Verfügbarkeit: Biotechnology and the law

Biotechnology and the law:

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Format:	Buch
Sprache:	English
Veröffentlicht:	Chicago, Ill. American Bar Assoc. 2007
Schlagworte:	Recht Biomedical Research > legislation & jurisprudence > United States Biomedical Technology > economics > United States Biomedical Technology > legislation & jurisprudence > United States Biotechnology industries > Law and legislation > United States Biotechnology > United States Health Care Sector > legislation & jurisprudence > United States Biotechnologische Industrie USA
Online-Zugang:	Inhaltsverzeichnis
Beschreibung:	L, 957 S.
ISBN:	9781590317617 1590317610

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adam_text	Contents Preface ..............................................................................................................xxxi About the Editors .............................................................................................xxxv About the Contributors ...................................................................................xxxix Chapter 1 Introduction to Biotechnology and the Law .........................................1 Robert E Coppie A. The Biotech Primer .........................................................................................4 B. Biotech Defined ..............................................................................................4 1. Three-Branch Approach ...........................................................................5 С The Biotech Company Life Cycle ..................................................................5 1. Phase I: Start-up ......................................................................................6 a. Intellectual Property ..........................................................................6 b. Company Formation ..........................................................................7 с Investment Capital .............................................................................7 2. Phase 11: Early Development ....................................................................8 a. Additional Investment ........................................................................8 b. The Regulatory Track ........................................................................9 с Business Growth and Complexity .....................................................9 3. Phase III: Later-Stage Development and Product Approval ..................10 4. Phase IV: Challenges Facing the Now Mature Company ......................10 a. Commercialization ...........................................................................11 b. Regulatory Oversight .......................................................................11 с Litigation ..........................................................................................11 D. Conclusion ....................................................................................................12 Glossary ...............................................................................................................13 Chapter II Managing Innovation: Patent Basics for Biotechnology Counsel .... 25 Dr. Michaeln. Brodowski, Thomas A. Turano, and Dr. Christine C. Vito A. Introduction ...................................................................................................25 B. U.S. Patent Portfolios ....................................................................................26 1. Patent Rights—The Claims ....................................................................26 2. Types of Patents ......................................................................................28 a. Provisional Patent Applications .......................................................29 b. Continuing Patent Application Practice ...........................................30 iii iv Biotechnology and the Law 3. Requirements for Patentability ...............................................................31 4. Preparation of a Patent Application ........................................................34 5. Patent Application Formalities ...............................................................35 6. Publication of Patent Applications .........................................................38 7. Patent Prosecution ..................................................................................39 a. Appeal of Patent Office Final Rejections ........................................41 b. Notice of Allowance ........................................................................42 8. Post-Issue Patent Considerations ...........................................................43 С Foreign Patent Portfolios ..............................................................................45 1. Protection Strategy .................................................................................46 2. Patentability Differences ........................................................................49 3. Other Considerations ..............................................................................51 4. Prerequisites to Filing .............................................................................52 5. Options for Filing in Other Jurisdictions ...............................................53 a. Additional Considerations ...............................................................57 D. Managing the Company s Patent Estate .......................................................58 1. A Family Portrait ....................................................................................58 2. Keeping It in the Family .........................................................................60 3. Skeletons in the Closet ...........................................................................62 a. Rights of Ownership ........................................................................63 b. Correspondence to Products or Business Strategies ........................64 с Freedom to Operate .........................................................................66 Chapter III Company Formation .............................................................................69 Andrew T. Hoyne, Steven E. Pozarle, and Mark L. Stoneman A. Introduction ...................................................................................................69 1. But will it help us get money? ............................................................69 2. The Importance of the Board of Directors .............................................70 3. Speed ......................................................................................................72 4. Simplicity ...............................................................................................73 5. The Role of the Company s Attorneys ...................................................73 B. Biotechnology Company Models .................................................................73 1. Company Formed Before In-Licensing While R&D Continues at University ...............................................................................................74 2. Technology Flip ......................................................................................75 3. Revenue-Funded Company ....................................................................75 4. Corporate Deal-Funded Company ..........................................................75 5. Venture Fund-Launched Company ........................................................76 6. Angel Investor-Funded Company ..........................................................76 7. Significant Self-Funded Company .........................................................77 8. Shoestring Self-Funded Company ..........................................................77 9. Charitable Corporation or Foundation ...................................................78 10. Debt-Funded Company ..........................................................................79 Contents v C. Entity Selection and Formation ....................................................................79 1. No Perfect Choice ..................................................................................79 2. Sole Proprietorships and Partnerships ....................................................80 3. C-corporations ........................................................................................81 a. Limited Liability ..............................................................................82 b. Centralized Management .................................................................82 с Owners .............................................................................................82 d. Transferability of Ownership ...........................................................82 e. Classes of Ownership .......................................................................83 f. Incentive Compensation ...................................................................83 g. Taxation ............................................................................................83 4. S -corporations ........................................................................................84 5. Limited Liability Companies .................................................................88 a. Problems Using an LLC ..................................................................88 b. LLC Organization ............................................................................91 6. Exotic Entity Types ................................................................................95 7. State of Organization ..............................................................................95 8. Name Selection .......................................................................................97 D. Capital Structure and Stock Grants ...............................................................99 1. Introduction ............................................................................................99 2. Securities Law Compliance ....................................................................99 3. Founders Stock, Restricted Stock, and Stock Options .........................100 4. Common and Preferred Stock ..............................................................105 E. Relationships with Early Participants .........................................................107 1. Founders ...............................................................................................108 2. Board of Directors ................................................................................109 3. Scientific Advisory Board (SAB) .........................................................110 4. Management ......................................................................................... Ill a. Chief Executive Officer ................................................................. Ill b. Chief Financial Officer ..................................................................112 с Chief Scientific Officer ..................................................................112 d. Clinical/Regulatory ........................................................................113 5. Employees ............................................................................................113 F. Incubators ....................................................................................................114 G. University Relationships .............................................................................115 H. Early-Stage Company Agreements .............................................................117 1. Brief Review of Intellectual Property for the Non-IP Attorney ...........117 a. Patents ............................................................................................118 b. Trade Secrets ..................................................................................118 с Trademarks ....................................................................................119 d. Copyrights ......................................................................................121 2. Confidentiality Agreements ..................................................................122 vi Biotechnology and the Law 3. Material Transfer Agreements ..............................................................124 4. Research Collaboration Agreements ....................................................126 I. Positioning for an Exit ................................................................................127 Appendix A: Mutual Confidentiality Agreement ..............................................132 Chapter IV Acquisition of Biotechnology—Technology Transfer .....................139 Hugh B. Wellons A. Technology Creation ...................................................................................140 1. Protecting Propriety of the Invention in the Early Stages ....................140 a. Confidentiality Agreements ...........................................................140 b. Who Was First? ..............................................................................141 с Company Records ..........................................................................142 2. Keeping Necessary Records .................................................................143 3. Who Owns What? (Employer v. Employee and JV Issues) .................143 a. Work Made for Hire .......................................................................143 b. Employee Rights ............................................................................145 с State Laws ......................................................................................145 d. Canadian and European Union Laws .............................................146 e. Trade Secrets ..................................................................................147 f. Joint Venture Ownership ................................................................148 4. Patent Filing: Protecting an Invention and Limiting Others Use ........149 a. Why File a Patent? .........................................................................149 b. Patent Requirements ......................................................................149 с Patent Claims and Rights ...............................................................150 d. Types and Stages of Patents ...........................................................150 e. Patent Prosecution ..........................................................................151 f. Post-Issue Considerations ..............................................................151 g. Foreign Patent Filing .....................................................................152 5. Possible Effects of Outside Funding ....................................................152 a. Ownership ......................................................................................152 b. Public Domain ...............................................................................154 с Manufacturing or Sales Restrictions ..............................................154 B. Forms of Technology Transfer ....................................................................155 1. Acquisition of Owner ...........................................................................155 a. Acquiring the Owner .....................................................................155 b. Employing the Owner ....................................................................155 2. Assignment ...........................................................................................156 3. License and Sublicense ........................................................................156 a. Common Form of Transfer ............................................................156 b. Alternative to Assignment .............................................................156 с Sublicense ..............................................................................,.......158 4. Fair Use Agreement ..............................................................................158 Contents vii a. Fair Use and Experimental Use .....................................................158 b. Fair Use Agreements ......................................................................160 с Doctrine and Agreements Effect on Intellectual Property Ownership and Due Diligence .......................................................160 5. Public Domain ......................................................................................161 C. Transfer from Academia .............................................................................162 1. University Considerations ....................................................................162 2. Material Transfer Agreements ..............................................................168 3. Principal Investigator Considerations ..................................................169 a. Conflict of Interest and Conflict of Commitment .........................169 b. Conflict of Interest .........................................................................169 c. Conflict of Commitment ................................................................170 d. Special Knowledge ........................................................................171 4. Licensee Considerations .......................................................................171 a. Policies and Procedures .................................................................172 b. It s a Long Way to Market, So Wrap Up the People You Need .....172 с Public Disclosure? .........................................................................173 d. Stakeholders ...................................................................................173 5. Interests of Other Stakeholders ............................................................174 a. Other Underwriters ........................................................................174 b. Government Agencies ....................................................................174 с Special Government Considerations ..............................................174 d. Nonprofits ......................................................................................175 6. Common Restrictions ...........................................................................175 