Bio Business July/Aug 2016

REGIONAL PROFILE

thailand looks to grow life sciences, commercialize products for export 8

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it’s a complicated question: are stem cells patentable?

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MOMENTS IN TIME

not all acute myeloid leukemia cells are created equal 23

JuLY/auGuSt 2016

Championing the Business of Biotechnology in Canada

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promise CANADA INVESTS IN STEM CELLS

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inside

feature

the C wOrd

With exciting new stem cell therapies on the horizon, Canadian scientists are cautiously optimistic.

tHe eVoLution of BanGKoK

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aRe SteM CeLLS PatentaBLe?

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Championing the Business of Biotechnology in Canada

Thailand wants to use its long history of healthcare innovation and infrastructure to create a thriving life sciences sector.

A legal perspective on stem cell IP issues in Canada, the U.S. and Europe.

Photo credit: Canadian Press imagesCCrM/salvatore sacco

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Thailand looks to grow life sciences, commercialize products for export 8

Law

It’s a complicated question: Are stem cells patentable?

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eDitoR’S note 5 CanaDian newS 6 woRLDwiDe newS 7 MoMentS in tiMe 23

moments in time

Not all acute myeloid leukemia cells are created equal 23

july/AugusT 2016

lean lab

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Championing the Business of Biotechnology in Canada

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more to

discover I

first became really aware of stem cells in late 2009 when I attended a biotech press junket to Tucson, AZ. At that time, personalized healthcare was abuzz, promising to deliver the right medicine in the right dose to treat an illness, eliminating trial and error prescriptions of expensive drugs that affect each patient differently. Tucson was taking steps to become one of the centres to take personalized medicine from theory to practice by amassing a combination of companies with the right diagnostic tools and drugs, top researchers, as well as sophisticated production facilities, computer systems and medical centres to evaluate knowledge gained in clinical trials.

It was on a tour of Ventana Medical Systems that one doctor blew my mind when he said stem cells no longer had to be harvested only from umbilical cord blood. They could be harvested from the back of a hand.

This was going to change everything, he said.

Then in early 2010 we interviewed Dr. Andras Nagy, world-renowned researcher from the Samuel Lunenfeld Research Institute at Toronto’s Mount Sinai Hospital. In 2005, his lab was the first in Canada to establish embryonic stem cells from human embryos. It’s interesting to look back on that interview and compare where we are now with our story on stem cells on page 14.

Nagy said then, there is so much more to discover. “It certainly is still at the state of infancy as far as the big picture is concerned. We don’t think we’re anywhere close to the end, although things are moving fast and lots is happening.”

This still holds true today. So much more is to come, even beyond defeating devastating diseases such as MS, leukemia and blindness mentioned in our article. Where else can stem cells be useful?

The Canadian Stem Cell Foundation has developed a strategy and a coalition of scientists, clinicians, business leaders, health charities and philanthropists to deliver “up to 10 new curative therapies within 10 years.” Now, with the strategy, the people, and the funding (see Prime Minister Trudeau on our cover), it is all coming together.

Theresa Rogers

executive Editor

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Publisher & CEO Christopher J. Forbes cforbes@jesmar.com

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canadian news

Evolution accelerates speed of plant migration

New research from the University of British Columbia suggests evolution is a driving mechanism behind plant migration. The study, which builds on previous research that has shown some plants and animals are moving farther north or to higher altitudes in an effort to escape rising global average temperatures due to climate change, found that after six generations, evolving plant populations dispersed seeds and migrated 11 per cent farther than non-evolving populations in landscapes with favourable conditions. Meanwhile, in landscapes where conditions were more challenging for the plants to disperse seeds, the evolving plant populations spread 200 per cent farther.

Alberta funds development of bioproducts

Canadian scientist chosen as Special Ambassador for International Year of Pulses

A Canadian researcher has been nominated by the UN’s Food and Agricultural Organization (FAO) as a Special Ambassador for the International Year of Pulses 2016. Dr. Joyce Boye is a research scientist with the Food Research and Development Centre of Agriculture and Agri-Food Canada. Boye’s research activities focus on developing techniques for the isolation, extraction and characterization of proteins from plant sources and identifying areas of application for the food industry. Her appointment as Special Ambassador was announced during an event hosted by the FAO in Washington, DC, in June.

