IMPROVEMENTS IN PRODUCTION OF CANNABIS FOR MEDICAL AND INDUSTRIAL USES AND THEIR PROTECTION - Uhthoff

IMPROVEMENTS IN PRODUCTION OF CANNABIS FOR MEDICAL AND INDUSTRIAL USES AND THEIR PROTECTION

The use of Cannabis has been stigmatized due to its psychoactive effects; however, it has several uses in industry and medicine.

Cannabis contains more than 500 components. Two of these have been the subject of scientific investigation due to their pharmacological properties: Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Other plant-derived cannabinoids include cannabinol (CBN).

Cannabis as a drug and industrial hemp both derive from the species Cannabis sativa and contain the psychoactive component tetrahydrocannabinol (THC), yet they are distinct strains with unique phytochemical compositions and uses. Hemp has lower concentrations of THC (0.3% or less) and higher concentrations of cannabidiol (CBD), which means minimal to no psychoactive effects. The legality of industrial hemp varies widely between countries. Some governments regulate the concentration of THC and allow only hemp that is bred with an especially low THC content.

The discussion on the use and legality of each of these plants, even if they are from the same family, must be carried out for each of them. Separating it into the legal, productive, and social fields would also make it possible to differentiate the recreational, medical, and wellness uses of marijuana from the industrial, medicinal, and useful properties of hemp. This would, in turn, motivate research, health, industrial, and economical advancement, improving the quality of life for hundreds of patients.

USES OF CANNABIS

Recent reports indicate that Cannabis production is increasing and that cannabinoid formulations have been changing over the last two decades, especially with regard to their THC and CBD concentrations.

Therapeutic applications of Cannabis and cannabinoids

THC is the psychoactive principle of Cannabis, inducing the Cannabis inebriation sought by many users. Its addictive potential and negative consequences are now well known. The effects of CBD are distinct and, in many cases, the opposite of THC’s effects. CBD seems not to induce euphoria and seems to have antipsychotic, anxiolytic, antiepileptic, and anti-inflammatory properties.

According to an evaluation (in 1999) by the Institute of Medicine in the United States, on Cannabis as a medication, the future of medical Cannabis lies in isolating its cannabinoid components and their synthetic derivatives. The variable composition within the raw Cannabis plant and especially the differing THC/CBD ratios make therapeutic applications of these products quite complex.

The following medical applications have been described for Cannabis:

THC Analgesic Anti-bacterial Anti-cancer Anti-inflammatory Anti-spasmodic Appetite Stimulant Bronchodilator Neuroprotective THCV Anti-convulsive Appetite Suppressant Bone Stimulant
CBD AnalgesicAnti-anxiety Anti-bacterial Anti-cancer Anti-convulsive Anti-depressant Anti-emetic Anti-inflammatory Anti-insomnia Anti-ischemic Anti-psychotic Anti-spasmodicBone Stimulant Immunosuppressive Neuroprotective
CBDV Anti-convulsive Bone StimulantCBC Analgesic Anti-bacterial Anti-cancer Anti-depressant Anti-fungalAnti-inflammatory Anti-insomnia Bone Stimulant CBG Analgesic Anti-bacterial Anti-cancer Anti-depressant Anti-fungal Bone Stimulant

Industrial uses

Hamp has been refined into a variety of commercial items, including the following listed below:

TEXTILESClothingDiapersHandbagsDenimShoesFine Fabrics
INDUSTRIAL TEXTILESRopeCanvasTarpsCarpetingNettingCaulkingMolded Parts
PAPERPrintingNewsprintCardboardPackaging
BUILDING MATERIALSOil PointsVarnishesPrinting InksFuelSolventsCoatingsFiberboardInsulationAcrylicsFiberglass Substitute
FOODSHemp Seed HeartsHemp Seed OilHemp Protein PowderEFA Food Supplements
BODY CARESoapsShampoosLotionsBalmsCosmetics

PRODUCTION OF CANNABIS

Millennia of selective breeding have resulted in varieties that display a wide range of traits; e.g. suited for particular environments/latitudes, producing different ratios and compositions of terpenoids and cannabinoids (CBD, THC, CBG, CBC, CBN…etc.), fiber quality, oil/seed yield, etc. Hemp grown for fiber, for example, is planted closely, resulting in tall, slender plants with long fibers.