a. License Only, Not an Assignment ..................................................175 b. Time Limitations ............................................................................176 с Restrictions on Participation by the Inventors ...............................176 d. Audit ..............................................................................................176 e. Scope of License ............................................................................176 f. Indemnification ..............................................................................176 g. Sublicense Approval ......................................................................176 h. Sublicensee Subject to License Terms ...........................................176 i. Original Licensee Always Liable ...................................................177 j. Cannot Use the Name of the University ........................................177 k. Government Has a License ............................................................177 1. Other General Restrictions You Would Find in Most Other Licensing Agreements ...................................................................177 7. Common Guidelines for Price and Provisions of the License .............177 a. Standstill Fee ..................................................................................177 b. Up-front License Fee .....................................................................177 с Minimum Annual Payment ............................................................178 d. Periodic Licensing Fees (Such as Quarterly or Annual) ................178 e. Participation in Third-Party Payments ...........................................178 viii Biotechnology and the Law f. Lump-Sum Royalties .....................................................................178 g. Milestone Payments .......................................................................178 h. Sales-Based Royalties ....................................................................178 i. Equity in the Licensee ....................................................................179 j. Equity Protections ..........................................................................179 k. Put of Shares ..................................................................................179 1. A Time for Sale ..............................................................................179 8. When Equity Is the Primary Consideration for the License ................179 9. Applicability of Bayh-Dole Act ...........................................................180 10. Application of CREATE Act of 2004..............................................183 11. Conflict between Publication and Protection of IP ..............................183 D. Transfer from Other Nonprofit Entities ......................................................184 1. Implications of Nonprofit Status ..........................................................184 2. Unrelated Business Income Tax ...........................................................185 3. Priorities of Nonprofit Technology Owner ...........................................185 4. Joint Venturing (especially qualification for STTR grants) .................186 a. SBIR Grants ...................................................................................186 b. STTR Grants ..................................................................................187 с Problems with STTR and SBIR Grants .........................................187 5. Common Misconceptions .....................................................................187 6. Case Study — Howard Hughes Medical Institute ..................................188 a. Assignment of Rights ....................................................................188 b. Sharing Patent Costs and Royalties ...............................................189 с Equity Ownership ..........................................................................189 d. Collaborations ................................................................................189 e. Time Limitations ............................................................................189 f. Start-up Companies .......................................................................189 g. Summary ........................................................................................190 E. Transfer from Individuals ...........................................................................190 1. Consideration of Terms ........................................................................190 a. Parties .............................................................................................190 b. Recitals ...........................................................................................190 с Definitions .....................................................................................190 d. Property Licensed ..........................................................................190 e. Scope of the Assignment or License .............................................. 191 f. Territory .........................................................................................191 g. Right to Sublicense .......................................................................192 h. Follow-on and Later-Developed Technology ...............................192 i. Term and Renewal of License ........................................................192 j. Termination ....................................................................................193 k. Deliveries .......................................................................................193 1. Retention of Rights ........................................................................193 Contents ix m. Payments, Including Fees, Royalties, Stock (Options, Warrants), Milestone, etc .................................................................................193 n. Audit Rights ...................................................................................194 o. Reporting and Marketing Responsibility .......................................194 p. Representations and Warranties of the Inventor ............................194 q. Indemnification ..............................................................................194 r. IP Protection ..................................................................................194 s. Insurance ........................................................................................194 t. Assignability ..................................................................................195 u. Amendments ..................................................................................195 v. Alternative Dispute Resolution (ADR) ..........................................195 w. Boilerplate Language .................................................................195 2. Common Negotiation Points ................................................................196 a. Price Paid/Consideration ................................................................196 b. Fees and Royalties Are Both Negotiable Points ............................196 с Records and Reporting ...................................................................197 d. Warranty .........................................................................................197 e. Indemnification ..............................................................................197 f. IP Matters .......................................................................................197 g. Confirmation of Ownership ...........................................................198 3. Patent Filing .........................................................................................199 F. Summary .....................................................................................................199 Chapter V Financing a Biotech Company ...........................................................203 William N. Wofford A. Overview .....................................................................................................204 1. Drug Development Costs .....................................................................204 2. Product Development Time Lines ........................................................206 B. Basic Securities Law Considerations ..........................................................209 1. Registration or Exemption Under the Securities Act ...........................209 2. Section 4(2) Exempt Transaction .........................................................210 3. Regulation D Exempt Transaction .......................................................210 4. Rule 701— Compensation Plans ...........................................................212 5. State Blue Sky Laws .........................................................................213 С Pre-seed and Seed Capital ...........................................................................214 1. Founders Stock ....................................................................................214 a. Restrictions on Transfer .................................................................215 b. Vesting ...........................................................................................215 с Lock-up ..........................................................................................216 d. Drag-along .....................................................................................217 2. Employee Stock ....................................................................................218 a. Plan Basics .....................................................................................218 b. Securities ........................................................................................219 Biotechnology and the Law с Tax .................................................................................................. 219 d. Corporate .......................................................................................220 e. Commercial ....................................................................................221 3. Stock to Service or Technology Providers ...........................................221 a. Securities ........................................................................................222 b. Tax ..................................................................................................222 с Conflicts of Interest .......................................................................223 4. Friends and Family ...............................................................................223 a. Securities ........................................................................................223 b. Corporate .......................................................................................224 5. Loans ....................................................................................................224 6. Generating Revenues to Reduce or Defer Need for Investment ..........225 a. Intellectual Property .......................................................................225 b. Commercial ....................................................................................226 7. Government Funding ............................................................................226 a. SBIR Grants ...................................................................................226 b. STTR Grants ..................................................................................227 c . Advantages to Receiving Federal Grant Funding ..........................228 d. Disadvantages to Receiving Federal Grant Funding .....................228 e. Eligibility/51 Percent Rule ............................................................228 f. State Resources ..............................................................................230 D. Venture Capital ............................................................................................230 1. Financial Rights ....................................................................................231 a. Valuation ........................................................................................231 b. Liquidation Preference ...................................................................231 с Participating Preferred ...................................................................231 d. Accruing Dividends .......................................................................232 e. Protection of Ownership Percentage .............................................232 2. Governance Rights ...............................................................................233 a. Board Representation .....................................................................233 b. Protective Provisions/Class Voting ................................................233 3. Exit Rights ............................................................................................233 a. Registration Rights ........................................................................234 b. Redemption Rights ........................................................................234 с Co-sale Rights ................................................................................235 4. Series B—Time to Start All Over .........................................................235 E. Corporate Investment ..................................................................................236 F. Initial Public Offering .................................................................................237 G. Post-IPO Financing .....................................................................................239 1. PIPES ....................................................................................................239 2. Convertible Debt ...................................................................................240 3. Project Finance .....................................................................................241 Contents xl H. Conclusion ..................................................................................................241 Glossary of Frequently Used Terms ..................................................................253 Chapter VI Employment Issues for Biotechnology Companies ........................265 Jeffrey A. Van Doren A. Employment At Will ...................................................................................265 B. Employee or Independent Contractor .........................................................266 1. The Common-Law Control Test ...........................................................267 2. The 1RS Control Test ............................................................................268 3. The Economic Reality Test ..................................................................270 4. Potential Liability .................................................................................271 С Employer Coverage Under Federal Civil Rights Laws ..............................272 1. Title VII of the Civil Rights Act of 1964 (42 U.S.C. § 2000e et seq.).....................................................................................272 a. Basic Coverage ..............................................................................272 b. Sexual Harassment .........................................................................273 2. Age Discrimination in Employment Act (ADEA) (29 U.S.C. § 621 et seq.)........................................................................................273 a. Basic Coverage ..............................................................................273 b. Older Workers Benefit Protection Act ..........................................273 3. Americans with Disabilities Act (42 U.S.C. § 12,101 et seq.).............274 a. Basic Coverage ..............................................................................274 b. Reasonable Accommodation .........................................................274 4. Equal Pay Act (29 U.S.C. § 206(d)) .....................................................275 D. Employer Coverage Under State and Local Civil Rights Laws ..................275 1. State Civil Rights Law ..........................................................................275 2. Local Laws and Ordinances .................................................................275 E. Equal Opportunity and Affirmative Action Obligations of Government Contractors and Subcontractors ..................................................................276 F. Other Federal Employment Laws ...............................................................277 1. Fair Labor Standards Act (FLSA) (29 U.S.C. § 201 et seq.)................277 a. Basic Coverage ..............................................................................277 b. Basic Requirements .......................................................................277 2. Family and Medical Leave Act (29 U.S.C. § 2601 et seq.)..................281 3. National Labor Relations Act (29 U.S.C. § 151 et seq.)......................281 a. Coverage of the NLRA ..................................................................281 b. Employee Rights under the NLRA ................................................282 с Protected Concerted Activity .....................................................282 d. Union Organizing ...........................................................................282 e. NLRA Applicability to Non-union Employers ..............................283 4. Employee Retirement Income Security Act (ERISA) (29 U.S.C. § 1001 et seq.)......................................................................................285 xii Biotechnology and the Law 5. Occupational Safety and Health Act (OSHA) (29 U.S.C. § 651 et seq.)..................................................................................................285 6. Immigration Reform and Control Act 1986 (IRCA) ( 18 U.S.C. Ş274A-274C) .......................................................................................286 7. Uniformed Services Employment and Reemployment Rights Act of 1994 (USERRA) (38 U.S.C. § 4301 et seq.)....................................287 8. Fair Credit Reporting Act (FCRA) (15 U.S.C. § 1681 et seq.)