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Songbird migratory patterns have genetic origins

Scientists have discovered a small cluster of genes that govern migratory behaviour in songbirds. The scientists used coin-sized light-level geolocators to track songbirds’ migrations, and next-generation sequencing techniques to get an in-depth view of their genomes. They applied these two recently developed techniques to two closely related groups of Swainson’s thrushes in BC and their hybrids. By linking the migratory behaviour of hybrids to their genetic makeup, these researchers pinpointed a single cluster of roughly 60 genes on one chromosome that largely accounts for the difference in migration patterns.

Steve Price, CEO, AI Bio

Alberta Innovates Bio Solutions (AI Bio) has approved funding for 61 projects it says will add value to Alberta’s renewable resources. Nearly $13 million in grants will go to researchers and companies that will develop new industrial bioproducts or technologies using Alberta agriculture and forestry byproducts or other biomass.

The funding is part of an effort to diversify and strengthen the Alberta economy, as well as reduce the province’s reliance on fossil fuel exports. Bioproducts and bioindustrial technologies have the potential to partially or fully replace petroleum-based products and energy sources, thereby potentially lowering GHG emissions and reducing the carbon footprint.

The approved projects span the The researchers and companies carrying out research and innovation the projects are using a variety of biomass types continuum from early applied research to to develop or produce advanced biomaterials, c o m m e r c i a l i z a t i o n . biofuels, biochemicals or biocomposites for a In addition to AI Bio broad range of applications. funding, 25 projects also receive industry funding. The researchers and companies carrying out the projects are using a variety of biomass types to develop or produce advanced biomaterials, biofuels, biochemicals or biocomposites for a broad range of applications. Examples include biofuels for transport and bioproducts that can be used in the energy, construction, forestry or manufacturing sectors.

Numerous projects involve cellulose nanocrystals (CNC) for construction, manufacturing or medical applications.

“Alberta is blessed with abundant biomass in our forests and crops, advanced infrastructure and universities, and highly qualified personnel in our academic community and bioindustrial sector,” says Steve Price, CEO, AI Bio. “AI Bio works as a catalyst to bring these together to accelerate growth in an area with great potential.”

worldwide news

Canadian innovators work to improve global health

New study assesses the cost of clinical trials

A new industry analysis will give biopharmaceutical companies data on how much clinical trials cost. KMR Group has completed the first-ever Clinical Trial Cost Study, identifying statistically significant cost drivers that cause some companies to run more expensive trials than others, prompting discussions and questions about trial design and operational plans. The Clinical Trial Cost Study helps quantify cost savings based on improved industry efficiencies, cycle times and study design considerations. Any combination of cost types and cost factors can be assessed in an online application available to participants.

Researchers identify a gene that can protect against neurodegenerative diseases

Grand Challenges Canada has committed scale-up funding to six Canadian projects that aim to improve global health. The new investments, matched by a wide range of partners, will enable the innovators to advance the development of their technologies and will build on significant results from seed projects also funded by Grand Challenges Canada. This included projects by innovators from companies based in BC, Ontario and Quebec, partnering with groups in several African countries.

Arbutus Medical of Vancouver, conducted clinical trials in East Africa to develop a safe, affordable drill cover system for bone surgeons to reduce tool cost and improve infection control practices. KA Imaging of Waterloo, Ontario, developed a prototype of a highresolution X-ray imager that can achieve the same levels of accuracy as a conventional chest X-ray, at a significantly lower X-ray dose and cost. Sympact-X and the Research Institute of McGill University Health Centre in Montreal, Quebec, developed a smartphone-based HIV self-test app called HIVSmart! that can help identify undiagnosed HIV cases and people at risk of infection.

Based on these outcomes funded by Grand Challenges The new investments, matched by a wide Canada, the innovators will range of partners, will enable the innovators now receive “transition-toscale” investments. The new to advance the development of their funding, totalling $5 million, technologies and will build on significant will be doubled by partners results from seed projects also funded by in the six projects, creating Grand Challenges Canada. a total investment of $10 million.

