nanomedicine as well. From my perspective, there is a combination of excitement, potential, confusion, hype and misinformation in this regard—all of this seen more than in other fields when they were evolving. It is true that in the heady days of any emerging technology, definitions tend to abound and are only gradually documented via reports, journals, books and dictionaries. Ultimately, standard-setting organizations like the International Organization for Standardization (ISO) and American Society for Testing and Materials (ASTM) International produce technical specifications. This evolution is typical and essential as the development of terminology is a prerequisite for creating a common language for effective communication in any field. Clearly, a similar need for an internationally agreed definition for key terms like nanotechnology, nanoscience, nanomedicine, nanobiotechnology, nanodrug, nanotherapeutic, nanopharmaceutical and nanomaterial, has gained urgency.7 Nomenclature, technical specifications, standards, guidelines and best practices are critically needed to advance nanotechnologies in a safe and responsible manner. Contrary to some commentators, terminology does matter because it prevents misinterpretation and confusion. It is essential for research activities, harmonized regulatory governance, accurate patent searching and prosecution, standardization of procedures, manufacturing and quality control, assay protocols, decisions by granting agencies, effective review by policymakers, ethical analysis, public dialogue, safety assessment, and more. Also, nomenclature is critical to any translational and commercialization efforts. All definitions of nanotechnology based on size or dimensions must be dismissed, especially in the context of medicine and pharmaceutical science, for the reasons elaborated in chapter 6

7Similar disagreements over terminology and nomenclature are seen in other fields as well. For example, the term “super resolution microscopy,” the subject of the 2014 Nobel Prize, is considered an inaccurate description of the technique. Since electron microscopes and scanning probe microscopes can resolve features at the nanometer, it is a misnomer to affix the “nano” prefix to these terms. Therefore, it may be more appropriate to refer to these “scopes” as “nanoscopes” instead. Inaccurate terminology often becomes the norm with time. It is hoped that this is not the case for nano where the prefix gets too entrenched for a corrective change to be made.

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of volume 1.8 It can be summarized that nanotherapeutics may have unique properties (nanocharacter) that can be beneficial for drug delivery and other applications but there is no specific size range or dimensional limit where superior properties are found. Hence, the size limitation below 100 nm cannot be touted as the basis of novel properties of nanotherapeutics. Viable sui generis definition of nano having a bright-line size range, especially as applied to nanodrugs, blurs with respect to what is truly nanoscale. Since the 100 nm boundary has no solid scientific or legal basis, this handbook series will avoid using the inaccurate sub-100 nm definition of nano. Instead, definitions along these lines will be employed9: “The design, characterization, production, and application of structures, devices, and systems by controlled manipulation of size and shape at the nanometer scale (atomic, molecular, and macromolecular scale) that produces structures, devices, and systems with at least one novel/superior characteristic or property.” The volumes in this series will extensively cover advances in drug delivery as this is leading all developments in nanomedicine. The prototype of targeted drug delivery can be traced back to the concept of a “magic bullet” that was postulated by Nobel Laureate Paul Ehrlich in 1908 (magische Kugel, his term for an ideal therapeutic agent) wherein a pathogenic organism or diseased tissue could be selectively targeted by a drug while leaving healthy cells unharmed.10 A century later, various classes of nanoscale “magic bullets” have been designed (nanoscale drug delivery systems 8See: Bawa, R. (2016). What’s in a name? Defining “nano” in the context of drug delivery.

In: Bawa, R., Audette, G., Rubinstein, I. eds. Handbook of Clinical Nanomedicine: Nanoparticles, Imaging, Therapy, and Clinical Applications, Pan Stanford Publishing, Singapore, Chapter 6, pages 127–168.

9See: Bawa, R. (2007). Patents and nanomedicine. Nanomedicine (London), 2(3), 351–374. This flexible definition has four key features:(i) It recognizes that the properties and performance of the synthetic, engineered “structures, devices, and systems” are inherently rooted in their nanoscale dimensions. The definition focuses on the unique physiological behavior of these “structures, devices, and systems” that is occurring at the nanoscale; it does not focus on any shape, aspect ratio, specific size or dimension.(ii) It focuses on “technology” that has commercial potential, not “nanoscience” or “basic R&D” conducted in a lab setting.(iii) The “structures, devices, and systems” that result from or incorporate nano must be “novel/superior” compared to their bulk/conventional counterparts.(iv) The concept of “controlled manipulation” (as compared to “self-assembly”) is critical.