............287 a. Written Notice and Authorization ..................................................287 b. Adverse Actions Procedures ..........................................................288 9. Employee Polygraph Protection Act (29 U.S.C. § 2001 et seq.)..........288 G. Use of Employment Contracts ....................................................................288 1. When Is an Employment Agreement Useful? ......................................289 a. Security ..........................................................................................289 b. Recruitment Incentive ....................................................................289 с Defined Performance Expectations ...............................................289 d. Defined Compensation Expectations .............................................289 e. Confidentiality and IP Ownership .................................................290 2. Items to Be Covered .............................................................................290 a. Duration .........................................................................................290 b. Position and Title ...........................................................................291 с Compensation ................................................................................291 H. Employee Handbooks .................................................................................299 1. Pros and Cons of Using ........................................................................299 a. Reasons for Using ..........................................................................299 b. Reasons for Not Using ...................................................................300 2. Items to Be Covered .............................................................................301 a. Disclaimers and At-Will Statements ..............................................301 b. EEO Policies ..................................................................................301 с Harassment Policy .........................................................................302 d. Family and Medical Leave Policy .................................................302 e. E-mail and Computer Usage Policy ..............................................303 f. Description of Benefits ..................................................................303 g. Discipline Policy ............................................................................303 I. Immigration Options for Biotech Employees .............................................304 1. Obtaining a Visa and U.S. Entry ...........................................................304 2. Non-immigrant Visas ............................................................................305 a. Н -IB Specialty Worker Visa ......................................................305 b. TN NAFTA Professional Visa ....................................................307 c. L-l Intracompany Transfer Visa .................................................308 d. Е -l Treaty Trader and E-2 Treaty Investor Visas ...................309 e. О -l Extraordinary Ability Alien Visa .........................................310 3. Immigrant Visas and Permanent Residence Status ..............................312 Contents x«» a. Employment-Based Preferences ....................................................312 b. Visa Backlogs and Priority Dates ..................................................314 с Labor Certification .........................................................................314 d. Immigrant Visa and Adjustment of Status .....................................315 Appendix A: Coverage of State Equal Rights Statutes .....................................318 Chapter VII Federal Regulation of Research Through Funding ..........................325 G. Melissa Ince and Jenny Kim A. Grants and Contracts ...................................................................................326 1. Federal Research Grants .......................................................................326 a. Subgrants .......................................................................................327 b. Terms and Conditions ....................................................................328 с Grantor Agencies ...........................................................................330 i. Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Program Grants .........330 ii. SBIR ........................................................................................331 iii. STTR .......................................................................................331 2. Contracts ...............................................................................................332 a. Sale of Commercial Items and Services ........................................332 b. Procurement Integrity: Off-limits Information ............................337 с Allowable and Unallowable Costs .................................................340 d. Product Substitution .......................................................................342 B. SBIR and STTR Grants ..............................................................................344 1. SBIR Grants .........................................................................................344 2. STTR Grants .........................................................................................345 3. Basic Characteristics ............................................................................346 4. NIH Guidance ........................:..............................................................347 a. Significance ...................................................................................347 b. Approach ........................................................................................348 с Innovation ......................................................................................348 d. Environment .............................................. .....................................349 5. Protection of Human Subjects ..............................................................349 6. Vertebrate Animals ...............................................................................350 7. Criteria ..................................................................................................351 8. Phase II Application Review Criteria ...................................................351 9. Amended Applications .........................................................................352 10. Phase I/Phase II Fast-Track Application Review Criteria ...................352 11. Phase II — Competing Continuation Application Review Criteria ......352 С Ethics, Outside Activities, and Employment ..............................................353 1. Grants ...................................................................................................353 a. Standards of Conduct .....................................................................353 b. Financial Conflict of Interest .........................................................353 xiv Biotechnology and the Law с Misconduct in Science and Engineering ........................................354 2. Contracts ...............................................................................................354 a. Organizational Conflicts of Interest ...............................................354 b. Employment Discussions With and Hiring of U.S. Government Personnel ........................................................................................356 с The National Institutes of Health (NIH) Government Employee Supplemental Regulations on Permitted Outside Activities ........................................................................................358 Chapter VIII Regulation of Preclinical Research ...................................................407 Daniel T. Pancamo A. Animal Use in Biomedical Research and Testing ......................................408 1. The Basic Regulatory Scheme—the Animal Welfare Act (7 U.S.C. §§ 2131-2159) and Regulations (9 C.F.R. Parts 1-4)...........................408 a. Overview of the AWA ....................................................................408 b. Overview of the AWA Regulations ................................................411 i. General Overview ....................................................................411 ii. Registration .............................................................................412 iii. The IACUC .............................................................................412 iv. Personnel Qualifications, Veterinary Care, Record Keeping ...................................................................................415 с Implementation and Enforcement of the AWA and the AWA Regulations by the USDA Animal and Plant Health Inspection Service (APHIS) ...........................................................417 2. U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training (50 Fed. Reg. 20,864-02 (1985))..........................................................418 3. Memorandum of Understanding Among APHIS/USD A, the FDA and the NIH ..........................................................................................419 4. NIH Considerations ..............................................................................420 a. Health Research Extension Act; NIH ............................................420 b. NIH Extramural Research ..............................................................421 c. Guide for the Care and Use of Laboratory Animals; Institutional Animal Care and Use Committee Guidebook ...............................422 5. FDA Considerations .............................................................................423 6. CDC Considerations .............................................................................424 7. State Law ..............................................................................................424 8. Conclusion ............................................................................................424 B. Other Regulatory Schemes Applicable to Preclinical Research — Protection of the Environment and Public Heath .......................................425 1. Introduction ..........................................................................................425 2. EPA Jurisdiction and RCRA ................................................................425 Contents xv 3 . Issues in Applying Environmental Law to Research Facilities ............433 4. IACUC Responsibility ..........................................................................434 5. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002; Select Agents and Toxins ................................434 C. Other Regulatory Schemes Applicable to Preclinical Research — Occupational Safety and Health Considerations and the Protection of Individuals Conducting Preclinical Research .............................................438 1. Introduction ..........................................................................................438 2. Occupational Safety and Health Administration (OSHA) Regulation; Standards; Resources ............................................................................439 3. Selected Resource Tools — Chemicals and Biohazards ........................441 4. Radioactive Materials in the Research Setting .....................................442 D. Conclusion ..................................................................................................442 Chapter IX Research and Development Collaborations .....................................445 Eileen Smith Ewing A. Introduction: The Collaborator as Biotechnology s White Knight .............445 B. Finding a Strategic Partner: Beating the Mathematical Odds ....................446 С Negotiating a Term Sheet ............................................................................449 1. The Importance of the Term Sheet to the Transaction .........................449 2. Issues Crucial to Address at the Term Sheet Stage ..............................450 3. Issues to Avoid Negotiating at the Term Sheet Stage ...........................451 D. Key Issues in a Research Collaboration Agreement ...................................452 1. Governance of the Research Collaboration ..........................................452 a. Composition of the Joint Steering Committee ..............................452 b. Duties of the Joint Steering Committee .........................................453 с Meetings of the Joint Steering Committee ....................................453 d. Decisionmaking by the Joint Steering Committee ........................453 2. The Scope of the Collaboration ............................................................454 a. Held ...............................................................................................455 b. Scope Limitations Based on Patent Family ...................................456 с Scope Limitations Based on Timing ..............................................456 d. Scope Limitations Based on Project Funding ................................456 3. Intellectual Property .............................................................................456 a. Core Intellectual Property of the Smaller Partner, Developed Prior to the Collaboration but Highly Relevant .............................457 b. Core Intellectual Property of the Larger Funding Partner, Developed Prior to the Collaboration but Highly Relevant ...........457 с Background Intellectual Property of the Smaller Partner, Developed Prior to the Collaboration but of Possible Utility ........457 d. Background Intellectual Property of the Larger Funding Partner, Developed Prior to the Collaboration but of Possible Utility .............................................................................................458 xvi Biotechnology and the Law e. Intellectual Property Developed by One or Both Parties Arising out of the Collaboration .................................................................458 f. Intellectual Property Developed by the Smaller Partner During, but Outside of, the Collaboration ...................................................458 g. Novel Intellectual Property Developed by One or Both Parties During the Collaboration That Does Not Arise out of the Existing Intellectual Property of Either Party ..........................459 4. License Grants ..................................,...................................................459 a. Research Licenses ..........................................................................460 b. Development and Commercialization License ..............................460 с Cross-Licenses; Freedom to Operate .............................................460 d. Enabling License ............................................................................461 e. License as Protection Against Infringement Claims ......................461 5. Financial Terms ....................................................................................462 a. Signature Payments ........................................................................462 b. Research Funding ..........................................................................463 с Equity Investments .........................................................................463 i. Pricing the Equity ....................................................................463 ii. Multiple Tranches ....................................................................464 iii. Advantages of Equity Investment by a Collaborator ..............464 iv. Disadvantages of Equity Investment by a Collaborator ..........465 d. Milestone Payments .......................................................................465 6. Option to Develop and Commercialize ................................................469 a. Notice of Exercise ..........................................................................469 b. Right of First Refusal .....................................................................469 c. Right of First Negotiation ..............................................................470 d. Rights in Unoptioned Intellectual Property ...................................470 7. Term and Termination ..........................................................................471 a. Term ...............................................................................................471 b. Early Termination ..........................................................................471 E. Post-Closing Pitfalls That Can Derail a Research and Development Collaboration ...............................................................................................472 1. Change in Strategic Fit or Commitment to the Project ........................472 2. Communication and Control Issues ............... ......................................475 3. Unrealistic Expectations .......................................................................475 F. Alliances with Third Parties— Keeping Other Options Open ....................475 1. Right of First Refusal May Preclude Other Transactions ....................476 2. Right of First Negotiation May Also Have a Chilling Effect ...............476 3. The Deal May Be Worth It; Rely on Contractual Protections ..............476 G. Conclusion: Where Do the Parties Go From Here? ....................................477 Contents xvii Chapter X FDA Regulation of Biomedical Research .........................................479 Robert B. Nicholas A. Introduction .................................................................................................479 1. Introductory Note on Biotechnology and Clinical Trials .....................480 B. Part One — Overview of the Regulatory Framework ..................................481 1. The History, Goals, and Purpose of Regulation ...................................481 2. Government Regulation of Clinical Research ......................................481 3. The Roles and Obligations of the Parties .............................................483 a. Sponsor ..........................................................................................484 b. Contract Research Organization (CRO) ........................................484 с Institutional Review Board (IRB) ..................................................485 d. Principal Investigator (PI) ..............................................................486 e. The Legal Relationships Between the Parties: Contractual Agreements ....................................................................................487 i. The Sponsor and Principal Investigator ..................................487 ii. The Sponsor and the CRO .......................................................488 iii. The Principal Investigator and the Study Subject ...................489 С Part Two—Anatomy of a Clinical Trial ......................................................490 1. Before the Trial Can Begin ...................................................................490 a. Drugs: Investigational New Drug Applications (IND) ..................490 b. Devices: Investigational Device Exemption (IDE) ........................490 с IRB Approval of the Protocol, ICF, and Study Advertisement ......491 2. Beginning and Conducting the Trial ....................................................491 a. Subject Enrollment and Test Article Administration .....................491 b. Control of the Trial: Record Keeping and Reporting ....................493 3. After the Trial .......................................................................................494 a. Submission and Audit ....................................................................494 b. FDA Inspection ......................................................:.......................495 с Administrative Actions — Civil and Criminal Penalties .................497 4. Preparing for FDA Inspections and Responding to FDA Allegations of Misconduct ...................................................................497 5. FDA Criminal Actions and Other Potential Consequences: Qui Tarn Suits and Adverse Publicity ...................................................498 D. Part Three — Conduct and Use of Non-U.S. Studies ...................................499 1. IMMDEorNot ....................................................................................499 2. FDA Acceptance and Use of Non-U.S. Clinical Data ..........................500 3. Export of Test Article ...........................................................................500 4. EU Clinical Trial Directive ...................................................................500 E. Conclusion ................................................... ...............................................501 xviii Biotechnology and the Law Chapter XI Privacy Issues for Biotechnology Companies .................................509 Steve A. Schwärm and Anne Stohr O Brien A. Introduction ..................................................................................................509 B. The National Approach to Health-Care Privacy ...........................................512 1. Health Insurance Portability and Accountability Act of 1996.............512 2. HIPAA Privacy Regulations .................................................................518 a. Individual Rights ............................................................................518 i. Notice of Privacy Practices .....................................................519 ii. Restriction of PHI by Individual Patient .................................521 iii. Access of Individuals to PHI ...................................................521 iv. Amendment or Change of PHI ................................................523 v. Accounting of Disclosures ......................................................524 b. Use and Disclosure for Treatment, Payment, and Health-Care Operations ......................................................................................525 с Disclosure of PHI with Authorization or by Agreement ...............526 i. Authorizations .........................................................................526 ii. Defective Authorization ..........................................................528 iii. Combined Authorizations ........................................................528 iv. Conditioning of Authorizations ...............................................528 v. Revocation of Authorizations ..................................................529 vi. Authorizations for Marketing ..................................................529 vii. Use or Disclosure Requiring Patient Opportunity to Agree or Object ..................................................................................529 d. Disclosure Pursuant to a Public Policy Exception .........................530 i. As Required by Law — 45 C.F.R. § 164.512(a) ....................530 ii. Uses and Disclosures for Public Health Activities — 45 CF.R. § 164.512(b) (Includes child abuse reporting) ........531 iii. Disclosures About Victims of Abuse, Neglect or Domestic Violence— 45 C.F.R. § 164.512(c) ..........................................532 iv. Uses and Disclosures for Health Oversight Activities — 45 CF.R. § 164.512(d) ............................................................534 v. Disclosures for Judicial and Administrative Proceedings — 45 C.F.R. § 164.512(e) ............................................................534 vi. Disclosure for Law Enforcement Purposes —45 C.F.R. § 164.512(f)* ...........................................................................536 vii. Uses and Disclosures about Decedents —45 C.F.R. § 164.512(g) ............................................................................536 viii. Uses and Disclosures for Cadaveric Organ, Eye or Tissue Donation Purposes— 45 C.F.R. § 164.512(h) ..........................536 ix. Uses and Disclosures for Research Purposes —45 C.F.R. § 164.512®.............................................................................537 Contents xix χ. Uses and Disclosures to Avert a Serious Threat to Health or Safety-^5 CRR. § 164.512(j) ...............................................539 xi. Specialized Government Function —45 C.F.R. § 164.512(k) ............................................................................539 xii. Disclosures for Workers Compensation —45 C.F.R. § 164.512 (1)............................................................................539 e. Disclosure Pursuant to a Business Associate Agreement — (45 CER. § 164.502(e) and § 164.504(e)) ....................................539 f. Disclosure Pursuant to a Data Use Agreement ..............................542 3. Preemption Issues .................................................................................543 C. Recognition of State Approach to Health-Care Privacy .............................544 D. HIPAA Interplay with Federal Common Rule and Federal Certificates of Confidentiality .....................................................................545 1. Introduction ..........................................................................................545 2. Research and HIPAA ............................................................................545 a. When Research Is Subject to HIPAA ............................................545 b. Permission to Use or Disclose Research Information ...................546 i. Use or Disclosure Without Authorization ...............................546 ii. Research Use/Disclosure with Individual Authorization ........547 3. The Common Rule and HIPAA ............................................................547 4. Research and Business Associate Status Under HIPAA ......................549 5. Federal Certificates of Confidentiality .................................................549 a. Certificates of Confidentiality Explained ......................................549 b. National Institutes of Health Statement on Certificates of Confidentiality ...............................................................................550 E. Research Issues and Academic Medical Centers ........................................551 F. Canadian Privacy Legislation .....................................................................551 1. Accountability ......................................................................................552 2. Identifying Purpose ..............................................................................553 3. Consent .................................................................................................553 4. Limiting Collection ..............................................................................554 5. Limit Use, Disclosure, and Retention ..................................................554 6. Accuracy ...............................................................................................554 7. Safeguards ............................................................................................554 8. Openness ..............................................................................................554 9. Individual Access .................................................................................555 10. Challenging Compliance ......................................................................555 Chapter XII Medical Reimbursement .....................................................................563 Paul W. Radensky A. Reimbursement Basics ................................................................................563 1. Key Terms and Concepts ......................................................................563 2. Coverage ...............................................................................................564 xx Biotechnology and the Law a. Determining the Scope of Benefits ................................................564 b. Checking for Specific Exclusions from Coverage .........................565 с The Reasonable and Necessary Test ..............................................565 d. Medical Necessity for the Particular Patient .................................566 e. Implications of Coverage/Non-coverage .......................................567 f. Coverage Process ...........................................................................567 3. Payment Law and Policy ......................................................................568 4. Coding ..................................................................................................569 5. Appeals .................................................................................................571 6. Who Are the Payers? ............................................................................574 B. Applying the Basics ....................................................................................574 1. Coverage, Payment, and Coding for Drugs and Biologicals ................574 2. Coverage, Payment, and Coding for Procedures Involving the Use of Medical Devices .......................................................................576 3. Coverage, Payment, and Coding for Durable Medical Equipment, . Prosthetics, Orthotics, and Supplies .....................................................578 4. Coverage, Payment, and Coding for In Vitro Diagnostics ...................579 С Special Payment Rules for New Technologies ...........................................579 1. Inpatient Prospective Payment System ................................................579 2. Outpatient Prospective Payment System ..............................................580 3. Ambulatory Surgical Centers — Payment for New Technology Intraocular Lenses ................................................................................580 4. Private Payer Carve-outs ......................................................................581 D. Reimbursement for Investigational Products ..............................................581 1. National Coverage Determination on Routine Costs of Qualifying Clinical Trials .......................................................................................581 2. Investigational Device Exemptions ......................................................582 E. Compliance Considerations ........................................................................583 1. Requirements for Proper Billing ..........................................................583 2. Reimbursement Support Services ........................................................586 3. Discounts and Related Fraud and Abuse Considerations .....................586 F. Conclusions .................................................................................................587 Table of Acronyms .............................................................................................588 Chapter Xiii Approval of Products for Human Use ...............................................591 Areta L. Kupchyk A. Standard Pathways to Market .....................................................................591 1. Drugs ....................................................................................................591 a. Preclinical ......................................................................................591 b. Investigational New Drug Applications ................................ .........592 i. Exemption from Law ...............................................................592 ii. Institutional Review Boards ..................................,.................593 iii. Clinical Hold ...........................................................................593 Contents iv. Types of INDs .........................................................................595 v. Phases of Clinical Trials ..........................................................595 с New Drug Applications ..................................................................596 i. New Drug Application Content and Format Requirements .... 597 ii. Facility Inspection ...................................................................600 iii. Labeling Review ......................................................................600 iv. Advisory Committees ..............................................................602 v. Completion of Review and Decision .......................................602 d. Generic Drugs ................................................................................603 i. Abbreviated New Drug Applications ......................................603 e. 505(b)(2) Applications ...................................................................605 2. Biological Products ..............................................................................605 3. Human Cells, Tissues, and Cellular and Tissue-Based Products .........607 4. Medical Devices ...................................................................................608 a. Device Classifications ....................................................................609 i. Class I Medical Devices ..........................................................609 ii. Class II Medical Devices .........................................................609 iii. Class III Medical Devices .......................................................609 b. The 51000 Notification Process ....................................................609 с The Premarket Application Process ...............................................610 d. Investigational Device Exemption .................................................610 5. Combination Products ..........................................................................610 B. Special Pathways to Market ........................................................................612 1. Fast-Track Programs ............................................................................612 2. Orphan Drug Designation ....................................................................614 С Future Pathways to Market .........................................................................615 Chapter XIV The Regulation of Biomedical Products for Animal Use ................623 Robert B. Nicholas and Kent D. McClure A. Regulation of Animal Health Products .......................................................623 B. The Animal Health Industry .......................................................................625 1. Development Incentives .......................................................................625 2. Size Matters ...................................................................................:......625 3. Complexity ...........................................................................................627 С Biotechnology-Derived Products ................................................................628 D. Overview of FDA Regulation of Animal Drugs .........................................629 1. FDA Regulates Animal Drugs: Defined ...............................................629 2. Critical Elements in the Regulatory Regime ........................................630 a. Approval of New Animal Drags ....................................................631 b. Denial and Withdrawal of Approval of New Animal Drags ..........632 с Post-approval Requirements ..........................................................632 d. Inspection, Enforcement, and Compliance ....................................632 xxii Biotechnology and the Law E. Distinguishing Factors Between FDA Regulation of Animal and Human Drugs .......................................................................................633 1. Drags for Food Animals: Human Food Safety .....................................633 2. Drags Administered in Animal Feed ....................................................635 3. Import of Use of an Approved Drag in Different Species; Minor Species and Uses; Use in Pets; Animal Drug Availability ...................636 4. Practical Considerations for Interacting with the Center for Veterinary Medicine (CVM) ................................................................637 F. CVM Regulation of Biotechnology Products .............................................639 G. Overview of USDA Regulation of Animal Biological Products ................641 1. USDA Regulates Veterinary Biologies .................................................641 2. Overview: Virus-Serum-Toxin Act .......................................................642 3. Critical Elements in the APHIS Regulatory Requirements ..................642 a. Veterinary Biologies Defined .........................................................642 b. Licensing ........................................................................................643 с Permits ...........................................................................................644 