generic drug approval in the united states - anda regulations
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Drug development in the US and FDA approval Procedures: Protection of Pharmaceutical Intellectual Property Rights.
Drug development in the US and FDA approval Procedures.Protection of Pharmaceutical Intellectual Property Rights
US rules for a Japanese audience (reprint of a talk originally given in 2008, partially updated for 2016)Stephen E. Zweig, Ph.D., JD.; Patent AttorneyPatentassociate.com
2008 Stephen Zweig
Speakers backgroundPh.D. Biophysics (UCSD), JD Taft Law SchoolFormer Pharmacology Asst. Prof. (Baylor)Director R&D, Johnson & JohnsonFounder, Avocet Medical, Inc. (VC backed startup)10 years CEO/CTO/Chairman experience Business, FDA, Clinical Trial, & R&D managementPresently patent attorney at patentassociate.com
Overview of talk:1: Cultural and legal differences between the US and Japan2: Review of US Food and Drug Administration (FDA)3: Review of US patent office (USPTO) and patent rulesBreak3
Overview of talk:4: Hatch-Waxman act: connecting the FDA and the USPTO (continued)5: Drug patent extension and regulatory exclusivity rules6: Patent issues during drug R&D, and the Bayh-Dole act7: Recent changes in US patent law: impact of KSR v TeleflexBreak
Overview of talk:
8: Orange Book examples of FDA & USPTO interconnections (topical drugs)
1: US and Japan differencesUS still has some Wild West influences: Japan has a higher preference for mediation and conciliation. US is more likely to litigate.US tends to view patent claims more broadly than Japan6
Tombstone, Arizona, 1882
1: US and Japan differencesDifferences in legal systems: Japan has a mixed common/civil law system Judges decisions mostly impact specific cases US & British common law system Judges decisions on specific cases have greater impact on establishing new law and impacting other casesUS lawyers always citing specific court cases as a result these court cases can act to redefine or reinterpret US regulations & laws
Where common law is used8
2: Review of the US FDA
History:In 1902, Biologics Control Act. started regulating vaccinesIn 1906, FDA started regulating drugs In 2008, the two parts are still somewhat separate: the biologics division is called CBER and handles biotech drugs, and the drug division is called CDER, and handles drugs and antibiotics. They dont always use the same rules!
FDA Drug approval stagesDrug approval stages: Investigational new drug (IND)Phase I (small numbers of humans for safety)Phase II (small numbers of humans for efficacy)Phase III (large numbers of humans for safety/efficacy)Phase IV (post marketing studies)
New drugs & generic drugsNew (first time) drugs filed by New Drug applications (NDA) massive effortGeneric (copy) drugs filed by Abbreviated New Drug Applications (ANDA). ANDA are easier to file because they can make use of previous NDA clinical studies and data.12
Hatch-Waxman actHistory1980s crisis: FDA drug approval time became so long that drugs were almost off-patent by the time of FDA approval. At the same time, generic drug companies could not start studies before patent expiration due to patent infringement issues. Both sides suffered.
Hatch-Waxman act1984 Hatch-Waxman act: Extended exclusive lifetime (patent, FDA exclusivity) for new drugs in exchange for allowing generic drug companies to start FDA approval studies before patent expiration.
Hatch-Waxman rules:Patent extension starts on day of initial filing, ends on FDA approval, get 1 day credit for every day of FDA delay, and day credit for every day of applicant delay, up to a maximum of 5 years, for the claims directed to the approved drug only. FDA communicates dates to patent office, which publishes patent term extension dates.
Effect of Hatch-Waxman16
The orange bookThe Orange book is the nickname for the FDAs Approved Drug Products List with Therapeutic Equivalence EvaluationsFirst published in 1979In 1984, FDA started adding patents to the Orange book to keep track of which drugs are covered by patentsWe will come back to this later in more detail
3: Review of the USPTOPatents are part of US constitution. First patent granted soon after federal government formed in 1790. Initially run by Thomas Jefferson, who stored patents in his old shoeboxes!Prior to 1995, US patent term was 17 years after issue
18 After 1995, US conformed to WIPO rules of 20 years after filing, but a US inventor can file a provisional patent to get an extra year (21 years total).