10See: Witkop, B. (1999). Paul Ehrlich and his magic bullets—Revisited. Proceedings of the American Philosophical Society, 143(4), 540–557.

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or NDDS), some in development while others commercialized. Obviously, the truly revolutionary ones will be those that can specifically deliver therapeutics to target tissue and even specific cells or organelles. This concept of a “magic bullet” was realized by the development of antibody-drug conjugates (ADCs), which are technically NDDS. The NDDS11 that have reached the marketplace have been approved by the FDA, EMA or foreign equivalent. Data from industry and the FDA shows that most of the approved or pending NDDS are oncology-related and based on protein-polymer conjugates or liposomes. The first FDA-approved nanotherapeutic was Doxil while AmBisome was the first one approved by EMA. It should be noted, however, that a nanoparticulate iron oxide intravenous solution in the market since the 1960s and certain nanoliposomal products approved in the 1950s and later should, in fact, be considered true first nanomedicines. The following points serve to highlight the major impact of nanoscale drug delivery systems: • Novel nanodrugs and nanocarriers are being developed

that address fundamental problems of traditional drugs because of the ability of these compounds to overcome poor water solubility issues, alter unacceptable toxicity profiles, enhance bioavailability, and improve physical/chemical stability. Additionally, via tagging with targeting ligands, these formulations can serve as innovative drug delivery systems for enhanced cellular uptake or site-specific targeted delivery of therapeutics into tissues of interest. Various FDA-approved liposomal, solid nanoparticle-based, antibody-drug conjugate and polymer-drug conjugate delivery platforms overcome associated issues such as (i) low solubility (Abraxane), (ii) extremely high drug toxicity (Brentuximab vedotin and Trastuzumab emtansine), and (iii) side effects related to high doses of free drug (Doxil, Marqibo, DaunoXome).

• Reformulation of old, shelved therapeutics into nanosized dosage forms could offer the possibility of adding new life to

11There is no universal definition for nanoscale drug delivery system or nanotherapeutic formulation, my definition being: (1) a formulation, often colloidal, containing therapeutic particles (nanoparticles) ranging in size from 1–1,000 nm; and (2) either (a) the carrier(s) is/are the therapeutic (i.e., a conventional therapeutic agent is absent) or (b) the therapeutic is directly coupled (functionalized, solubilized, entrapped, coated, etc.) to a carrier.

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old therapeutic compounds. Classic examples include drugs developed as nanocrystalline products (Rapamune, Emend, Triglide).

• Coupled with advances in pharmacogenomics, epigenetics, synthetic biology, biomarkers, smart nanomachines, information technology and personalized or precision medicine, upcoming innovations in nanodrug delivery may even generate multifunctional entities enabling simultaneous diagnosis, delivery and monitoring of therapeutic agents. In fact, there is a large body of literature reporting on preclinical advances in these so-called “theranostics,” the integration of molecular imaging and molecular therapy (i.e., the concept of delivering therapy and then examining its effect). With respect to oncology, there is already a sort of personalized medicine being practiced where the patient is prescribed drugs based on a specific gene mutation in the patient’s tumor. This could be eventually extended to nanomedicine, especially cancer nanomedicine, where specific nanotherapeutics could be delivered to a patient over other less favorable ones or those that are less likely to leak into and be retained by the tumor tissue.12 Here, this delivery with precision (personalized

12There are two major concepts in drug delivery in oncology: (i) active targeting that involves tumor targeting via the specific binding ability between an antibody and antigen or between the ligand and its receptor; and (ii) passive targeting achieved via the enhanced permeability and retention (EPR) effect. Although not a generalization, if the nanoparticle is too small (<10 nm?), it is generally rapidly excreted via renal filtration while particles too large (>~150 nm?) may not penetrate deep inside tumor tissue. It should be pointed out that these are general statements as there is a wide variability in nanoparticles types and sizes employed to achieve the desired result or therapeutic outcome. For example, sterically-stabilized liposomes of 400 nm diameter were shown to penetrate into tumor interstitium. One has to examine the specific nanoparticle on a case-by-case basis to see whether it is scavenged by RES (e.g., Kupffer cells in liver) or internalized by target cells through endocytosis. Size obviously is important while engineering nanoparticles for tumor applications but it needs to be fine-tuned depending upon the nanomaterial used, route of delivery, application sought, toxicity issues, etc.The National Cancer Institute (NCI) established the Nanotechnology Characterization Laboratory (NCL) that has developed a “standardized analytical cascade that tests the preclinical toxicological, pharmacology, and efficacy of nanoparticles and devices.” The NCL has characterized over 200 nanomaterials from academia, government and industry. The counterpart to the NCL is the European Nanotechnology Characterization Laboratory (EU-NCL), established in 2015. The

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nanomedicine?) will have the classical advantages contemplated for nanoscale drug delivery systems, though barriers (being complicated, time-consuming, often invasive and high cost) will need to be overcome.