d. Standard Requirements ..................................................................644 e. Record Keeping .............................................................................644 f. Adverse Event Reports ..................................................................645 g. Enforcement Procedures ................................................................645 h. Exemptions to the Regulations ......................................................645 4. The Agricultural Bioterrorism Protection Act of 2002........................646 5. Animal Health Protection Act ..............................................................646 6. Special Consideration for Biotech Biologies .......................................647 H. Conclusion ..................................................................................................648 Chapter XV Approval Process for Biotechnology Products in Agricultural Use ..................................................................................................661 Dr. J. Winston Porter A. Coordinated Federal Framework ................................................................662 B. Role of the Environmental Protection Agency ...........................................664 С Role of the U.S. Department of Agriculture ...............................................666 D. Role of the Food and Drag Administration ................................................668 E. Role of the States in Regulation of Biotech Crops .....................................670 1. EPA and the States ................................................................................670 2. USDA and the States ............................................................................670 3. FDA and the States ...............................................................................671 F. Biotech Crop Regulation in Other Countries ..............................................671 1. Argentina ..............................................................................................672 2. Brazil ....................................................................................................672 3. Canada ..................................................................................................673 4. China ....................................................................................................674 5. European Union ....................................................................................674 Contents xxiii Chapter XVI Legal Requirements After Approval ..................................................677 Areta L. Kupchyk A. The Food and Drug Administration ............................................................677 B. Office of Inspector General, Department of Health and Human Services .......................................................................................................679 С The Neurontin Case .....................................................................................679 D. Import and Export Requirements ................................................................680 E. Current Good Manufacturing Practice Requirements ................................682 F. Reporting Requirements to FDA ................................................................683 1. Drug and Biological Products ..............................................................683 2. Medical Devices ...................................................................................684 3. Promotional Materials: Form FDA-2253 .............................................686 G. Sales and Marketing Regulations ................................................................686 1. Prescription Drug Marketing Act .........................................................686 2. FDA Regulation of Advertising ............................................................687 3. Three Basic Types of Advertisements ..................................................691 a. Product-Claim Advertisements ......................................................691 b. Reminder Advertisements ..............................................................691 с Help-Seeking Advertisements ........................................................691 4. Requirements for Product Claim Advertisements ................................691 5. Print Advertisements: the Brief Summary ...........................................692 6. Broadcast Advertisements: the Major Statement .................................692 7. Prior Approval and Post-Marketing Notification .................................693 8. FDA Notification ..................................................................................694 9. Promotion of Off-Label Use .................................................................694 10. Exchange of Scientific Information ....................................................695 11. The First Amendment ...........................................................................696 12. Other Cases of Interest—Product Liability ..........................................699 13. The Federal Trade Commission ...........................................................699 H. Withdrawal of FDA Approval .....................................................................700 I. False Claims Act ...................................................................................701 J. Anti-kickback Statute and Other Illegal Remuneration .......................701 Chapter XVII Development and Commercialization Alliances ..............................707 Eileen Smith Ewing A. Introduction: Why Choose to Partner? .......................................................707 B. Considerations in Choosing a Partner .........................................................708 С The Stage of the Drug Candidate Will Define the Alliance ........................708 1. Early-Stage Deals .................................................................................709 a. Target Identification and Validation ...............................................709 b. Hits .................................................................................................710 с Leads ..............................................................................................710 xxiv Biotechnology and the Law d. Optimized Leads ............................................................................710 2. Preclinical-Stage Licensing ..................................................................710 a. ADME/Tox Studies ........................................................................710 b. Investigational New Drug Application ..........................................711 3. Clinical-Stage Licensing ......................................................................711 a. Phase 1 ............................................................................................711 b. Phase II ..........................................................................................711 с Clinical Trials (Phase Ш) ...............................................................711 4. Pre-launch Licensing ............................................................................711 D. The Development and Commercialization License Agreement ................. 712 1. Nature and Scope of License Grant ......................................................712 a. Identifying the Subject Technology ...............................................712 b. The Rights Granted ........................................................................713 с Scope of Rights ..............................................................................714 d. Retained Rights of the Licensor ....................................................715 2. Consideration for the License Grant ....................................................716 a. Milestone Payments .......................................................................716 b. Royalty Payments, Generally ........................................................718 с Term of Royalty Payments ............................................................721 d. Punitive Reduction in Royalty Rates .............................................722 e. Reduction in Royalty Rates for Third-Party Licenses ...................723 3. Other Intellectual Property Issues ........................................................723 a. Responsibility for Patent Prosecution and Maintenance ...............723 b. Abandoned Jurisdictions ................................................................723 с Ongoing Cooperation .....................................................................724 d. Trademarks, etc ..............................................................................724 e. Prosecution of Infringers ...............................................................724 4. Cooperation of the Parties During the Regulatory Approval Process ..................................................................................................725 5. Participation in the Upside ...................................................................726 a. Co-rights .....................................................................................726 b. Bulk Supply Rights ........................................................................728 E. Anticipating Changes of Control of Either Party ........................................728 a. Licensor Issues ...............................................................................729 b. Licensee Issues ..............................................................................729 с Tailoring a Solution .......................................................................730 F. Terminating the Agreement if the Alliance Fails ........................................730 1. Material Breach by the Licensee ..........................................................731 a. The Licensor s Perspective ..............................................,.............731 b. The Licensee s Perspective ............................................................ 73I 2. Material Breach by the Licensor ..........................................................732 a. The Licensor s Perspective ............................................................732 Contents xxv b. The Licensee s Perspective ............................................................732 3. Termination Without Cause ..................................................................732 G. Conclusion: The Importance of Getting It Right ........................................733 Chapter XVIII Expansion: European and International Considerations for Biotechnology Companies ...........................................................735 Daniel Pavin A. An Overview of Relevant European Institutions, Regulatory Bodies, and Legislative Framework .........................................................................737 1. The European Commission ..................................................................737 2. The European Medicines Agency .........................................................737 3. National Regulatory Bodies (Competent Authorities) .........................739 4. European Legislation and Other Instruments .......................................739 B. The Definition of Medicinal Products Under European Law .................740 С Standards for Non-clinical Tests: Good Laboratory Practice and Laboratory Animal Welfare ........................................................................741 1. Introduction ..........................................................................................741 2. Guidance from the ICH and the EMEA ...............................................742 3. Laboratory Animal Welfare ..................................................................742 4. Non-clinical Studies and Animal Testing: Other Countries .................742 a. GLP ................................................................................................742 b. Animal Testing ...............................................................................743 D. Clinical Trials in the EEA ...........................................................................743 1. Introduction: The Regulatory Framework ............................................743 2. Provisions of the Clinical Trials Directive ...........................................744 3. Scope of the Clinical Trials Directive: What Is a Clinical Trial ? .....745 4. What Is an Investigational Medicinal Product ? ................................745 5. Who Is the Sponsor under the Clinical Trials Directive? .................746 6. Sponsors Who Are Not Established in the EEA ...................................747 7. Applying for Clinical Trial Authorization ............................................747 8. Manufacture and Importation of Investigational Medicinal Products (ĽVIPs) ....................................................................................748 9. GMP and GCP Inspections ...................................................................749 10. Notification of Adverse Events and Suspected Unexpected Serious Adverse Reactions ...................................................................750 11. Suspension of Trials .............................................................................750 12. Effect of Noncompliance ......................................................................751 13. Liability and Insurance .........................................................................751 14. Clinical Trials and Data Protection (Privacy) Law ...............................751 15. GCP and the GCP Directive ................................................................753 E. Obtaining a Marketing Authorization in Europe ........................................753 1. Introduction ..........................................................................................753 xxvi Biotechnology and the Law 2. What Information Must Be Contained in a Marketing Authorization Application? ..................................................................755 3. What Is the Format of a Marketing Authorization Application? ..........756 4. Summary of the Centralized Procedure ...............................................756 5. Duration of a Marketing Authorization ................................................757 6. Responsibilities of the Holder of the Marketing Authorization ...........757 7. Can Patented Inventions Be Used for Uses Relating to Applying for a Marketing Authorization? ............................................................758 a. The Historical Position in Europe ..................................................758 b. The New Bolar Exemption ............................................................758 F. Clinical Trials and Marketing Authorizations: International Strategies and Issues ....................................................................................................759 1. Product Development Strategies ..........................................................759 2. Where to Conduct a Clinical Trial ........................................................761 3. Use of U.S. Non-clinical and Clinical Trials Data to Support a Marketing Authorization Application ...................................................762 4. International Coordination ...................................................................763 a. Introduction: The ICH...................................................................763 b. The Common Technical Document ...............................................763 G. Post-marketing Issues in the EEA ..............................................................764 1. Pharmacovigilance ...............................................................................764 a. Introduction ....................................................................................764 b. Roles and Responsibilities of an MAH .........................................764 c. Supervision and Enforcement ........................................................765 2. Advertising, Promotion, and Labeling .................................................766 3. Manufacture, Importation, Classification, and Inspections .................767 a. Manufacturing and Importing ........................................................767 b. Classification .................................................................................767 с Inspections .....................................................................................767 4. Abridged Applications ..........................................................................768 a. Introduction ....................................................................................768 b. Abridged Applications for Generic Medicinal Products ............768 с Abridged Applications for Similar Biological Medicinal Products .........................................................................................769 5. Bibliographic or Well-Established Use Applications .......................769 6. Regulatory Data and Marketing Exclusivity ........................................769 7. Price Controls and Government Purchasing ........................................771 8. Parallel Importation and Parallel Distribution .....................................771 a. Parallel Importation .......................................................................771 b. Trademark Issues: Repackaging and Relabeling ...........................772 с Medicines Legislation ....................................................................773 d. Parallel Distribution .......................................................................773 Contents xxvii 9. Confidentiality and Freedom ofinformation....................................... 