Canada’s Minister of Health in South Africa

In a visit to Durban, South Africa, Canada’s Minister of Health, Jane Philpott, attended the 21st International AIDS Conference, took part in several key meetings with Canadian community-based organization and researchers, and met with the South African Minister of Health, Aaron Motsoaledi, and with the Executive Director of the Global Fund to Fight AIDS, Tuberculosis and Malaria, Mark Dybul. Philpott confirmed Canada’s commitment to work alongside communities to improve indigenous health outcomes and called on donor countries to reconfirm their commitment to the Global Fund.

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Dr. Yuma and Aidan Chale in training for the Queen’s University/Wema Inc. women’s health management through mobile health platforms project.

New research, led by the University of Glasgow, has identified how cells protect themselves against protein clumps known to be the cause of neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s disease. Researchers discovered that a gene called UBQLN2 helps the cell remove toxic protein clumps by detangling them and then shredding them to prevent future tangles. Previous work has shown that when the UBQLN2 gene is faulty, it leads to a neurodegenerative disease called Amyotrophic Lateral Sclerosis with Frontotemporal Dementia. Until this study, it was not fully understood why mutation of this gene caused disease.

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regional profile

The

Evolution of

Thailand’s capital city is at the centre of the country’s life sciences progress By hermione wilson

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Bangkok

regional profile

hailand wants to become a vital part of the global value chain, says Panit Kitsubun, Director of the National Biopharmaceutical Facility (NBF). Almost two years removed from a military coup and contending with a floundering economy, the kingdom’s life sciences sector is treading water and looking to the future. The key to that future is Thailand’s capital city of Bangkok, home to the country’s highest concentration of hospitals, research institutions and biotech companies.

“All the larger scale healthcare facilities and hospitals are in Bangkok,” Kitsubun says. “I believe we have the second or third-highest number of JCI [Joint Commission International) certified hospitals in Asia just behind China, although China is much larger than us.”

One of the largest hospitals in Bangkok is also the country’s first. Established in 1888 by King Chulalongkorn (whose father was famously portrayed in The King and I), Siriraj Hospital is managed by Mahidol University and serves as a teaching hospital for its medical school. “It has now become one of the biggest hospitals in Asia in terms of numbers of beds and patient enrolment,” says Nares Damrongchai, CEO of the Thailand Center of Excellence for Life Sciences (TCELS), an arm of the Thai government whose mission is to support the growth of the nation’s life science industry.

With its cluster of world-class private hospitals, Bangkok has become a hub for medical tourism, Damrongchai explains. Patients come from the U.S., Europe, Australia, The Middle East, and a large majority from Japan, he says.

Needless to say, the focus of Bangkok’s life sciences sector tends to centre on medical services, as well as the manufacture of pharmaceuticals and medical devices.

A combination of highly trained clinicians and a large population means that Thailand’s capital also happens to be a great place for doing late stage clinical trials, not to mention much cheaper when compared to the U.S. or Europe. In the last couple of years the sector has made an effort to transition from late stage to early stage clinical trials, Kitsubun says. “We have invested

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regional profile

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in facilities throughout the country,” he says. The Medical Research Network of the Consortium of Thai Medical Schools, or MedResNet, coordinates all medical schools and clinical trial sites in the country.

“In Thailand... most of the R&D is carried out in public research institutions and academia,” Kitsubun says. “We do have a number of biopharmaceutical and vaccine companies here, but of course they are more focused on the manufacturing part.”

Kitsubun’s company, NBF, is a public institution that was established to serve as Thailand’s first CGMP-compliant (Drug Applications and Current Good Manufacturing Practice) contract manufacturing organization for the production of biopharmaceuticals for phase I and II clinical trials. The facility was jointly developed by KMUTT University and the National Center for Genetic Engineering and Biotechnology (BIOTEC).