Unlike other texts in nanomedicine, another critical theme that will be found throughout this handbook series is intellectual property, particularly patent law issues. Patents and the protection that they afford are the lifeblood of big pharma. The protection of inventions via patents provides an opportunity for pharma to recoup the high cost of discovery by preventing competitors from entering the marketplace while the patent is in force. Securing valid and defensible patent protection from the patent offices around the world, including the US Patent and Trademark Office (PTO), is essential to any commercialization effort. Valid patents stimulate market growth and innovation, generate revenue, prevent unnecessary licensing and reduce infringement lawsuits. One interesting aspect of nanopatents is that in spite of anemic product development, patent filings and grants have continued unabated.13 However, it is no secret that nanopatents of dubious

mission statement of the NCL reads: It “performs and standardizes the pre-clinical characterization of nanomaterials intended for cancer therapeutics and diagnostics developed by researchers from academia, government, and industry. The NCL serves as a national resource and knowledge base for cancer researchers, and facilitates the development and translation of nanoscale particles and devices for clinical applications.”

13For over a decade now, the PTO continues to classify US nanopatents into Class 977, where, according to its own recent data, they currently number 5,000+. But, it is immediately apparent to any patent practitioner that there is something wrong with this statistic since there are 15,000+ issued US patents on nanoparticles alone. In fact, this classification system is imprecise because of the simple fact that the PTO’s definition of “nano” is incorrectly based on the flawed NNI definition that limits all nanostructures and nanoproducts to a sub-100 nanometer size range. For example, see U.S. Patent and Trademark Office (USPTO); Available at: http://www.nano.gov/node/599 (accessed on February 1, 2016): “Notably, the USPTO adopted the NNI definition of nanotechnology in its development of the first detailed, patent-related nanotechnology classification hierarchy of any major intellectual property office in the world.” As a result, the PTO numbers are a gross underestimate and miss the majority of nanotech-related patents (out of ~9 million US patents issued). Therefore, PTO statistics on nanopatents should be considered as indicative of the overall trend, not actual number of nanonotech-related patents. Also, see: Top countries in field of nanotechnology patents in 2013; Available at: http://statnano.com/news/45648 (accessed on February 1, 2016): “According to the statistics released by Statnano based on nanotechnology

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scope and breath, especially on foundational nanomaterials and upstream nanotechnologies, have been granted by patent offices around the world. In fact, “patent prospectors” have been on a global quest for “nanopatent land grabs” since the 1980s. As a result, patent thickets in certain sectors of nanotechnology have arisen that could have a chilling impact on commercialization activities.14 In the US, the PTO continues to be under enormous strain and scrutiny. Issues that need reform of this governmental agency range from poor patent quality, questionable examination practices, inadequate examiner search capabilities, rising employee attrition, poor examiner morale and an enormous patent backlog. Emerging technologies are particularly problematic for governmental regulatory agencies. Major global regulatory systems, bodies and regimes regarding nanomedicines are not fully mature, hampered in part by a lack of specific protocols for preclinical development and characterization. Additionally, in spite of numerous harmonization talks and meetings, there is a lack of consensus on the different procedures, assays and protocols to be employed during pre-clinical development and characterization of nanomedicines. In fact, the “baby steps” undertaken by the FDA over the past decade have led to regulatory uncertainty. There are potentially serious and inhibitory consequences if nanomedicine

patents and nanotechnology published patent applications, a sum total of 21,379 patents related to nanotechnology have been granted in USPTO in 2013, and about 31,350 nanotechnology patents have been published. A growth of more than 60% is observed in the number of nanotechnology patents in USPTO in comparison with 2012….”

