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“Mars 101-International and Interplanetary Considerations for GMOs: Patents, Export control, Biodiversity and Regulation” JOINT BIOTECH AND FDA COMMITTEE CLE MAY 18, 2016 , 3:30-5:30 pm 1 INTRODUCTIONS Marian Flattery, Assistant Chief IP Counsel, DuPont Pioneer and DuPont Crop Protection, featured as “Soteria’s General Counsel” Kan Wang, professor in the Department of Agronomy, Director of the Center for Plant Transformation and Co-PI of the Crop Bioengineering Consortium at Iowa State University, featured as Soteria’s CSO. Vicki G. Norton, Co-Leader, Global Life Sciences at Duane Morris LLP featured as the Host of “VicIPdia”—for all your IP news! 2 INTRODUCTIONS Debora Plehn-Dujowich, partner at Prismatic Law Group and Chair of AIPLA’s Biotech Committee, featured as “genetic resources” outside counsel John Ursu, litigator at Greene Espel, one of Minnesota Lawyer’s 28 “Up and Coming Attorneys” as “Soteria’s Chief Litigation Counsel” Mark Pidkowich, Associate at Smart & Biggar, Vancouver, as ace investigative journalist Alice O. Martin, Partner at Barnes & Thornburgh, as founder of “Put the Genie in a Bottle” NGO 3 Soteria Biosciences Timeline (1 of 2) 2001: Launched its 1st drug, NoPainNoGain (based on extract from Humor plants) 2015 Launched its 2nd generation therapeutic, Soterigen® NPGB, a biologic drug (polypeptide) with pain relieving effects, which does not cause weight gain or memory loss (NoPain/NoGain/Better Brain (NPGB)) Find out more about Soteria at http://www.aipla.org/committees/committee_pages/Biotechnology/Soteria/SitePa ges/Home.aspx Soteria Biosciences Timeline (2 of 2) 2020: After winning a contest to run an experiment on the US Mars Space Station—Soteria developed high CO2/drought tolerant plants (Gene-E Strain); Off target effect resulted in production of “Sweeteria”–a natural sweetener. 2022: Mars mutation of non GMO control plants yielded Humor plants more CO2/drought tolerant than GMO version (Red Genie) 2022: Filed patent applications on the Gene-E, Red Genie and Sweeteria technologies When Gene-E plants and Red Genie plants were sent back to Earth they were quarantined on the landing pad VICIPDIA NEWSFLASH Breeding technologies Conventional Natural mutation and recombination Selection Observation-based, trial/error Time consuming Kan Wang (Iowa State U) Modern Targeted mutation and recombination Selection Data-based, in vitro analysis Expensive May 18, 2016 7 Genetic diversity: source for trait improvement Natural variations Point mutation, deletion, rearrangement, gene duplication, transposable elements Genome is dynamic and fluid www.lowes.com en.wikipedia.org Kan Wang (Iowa State U) *http://www.harvesttotable.com May 18, 2016 8 Modern strawberries never existed in nature Marina Gambardella, Santiago, Chile http://www.ncwildflower.org Fragaria chiloensis Chile Fragaria virginiana Eastern North America X Fragaria ananassa Europe, 1740's Corbis Kan Wang (Iowa State U) May 18, 2016 9 Gene transfer, 1950’s style Ln-9 gene for leaf rust resistance from Aegilops to wheat Problem: Grass will not cross with wheat Need to move gene from grass to wheat Cross hybrid repeatedly to wheat So cross with wheat relative x x Grass with trait Wheat Grass chromosome with desired gene } Kan Wang (Iowa State U) •Break grass chromosome with X-Rays •Let pieces integrate into wheat •Get wanted gene + many unknown Wheat chromosomes Final product May 18, 2016 10. Sears, E.R. 1956. The transfer of leaf-rust resistance form Aegilops umbellulata to wheat. Genetics in Plant Breeding Brookhaven Symposium #9 Gene transfer, 1950’s style Ln-9 gene for leaf rust resistance from Aegilops to wheat Things to notice Move many genes No one knows what genes got moved No regulations Kan Wang (Iowa State U) May 18, 2016 11 Mutation breeding 3217 known varieties developed from mutation breeding FAO/IAEA database (http://wwwinfocris.iaea.org/MVD/) DNA changes 4 bp to 8 kb deletions Inversions of up to 1.5 kb Insertions ~200 bp Frame-shift mutations Premature stop codons Institute of Radiation Breeding Ibaraki-ken, JAPAN www.irb.affrc.go.jp/ Kan Wang (Iowa State U) May 18, Specialtyproduce.com Corbis.com www.nationalpastaday.com 2016 12 Top: Peggy Lemaux, John Meade, Raúl Coronado Bottom: Corbis 13 May 18, 2016 Kan Wang (Iowa State U) Examples of genetic modification Photos Corbis Cauliflower, Li Li, ARS Kan Wang (Iowa State U) May 18, 2016 14 Feeding the world Energy Population Grain Kan Wang (Iowa State U) May 18, 2016 15 Feeding the world: more