“We cater to both the research and development part of the story,” Kitsubun says. “We help scientists, whether they are in academia or in public research institutions, or startup companies, or pharmaceutical companies, we help them go into clinical trials.” NBF also uses its facilities to develop human resources for the industry. It runs a graduate program called Biopharmaceutical Engineering Practice School which trains 10 students a year in the inner workings of a biopharmaceutical pilot plant. Students attend lectures for two semesters, spend one semester in the TCELS is an arm of the Thai government charged with supporting the growth of the life science sector. work-integrated learning program, and in their final semester conduct an independent research thesis in Vonghangool explains that, despite Bangkok’s many prominent research biopharmaceutical R&D. universities, like Mahidol, Chulalongkorn, Chiang Mai, and Khon Kaen, most All of this is an effort to harness institutions operate only small-scale lab research and don’t have much translational Thailand’s strengths in research research they can develop in a pilot plant. “They don't have that capacity yet, because and manufacturing, and translate it that involves a lot of funding and experimentation,” Vonghangool says, speaking into commercialized products for specifically to vaccine development. “Making vaccines, you need a minimum of 10 to export overseas. The government 15 years.” has been concentrating on making Thailand self-sufficient, says Vitoon Vonghangool, President of privately owned vaccine We need to build up an ecosystem. What we have now is a manufacturer BioNet-Asia. “But scattered picture of many pieces of manufacturing capabilities for privately owned companies, and researchers, but these are not very well connected still. We we have to think about our own self-sufficiency. That means we need to have a better understanding of how we can link all the have to sell small and export more, actions and all the efforts and commercialize those research at least within Asia. You have to results as well. think about export, because the – Nares Damrongchai, CEO, Thailand Center of Excellence for Life Sciences (TCELS) domestic [market] is too small.”

regional profile

Thailand Facts and Figures » Bloomberg Markets magazine ranked Thailand third among its Top 20 Emerging Markets in 2013 behind South Korea and China. » Thailand’s export of pharmaceutical products has seen a growth of 6.12 per cent over the past five years. » National Biopharmaceutical Facility (NBF) is Thailand’s first CMO for manufacturing of biopharmaceuticals for phase I/II clinical trials. » BioNet-Asia is the only vaccine company in Thailand that is 100 per cent privately owned. » Thailand has more than 1,000 public hospitals and more than 300 private hospitals. » Thailand is a hub of medical tourism with 2.35 million foreign patients receiving treatment in 2014. » S iriraj Hospital in Bangkok was founded more than 120 years ago by King Chulalongkorn. » T he Thai government spends 14 per cent of its total budget on the healthcare industry, which accounts for 4.6 per cent of the country’s GDP. Below: BioNet-Asia vaccine plant facilities.

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Part of the reason the government is more inclined to fund smaller scale research projects is that they tend to publish studies faster. Thai universities publish 300 to 400 studies per year, Vonghangool says, but when it comes to development, they struggle to sustain funding.

BioNet-Asia is one of the few Thai vaccine companies that handles every part of the process, but it didn’t start off that way. “We started as a consulting company,” Vonghangool says. “We had the knowledge in terms of marketing, the market, and connections with vaccine makers all over the world.”

Vonghangool worked for Sanofi Pasteur for 22 years before leaving in 1992 to set up his own company. “We started with a bit of trading and diversified to manufacturing in 2007,” he says. “Today we cover the full range of the vaccine supply chain, from trading, domestic, international and also manufacturing.”

About 90 years ago Thailand was one of the first countries in southeast Asia to produce vaccines, Kitsubun says.

“The thing is, in the past 20 or 30 years, Thailand has missed opportunities in investing in newer technologies.”

Still, Thailand is catching up fast in the biotech space, he says. After years of buying and selling vaccines, BioNetAsia will soon launch a product of its own, a vaccine for whooping cough.

Meanwhile, Bangkok company Siam Bioscience is making inroads into the biosimilars space.

“Siam Bioscience is in the process of registering its G-CSF at the Thai FDA,” Kitsubun says. “I believe they are trying to crack the EU market as well, and they are also looking into monoclonal antibodies.” G-CSF is a growth factor used to increase white blood cells after cancer treatment. Kitsubun says biosimilars like this would greatly reduce the costs of pharmaceuticals in the country.

Thailand Science Park in northern Bangkok is home to a cluster of research institutes and companies from a variety of industries, including cosmetic companies like Shiseido, food companies, as well as pharmaceuticals and biotechs. TCELS is planning to build a facility there that would provide startups with leased R&D space, as well as special facilities for cell production.

Construction is expected to start later this year and companies are already lining up to move in, Damrongchai says.

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regional profile The incubator will be called the GMP Facility for Cell and Gene Therapy Products.

“We really have strong R&D and vaccine companies, and supporting systems like university R&D,” he says.