14For example, the carbon nanotube (CNT) patent landscape is a tangled mess, mainly due to issuance of multiple US patents in error by the PTO. Also to blame is the fact that there is a lack of nano-nomenclature because of which inventors and scientists have employed distinct terms to refer to CNTs. As a result, contrary to the foundation of US patent law, various US patents on CNTs have been granted with legally identical claims. See: Harris, D., Bawa, R. (2007). The carbon nanotube patent landscape in nanomedicine: An expert opinion. Expert Opinion on Therapeutic Patents, 17(9), 1165–1174. The expected negative impact on commercialization and patent litigation has not arrived because CNTs have failed to deliver on the hype. Fabrication of affordable and high-quality CNTs has not materialized and scientists are now pursuing other exciting materials such as graphene instead. Hype and technology often evolve together and, in this case, the “peak of inflated expectations” of the 1990s was replaced by the “trough of disillusionment” in the early 2000s. See: Davenport, M. (2015). Much ado about small things. Chem. Eng. News, 93(23), 10–15.

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is overregulated. A balanced approach is required here, at least on a case-by-case basis, which addresses the needs of commercialization against mitigation of inadvertent harm to patients or the environment. Obviously, not everything “nanomedical” needs to be regulated. However, more is clearly needed from regulatory agencies like the FDA and EMA than a stream of guidance documents that are generally in draft format,15 position papers that lack any legal implication and policy papers that are often short on specifics. There is a very real need for regulatory guidelines that follow a science-based (not policy-based) approach that are responsive to the associated shifts in knowledge and risks. However, is nano arriving faster than other previous technologies like steam engines, telephones, digital computers, genetic engineering and synthetic biology? Is it proceeding too rapidly or in a vacuum to generate any meaningful discussion, formulation of regulations, safety guidelines, governmental policy or patent prosecution parameters? Ultimately, the true value of a particular nanoproduct lies in its clinical utility balanced against any potential adverse effects. Therefore, effective translation of nanomedicine candidates requires a “technological push” coupled with a “clinical pull” guided or catalyzed by regulatory agencies, patent offices and the venture community. All of this has to be bridged by logical intermediary data that mechanistically demonstrate the efficacy and biosafety. Whether regulatory agencies eventually create new regulations, tweak existing ones, or establish new regulatory centers to handle nanoproducts, for the time being they should at least look at nanoproducts on a case-by-case basis. Two critically important and interrelated regulatory law themes that will permeate this series include (i) nanosimilars; and (ii) non-

15The FDA’s use of “unofficial” definitions and “draft” guidance documents is legendary and the subject of concern, ridicule and criticism. Such FDA recommendations are nonbinding and come with a standard disclaimer: “This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations ...” For example, see: Watson, E. (2014). Senators to FDA: Stop using draft guidance to make substantive policy changes. Available at: http://www.foodnavigator-usa.com/Regulation/Senators-to-FDA-Stop-using-draft-guidance-to-make-big-policy-changes (accessed on March 6, 2016).

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biological complex drugs (NBCDs) (e.g., iron oxide nanoparticles, glatiramoids, liposomes, polymeric micelles). Topics discussed in the current volume are: transnational regulatory harmonization, generic biowaivers, combination products (nanotheranostics), patent law, FDA law, ethics, personalized medicine, risk analysis, toxicology, nano-characterization, translational nanomedicine, and commercialization activities. Translational issues and efforts pertaining to nanomedical products, especially nanodrugs, are analogous to classic drug research and development (R&D). Creating drugs today is time-consuming, expensive and enormously challenging.16 According to a 2014 study by the Tufts Center for the Study of Drug Development, developing a new prescription medicine that gains marketing approval is estimated to cost nearly $2.6 billion.17 It is clear to everyone that in the past decades, great strides have been made in basic science and research. However, in my view, the enormous medical advances that should have come from the large public investment in biomedical research are largely absent from a translation point-of-view. All stakeholders—pharma, patients, regulatory bodies, diseases foundations, academia, NIH—have suffered and are to blame for the “valley of death.” Similarly, although great strides have been made in nanomedicine generally at the “science” level, especially with respect to drug delivery and imaging, it continues to be dogged by challenges and bottlenecks at the “translational” level. Preclinical drug discovery research is primarily conducted and managed by pharma. Academia has traditionally contributed to this joint effort by conducting basic research into fundamental aspects of human disease biology and discovery of targets whose modulation could have therapeutic potential. The resultant “gold nuggets” that are thus generated are then selected by pharma to discover and develop drugs that modulate those targets, thereby driving the drug discovery engine. However, this common arrangement is in trouble and the collaborative paradigm is breaking down. Academic

16See: Bruno, J. R. (2015). Improving the bio-availability of drugs through their chemistry. Am. Pharm. Rev., 15(4), 34–39.

17See: Tufts Center for the Study of Drug Development. Available at: http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study (accessed on March 12, 2016).