774 H. Other Areas of Regulation ..........................................................................775 1. Regulation of Human Embryonic Stem Cell Research ........................775 a. Introduction ....................................................................................775 b. The Council of Europe s Convention on Human Rights and Biomedicine ...................................................................................775 c . European Harmonizing Legislation — The Current Position .........776 d. National Regulation within the EEA .............................................776 e. Other Countries ..............................................................................777 2. Human Tissue and Cells .......................................................................777 a. Introduction ....................................................................................777 b. The Human Tissues and Cells Directive ........................................777 3. Advanced Therapies .............................................................................779 a. Europe ............................................................................................779 b. International ...................................................................................780 4. Blood and Blood Components .............................................................780 5. Medical Devices ...................................................................................781 I. Regulation of GMOs ...................................................................................781 1. Regulation of GMOs : Legislation and Practice in the EEA .................781 2. The EEA Legislative Framework with Respect to GMOs ...................782 a. Experimental Release of GMOs into the Environment .................782 b. Placing on the Market of GMOs for Cultivation, Import, or Processing into Industrial Products ...............................................782 с Placing on the Market of GMOs for Food or Feed/Food or Feed Containing GMOs ..........................................................................783 d. Safeguard Clause ...........................................................................783 e. Labeling and Traceability ..............................................................783 f. Sanctions ........................................................................................784 g. Practical Implications for Industry ................................................785 h. Developing and Marketing Authorizations for Medicinal Products Consisting of or Containing GMOs ................................786 3. International GMO Regulation .............................................................787 J. Intellectual Property ....................................................................................788 1. Introduction ..........................................................................................788 2. Patents ..................................................................................................788 a. Legislative Background .................................................................788 b. Obtaining Patents in Europe ..........................................................789 с Substantive Patentability Criteria; Differences to the U.S. Position ..........................................................................................790 d. Excluded Subject Matter ................................................................791 e. Microbiological Processes and Products .......................................791 f. Human Material .............................................................................792 g. Morality: Stem Cells ......................................................................792 xxviii Biotechnology and the Law h. Morality: Transgenic Animals .......................................................793 i. Transgenic Plants ...........................................................................793 3. Trademarks ...........................................................................................793 4. Copyright and Database Right .............................................................794 5. Plant Breeders Rights ..........................................................................795 6. The Interplay Between Intellectual Property Rights and European Community Law ...................................................................................795 7. Enforcement of Intellectual Property Rights ........................................796 K. EC Competition Law ..................................................................................796 1. Introduction ..........................................................................................796 2. EC Competition Procedures .................................................................796 3. Article 81..............................................................................................797 a. Introduction ....................................................................................797 b. Block Exemptions ..........................................................................798 4. Article 82..............................................................................................798 Chapter XIX Biotechnology Patent Litigation for the Non-Patent Attorney ........813 Julie Fleming Brown A. Judicial and Extrajudicial Proceedings .......................................................815 1. Reexamination ......................................................................................816 a. Ex Parte Reexamination .................................................................816 b. Inter Partes Reexamination ............................................................817 с Director-Initiated Reexamination ..................................................818 2. Reissue ..................................................................................................819 B . General Overview of Patent Litigation Issues (Substantive) ......................819 1. Claim Interpretation .............................................................................821 2. Definition of Infringement ...................................................................822 a. Types of infringement ....................................................................824 3. Proof of Infringement ...........................................................................825 a. Possible Defenses and Counterclaims ...........................................825 b. Non-infringement ..........................................................................826 с Patent Invalidity (§§ 102, 103, 112)..............................................828 i. Anticipation .............................................................................829 ii. Obviousness .............................................................................830 iii. Section 112 defenses ...............................................................831 d. Patent Unenforceability .................................................................833 e. Antitrust .........................................................................................834 i. Patent Misuse ..........................................................................834 ii. Walker Process Counterclaim .................................................835 iii. Handgards Counterclaim .........................................................836 f. Other Defenses Not Special to Patent Cases .................................836 4. Damages Issues ....................................................................................837 Contents a. No Less than a Reasonable Royalty ...........................................838 b. Lost Profits .....................................................................................840 с Enhanced Damages ........................................................................841 i. Willfulness ...............................................................................842 ii. Attorneys Fees ........................................................................843 d. Equitable Relief .............................................................................843 С Phases of a Patent Case (Procedural/Strategic) ..........................................843 Chapter XX Litigation Issues ..................................................................................857 Robert E Coppie A. Intellectual Property and Confidential Business Information ....................85 8 1. Trademark Issues ..................................................................................859 a. Registration and Protection ............................................................859 b. Litigation Claims — Infringement and Dilution .............................859 2. Trade Secrets ........................................................................................863 a. Trade Secrets Defined ....................................................................863 b. Establishing the Foundation for Trade Secret Protection ..............864 с Misappropriation ............................................................................865 d. Inevitable Disclosure Doctrine ......................................................866 B. Products Liability ........................................................................................867 1. Defects and Causation ..........................................................................868 2. Establish a Record of Compliance and Responsibility ........................868 C. Business Liability .......................................................................................869 1. Corporate Disclosures and Insider Trading ..........................................870 a. Misstatements and Omissions .......................................................870 b. Insider Trading ...............................................................................871 2. Corporate Governance ..........................................................................871 3. False Claims and Whistleblowers ........................................................872 4. Average Wholesale Price Drug Litigation ............................................873 D. Document and Information Retention ........................................................873 1. Regulatory Record-Keeping Requirements ..........................................874 2. Litigation Discovery Issues ..................................................................874 3. Data Management Policy .....................................................................875 E. Alternative Dispute Resolution ...................................................................880 1. ADR Defined ........................................................................................880 a. Arbitration ......................................................................................880 b. Mediation .......................................................................................881 2. ADR Myths and Misconceptions .........................................................881 a. A Sign of Weakness .......................................................................881 b. Free Discovery ...............................................................................882 3. An Integrated Strategy for ADR ...........................................................882 a. Before the Dispute Arises ..............................................................882 b. In the Early Stages of the Dispute .................................................883 с Parallel Strategies ..........................................................................884 d. Private Forums and Confidentiality ...............................................884 4. A Special Case for Patent Litigation ....................................................885 a. Participation by Senior Management .............................................886 b. Advantages of ADR Confidentiality ..............................................886 c. ADR as an Alternative to Foreign Litigation .................................887 5. ADR Guidelines ................................................................................. Chapter XXI Biotechnology Resources ..................................................................893 Jennifer Korpacz Treatises .............................................................................................................893 National Academies Press .................................................................................894 Major Federal Acts ............................................................................................896 Selected Federal Register Documents ...............................................................900 Federal Agency Resources ................................................................................900 Key Federal Cases .............................................................................................912 State Laws .........................................................................................................918 Additional Resources ........................................................................................918 Europe ................................................................................................................923 Foreign Countries ..............................................................................................933 Index .....................................................................................................935
adam_txt	Contents Preface .xxxi About the Editors .xxxv About the Contributors .xxxix Chapter 1 Introduction to Biotechnology and the Law .1 Robert E Coppie A. The Biotech Primer .4 B. Biotech Defined .4 1. Three-Branch Approach .5 С The Biotech Company Life Cycle .5 1. Phase I: Start-up .6 a. Intellectual Property .6 b. Company Formation .7 с Investment Capital .7 2. Phase 11: Early Development .8 a. Additional Investment .8 b. The Regulatory Track .9 с Business Growth and Complexity .9 3. Phase III: Later-Stage Development and Product Approval .10 4. Phase IV: Challenges Facing the Now Mature Company .10 a. Commercialization .11 b. Regulatory Oversight .11 с Litigation .11 D. Conclusion .12 Glossary .13 Chapter II Managing Innovation: Patent Basics for Biotechnology Counsel . 25 Dr. Michaeln. Brodowski, Thomas A. Turano, and Dr. Christine C. Vito A. Introduction .25 B. U.S. Patent Portfolios .26 1. Patent Rights—The Claims .26 2. Types of Patents .28 a. Provisional Patent Applications .29 b. Continuing Patent Application Practice .30 iii iv Biotechnology and the Law 3. Requirements for Patentability .31 4. Preparation of a Patent Application .34 5. Patent Application Formalities .35 6. Publication of Patent Applications .38 7. Patent Prosecution .39 a. Appeal of Patent Office Final Rejections .41 b. Notice of Allowance .42 8. Post-Issue Patent Considerations .43 С Foreign Patent Portfolios .45 1. Protection Strategy .46 2. Patentability Differences .49 3. Other Considerations .51 4. Prerequisites to Filing .52 5. Options for Filing in Other Jurisdictions .53 a. Additional Considerations .57 D. Managing the Company's Patent Estate .58 1. A Family Portrait .58 2. Keeping It in the Family .60 3. Skeletons in the Closet .62 a. Rights of Ownership .63 b. Correspondence to Products or Business Strategies .64 с Freedom to Operate .66 Chapter III Company Formation .69 Andrew T. Hoyne, Steven E. Pozarle, and Mark L. Stoneman A. Introduction .69 1. "But will it help us get money?" .69 2. The Importance of the Board of Directors .70 3. Speed .72 4. Simplicity .73 5. The Role of the Company's Attorneys .73 B. Biotechnology Company Models .73 1. Company Formed Before In-Licensing While R&D Continues at University .74 2. Technology Flip .75 3. Revenue-Funded Company .75 4. Corporate Deal-Funded Company .75 5. Venture Fund-Launched Company .76 6. Angel Investor-Funded Company .76 7. Significant Self-Funded Company .77 8. Shoestring Self-Funded Company .77 9. Charitable Corporation or Foundation .78 10. Debt-Funded Company .79 Contents v C. Entity Selection and Formation .79 1. No Perfect Choice .79 2. Sole Proprietorships and Partnerships .80 3. C-corporations .81 a. Limited Liability .82 b. Centralized Management .82 с Owners .82 d. Transferability of Ownership .82 e. Classes of Ownership .83 f. Incentive Compensation .83 g. Taxation .83 4. S -corporations .84 5. Limited Liability Companies .88 a. Problems Using an LLC .88 b. LLC Organization .91 6. Exotic Entity Types .95 7. State of Organization .95 8. Name Selection .97 D. Capital Structure and Stock Grants .99 1. Introduction .99 2. Securities Law Compliance .99 3. Founders Stock, Restricted Stock, and Stock Options .100 4. Common and Preferred Stock .105 E. Relationships with Early Participants .107 1. Founders .108 2. Board of Directors .109 3. Scientific Advisory Board (SAB) .110 4. Management . Ill a. Chief Executive Officer . Ill b. Chief Financial Officer .112 с Chief Scientific Officer .112 d. Clinical/Regulatory .113 5. Employees .113 F. Incubators .114 G. University Relationships .115 H. Early-Stage Company Agreements .117 1. Brief Review of Intellectual Property for the Non-IP Attorney .117 a. Patents .118 b. Trade Secrets .118 с Trademarks .119 d. Copyrights .121 2. Confidentiality Agreements .122 vi Biotechnology and the Law 3. Material Transfer Agreements .124 4. Research Collaboration Agreements .126 I. Positioning for an Exit .127 Appendix A: Mutual Confidentiality Agreement .132 Chapter IV Acquisition of Biotechnology—Technology Transfer .139 Hugh B. Wellons A. Technology Creation .140 1. Protecting Propriety of the Invention in the Early Stages .140 a. Confidentiality Agreements .140 b. Who Was First? .141 с Company Records .142 2. Keeping Necessary Records .143 3. Who Owns What? (Employer v. Employee and JV Issues) .143 a. Work Made for Hire .143 b. Employee Rights .145 с State Laws .145 d. Canadian and European Union Laws .146 e. Trade Secrets .147 f. Joint Venture Ownership .148 4. Patent Filing: Protecting an Invention and Limiting Others' Use .149 a. Why File a Patent? .149 b. Patent Requirements .149 с Patent Claims and Rights .150 d. Types and Stages of Patents .150 e. Patent Prosecution .151 f. Post-Issue Considerations .151 g. Foreign Patent Filing .152 5. Possible Effects of Outside Funding .152 a. Ownership .152 b. Public Domain .154 с Manufacturing or Sales Restrictions .154 B. Forms of Technology Transfer .155 1. Acquisition of Owner .155 a. Acquiring the Owner .155 b. Employing the Owner .155 2. Assignment .156 3. License and Sublicense .156 a. Common Form of Transfer .156 b. Alternative to Assignment .156 с Sublicense .,.158 4. Fair Use Agreement .158 Contents vii a. Fair Use and Experimental Use .158 b. Fair Use Agreements .160 с Doctrine and Agreements' Effect on Intellectual Property Ownership and Due Diligence .160 5. Public Domain .161 C. Transfer from Academia .162 1. University Considerations .162 2. Material Transfer Agreements .168 3. Principal Investigator Considerations .169 a. Conflict of Interest and Conflict of Commitment .169 b. Conflict of Interest .169 c. Conflict of Commitment .170 d. Special Knowledge .171 4. Licensee Considerations .171 a. Policies and Procedures .172 b. It's a Long Way to Market, So Wrap Up the People You Need .172 с Public Disclosure? .173 d. Stakeholders .173 5. Interests of Other Stakeholders .174 a. Other Underwriters .174 b. Government Agencies .174 с Special Government Considerations .174 d. Nonprofits .175 6. Common Restrictions .175 a. License Only, Not an Assignment .175 b. Time Limitations .176 с Restrictions on Participation by the Inventors .176 d. Audit .176 e. Scope of License .176 f. Indemnification .176 g. Sublicense Approval .176 h. Sublicensee Subject to License Terms .176 i. Original Licensee Always Liable .177 j. Cannot Use the Name of the University .177 k. Government Has a License .177 1. Other General Restrictions You Would Find in Most Other Licensing Agreements .177 7. Common Guidelines for Price and Provisions of the License .177 a. Standstill Fee .177 b. Up-front License Fee .177 с Minimum Annual Payment .178 d. Periodic Licensing Fees (Such as Quarterly or Annual) .178 e. Participation in Third-Party Payments .178 viii Biotechnology and the Law f. Lump-Sum Royalties .178 g. Milestone Payments .178 h. Sales-Based Royalties .178 i. Equity in the Licensee .179 j. Equity Protections .179 k. Put of Shares .179 1. A Time for Sale .179 8. When Equity Is the Primary Consideration for the License .179 9. Applicability of Bayh-Dole Act .180 10. Application of "CREATE" Act of 2004.183 11. Conflict between Publication and Protection of IP .183 D. Transfer from Other Nonprofit Entities .184 1. Implications of Nonprofit Status .184 2. Unrelated Business Income Tax .185 3. Priorities of Nonprofit Technology Owner .185 4. Joint Venturing (especially qualification for STTR grants) .186 a. SBIR Grants .186 b. STTR Grants .187 с Problems with STTR and SBIR Grants .187 5. Common Misconceptions .187 6. Case Study — Howard Hughes Medical Institute .188 a. Assignment of Rights .188 b. Sharing Patent Costs and Royalties .189 с Equity Ownership .189 d. Collaborations .189 e. Time Limitations .189 f. Start-up Companies .189 g. Summary .190 E. Transfer from Individuals .190 1. Consideration of Terms .190 a. Parties .190 b. Recitals .190 с Definitions .190 d. Property Licensed .190 e. Scope of the Assignment or License . 