“Everybody is in Bangkok.”

What’s needed to push the Bangkok life sciences sector – and Thailand’s life sciences by extension – to the next level is a strong commitment of support from the government, Kitsubun says.

“We need to build up an ecosystem,” he says. “What we have now is a scattered picture of many pieces of manufacturing capabilities and researchers, but these are not very well connected still. We need to have a better understanding of how we can link all the actions and all the efforts and commercialize those research results as well.”

Also missing is the involvement of private investors, Kitsubun says. Most Thai investors are focused on tech and engineering startups, but when it comes to biotech, he says, they don’t understand that the development stage takes much longer than in other industries. In biotech you many have to wait 10 to 15 years before you see a commercialized product, but the returns at the end of the day are high. That’s something Kitsubun says venture capitalists from overseas seem to have a better grasp of and many have come to Thailand to shop around.

Because of that, it is key to the further growth of Thailand’s life sciences sector that Bangkok becomes a welcoming place for foreign investors and VCs. To that end, the Thai government has begun to offer new policies like an eight-year

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Dr. Nares Damrongchai (bottom), CEO at TCELS, speaks at an event in Seoul, South Korea.

Most Thai investors are focused on tech and engineering startups, but when it comes to biotech, they don’t understand that the development stage takes much longer than in other industries. – Panit Kitsubun tax break for foreign companies. The government is also discussing whether to offer exemptions from personal income tax and a streamlined visa and work permit application service for expats who come to work in Thailand.

“That’s not enough,” Vonghangool

says. “In the life sciences you may need 10 to 15 years to have success, but before that, how will the government support you?”

Damrongchai and his colleagues at TCELS, along with consortium of Thai pharmaceutical companies, have been working together on a policy package for the government that will improve the investment incentives for multinational biopharmaceutical companies looking to come to Thailand. The policy package includes things like a multi-year tender policy, extending the period of tax breaks, and importing equipment tax-free, and is expected to be adopted in the next few months, Damrongchai says.

Damrongchai is optimistic about the future of Thailand’s life science sector. “The quality of the medical service here, which attracts customers from all over the world, the world-class universities, the number of JCI institutes... I look at this as really good infrastructure, which attracts investment, attracts people and technology.” BB

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feature storY

By hermione wilson

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W

hen a medical treatment is as effective as the stem cell therapy out of Ottawa has been, it’s not surprising that the press is throwing around the word “cure”. In 2001, researchers from The Ottawa Hospital and the University of Ottawa, led by Harold Atkins and Mark S. Freedman, treated 24 patients who had aggressive forms of multiple sclerosis with a stem cell transplantation technique originally developed to treat leukemia. They began by completely decimating the patients’ immune systems with chemotherapy and then transplanting them with their own newly purified hematopoietic stem cells in an effort to regenerate a new immune system.

The patients were followed for the next 13 years and what they observed was nothing short of remarkable. While a third of the patients continued to develop disabilities associated with rapid onset MS, the other two-thirds of patients either stabilized or saw improvements to their disabilities. Failing vision improved, mobility returned; one participant named Jennifer Molson went from using a wheelchair to skiing and getting her driver’s license. The treatment seemed to stop the inflammation caused by MS in its tracks.

feature story

Stem cell areNa explodes with promising research but scientists

Prime Minister Justin Trudeau pledges his government’s financial support for a centre of advanced therapeutic cell technologies in Toronto.

Photo credit: Canadian Press Images/ CCRM/Salvatore Sacco

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remain cautious

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Left: Ottawa Hospital Research Institute researchers Mark S. Freedman, Harold Atkins and Marjorie Bowman were part of a $6.47-million trial that used blood stem cells to regenerate the immune systems of people with early, aggressive multiple sclerosis (MS). Right: Jennifer Molson, an MS sufferer who saw dramatic improvements in her condition, was one of that trial’s most successful participants. Photo credit: 2015 Trevor Lush.

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Still, Atkins is hesitant to invoke the “c” word.

“A cure, for me, would be a patient living their life and never having a symptom or suffering from multiple sclerosis again,” he says. “We don’t know if this is a cure or not because our longest patient is only 13 or 14 years after her transplant, so time will tell. What we can say is the active inflammation has stopped and it has been controlled for a long time.”

