The medicinal qualities of cannabis have been recognised since at least 2800 BC, with cannabis featuring in ancient Chinese and Indian medical texts. Although the use of cannabis for medicinal purposes has been known for centuries, research into the pharmacological properties of the plant has largely been limited due to its illegal status. Despite this, the recent legalisation of cannabis for medicinal use in Australia has fuelled interest in research on the biochemistry of cannabis and how the chemical components of cannabis mediate its therapeutic effects. Importantly, legalisation has occurred in conjunction with an injection of funds to support clinical research on medicinal cannabis, resulting in the establishment of a number of specialised research centres and clinical trial programs (e.g., The Lambert Initiative for Cannabinoid Therapeutics and the Centre for Medicinal Cannabis Research and Innovation). The outcome of this research activity is essential to develop robust treatment regimens that are effective and safe for patients and to support the commercialisation of new cannabis-related therapeutics.
In this second part of our three-part series, we explore some of the considerations associated with the commercialisation of therapeutic isolates and compositions derived from medicinal cannabis and highlight the options available for protecting such products under Australia’s intellectual property regimes.
Medicinal cannabis: plant chemistry and biology
Aside from whole extracts of cannabis flowers, resins and oils, it is recognised that cannabis contains many individual compounds with therapeutic potential. Currently, it is estimated that the cannabis plant produces more than 400 different molecules, including cannabinoids, terpinoids and flavonoids. These molecules interact with the endocannabinoid system to exert a number of regulatory effects on the neuronal, vascular, metabolic, immune and reproductive systems.
Cannabinoids are the most commonly known and researched cannabis compounds, and include delta-9-tetrahydrocannibinol (THC) and cannibidiol (CBD). THC is responsible for the psychoactive effects associated with recreational cannabis, while CBD is non-psychoactive and has been associated with anti-psychotic and anxiolytic effects. More recently, research has also focused on cannabis terpinoids, which are responsible for the distinct smell of cannabis. Common terpiniods found in cannabis include, α-pinene, linalool, myrcene, β-caryophllene, caryophllene oxide, neroidol, phytol and limonene (Russo, 2011, British Journal of Pharmacology, 163: 1344-1364). The combination of terpiniods present in cannabis, i.e. the terpiniod profile, can result in distinctive fragrances and/or tastes, that are often selectively bred for in the recreational market (e.g. “Birthday Cake”). However, terpiniods can also mediate independent therapeutic effects or act directly or indirectly with cannabinoids to potentiate their effects. For example, limonene has been shown to induce apoptosis in breast cancer cells (Vigushin et al. 1998, Cancer Chemotherapy Pharmacology, 42: 111-117), while the combination of limonene and CBD has been suggested to synergise for the treatment of acne (Kim et al., 2008, Bioscience Biotechnology Biochemistry, 100: 884-886 and Wagner and Ulrich-Merzenich, 2009, Phytomedicine, 16: 97-110).
Whilst many cannabis-derived compounds may act independently in a therapeutic context, specific combinations of compounds (e.g. cannabioniods and terpinoids) may act synergistically to potentiate any therapeutic effects. In fact, research is ongoing to investigate the “entourage effect”, which has been proposed as a “sum of the parts” explanation for the effects of cannabis in both a recreational and therapeutic context (Ben-Shabat et al., 1998, European Journal of Pharmacology, 353(1): 23-31 and Mechoulam and Ben-Shabat et al. 1999, Natural Products Reports, 16(2): 131-143). The “entourage effect” has been illustrated by Ryan et al. in the action of THC or CBD on neuronal activity when compared to whole cannabis extracts or flowers, noting that THC and CBD act synergistically to elevate Ca2+ levels in hippocampal neurones and glia (Ryan et al., 2006, Neuroscience Letters, 408(3): 236-241). Further research into this area is likely to identify unexpected combination therapies and compositions of cannabis-derived compounds with enhanced efficacy.
Clinical evaluation and use
In order for cannabis-derived products to enter the market, they must be supported by extensive pre-clinical and clinical trial data to establish efficacy and safety. Unfortunately, the legalisation of medicinal cannabis in a number of jurisdictions has not been accompanied by strict or consistent regulation, which has resulted in an insufficient level of clinical evidence for the health benefits of medicinal cannabis use. For example, prior to the full legalisation of cannabis in California for both medicinal and recreational use, it was possible for patients to obtain a medicinal marijuana licence from a doctor who performed a “good faith physical examination” and determined that the patient could benefit from using medicinal cannabis. From all reports, it was not difficult for patients to obtain a licence, and once granted, patients could obtain an unfettered supply of medicinal cannabis from any medicinal cannabis dispensary.