land? http://static.guim.co.uk/sys-images/Guardian/Pix/pictures/2008/07/01/deforest3.jpg http://www.iccfoundation.us/e-updates/20080331cleanenergy/1.jpg Kan Wang (Iowa State U) http://www.usnews.com/dbimages/master/5042/FE_DA_080523brazil.jpg May 18, 2016 16 3 Statement of Achievement Marc Van Montagu Mary-Dell Chilton Robert T. Fraley … each conducted groundbreaking molecular research on how a plant bacterium could be adapted as a tool to insert genes from another organism into plant cells, which could produce new genetic lines with highly favorable traits. The revolutionary biotechnology discoveries of these three individuals —each working in separate facilities on two continents—unlocked the key to plant cell transformation using recombinant DNA. Their work led to the development of a host of genetically enhanced crops, which, by 2012, were grown on more than 170 million hectares around the globe by 17.3 million farmers, over 90 percent of whom were small resource-poor farmers in developing countries. The combined achievements of the 2013 World Food Prize Laureates, from their work in the laboratory to applying biotechnology innovations in farmers’ fields, have contributed significantly to increasing the quantity and availability of food, and can play a critical role as we face the global challenges of the 21st century of producing more food, in a sustainable way, while confronting an increasingly volatile climate. Kan Wang (Iowa State U) May 18, 2016 17 How did we convert a pathogen to a tool Agrobacterium tumefaciens Crown Gall Kan Wang (Iowa State U) May 18, 2016 18 Genetic Transformation, a natural process Tumor on a walnut-tree Transgenic wood bowl Kan Wang (Iowa State U) May 18, 2016 19 Agrobacterium tumefaciens – a genetic hijacker Plant cell • Eukaryotic promoters • Plant growth hormone synthesis • Special amino acids production only for Agrobacterium Agrobacterium Kan Wang (Iowa State U) May 18, 2016 20 Agrobacterium – mediated transformation Disarmed Engineered plasmid bearing the gene of interest and an antidote gene Agrobacterium tumefasciens Infection Transformable plant Isolated tissue (immature embryo, wounded cotyledon,…) Infected tissues are cultured on media containing poison Only the transformed cell can resist the poison thanks to the antidote gene. Transgenic plantlets are isolated and transferred to the greenhouse Transgenic tissue is isolated and plant regeneration is induced Transgenic plant ready for further analysis Kan Wang (Iowa State U) May 18, 2016 21 Sweet Potato Is a Natural GMO Kyndt et al. (2015) The genome of cultivated sweet potato contains Agrobacterium TDNAs with expressed genes: An example of a naturally transgenic food crop. PNAS, 112: 5844-5849 The Agrobacterium genes were present in 291 sweet potato cultivars tested, as well as a few wild related species. One of the T-DNAs was present in all cultivated sweet potato clones, but not in the crop’s closely related wild relatives, which would suggest that the T-DNA provided an advantageous trait that was selected for during domestication. Kan Wang (Iowa State U) May 18, 2016 22 Two traits Insect resistance gene www.ediblegeography.com Herbicide tolerance genes Bt corn Kan Wang (Iowa State U) RR soybean May 18, 2016 23 Damage of corn field by European Corn Borer Kan Wang (Iowa State U) May 18, 2016 24 Reduced fumonisin concentrations in Bt corn www.pioneer.com Kan Wang (Iowa State U) May 18, 2016 25 Bt corn uptake and insecticide use in US corn fields • Insecticide use on corn farms declined from 0.21 pound per planted acre in 1995 to 0.02 pound in 2010. • The establishment of minimum refuge requirements (planting sufficient acres of the non-Bt crop near the Bt crop) has helped delay the evolution of Bt resistance. Enserink et al., 2013, Science 16: 728-729 Kan Wang (Iowa State U) May 18, 2016 26 Government regulations Process based: • EU • Japan • …… Both product and process based: • USA Product-based: Canada Kan Wang (Iowa State U) May 18, 2016 Classification: PUBLIC 27 Crop Bioengineering Consortium New Breeding Technologies (NBT) - Precise, Targeted Double-strand Breaks • TALENs (Transcription activator-like effector nuclease): effector proteins from plant pathogenic bacteria, combined with nuclease domain of FokI • CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats): bacterial immunity systems for targeted disruption of viral DNA DNA double strand breaks (DSBs) Random DNA breaks caused by chemicals, radiation DSBs repair mechanisms Homologous recombination Non-homologous end join (NHEJ) Restoration or disruption • Homologous recombination occur but rare in eukaryotic organisms (1x10-3 to 1x10-6) • Nuclease mediated DNA DSBs increases recombination up to 1x10-2 to 10-3 Kan Wang (Iowa State U) http://www.hindawi.com/journals/jna/2010/646109/fig1/ May 18, 2016 29 Nature (April 21, 2016) U Penn browning resistant white button mushroom Kan Wang (Iowa State U) May 18, 2016 30 Science (April 20, 2016) Dupont Pioneer high quality waxy corn Kan Wang (Iowa State U) May 18, 2016 31 High-efficiency TALEN-based gene editing produces disease-resistant rice Li et al., Nat Biotechnol. 