US patent rulesUS has a modified first to file systemUS rules allow for continuations, new patents based on old patents. Japanese patent applications treated favorably using PCT system
US patent requirementsUtility: - 35 USC 101 (compounds and targets must have a plausible function)Novel: - 35 USC 102 (defeated by single reference)Non-obvious: 35 USC 103 (defeated by a combination of references) the 2007 KSR decision now makes it easier to challenge on the basis of obviousness20
US patent requirementsContain detail: - 35 USC 112 described with enough detail (how to manufacture)Be invented by the applicant for the client (must get proper assignment)Must be filed within 1 year of publication anywhere or first US sale.
Public use bar:Patent aspects of clinical trials in the US: the public use bar: Although filing before public use is best, patents can be filed within one year of first public use or sale in the US.
Patents relevant to drugs1: Compound patents (broadest drug, salts, esters, hydrates)2: Medical use patents (treating specific diseases)3: Formulation patents (stabilizers, preservatives4: Other (manufacturing, device, etc.)
Types of drug patentsUS drug patents can be on the form of the active compound: sterioisomers, polymorphs, salt forms, in-vivo conversion, particle size, formulations, manufacturing process, combination of therapies, methods of treatment, drug delivery systems, and other areas.
Other US patent aspectsUS Patent office overburdened and patents take years to issuePatents may have continuations and continuations in part Patents may be reissued sometimes may have broader claims No opposition, but patents can be reexamined only publications usedMain way to challenge patents is in the courts
TrademarksThe US patent office also handles trademarks -- drug color, pill size and shape, name can also be protected26
25 trademarks with the words skin cream
Where did Thomas Jefferson, first commissioner of the US patent office, and later the 3rd US president, store the first US patents?
AnswerLegend has it that he stored them in his shoeboxes under his bed.28
4: Hatch-Waxman act: connecting the FDA and the USPTOThe Orange book: FDA list of approved drugs, approval dates, indication, regulatory exclusivity, and the patents that cover each drug.The patent list includes active drug, formulation, inactive ingredients or excipients, approved medical indications.The patent list does not cover manufacturing method patents, metabolites of the active drug, manufacturing intermediates, packaging and container patents29
Generic drug approvalGeneric drugs can get approval if they show that their drug is bioequivalent to original drug by filing an ANDA that can reference the original drug NDA
Generic drugs and patentsWhen a generic drug company files an ANDA application, it must examine the status of the drug patents from the Orange Book, and certify that either: 1: There is no patent information listed2: There is a listed patent but it is expired3: That the listed expired will expire on a stated date (usually soon)4: That the listed patent is invalid or will not be infringed.
Examples:1: There is no patent information listed2: There is a listed patent but it is expired
If a generic drug manufacturer certifies 1 & 2, then the FDA starts processing the generic ANDA right away
Examples:3: That the listed patent has expired or will expire on a stated date (usually soon)
If a generic drug manufacturer certifies 3, then the FDA starts processing the ANDA, and gives approval when the patent expires
The start of a patent fight!4: That the listed patent is invalid or it will not be infringed.ANDA filer notifies patent holder within 20 daysPatent holder must sue for infringement within 45 days If the patent holder sues, FDA must withhold approval for 30 months (one time only)If the patent holder does not sue, FDA may approve ANDA at any timeIf a court rules that the patent is not infringed or invalid, FDA may proceed after decision.34
Be carefulA US company may also wait, and then sue after the generic drug is approved.
5: Drug patent extension and regulatory exclusivity rulesA: A new drug can get up to 5 years patent extension to make up for FDA delaysB: The first generic ANDA filer gets 180 days exclusivity (per product)C: New chemical entities get a 5 year ban on use of their NDA data for gener