Despite the current lack of clinical evidence, pre-clinical animal studies suggest there is a role for cannabis and cannabis-derived compounds and derivatives for pain management, inflammatory and neurodegenerative disorders, appetite and weight gain, malignant disorders, epilepsy and inflammatory bowel disease. Such data has led to the establishment of a number of clinical trials across the world to assess the efficacy of these products. In Australia, clinical trials are currently underway to investigate the therapeutic benefit of cannabis-derived compounds (i.e. cannabis oil, CBD oil) in the treatment of children with severe, drug-resistant epilepsy, for adult palliative care patients and for relieving chemotherapy-induced nausea and vomiting in adults where standard treatment is ineffective. These trials are on-going, in both New South Wales and Victoria. Further clinical trials are also recruiting to assess the use of vaporised cannabis flowers to provide relief for adult cancer patients in palliative care and the use of medicinal cannabis for the prevention of nausea and vomiting from chemotherapy in patients with cancer and HIV/AIDS.
Currently, there is only a single cannabis-derived product registered on the Australia Register of Therapeutic Goods (ARTG). Sativex (Nabiximols), an oral spray comprising THC and CBD, became the world’s first cannabis extract-based prescription medicine to be approved for clinical use. It is prescribed for the relief of pain and spasticity associated with multiple sclerosis, as well as for the treatment of pain in cancer patients. Sativex has also been approved for clinical use in Europe and Canada.
In recognition of the lag in obtaining clinical data to support registration on the ARTG, there are a number of alternative access schemes that are available to patients in Australia. Access to medicinal cannabis via both the traditional and alternative access schemes will be discussed in the third and final part of this series.
Obtaining intellectual property protection for cannabis-derived compounds
The identification and clinical evaluation of cannabis-derived compounds requires significant financial investment to bring these products to market. Accordingly, it is essential that any pre-clinical or clinical research is supported by adequate intellectual property protection.
As set out in our previous article (here), patent protection is available for newly identified, naturally-occurring proteins and small molecules isolated from cannabis plants, as long as they satisfy the requirements for patentability, including novelty and non-obviousness. It is important to note, however, that patent eligibility will vary across jurisdictions.
In Australia and Europe, newly identified, naturally-occurring proteins and other small molecules isolated from cannabis plants are eligible for patent protection. In Australia, isolated nucleic acid molecules are currently ineligible from patent protection where they merely replicate the genetic information of the plant variety, unless they have been modified further (e.g., double-stranded interfering RNA molecules, DNA constructs comprising one or more heterologous promoters, codon-optimised nucleic acid sequences, etc).
By contrast, patent eligibility in the US is far more limiting. At present, it is difficult to secure patent protection in the US for any isolated, naturally-occurring compound. However, non-naturally-occurring derivatives of cannabis-derived compounds are still eligible for patent protection in the US (and elsewhere).
As most cannabis-derived compounds are now well characterised, it is likely that further research and development in this area will focus not only on derivatives but also specific combinations of cannabis-derived compounds that provide favourable therapeutic outcomes, such as enhanced efficacy and reduced adverse side effects. In most jurisdictions, including Australia, Europe and the US, patent protection is available for new combinations of naturally-occurring compounds, even where those compounds are known. It is important to bear in mind, however, that patent protection around combinations is likely to depend on having sufficient comparative data to show that a claimed combination provides some unexpected effect or advantage over and above what is seen with the individual compounds alone (e.g., a synergistic effect, reduced side effects). Comparative data is therefore likely to be critical to securing patent protection to a combination of cannabis-derived compounds.
The interest in patent protection for cannabis and cannabis-based products is not limited to the plant varieties or compounds derived from them. The desire to produce cannabis products with different cannabinoid constituents, depending on the intended use of the product, is also leading to increasing patent activity surrounding cannabis and cannabis extract processing and production techniques and cannabinoid extraction processes. Additionally, patent protection is being sought for novel delivery vehicles and mechanisms to maximise therapeutic efficacy and for the use of cannabis extracts and cannabis derived compounds as adjuvants to existing therapies and treatments. In fact, there are number of benefits associated with obtaining protection for these cannabis-related innovations, as they are often simpler, quicker and cheaper to develop than novel compounds or combinations. Furthermore, obtaining protection for such innovations can provide over-arching patent protection providing a freedom to operate barrier, which can assist in establishing a strong market position.
Cannabis-derived extracts, compounds and compositions have the potential to treat a broad range of conditions in both children and adults. However, it is well recognised that the development of new therapeutics, even those derived from plants, require significant financial investment to bring to market. It is also well recognised that investment in research and development is largely dependent on adequate intellectual property protection to ensure a return on that investment. Therefore, it is essential that the identification and development of new cannabis-derived extracts, compounds and therapeutic formulations is supported by adequate intellectual property rights. To this end, Australia provides several options for pursuing patent protection around isolated biological materials from plants, including proteins, small molecules and compositions comprising a combination of plant-derived compounds. Methods of medical treatment and second medical uses are also eligible for patent protection in Australia.