The high THC concentrations obtained from the various Cannabis varieties result from technical advances in production, such as genetic manipulations, cross-breeding, and improvements in indoor hydroponic cultivation. As advanced techniques and more potent seeds have become more widely available, a steady increase of THC concentrations in Cannabis has been made possible.

Genetic modification and engineering could enable industrial-scale production of cannabinoids that have pharmaceutical potential, and provide more efficient alternatives.

The PCT application No. PCT/US2019/017433 describes a method of increasing the cannabinoid levels in a genetically modified Cannabis sativa plant which includes genetically modifying the plant to induce the overexpression of the gene that controls the expression of tetrahydrocannabinolic acid (THCA) synthase and/or cannabidiolic acid (CBDA) synthase.

The PCT application No. PCT/IL2019/050653 discloses methods of in vitro clonal propagation, regeneration and transformation in Cannabis.

Some researchers and biotechnology companies are aspiring to replace Cannabis plants with microorganisms that have been genetically enhanced to produces THC, the non-psychoactive compound cannabidiol (CBD) and many other cannabinoids of pharmaceutical interest. Others are aiming to modify chemical synthesis in the Cannabis plant by genetically altering its cells to make the desired molecules from shoot to tip, thereby boosting yield.

US patent application No. 16/594,733 discloses a method of generating and selecting mutant new varieties of Cannabis plants through chemical mutagenesis of Cannabis cell suspensions.

Benefits of microbial synthesis include the ability to mass-produce rare cannabinoids that are usually present in plants only in trace amounts or even molecules not found in nature. Transgenic plants can also be engineered for superior resistance to pests and environmental stresses.

Ploidy manipulation is a valuable tool in plant breeding. Important consequences of genome doubling can include larger organs and improved production of secondary metabolites, often linked to increased tolerance to biotic and abiotic stress. Polyploid forms also provide a wider germplasm base for breeding. Polyploids have yet to be implemented in most breeding programs for Cannabis.

US patent application No. 16/357,999 describes a method for inducing polyploidy in a Cannabis plant, the method comprising treating the Cannabis plant or a part thereof with an amount of a dinitroaniline compound effective to induce polyploidy.

The PCT application No. PCT/US2017/027643 discloses a plant of the genus Cannabis that does not require flowering in order to produce trichomes comprising secondary compounds. The disclosed plants have a high mass% of secondary compounds and a high degree of trichome coverage on the surface of the plant.

US patent applications Nos. 16/560,260 and 16/510,032 describe the identification and use of particular CBDa synthase alleles, more particularly the use of these alleles to produce Cannabis plants having very high rations of CBGa to CBDa and/or THCa.

IP RIGHTS OF CANNABIS

In recent years, the protection of products, methods, productions, etc. of Cannabis has increased, being China the main country in terms of filed patent applications related to Cannabis. Also, the main field of protection is that related with medical applications.

Statistics obtained with data published by WIPO show who is using PCT system and how it is being used.

Applications filed by Country

Country Number of applications
China 1,842
United States of America 691
PCT 424
Canada 233
European Patent Office 151
Australia 119
United Kingdom 55
Republic of Korea 50
Mexico 37
Israel 27

Examples of filed PCT applications referred to improvement of Cannabis production are cited hereinbelow.

No. No. PCT Publication Title
1 WO2020102905A1 Dual droplet aeroponic systems and methods for growing plants
2 WO2020102905A1
Cannabis variety which produces greater than 50% female plants
3 WO/2020/035869 Modulation of cannabinoid profile in Cannabis
4 WO/2019/186568 Physical means and methods for affecting Cannabis plants
5 WO/2017/051398 Methods for the production of different Cannabis product compositions
6 WO/2017/181018 Enhanced Cannabis plants and methods of making and using the same
7 WO/2019/164689 Genetically modified Cannabis sativa plants and modified cannabinoid compounds for treatment of substance addiction and other disorders
8 WO/2020/084455 Post-harvest optimization
9 WO/2019/234750 Methods of regenerating and transforming Cannabis
10 WO/2019/113497 High cannabigerol Cannabis plants, methods of producing and methods of using them
11 WO/2020/093103 Cannabis plants with a cannabinoid profile enriched for Δ-9-tetrahydrocannabinol and cannabigerol
12 WO/2019/069309 A novel Cannabis production process and products thereof

In Mexico there have been few patents granted, but there are several patent applications pending to be examined. These cases involve all the fields related with Cannabis. It also should be noted that during 2019 the number of applications increased.