2012. 30(5):390-2. Resistance phenotype displayed by two T2 mutant plants Lesion lengths of mutant plants caused Xoo(AvrXa7) by 20 T1 mutant plants generated from TALEN pair 2 Kan Wang (Iowa State U) May 18, 2016 From B. Yang 32 GMO vs CRISPR: what are the differences? Traditional genetic engineering Gene of interest cross with wild type + Segregation transformation GMO Wild type GMO Wild type CRISPR/Cas9 Edits CRISPR/Cas9 Genome editing CRISPR/Cas9 cross with wild type Segregation transformation Wild type CRISPR/Cas9 Edits Edits Kan Wang (Iowa State U) + Wild type May 18, 2016 33 Government regulations Process based: • EU • Japan • …… Both product and process based: • USA Product-based: Canada Kan Wang (Iowa State U) May 18, 2016 Classification: PUBLIC 34 Are Soteria’s new techologies patent eligible? CRISPR or GEEN engineered vs. Mars mutants Are Mars mutants patent eligible on Earth? What about on Mars? (Under Commissioner Kappos the interplanetary patent office does not have 101, but does US patent law control?) Does the 1967 Outer Space Treaty prohibit patenting Red Genie Will a genetic diversity database have ramifications on 101 for engineered traits which had a previously unidentified “natural” counterpart Patent Eligibility Gene-E vs. Red Genie PTO Guidance: Life Science Examples for Claims to Sweeteners Example 30 – Dietary Sweeteners Eligible? claim 1 2 3 4 5 6 A dietary sweetener comprising: texiol; and water A dietary sweetener comprising: 1-5 percent texiol; and at least 90 percent water A dietary sweetener comprising: 1-5 percent texiol; at least 90 percent water; and 1-2 percent compound N A dietary sweetener comprising: 5 percent texiol; water, fruit juice, or a combination of water and fruit juice; and sufficient amounts of pectin to form a solid gel A dietary sweetener comprising: granular particles of texiol having a particle diameter of X10 of 80 microns and X90 of 300 microns A dietary sweetener comprising texiol in a controlled release formulation Directed to a Judicial Exception? no yes – product of nature no yes – product of nature yes no – markedly different yes no – markedly different yes no – markedly different yes no – markedly different Genetic Resources Related Treaties and Conferences Copyright © 2016 Debora Plehn-Dujowich Will cover: Convention on Biological Diversity Nagoya Protocol Intergovernmental Conference on Genetic Resources and Traditional Knowledge (IGC) The Convention on Biological Diversity Treaty Considerations Background-Doha Declaration The Doha Declaration was passed in 2001 in Doha, Qatar, as part of the World Trade Organization negotiations. It stated that each member has the right to grant compulsory licenses and to determine the grounds upon which such licenses are granted. Convention on Biological Diversity The main goals of CBD are: Conservation of biological diversity Sustainable use of its components Fair and equitable sharing of benefits arising from genetic resources Nagoya Protocol The Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization is a supplementary agreement to the CBD. It was adopted on October 29, 2010 and entered into force on October 12, 2014. The focus of the Nagoya Protocol is on access and benefit sharing (ABS) for genetic resources. Intergovernmental Committee on GR and TK WIPO Background on IGC Intergovernmental Committee on Intellectual Property and Genetic Resources, Traditional Knowledge and Folklore (IGC) Has been meeting for fifteen years Meetings are held at WIPO Holds plenary sessions and seminars Positions of IGC participating countries: Developing countries such as India and Brazil are in favor of a mandatory disclosure requirement. Developed countries such as the US, Canada, Japan and Korea are opposed to it. Remedies for failure to disclose origin or source Proposed remedies: Some developing countries propose that the remedies available for failure to disclose the origin or source of genetic resources include the revocation of the patent. The US is opposed to any remedy that would include