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target discovery research reproducibility has become suspect18: “Much of the innovation landscape involves breakthroughs made in academia—but much of the research published in academia has proven not to be reproducible in pharma companies’ hands.” This reproducibility crisis has coincided with major changes in pharma’s productivity itself as numerous market forces and drivers have continued to dictate a change in its quest for discovering, developing and delivering novel therapeutics. It is also worth mentioning here that shortcuts taken by antibody manufacturers and researchers alike have led to a crisis of reproducibility in antibody performance.19 Obviously, all this impacts preclinical nanomedical research. Frankly, research institution administrators, faculty members and trainees must do far more for reproducibility so that robust biomedical research can be generated.20

So far, the process of converting basic research in nanomedicine into commercially viable products has been difficult. As discussed earlier, securing valid, defensible patent protection from the patent offices along with clearer regulatory/safety guidelines from regulatory agencies is essential to commercialization. This has been a mixed bag at best and much more is warranted. I strongly believe that issues such as effective patent reform, adaptive regulatory guidance, commercialization efforts and consumer health are all intertwined and need special attention while addressing nanotechnology. In this regard, science-based governance that promotes commercialization on one hand and balances consumer health on the other is critically needed. If the translation of nanomedicine is to be a stellar success, it is important that some order, central coordination and uniformity be introduced at the transnational level. It is true that this decade has witnessed relatively more advances and product development in nanomedicine than the previous. Many point to the influence of nanomedicine on the pharmaceutical, device and biotechnology industries. It is hoped that nanomedicine will eventually blossom into a robust industry. It is yet to be seen whether there will be giant technological leaps (that can leave giant scientific, ethical and 18See: Fishburn, C. S. (2015). Translational medicine: The changing role of big

pharma. In: Wehling, M., ed. Principles of Translational Science in Medicine: From Bench To Bedside, 2nd ed., Elsevier, pages 313–325.

19See: Baker, M. (2015). Blame it on the antibodies. Nature, 521, 274–276.20See: Begley, C. G., Buchan, A. M., Dirnagl, U. (2015). Institutions must do their part

for reproducibility. Nature, 525, 25–27.

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regulatory gaps) or paradigm-shifting advances (that necessitate extraordinary proof and verification). In the meantime, tempered expectations are in order. Key players must come together on a global platform to address these crucial issues affecting translational efforts. It is important that the public’s desire for novel nanomedical products, venture community’s modest investment, federal infusion of funds and big pharma’s lingering interest in nanomedicine continue. In the end, the long-term prognosis and development of nanomedicine will hinge on effective nanogovernance, issuance of valid patents, clearer safety guidelines, transparency and full commitment of all the stakeholders involved—big pharma, academia, governmental regulatory agencies, policy-makers, the venture community and the consumer-patient. We need everyone on board so that translation becomes more widespread. We must endure and traverse the valley of death. Together, we can help drive progress and make the future happen faster. Why not seek inspiration from George Bernard Shaw: “You see things; and you say ‘Why?’ But I dream things that never were; and I say ‘Why not?’” Science fiction may become science fact. Not only is this possible, but it will happen. For the times they are a-changin’.21 However, as we race ahead, we must keep proper perspective and heed Anton von Leeuwenhoek’s words of wisdom: “All we have yet discovered is but a trifle in comparison with what lies hid in the great treasury of Nature.”

Raj Bawa, MS, PhDSeries Editor

Ashburn, Virginia, USAMarch 10, 2016

21These words are attributed to the remarkable Steve Jobs during his opening of the 1984 annual Apple shareholders meeting where he unveiled the Macintosh computer for the first time. The Times They Are a-Changin’ is a classic song written by Bob Dylan and released as the title track of his 1964 album.

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Acknowledgements

Richard J. Apley, Litman Law Offices/Becker & Poliakoff, Washington, DC, USA

Yechezkel (Chezy) Barenholz, Hebrew University-Hadassah Medical School, Israel

S. R. Bawa, Bawa Biotech LLC, Schenectady, New York, USASangita Bawa, Novo Nordisk Inc., Princeton, New Jersey, USACharles W. Boylen, Rensselaer Polytechnic Institute, New York, USANancy A. Blair-DeLeon, Institute of Electrical and Electronics Engineers,

New York, New York, USAEsther H. Chang, Lombardi Comprehensive Cancer Center, Georgetown

University Medical Center, Washington DC, USAStanford Chong, Pan Stanford Publishing Pte. Ltd., SingaporeEileen S. Ewing, American Bar Association, Chicago, USAHoward E. Gendelman, University of Nebraska Medical Center, Omaha,