191 f. Territory .191 g. Right to Sublicense .192 h. Follow-on and Later-Developed Technology .192 i. Term and Renewal of License .192 j. Termination .193 k. Deliveries .193 1. Retention of Rights .193 Contents ix m. Payments, Including Fees, Royalties, Stock (Options, Warrants), Milestone, etc .193 n. Audit Rights .194 o. Reporting and Marketing Responsibility .194 p. Representations and Warranties of the Inventor .194 q. Indemnification .194 r. IP Protection .194 s. Insurance .194 t. Assignability .195 u. Amendments .195 v. Alternative Dispute Resolution (ADR) .195 w. "Boilerplate" Language .195 2. Common Negotiation Points .196 a. Price Paid/Consideration .196 b. Fees and Royalties Are Both Negotiable Points .196 с Records and Reporting .197 d. Warranty .197 e. Indemnification .197 f. IP Matters .197 g. Confirmation of Ownership .198 3. Patent Filing .199 F. Summary .199 Chapter V Financing a Biotech Company .203 William N. Wofford A. Overview .204 1. Drug Development Costs .204 2. Product Development Time Lines .206 B. Basic Securities Law Considerations .209 1. Registration or Exemption Under the Securities Act .209 2. Section 4(2) Exempt Transaction .210 3. Regulation D Exempt Transaction .210 4. Rule 701— Compensation Plans .212 5. State "Blue Sky" Laws .213 С Pre-seed and Seed Capital .214 1. Founders' Stock .214 a. Restrictions on Transfer .215 b. Vesting .215 с Lock-up .216 d. Drag-along .217 2. Employee Stock .218 a. Plan Basics .218 b. Securities .219 Biotechnology and the Law с Tax . 219 d. Corporate .220 e. Commercial .221 3. Stock to Service or Technology Providers .221 a. Securities .222 b. Tax .222 с Conflicts of Interest .223 4. Friends and Family .223 a. Securities .223 b. Corporate .224 5. Loans .224 6. Generating Revenues to Reduce or Defer Need for Investment .225 a. Intellectual Property .225 b. Commercial .226 7. Government Funding .226 a. SBIR Grants .226 b. STTR Grants .227 c . Advantages to Receiving Federal Grant Funding .228 d. Disadvantages to Receiving Federal Grant Funding .228 e. Eligibility/51 Percent Rule .228 f. State Resources .230 D. Venture Capital .230 1. Financial Rights .231 a. Valuation .231 b. Liquidation Preference .231 с Participating Preferred .231 d. Accruing Dividends .232 e. Protection of Ownership Percentage .232 2. Governance Rights .233 a. Board Representation .233 b. Protective Provisions/Class Voting .233 3. Exit Rights .233 a. Registration Rights .234 b. Redemption Rights .234 с Co-sale Rights .235 4. Series B—Time to Start All Over .235 E. Corporate Investment .236 F. Initial Public Offering .237 G. Post-IPO Financing .239 1. PIPES .239 2. Convertible Debt .240 3. Project Finance .241 Contents xl H. Conclusion .241 Glossary of Frequently Used Terms .253 Chapter VI Employment Issues for Biotechnology Companies .265 Jeffrey A. Van Doren A. Employment At Will .265 B. Employee or Independent Contractor .266 1. The Common-Law Control Test .267 2. The 1RS Control Test .268 3. The Economic Reality Test .270 4. Potential Liability .271 С Employer Coverage Under Federal Civil Rights Laws .272 1. Title VII of the Civil Rights Act of 1964 (42 U.S.C. § 2000e et seq.).272 a. Basic Coverage .272 b. Sexual Harassment .273 2. Age Discrimination in Employment Act (ADEA) (29 U.S.C. § 621 et seq.).273 a. Basic Coverage .273 b. Older Workers' Benefit Protection Act .273 3. Americans with Disabilities Act (42 U.S.C. § 12,101 et seq.).274 a. Basic Coverage .274 b. Reasonable Accommodation .274 4. Equal Pay Act (29 U.S.C. § 206(d)) .275 D. Employer Coverage Under State and Local Civil Rights Laws .275 1. State Civil Rights Law .275 2. Local Laws and Ordinances .275 E. Equal Opportunity and Affirmative Action Obligations of Government Contractors and Subcontractors .276 F. Other Federal Employment Laws .277 1. Fair Labor Standards Act (FLSA) (29 U.S.C. § 201 et seq.).277 a. Basic Coverage .277 b. Basic Requirements .277 2. Family and Medical Leave Act (29 U.S.C. § 2601 et seq.).281 3. National Labor Relations Act (29 U.S.C. § 151 et seq.).281 a. Coverage of the NLRA .281 b. Employee Rights under the NLRA .282 с "Protected Concerted Activity" .282 d. Union Organizing .282 e. NLRA Applicability to Non-union Employers .283 4. Employee Retirement Income Security Act (ERISA) (29 U.S.C. § 1001 et seq.).285 xii Biotechnology and the Law 5. Occupational Safety and Health Act (OSHA) (29 U.S.C. § 651 et seq.).285 6. Immigration Reform and Control Act 1986 (IRCA) ( 18 U.S.C. Ş274A-274C) .286 7. Uniformed Services Employment and Reemployment Rights Act of 1994 (USERRA) (38 U.S.C. § 4301 et seq.).287 8. Fair Credit Reporting Act (FCRA) (15 U.S.C. § 1681 et seq.).287 a. Written Notice and Authorization .287 b. Adverse Actions Procedures .288 9. Employee Polygraph Protection Act (29 U.S.C. § 2001 et seq.).288 G. Use of Employment Contracts .288 1. When Is an Employment Agreement Useful? .289 a. Security .289 b. Recruitment Incentive .289 с Defined Performance Expectations .289 d. Defined Compensation Expectations .289 e. Confidentiality and IP Ownership .290 2. Items to Be Covered .290 a. Duration .290 b. Position and Title .291 с Compensation .291 H. Employee Handbooks .299 1. Pros and Cons of Using .299 a. Reasons for Using .299 b. Reasons for Not Using .300 2. Items to Be Covered .301 a. Disclaimers and At-Will Statements .301 b. EEO Policies .301 с Harassment Policy .302 d. Family and Medical Leave Policy .302 e. E-mail and Computer Usage Policy .303 f. Description of Benefits .303 g. Discipline Policy .303 I. Immigration Options for Biotech Employees .304 1. Obtaining a Visa and U.S. Entry .304 2. Non-immigrant Visas .305 a. Н -IB "Specialty Worker" Visa .305 b. TN "NAFTA Professional" Visa .307 c. L-l "Intracompany Transfer" Visa .308 d. Е -l "Treaty Trader" and E-2 "Treaty Investor" Visas .309 e. О -l "Extraordinary Ability Alien" Visa .310 3. Immigrant Visas and Permanent Residence Status .312 Contents x«» a. Employment-Based Preferences .312 b. Visa Backlogs and Priority Dates .314 с Labor Certification .314 d. Immigrant Visa and Adjustment of Status .315 Appendix A: Coverage of State Equal Rights Statutes .318 Chapter VII Federal Regulation of Research Through Funding .325 G. Melissa Ince and Jenny Kim A. Grants and Contracts .326 1. Federal Research Grants .326 a. Subgrants .327 b. Terms and Conditions .328 с Grantor Agencies .330 i. Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Program Grants .330 ii. SBIR .331 iii. STTR .331 2. Contracts .332 a. Sale of Commercial Items and Services .332 b. Procurement Integrity: Off-limits Information .337 с Allowable and Unallowable Costs .340 d. Product Substitution .342 B. SBIR and STTR Grants .344 1. SBIR Grants .344 2. STTR Grants .345 3. Basic Characteristics .346 4. NIH Guidance .:.347 a. Significance .347 b. Approach .348 с Innovation .348 d. Environment .'.349 5. Protection of Human Subjects .349 6. Vertebrate Animals .350 7. Criteria .351 8. Phase II Application Review Criteria .351 9. Amended Applications .352 10. Phase I/Phase II Fast-Track Application Review Criteria .352 11. Phase II — Competing Continuation Application Review Criteria .352 С Ethics, Outside Activities, and Employment .353 1. Grants .353 a. Standards of Conduct .353 b. Financial Conflict of Interest .353 xiv Biotechnology and the Law с Misconduct in Science and Engineering .354 2. Contracts .354 a. Organizational Conflicts of Interest .354 b. Employment Discussions With and Hiring of U.S. Government Personnel .356 с The National Institutes of Health (NIH) Government Employee Supplemental Regulations on Permitted Outside Activities .358 Chapter VIII Regulation of Preclinical Research .407 Daniel T. Pancamo A. Animal Use in Biomedical Research and Testing .408 1. The Basic Regulatory Scheme—the Animal Welfare Act (7 U.S.C. §§ 2131-2159) and Regulations (9 C.F.R. Parts 1-4).408 a. Overview of the AWA .408 b. Overview of the AWA Regulations .411 i. General Overview .411 ii. Registration .412 iii. The IACUC .412 iv. Personnel Qualifications, Veterinary Care, Record Keeping .415 с Implementation and Enforcement of the AWA and the AWA Regulations by the USDA Animal and Plant Health Inspection Service (APHIS) .417 2. U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training (50 Fed. Reg. 20,864-02 (1985)).418 3. Memorandum of Understanding Among APHIS/USD A, the FDA and the NIH .419 4. NIH Considerations .420 a. Health Research Extension Act; NIH .420 b. NIH Extramural Research .421 c. Guide for the Care and Use of Laboratory Animals; Institutional Animal Care and Use Committee Guidebook .422 5. FDA Considerations .423 6. CDC Considerations .424 7. State Law .424 8. Conclusion .424 B. Other Regulatory Schemes Applicable to Preclinical Research — Protection of the Environment and Public Heath .425 1. Introduction .425 2. EPA Jurisdiction and RCRA .425 Contents xv 3 . Issues in Applying Environmental Law to Research Facilities .433 4. IACUC Responsibility .434 5. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002; Select Agents and Toxins .434 C. Other Regulatory Schemes Applicable to Preclinical Research — Occupational Safety and Health Considerations and the Protection of Individuals Conducting Preclinical Research .438 1. Introduction .438 2. Occupational Safety and Health Administration (OSHA) Regulation; Standards; Resources .439 3. Selected Resource Tools — Chemicals and Biohazards .441 4. Radioactive Materials in the Research Setting .442 D. Conclusion .442 Chapter IX Research and Development Collaborations .445 Eileen Smith Ewing A. Introduction: The Collaborator as Biotechnology's White Knight .445 B. Finding a Strategic Partner: Beating the Mathematical Odds .446 С Negotiating a Term Sheet .449 1. The Importance of the Term Sheet to the Transaction .449 2. Issues Crucial to Address at the Term Sheet Stage .450 3. Issues to Avoid Negotiating at the Term Sheet Stage .451 D. Key Issues in a Research Collaboration Agreement .452 1. Governance of the Research Collaboration .452 a. Composition of the Joint Steering Committee .452 b. Duties of the Joint Steering Committee .453 с Meetings of the Joint Steering Committee .453 d. Decisionmaking by the Joint Steering Committee .453 2. The Scope of the Collaboration .454 a. Held .455 b. Scope Limitations Based on Patent Family .456 с Scope Limitations Based on Timing .456 d. Scope Limitations Based on Project Funding .456 3. Intellectual Property .456 a. Core Intellectual Property of the Smaller Partner, Developed Prior to the Collaboration but Highly Relevant .457 b. Core Intellectual Property of the Larger Funding Partner, Developed Prior to the Collaboration but Highly Relevant .457 с Background Intellectual Property of the Smaller Partner, Developed Prior to the Collaboration but of Possible Utility .457 d. Background Intellectual Property of the Larger Funding Partner, Developed Prior to the Collaboration but of Possible Utility .458 xvi Biotechnology and the Law e. Intellectual Property Developed by One or Both Parties Arising out of the Collaboration .458 f. Intellectual Property Developed by the Smaller Partner During, but Outside of, the Collaboration .458 g. Novel Intellectual Property Developed by One or Both Parties During the Collaboration That Does Not Arise out of the Existing Intellectual Property of Either Party .459 4. License Grants .,.459 a. Research Licenses .460 b. Development and Commercialization License .460 с Cross-Licenses; Freedom to Operate .460 d. Enabling License .461 e. License as Protection Against Infringement Claims .461 5. Financial Terms .462 a. Signature Payments .462 b. Research Funding .463 с Equity Investments .463 i. Pricing the Equity .463 ii. Multiple Tranches .464 iii. Advantages of Equity Investment by a Collaborator .464 iv. Disadvantages of Equity Investment by a Collaborator .465 d. Milestone Payments .465 6. Option to Develop and Commercialize .469 a. Notice of Exercise .469 b. Right of First Refusal .469 c. Right of First Negotiation .470 d. Rights in Unoptioned Intellectual Property .470 7. Term and Termination .471 a. Term .471 b. Early Termination .471 E. Post-Closing Pitfalls That Can Derail a Research and Development Collaboration .472 1. Change in Strategic Fit or Commitment to the Project .472 2. Communication and Control Issues .'.475 3. Unrealistic Expectations .475 F. Alliances with Third Parties— Keeping Other Options Open .475 1. Right of First Refusal May Preclude Other Transactions .476 2. Right of First Negotiation May Also Have a Chilling Effect .476 3. The Deal May Be Worth It; Rely on Contractual Protections .476 G. Conclusion: Where Do the Parties Go From Here? .477 Contents xvii Chapter X FDA Regulation of Biomedical Research .479 Robert B. Nicholas A. Introduction .479 1. Introductory Note on Biotechnology and Clinical Trials .480 B. Part One — Overview of the Regulatory Framework .481 1. The History, Goals, and Purpose of Regulation .481 2. Government Regulation'of Clinical Research .481 3. The Roles and Obligations of the Parties .483 a. Sponsor .484 b. Contract Research Organization (CRO) .484 с Institutional Review Board (IRB) .485 d. Principal Investigator (PI) .486 e. The Legal Relationships Between the Parties: Contractual Agreements .487 i. The Sponsor and Principal Investigator .487 ii. The Sponsor and the CRO .488 iii. The Principal Investigator and the Study Subject .489 С Part Two—Anatomy of a Clinical Trial .490 1. Before the Trial Can Begin .490 a. Drugs: Investigational New Drug Applications (IND) .490 b. Devices: Investigational Device Exemption (IDE) .490 с IRB Approval of the Protocol, ICF, and Study Advertisement .491 2. Beginning and Conducting the Trial .491 a. Subject Enrollment and Test Article Administration .491 b. Control of the Trial: Record Keeping and Reporting .493 3. After the Trial .494 a. Submission and Audit .494 b. FDA Inspection .:.495 с Administrative Actions — Civil and Criminal Penalties .497 4. Preparing for FDA Inspections and Responding to FDA Allegations of Misconduct .497 5. FDA Criminal Actions and Other Potential Consequences: Qui Tarn Suits and Adverse Publicity .498 D. Part Three — Conduct and Use of Non-U.S. Studies .499 1. IMMDEorNot .499 2. FDA Acceptance and Use of Non-U.S. Clinical Data .500 3. Export of Test Article .500 4. EU Clinical Trial Directive .500 E. Conclusion .'