the invalidation of a patent. th 29 IGC During the conference, attendees focused on the following two issues: Whether there should be a disclosure requirement for the use of genetic resources and/or traditional knowledge; and Whether databases should be set up where patent offices (and possibly applicants) could search for genetic resources and/or traditional knowledge to prevent the erroneous granting of patents. Federal Register Notice of March 24, 2016 Notice of commercial marketing must be given after FDA licensure: USPTO representatives before the IGC requested input from patent practitioners regarding issues to be discussed at upcoming IGC meetings. The deadline for submissions is May 23, 2016. Issues below would be particularly helpful to the USPTO Are there additional databases with information about genetic resources and traditional knowledge that patent examiners should use to assess patentability? What are the best practices for establishing such a database? Database Issues continued… Before such a database is made publicly available, what steps should be taken to ensure that it does not include confidential information? What studies have been done regarding national laws and practices that require patent applications to disclose the country of source or origin for genetic resources or traditional knowledge that may be implicated in the patent application? Other Issues What codes of conduct (e.g., University or industry regarding research), practices (e.g., State park procedures to obtain prior informed consent), and laws (e.g., tribal laws regarding sharing of culture and granting prior informed consent) are relevant to the protection of genetic resources and traditional knowledge? What studies have been done regarding national laws and practices requiring patent applications to disclose the country of source or origin for genetic resources or traditional knowledge? Seminars In order to educate stakeholders, WIPO has organized a series of workshops and seminars on the topics of Genetic Resources and Traditional Knowledge. The next seminar on Genetic Resources will be held in Geneva on May 26-27, 2016. For those who cannot attend in person, a webcast will be made available for the seminars as well as for the plenary session of the 30th IGC. What international agreements regulate GMOs? • Cartagena Protocol: regulates transboundary movement of “living modified organisms”—requires advanced informed agreement of the parties • Nagoya-Kuala Lumpur Supplementary Protocol: provides international rules and procedures on liability and redress for damage to biodiversity resulting from living modified organisms Compliance: Export Controls Export Controls 1. What risks should Soteria keep in mind with respect to export markets? 2. How should foreign approvals affect Soteria's decision to commercialize Gene-E? 3. Do supply chain participants have a right not to handle Gene-E? 4. What litigation risks exist with respect to the commercialization of Gene-E without foreign approvals? VICIPDIA NEWSFLASH Thank You! Debora Plehn-Dujowich Ph.D., J.D. [email protected] www.prismaticlaw.com Copyright © 2016 Debora Plehn-Dujowich Disclaimer These materials have been prepared solely for educational and entertainment purposes to contribute to the understanding of U.S. intellectual property law. These materials reflect only the personal views of the author and are not individualized legal advice. The presentation of these materials does not establish any form of attorney-client relationship with these authors. While every attempt was made to ensure that these materials are accurate, errors or omissions may be contained therein, for which any liability is disclaimed. Copyright © 2016 Debora Plehn-Dujowich EXTRA Patent Family Claimed Subject Matter Filing Date Term (+PTE) NPGB Main NPGB--Compositions; formulations 3/17/01 Expired NPGB Main NPGB Gene, constructs; recombinantly expressed NPGB; mammalian expression systems 3/17/01 Expired NPGB Humor (Post AIA) NPGB-BG Engineered plants; Methods of expressing in plants 3/17/13 3/17/33 NPGB Humor Methods of expressing NPGB in plants 3/17/13 3/17/33 NPGB Neuro Methods of treating neurodegenerative (Post AIA) diseases 3/17/13 3/17/33 1 Soteria secured 3 years PTE for its NPGB composition patent 62 Patent Family Claimed Subject Matter Filing Date Gene-E Methods of CRISPR editing to produce high CO2/drought tolerant plants; Gene-E plants 5/01/20 Red Genie Methods of producing high CO2/drought tolerant plants under Mars Space Station growth conditions; Red Gene plants 5/01/22 Term (+PTE) 63