A real cure, Atkins says, would mean no further damage caused by the immune system’s deranged attack on the brain.

In fact, it would mean the damage would be repaired and everything would go back to normal. Of course, the results of the Ottawa trial are encouraging, but Timothy Caulfield is cautious in his praise.

“I’m always hesitant to use that word ‘cure,’” says the Canada Research Chair in Health Law and Policy and professor at the University of Alberta. “The results here have been very good but it’s a serious process. Here you have Harry [Atkins]’s approach where you completely ablated the immune system using chemotherapy... then the very specific and measured introduction of stem cells in a very particular kind of way, in a highly monitored clinical setting, versus a lot of these clinics where they’re just injecting stem cells – or who

knows what they’re injecting – to treat the same condition.”

Caulfield is referring to the proliferation of unregulated stem cell clinics in countries where the regulatory framework is not as strict. These unscrupulous clinics offer supposedly miraculous stem cell treatments, based on unproven science, to mostly rich and desperate foreigners searching for a cure. It’s called stem cell tourism and the results can range from merely ineffective to potentially harmful.

While the tantalizing promise of miraculous cures tempt patients overseas, it puts pressure on the industry here in North America to get effective therapies to the clinic faster, Caulfield says.

“I think that the science really isn’t there yet for most therapies and the work that’s been done by Harry [Atkins] and his team really shows the slow, and thankfully positive, progress of science towards the clinic.”

Despite it being early days yet, Canadian scientists have been steeped in stem cell research since their discovery at the Ontario Cancer Institute in Toronto in the 1960s. Continuing the work is a network of institutions and investigators intent on translating current stem cell research into working therapies and treatments. Besides the Ottawa MS trial, however, there haven’t been many that have made it to the clinic.

“The historic problem is we’ve got these discoveries to a point but then can’t take it beyond and actually commercialize the technology,” says Michael Israels, CFO of Centre for Commercialization of

A coalition of Canadian stem cell scientists, clinicians, business leaders, health charities and philanthropists have outlined a plan to deliver “up to 10 new curative therapies within 10 years.”

feature story

Highlights from U of T

Molly Shoichet and her colleagues at U of T are working on delivery methods for stem cell therapies. Photo credit: Brigitte Lacombe.

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Regenerative Medicine (CCRM), of Canadian stem cell research. “We have funding in the early stages... but as you go along, industry at the back end, pharma and other large organizations, are happy to spend money on things that are close to being able to go to market.”

Israels is hoping a recent allocation of funds from the federal government will change that. The government announced in January that it would be committing $20 million to CCRM to help build a stem cell therapy development facility in Toronto, and GE Healthcare is matching those funds with another $20 million. Alongside the new facility, Israels says, CCRM plans to build a cell manufacturing facility that will focus on manufacturing human cells for clinical trial use.

In March, the Canadian government’s 2016 budget allocated $12 million over two years to support the Stem Cell Network’s research, training and outreach activities, according to a press release from the Canadian Stem Cell Foundation. The release goes on to say that a coalition of Canadian stem cell scientists, clinicians, business leaders, health charities and philanthropists have outlined a plan to deliver “up to 10 new curative therapies within 10 years,” according to a proposed Canadian Stem Cell Strategy.

Bold words, but can the Canadian stem cell sector back them up? The stem cell transplantation technique used by Atkins and his colleagues in Ottawa has certainly borne fruit, albeit after several decades of development.

“The technology that we’re using for hematopoietic stem cell transplantation took 20 years to become mainstream, from the time it was thought of to treat leukemia, to when it really started to be used broadly,” Atkins says. “I think these other stem cell [therapies will] have the same learning curve. I think it will happen but I don’t think it will happen overnight.” BB

The University of Toronto is pulling its weight in the stem cell space, with a number of projects underway. CCRM is collaborating with ExcellThera Inc. on a technique that uses technology from U of T to expand the volume of hematopoietic stem cells in umbilical cord blood so that it can be used in adult leukemia patients. Clinical trials are currently in progress.

Meanwhile, U of T biomedical engineer Molly Shoichet and her colleagues Derek van der Kooy and Valerie Wallace have been investigating the use of stem cells in treating blindness. Shoichet’s work involves bioengineering cell delivery platforms that will ensure the survival of these cells when they are injected into the patient. Their research has shown some functional improvement in mouse models of blindness after the injection of rod photoreceptor cells derived from adult retinal stem cells.