.501 xviii Biotechnology and the Law Chapter XI Privacy Issues for Biotechnology Companies .509 Steve A. Schwärm and Anne Stohr O'Brien A. Introduction .509 B. The National Approach to Health-Care Privacy .512 1. Health Insurance Portability and Accountability Act of 1996.512 2. HIPAA Privacy Regulations .518 a. Individual Rights .518 i. Notice of Privacy Practices .519 ii. Restriction of PHI by Individual Patient .521 iii. Access of Individuals to PHI .521 iv. Amendment or Change of PHI .523 v. Accounting of Disclosures .524 b. Use and Disclosure for Treatment, Payment, and Health-Care Operations .525 с Disclosure of PHI with Authorization or by Agreement .526 i. Authorizations .526 ii. Defective Authorization .528 iii. Combined Authorizations .528 iv. Conditioning of Authorizations .528 v. Revocation of Authorizations .529 vi. Authorizations for Marketing .529 vii. Use or Disclosure Requiring Patient Opportunity to Agree or Object .529 d. Disclosure Pursuant to a Public Policy Exception .530 i. As "Required by Law"— 45 C.F.R. § 164.512(a) .530 ii. Uses and Disclosures for Public Health Activities — 45 CF.R. § 164.512(b) (Includes child abuse reporting) .531 iii. Disclosures About Victims of Abuse, Neglect or Domestic Violence— 45 C.F.R. § 164.512(c) .532 iv. Uses and Disclosures for Health Oversight Activities — 45 CF.R. § 164.512(d) .534 v. Disclosures for Judicial and Administrative Proceedings — 45 C.F.R. § 164.512(e) .534 vi. Disclosure for Law Enforcement Purposes —45 C.F.R. § 164.512(f)* .536 vii. Uses and Disclosures about Decedents —45 C.F.R. § 164.512(g) .536 viii. Uses and Disclosures for Cadaveric Organ, Eye or Tissue Donation Purposes— 45 C.F.R. § 164.512(h) .536 ix. Uses and Disclosures for Research Purposes —45 C.F.R. § 164.512®.537 Contents xix χ. Uses and Disclosures to Avert a Serious Threat to Health or Safety-^5 CRR. § 164.512(j) .539 xi. Specialized Government Function —45 C.F.R. § 164.512(k) .539 xii. Disclosures for Workers' Compensation —45 C.F.R. § 164.512 (1).539 e. Disclosure Pursuant to a Business Associate Agreement — (45 CER. § 164.502(e) and § 164.504(e)) .539 f. Disclosure Pursuant to a Data Use Agreement .542 3. Preemption Issues .543 C. Recognition of State Approach to Health-Care Privacy .544 D. HIPAA Interplay with Federal Common Rule and Federal Certificates of Confidentiality .545 1. Introduction .545 2. Research and HIPAA .545 a. When Research Is Subject to HIPAA .545 b. Permission to Use or Disclose Research Information .546 i. Use or Disclosure Without Authorization .546 ii. Research Use/Disclosure with Individual Authorization .547 3. The Common Rule and HIPAA .547 4. Research and Business Associate Status Under HIPAA .549 5. Federal Certificates of Confidentiality .549 a. Certificates of Confidentiality Explained .549 b. National Institutes of Health Statement on Certificates of Confidentiality .550 E. Research Issues and Academic Medical Centers .551 F. Canadian Privacy Legislation .551 1. Accountability .552 2. Identifying Purpose .553 3. Consent .553 4. Limiting Collection .554 5. Limit Use, Disclosure, and Retention .554 6. Accuracy .554 7. Safeguards .554 8. Openness .554 9. Individual Access .555 10. Challenging Compliance .555 Chapter XII Medical Reimbursement .563 Paul W. Radensky A. Reimbursement Basics .563 1. Key Terms and Concepts .563 2. Coverage .564 xx Biotechnology and the Law a. Determining the Scope of Benefits .564 b. Checking for Specific Exclusions from Coverage .565 с The Reasonable and Necessary Test .565 d. Medical Necessity for the Particular Patient .566 e. Implications of Coverage/Non-coverage .567 f. Coverage Process .567 3. Payment Law and Policy .568 4. Coding .569 5. Appeals .571 6. Who Are the Payers? .574 B. Applying the Basics .574 1. Coverage, Payment, and Coding for Drugs and Biologicals .574 2. Coverage, Payment, and Coding for Procedures Involving the Use of Medical Devices .576 3. Coverage, Payment, and Coding for Durable Medical Equipment, . Prosthetics, Orthotics, and Supplies .578 4. Coverage, Payment, and Coding for In Vitro Diagnostics .579 С Special Payment Rules for New Technologies .579 1. Inpatient Prospective Payment System .579 2. Outpatient Prospective Payment System .580 3. Ambulatory Surgical Centers — Payment for New Technology Intraocular Lenses .580 4. Private Payer Carve-outs .581 D. Reimbursement for Investigational Products .581 1. National Coverage Determination on Routine Costs of Qualifying Clinical Trials .581 2. Investigational Device Exemptions .582 E. Compliance Considerations .583 1. Requirements for Proper Billing .583 2. Reimbursement Support Services .586 3. Discounts and Related Fraud and Abuse Considerations .586 F. Conclusions .587 Table of Acronyms .588 Chapter Xiii Approval of Products for Human Use .591 Areta L. Kupchyk A. Standard Pathways to Market .591 1. Drugs .591 a. Preclinical .591 b. Investigational New Drug Applications .'.592 i. Exemption from Law .592 ii. Institutional Review Boards .,.593 iii. Clinical Hold .593 Contents iv. Types of INDs .595 v. Phases of Clinical Trials .595 с New Drug Applications .596 i. New Drug Application Content and Format Requirements . 597 ii. Facility Inspection .600 iii. Labeling Review .600 iv. Advisory Committees .602 v. Completion of Review and Decision .602 d. Generic Drugs .603 i. Abbreviated New Drug Applications .603 e. 505(b)(2) Applications .605 2. Biological Products .605 3. Human Cells, Tissues, and Cellular and Tissue-Based Products .607 4. Medical Devices .608 a. Device Classifications .609 i. Class I Medical Devices .609 ii. Class II Medical Devices .609 iii. Class III Medical Devices .609 b. The 51000 Notification Process .609 с The Premarket Application Process .610 d. Investigational Device Exemption .610 5. Combination Products .610 B. Special Pathways to Market .612 1. Fast-Track Programs .612 2. Orphan Drug Designation .614 С Future Pathways to Market .615 Chapter XIV The Regulation of Biomedical Products for Animal Use .623 Robert B. Nicholas and Kent D. McClure A. Regulation of Animal Health Products .623 B. The Animal Health Industry .625 1. Development Incentives .625 2. Size Matters .:.625 3. Complexity .627 С Biotechnology-Derived Products .628 D. Overview of FDA Regulation of Animal Drugs .629 1. FDA Regulates Animal Drugs: Defined .629 2. Critical Elements in the Regulatory Regime .630 a. Approval of New Animal Drags .631 b. Denial and Withdrawal of Approval of New Animal Drags .632 с Post-approval Requirements .632 d. Inspection, Enforcement, and Compliance .632 xxii Biotechnology and the Law E. Distinguishing Factors Between FDA Regulation of Animal and Human Drugs .633 1. Drags for Food Animals: Human Food Safety .633 2. Drags Administered in Animal Feed .635 3. Import of Use of an Approved Drag in Different Species; Minor Species and Uses; Use in Pets; Animal Drug Availability .636 4. Practical Considerations for Interacting with the Center for Veterinary Medicine (CVM) .637 F. CVM Regulation of Biotechnology Products .639 G. Overview of USDA Regulation of Animal Biological Products .641 1. USDA Regulates Veterinary Biologies .641 2. Overview: Virus-Serum-Toxin Act .642 3. Critical Elements in the APHIS Regulatory Requirements .642 a. Veterinary Biologies Defined .642 b. Licensing .643 с Permits .644 d. Standard Requirements .644 e. Record Keeping .644 f. Adverse Event Reports .645 g. Enforcement Procedures .645 h. Exemptions to the Regulations .645 4. The Agricultural Bioterrorism Protection Act of 2002.646 5. Animal Health Protection Act .646 6. Special Consideration for Biotech Biologies .647 H. Conclusion .648 Chapter XV Approval Process for Biotechnology Products in Agricultural Use .661 Dr. J. Winston Porter A. Coordinated Federal Framework .662 B. Role of the Environmental Protection Agency .664 С Role of the U.S. Department of Agriculture .666 D. Role of the Food and Drag Administration .668 E. Role of the States in Regulation of Biotech Crops .670 1. EPA and the States .670 2. USDA and the States .670 3. FDA and the States .671 F. Biotech Crop Regulation in Other Countries .671 1. Argentina .672 2. Brazil .672 3. Canada .673 4. China .674 5. European Union .674 Contents xxiii Chapter XVI Legal Requirements After Approval .677 Areta L. Kupchyk A. The Food and Drug Administration .677 B. Office of Inspector General, Department of Health and Human Services .679 С The Neurontin Case .679 D. Import and Export Requirements .680 E. Current Good Manufacturing Practice Requirements .682 F. Reporting Requirements to FDA .683 1. Drug and Biological Products .683 2. Medical Devices .684 3. Promotional Materials: Form FDA-2253 .686 G. Sales and Marketing Regulations .686 1. Prescription Drug Marketing Act .686 2. FDA Regulation of Advertising .687 3. Three Basic Types of Advertisements .691 a. Product-Claim Advertisements .691 b. Reminder Advertisements .691 с Help-Seeking Advertisements .691 4. Requirements for Product Claim Advertisements .691 5. Print Advertisements: the Brief Summary .692 6. Broadcast Advertisements: the Major Statement .692 7. Prior Approval and Post-Marketing Notification .693 8. FDA Notification .694 9. Promotion of Off-Label Use .694 10. Exchange of Scientific Information .695 11. The First Amendment .696 12. Other Cases of Interest—Product Liability .699 13. The Federal Trade Commission .699 H. Withdrawal of FDA Approval .700 I. False Claims Act .701 J. Anti-kickback Statute and Other Illegal Remuneration .701 Chapter XVII Development and Commercialization Alliances .707 Eileen Smith Ewing A. Introduction: Why Choose to Partner? .707 B. Considerations in Choosing a Partner .708 С The Stage of the Drug Candidate Will Define the Alliance .708 1. Early-Stage Deals .709 a. Target Identification and Validation .709 b. Hits .710 с Leads .710 xxiv Biotechnology and the Law d. Optimized Leads .710 2. Preclinical-Stage Licensing .710 a. ADME/Tox Studies .710 b. Investigational New Drug Application .711 3. Clinical-Stage Licensing .711 a. Phase 1 .711 b. Phase II .711 с Clinical Trials (Phase Ш) .711 4. Pre-launch Licensing .711 D. The Development and Commercialization License Agreement . 712 1. Nature and Scope of License Grant .712 a. Identifying the Subject Technology .712 b. The Rights Granted .713 с Scope of Rights .714 d. Retained Rights of the Licensor .715 2. Consideration for the License Grant .716 a. Milestone Payments .716 b. Royalty Payments, Generally .718 с Term of Royalty Payments .721 d. Punitive Reduction in Royalty Rates .722 e. Reduction in Royalty Rates for Third-Party Licenses .723 3. Other Intellectual Property Issues .723 a. Responsibility for Patent Prosecution and Maintenance .723 b. Abandoned Jurisdictions .723 с Ongoing Cooperation .724 d. Trademarks, etc .724 e. Prosecution of Infringers .724 4. Cooperation of the Parties During the Regulatory Approval Process .725 5. Participation in the Upside .726 a. "Co-rights" .726 b. Bulk Supply Rights .728 E. Anticipating Changes of Control of Either Party .728 a. Licensor Issues .729 b. Licensee Issues .729 с Tailoring a Solution .730 F. Terminating the Agreement if the Alliance Fails .730 1. Material Breach by the Licensee .731 a. The Licensor's Perspective .,.731 b. The Licensee's Perspective . 73I 2. Material Breach by the Licensor .732 a. The Licensor's Perspective .732 Contents xxv b. The Licensee's Perspective .732 3. Termination Without Cause .732 G. Conclusion: The Importance of Getting It Right .733 Chapter XVIII Expansion: European and International Considerations for Biotechnology Companies .735 Daniel Pavin A. An Overview of Relevant European Institutions, Regulatory Bodies, and Legislative Framework .737 1. The European Commission .737 2. The European Medicines Agency .737 3. National Regulatory Bodies (Competent Authorities) .739 4. European Legislation and Other Instruments .739 B. The Definition of "Medicinal Products" Under European Law .740 С Standards for Non-clinical Tests: Good Laboratory Practice and Laboratory Animal Welfare .741 1. Introduction .741 2. Guidance from the ICH and the EMEA .742 3. Laboratory Animal Welfare .742 4. Non-clinical Studies and Animal Testing: Other Countries .742 a. GLP .742 b. Animal Testing .743 D. Clinical Trials in the EEA .743 1. Introduction: The Regulatory Framework .743 2. Provisions of the Clinical Trials Directive .744 3. Scope of the Clinical Trials Directive: What Is a "Clinical Trial"? .745 4. What Is an "Investigational Medicinal Product"? .745 5. Who Is the "Sponsor" under the Clinical Trials Directive? .746 6. Sponsors Who Are Not Established in the EEA .747 7. Applying for Clinical Trial Authorization .747 8. Manufacture and Importation of Investigational Medicinal Products (ĽVIPs) .748 9. GMP and GCP Inspections .749 10. Notification of Adverse Events and Suspected Unexpected Serious Adverse Reactions .750 11. Suspension of Trials .750 12. Effect of Noncompliance .751 13. Liability and Insurance .751 14. Clinical Trials and Data Protection (Privacy) Law .751 15. GCP and the GCP Directive .753 E. Obtaining a Marketing Authorization in Europe .753 1. Introduction .753 xxvi Biotechnology and the Law 2. What Information Must Be Contained in a Marketing Authorization Application? .755 3. What Is the Format of a Marketing Authorization Application? .756 4. Summary of the Centralized Procedure .756 5. Duration of a Marketing Authorization .757 6. Responsibilities of the Holder of the Marketing Authorization .757 7. Can Patented Inventions Be Used for Uses Relating to Applying for a Marketing Authorization? .758 a. The Historical Position in Europe .758 b. The New Bolar Exemption .758 F. Clinical Trials and Marketing Authorizations: International Strategies and Issues .759 1. Product Development Strategies .759 2. Where to Conduct a Clinical Trial .761 3. Use of U.S. Non-clinical and Clinical Trials Data to Support a Marketing Authorization Application .762 4. International Coordination .763 a. Introduction: The ICH.763 b. The Common Technical Document .763 G. Post-marketing Issues in the EEA .764 1. Pharmacovigilance .764 a. Introduction .764 b. Roles and Responsibilities of an MAH .764 c. Supervision and Enforcement .765 2. Advertising, Promotion, and Labeling .766 3. Manufacture, Importation, Classification, and Inspections .767 a. Manufacturing and Importing .767 b. Classification .767 с Inspections .767 4. Abridged Applications .768 a. Introduction .768 b. Abridged Applications for "Generic Medicinal Products" .768 с Abridged Applications for Similar Biological Medicinal Products .769 5. Bibliographic or "Well-Established Use" Applications .769 6. Regulatory Data and Marketing Exclusivity .769 7. Price Controls and Government Purchasing .771 8. Parallel Importation and Parallel Distribution .771 a. Parallel Importation .771 b. Trademark Issues: Repackaging and Relabeling .772 с Medicines Legislation .773 d. Parallel Distribution .773 Contents xxvii 9. Confidentiality and Freedom ofinformation. 774 H. Other Areas of Regulation .775 1. Regulation of Human Embryonic Stem Cell Research .775 a. Introduction .775 b. The Council of Europe's Convention on Human Rights and Biomedicine .775 c . European Harmonizing Legislation — The Current Position .776 d. National Regulation within the EEA .776 e. Other Countries .777 2. Human Tissue and Cells .777 a. Introduction .777 b. The Human Tissues and Cells Directive .777 3. Advanced Therapies .779 a. Europe .779 b. International .780 4. Blood and Blood Components .780 5. Medical Devices .781 I. Regulation of GMOs .781 1. Regulation of GMOs : Legislation and Practice in the EEA .781 2. The EEA Legislative Framework with Respect to GMOs .782 a. Experimental Release of GMOs into the Environment .782 b. Placing on the Market of GMOs for Cultivation, Import, or Processing into Industrial Products .782 с Placing on the Market of GMOs for Food or Feed/Food or Feed Containing GMOs .783 d. Safeguard Clause .783 e. Labeling and Traceability .783 f. Sanctions .784 g. Practical Implications for Industry .785 h. Developing and Marketing Authorizations for Medicinal Products Consisting of or Containing GMOs .786 3. International GMO Regulation .787 J. Intellectual Property .788 1. Introduction .788 2. Patents .788 a. Legislative Background .788 b. Obtaining Patents in Europe .789 с Substantive Patentability Criteria; Differences to the U.S. Position .790 d. Excluded Subject Matter .791 e. Microbiological Processes and Products .791 f. Human Material .792 g. Morality: Stem Cells .792 xxviii Biotechnology and the Law h. Morality: Transgenic Animals .793 i. Transgenic Plants .793 3. Trademarks .793 4. Copyright and Database Right .794 5. Plant Breeders' Rights .795 6. The Interplay Between Intellectual Property Rights and European Community Law .795 7. Enforcement of Intellectual Property Rights .796 K. EC Competition Law .796 1. Introduction .796 2. EC Competition Procedures .796 3. Article 81.797 a. Introduction .797 b. Block Exemptions .798 4. Article 82.798 Chapter XIX Biotechnology Patent Litigation for the Non-Patent Attorney .813 Julie Fleming Brown A. Judicial and Extrajudicial Proceedings .815 1. Reexamination .816 a. Ex Parte Reexamination .816 b. Inter Partes Reexamination .817 с Director-Initiated Reexamination .818 2. Reissue .819 B . General Overview of Patent Litigation Issues (Substantive) .819 1. Claim Interpretation .821 2. Definition of Infringement .822 a. Types of infringement .824 3. Proof of Infringement .825 a. Possible Defenses and Counterclaims .825 b. Non-infringement .826 с Patent Invalidity (§§ 102, 103, 112).828 i. Anticipation .829 ii. Obviousness .830 iii. Section 112 defenses .831 d. Patent Unenforceability .833 e. Antitrust .834 i. Patent Misuse .834 ii. Walker Process Counterclaim .835 iii. Handgards Counterclaim .836 f. Other Defenses Not Special to Patent Cases .836 4. Damages Issues .837 Contents a. "No Less than a Reasonable Royalty" .838 b. Lost Profits .840 с Enhanced Damages .841 i. Willfulness .842 ii. Attorneys' Fees .843 d. Equitable Relief .843 С Phases of a Patent Case (Procedural/Strategic) .843 Chapter XX Litigation Issues .857 Robert E Coppie A. Intellectual Property and Confidential Business Information .85 8 1. Trademark Issues .859 a. Registration and Protection .859 b. Litigation Claims — Infringement and Dilution .859 2. Trade Secrets .863 a. Trade Secrets Defined .863 b. Establishing the Foundation for Trade Secret Protection .864 с Misappropriation .865 d. Inevitable Disclosure Doctrine .866 B. Products Liability .867 1. Defects and Causation .868 2. Establish a Record of Compliance and Responsibility .868 C. Business Liability .869 1. Corporate Disclosures and Insider Trading .870 a. Misstatements and Omissions .870 b. Insider Trading .871 2. Corporate Governance .871 3. False Claims and Whistleblowers .872 4. Average Wholesale Price Drug Litigation .873 D. Document and Information Retention .873 1. Regulatory Record-Keeping Requirements .874 2. Litigation Discovery Issues .874 3. Data Management Policy .875 E. Alternative Dispute Resolution .880 1. ADR Defined .880 a. Arbitration .880 b. Mediation .881 2. ADR Myths and Misconceptions .881 a. A Sign of Weakness .881 b. Free Discovery .882 3. An Integrated Strategy for ADR .882 a. Before the Dispute Arises .882 b. In the Early Stages of the Dispute .883 с Parallel Strategies .884 d. Private Forums and Confidentiality .884 4. A Special Case for Patent Litigation .885 a. Participation by Senior Management .886 b. Advantages of ADR Confidentiality .886 c. ADR as an Alternative to Foreign Litigation .887 5. ADR Guidelines . Chapter XXI Biotechnology Resources .893 Jennifer Korpacz Treatises .893 National Academies Press .894 Major Federal Acts .896 Selected Federal Register Documents .900 Federal Agency Resources .900 Key Federal Cases .912 State Laws .918 Additional Resources .918 Europe .923 Foreign Countries .933 Index .935
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