Nebraska, USASusan P. Gilbert, Rensselaer Polytechnic Institute, Troy, New York, USAPaulette Goldweber, John Wiley & Sons, Inc., Hoboken, New Jersey, USAJyotsna Gupta, McLean Medical Center and Urgent Care, McLean, Virginia, USADrew Harris, Nanotechnology Law & Business, Austin, Texas, USAJim Hurd, NanoScience Exchange, San Francisco, California, USAMeghana Hemphill, John Wiley & Sons, Inc., Hoboken, New Jersey, USAArvind Kanswal, Pan Stanford Publishing Pte. Ltd., SingaporeFrancesca Lake, Future Medicine Ltd., London, UKGregory N. Mandel, Temple University Beasley School of Law, Philadelphia,

Pennsylvania, USALucinda Miller, Northern Virginia Community College, Annandale, Virginia,

USAShaker A. Mousa, Albany College of Pharmacy and Health Sciences, Albany,

New York, USAWilliam L. Rich, III, Northern Virginia Ophthalmology, Fairfax, Virginia, USARobin Taylor, University of Nebraska Medical Center, Omaha, Nebraska, USAMary A. Vander Maten, Northern Virginia Community College, Annandale,

Virginia, USATracy Wold, Morton Publishing, Englewood, Colorado, USA

“The distinguished editors have secured contributions from the leading experts in nanomedicine law, business, regulation and policy. This handbook represents possibly the most comprehensive and advanced collections of materials on these critical topics. An invaluable standard resource.”

Gregory N. Mandel, JDPeter J. Liacouras Professor of Law and Associate Dean

Temple University Beasley School of Law, USA

“This is an outstanding volume for those looking to become familiar with nanotechnology research and its translation from the bench to market. Way ahead of the competition, a standard reference on any shelf.”

Shaker A. Mousa, PhD, MBAVice Provost and Professor of Pharmacology, Albany College of Pharmacy, USA

“The editors have gathered the distilled experience of leaders addressing the most salient issues confronted in R&D and translation. Knowledge is power, particularly in nanotechnology translation, and this handbook is an essential guide that illustrates and clarifies our way to commercial success.”

Gregory Lanza, MD, PhDProfessor of Medicine and Oliver M. Langenberg Distinguished Professor

Washington University Medical School, USA

“The title of the handbook reflects its broad-ranging contents. The intellectual property chapters alone are worthy of their own handbook. Dr. Bawa and his coeditors should be congratulated for gathering the important writings on nanotech law, business and commercialization.”

Richard J. Apley, JDChief Patent Officer, Litman Law Offices/Becker & Poliakoff, USA

“It is clear that this handbook will serve the interdisciplinary community involved in nanomedicine, pharma and biotech in a highly comprehensive way. It not only covers basic and clinical aspects but the often missing, yet critically important, topics of safety, risk, regulation, IP and licensing. The section titled ‘Perspectives and Editorials’ is superb.”

Yechezkel (Chezy) Barenholz, PhDProfessor Emeritus of Biochemistry and Daniel Miller Professor of Cancer Research

Hebrew University-Hadassah Medical School, Israel

This handbook examines the entire “product life cycle,” from the creation of nanomedical products to their final market introduction. While focusing on critical issues relevant to nanoproduct development and translational activities, it tackles topics such as regulatory science, patent law, FDA law, ethics, personalized medicine, risk analysis, toxicology, nano‐characterization and commercialization activities. A separate section provides fascinating perspectives and editorials from leading experts in this complex interdisciplinary field.

About the Series EditorDr. Raj Bawa is president of Bawa Biotech LLC, a biotech/pharma consultancy and patent law firm based in Ashburn, VA, USA, that he founded in 2002. He is an entrepreneur, professor, researcher, inventor and registered patent agent licensed to practice before the U.S. Patent & Trademark Office. Trained as a biochemist and microbiologist, he is currently an adjunct professor at Rensselaer Polytechnic Institute in Troy, NY, and a scientific advisor to Teva Pharmaceutical Industries, Israel.

edited by

Pan Stanford Series on Nanomedicine Vol. 2

Raj BawaGerald F. AudetteBrian E. Reese

Baw

aA

udetteR

eese

Handbook of

Clinical Nanom

edicine

Vol. 2Pan Stanford Series on Nanomedicine Vol. 2

Handbook of

Clinical NanomedicineLaw, Business, Regulation, Safety,and Risk

ISBN 978-981-4669-22-1V487