“What we’re trying to do is come up with a strategy that will actually reverse blindness,” Shoichet says.

Shoichet is also collaborating on stroke research with Professors Cindi Morshead, Andras Nagy and Dale Corbett. They have observed some functional repair after delivering neuronal cells derived from human induced pluripotent stem cells to the brains of rat models of stroke.

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LAW

ARE STEM CELLS

PATENTABLE?

By Chuan Gao, Brian Kingwell, Andrej Michalik

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his article is about the law, and so the answer to a simple question is inevitably complicated. Some stem cells are patentable, and some are not, and it varies from place to place. What follows is an attempt to be briefly informative about this spectrum of complexities, by looking in particular at a few jurisdictions: Europe, the U.S. and Canada.

European patents are granted centrally by the European Patent Office (EPO) for 38 member states of the European Patent Organisation. Membership is independent of membership to the European Union (EU), although all current EU countries are also members of the European Patent Organisation. The EPO operates under a self-contained legal framework, the European Patent Convention (EPC). To align the EPO’s practice on the patentability of biotechnological inventions with EU legislation, relevant provisions of the EU “Biotech Directive” (98/44/EC) have been adopted as EPC rules, and the EPO Boards of Appeal consider the European Court of Justice’s (CJEU) interpretation of the Biotech Directive persuasive, albeit not legally binding.

The EPO is mandated to grant patents for biotechnological inventions, including patents for biological material isolated from its natural environment or produced by technical means even if it previously occurred in nature. Accordingly, European patents are in general available for cell products, including isolated stem cells; and inventions relating to adult stem cells and non-human embryonic stem cells have not caused controversy. Patenting of inventions involving human embryonic stem (hES) cells proved more problematic in view of EPC rules prohibiting patenting of “the human body, at the various stages of its formation and development” and “uses of human embryos for industrial or commercial purposes”.

The former provision precludes patents for human germ cells, human embryos and cells that can develop into a human being. The latter provision was interpreted by the EPO Enlarged Board of Appeal in the WARF decision (G 2/06) as forbidding claims to products which at the filing date could be prepared exclusively by a method necessarily involving the destruction of human embryos. Subsequent decisions confirmed that the point in time at which the destruction took place was irrelevant, and

The EPO is mandated to grant patents for biotechnological inventions, including patents for biological material isolated from its natural environment or produced by technical means even if it previously occurred in nature.

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Most recently, the CJEU in C-364/13 ruled that an unfertilised human ovum whose division and further development had been stimulated by parthenogenesis does not constitute a “human embryo”, due to its lack of inherent capacity to develop into a human being.

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inventions using publicly available hES cell lines initially derived destructively were also excluded (T 2221/10).

There have been a variety of EPO Board and CJEU decisions related to this issue. Most recently, the CJEU in C-364/13 ruled that an unfertilised human ovum whose division and further development had been stimulated by parthenogenesis does not constitute a “human embryo”, due to its lack of inherent capacity to develop into a human being.

This motivated the EPO to revise its examination practice.

Having identified WO 03/046141 published on 5 June 2003 as the first enabling disclosure of hES cells derived from parthenotes (thus, without destruction of human embryos), the EPO Examining Divisions are prepared to allow hES cellrelated inventions filed after this date. However, the EPO Boards of Appeal have not yet endorsed the applicability of the 2003 cut-off date.

Turning to the U.S., a famous quote succinctly describes a patentable invention as “anything under the sun made by man.” In keeping with that sentiment, and the broad statutory definition of a patentable invention, U.S. patents have since the late 1980s consistently issued with claims covering isolated stem cells (including both adult or somatic stem cells and human embryonic stem cells) or induced pluripotent stem cells (iPSC), their compositions, methods of use, methods for generating such stem cells, non-human animals resulting from genetic manipulation involving stem cells, and associated subject matter (such as reagents, media, and scaffolding for culturing stem cells).

A pair of recent U.S. Supreme Court decisions have, however, complicated the issue. The Supreme Court ruled in Prometheus that an invention is not patent-eligible if it is drawn to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without substantially more. In the Myriad decision, the Court ruled that a naturally occurring polynucleotide is not patent-eligible merely because it has been isolated.

In its effort to implement the Myriad decision, the USPTO has established patent examination guidelines that extend the prohibition of patenting natural products from polynucleotides to proteins, cells, and beyond. Under the current guidelines, a nature-based product is not patenteligible unless (1) it is shown to exhibit characteristics “markedly different” from that of a naturally occurring counterpart, or (2) additional components are present that

amount to “significantly more” than the naturally occurring substance. Under these examination guidelines, isolated stem cells that are not per se distinguishable from their naturally occurring counterparts are no longer eligible for patent protection, whereas iPSC claims remain patent-eligible if the resultant stem cells can be characterized as “markedly different” from any naturally occurring cells due to their structural distinctions, such as genetic makeup or protein expression pattern. Similar principles apply to a variety of stem cell compositions that include stem cells and additional components. Relatively unaffected by the recent Supreme Court rulings, claims drawn to methods of using stem cells (such as differentiating or trans-differentiating stem cells), methods of generating stem cells, and associated composition claims (e.g., reagents, culture media, or scaffolding) generally remain patentable in the U.S. Patent applicants in Canada do not face the new challenges posed in the U.S. by the Myriad and Prometheus decisions.

However, the Canadian Intellectual Property Office (CIPO) takes the position that multicellular plants and animals at any stage of development are higher life forms, and are thus not patentable. Totipotent stem cells are taken to have the same potential as fertilized eggs or seeds to develop into an entire organism, and are accordingly considered to be higher life forms that are not patentable subject matter. Embryonic, multipotent and pluripotent stem cells, which are understood not to have the potential to develop into an entire organism, are patentable subject matter. The language used by CIPO to define its exclusion of totipotent stem cells from patentable subject matter echoes aspects of Article 5 of the European Biotech Directive. There are, however, no analogous provisions in the Canadian Patent Act or Rules, and the Biotech Directive is not part of Canadian law. In fact, the administrative policy of CIPO directly contradicts statements made by the Supreme Court of Canada in

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crafted with this evolving legal landscape in mind, ensuring that the full scope and range of every stem cell innovation is fully characterized. This sets the groundwork for obtaining commercially meaningful patent protection in a variety of important jurisdictions, although not always by following the same path. Innovators in the field have persevered in the face of sometimes unexpected obstacles to bring the promise of stem cell technologies ever closer to realization.

The same optimistic perseverance may be required of patent applicants as patent law adjusts to accommodate technical and commercial imperatives and thereby serve its intended purpose, as expressed in the U.S. Constitution, of promoting the progress of science and the useful arts. BB

Chuan Gao is Partner, Kilpatrick Townsend. Brian Kingwell is Partner, Gowling WLG (Canada). Andrej Michalik is European Patent Attorney, De Clercq & Co.

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its leading decision on the patentability of higher life forms, the Harvard Mouse decision, in which one Justice explicitly indicated that a fertilized egg is patentable subject matter.

Time, or more particularly jurisprudence, will tell if CIPO’s policy becomes law. In the meantime, claims can successfully be made in Canada to a wide variety of stem cell-related innovations, including new medical uses of stem cells, even where claims to the cells themselves will be refused.

Stem cells are uniquely characterized by their capacity to become many things. Perhaps then it should not be surprising that stem cell patentability around the world is characterized more by diversity than by harmonization. From a practical perspective, this means that patent applications need to be

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MOMeNts iN TIME

cancer sTeM cells n

ot all acute myeloid leukemia (AML) cells are created equal, as Canadian researcher John Dick discovered in 1994. According to study published in Nature, 1994, most AML cells have a limited ability to reproduce, pointing to the existence of rare AML-initiating cells, called leukemia stem cells (LSC). Dick was able to isolate and identify LSCs by transplanting them into severe combined immune-deficient (SCID) mice. The idea is that by targeting these stem cells, which allow the leukemia cells to proliferate, you can design a more effective cancer treatment and reduce the risk of a relapse. Dick followed up his discovery of LSCs by identifying colon cancer stem cells in 2007. BB

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John dick was recently part of a proof-of-concept study which discovered a new method of making more stem cells from cord blood.

Photo credit: university health Network.

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