No. No. MX application Title
1 MX/a/2019/015673 Veterinary granules composition containing hemp extract
2 MX/a/2019/015315 Sleep disorder compositions and treatments thereof
3 MX/a/2019/014715 Use of cannabidiol in the treatment of tuberous sclerosis complex
4 MX/a/2019/012109 Cannabinoid extraction process using brine
5 MX/a/2019/009708 Method and cell line for production of phytocannabinoids and phytocannabinoid analogues in yeast
6 MX/a/2019/011583 Process for purification and separation of cannabinoids from dried hemp and Cannabis leaves
7 MX/a/2019/012779 Cannabis fiber, absorbent cellulosic structures containing Cannabis fiber and methods of making the same
8 MX/a/2019/009463 Methods and apparatus for low-pressure radiant energy processing of Cannabis
9 MX/a/2017/005833 Pat. MX 369078 B
Cannabis fiber, absorbent cellulosic structures containing Cannabis fiber and methods of making the same
10 MX/a/2019/003063 Trichome specific promoters for the manipulation of cannabinoids and other compounds in glandular trichomes
11 MX/a/2019/001968 Plants and methods for increasing and decreasing synthesis of cannabinoids
12 MX/a/2019/001121 New Cannabis tablet formulations and compositions and methods of making the same
13 MX/a/2014/003310 Pat. MX 367758 B
A pharmaceutical composition comprising the phytocannabinoids cannabidivarin (CBDV) and cannabidiol (CBD)
14 MX/a/2019/003269 Leak resistant vaporizer device
15 MX/a/2019/001286 Cannabis composition
16 MX/a/2019/001285 Cannabis composition
17 MX/a/2017/015304 Cannabis plants having modified expression of THCA synthase
18 MX/a/2014/000535 Pat. MX 346923 B Genes and proteins for alkanoyl-CoA synthesis
19 MX/a/2015/013202 Breeding, production, processing and use of specialty Cannabis

The following Variety Plants of Cannabis has been filed at UPOV

Applications filed by Country

Country No. Appln.
NL 351
IT 313
HU 309
PL 303
FR 302
CZ 298
GB 292
SI 291
RO 289
DE 288

Applications filed according to UPOV Code

UPOV Code Botanical Names No. Applications
CANNB Cannabis L. 7
CANNB_SAT Cannabis sativa L. 807
CANNB_SAT_IND Cannabis sativa L. subsp. indica (Lam.) E. Small & CronquistCannabis indica Lam. 1
CANNB_SAT_SAT Cannabis sativa L. ssp. sativa 53
CANNB_SIN Cannabis sativa ssp. sativa x Cannabis sativa subsp. indica 1

CONCLUSIONS

Known uses of Cannabis and new medical and industrial uses thereof have raised an interest to improve Cannabis production to increase industrial-scale production of cannabinoids. The use of different methods has allowed for these improvements. The methods include, for example, genetic modifications, cultivation methods that increase the content of the substance in interest (CBD), and obtaining plant varieties. It follows that new technologies developed in order to achieve such objectives need to be protected through patents, plant varieties, or any other industrial property rights.

Furthermore, due to the nature and psychoactive effects of Cannabis, there is the need of domestic regulations for the production, use, and marketing of Cannabis for medical and industrial uses.

In recent years, the number of patent applications related to Cannabis around the world has grown significantly and will continue increasing as legal frameworks progress in each country. The research and development of new applications of Cannabis will promote such increase. It is also expected also for other ways of protection to increase, e.g. Plant Variety, or Seed Certification.

In Mexico, the legalization for the use of Cannabis sativa for medicinal and research purposes has been approved. The laws regarding this subject-matter will apply to the following activities:

I. The sowing, harvesting, production, transportation, distribution, marketing, carrying, and consumption of Cannabis and its derivatives for personal, therapeutic and scientific purposes.

II. Public Health control of Cannabis.

In consequence, Universities, Research Centers, and Pharmaceutical Companies will now be able to do research on Cannabis sativa.

Janett Lumbreras

REFERENCES

1. Pertwee R. ed. Handbook of Cannabis. Oxford University Press; 2014. Available at: http://www.oxfordscholarship.eom/view/10.1093/acprof:oso/9780199662685.001.0001/acprof-9780199662685. Published online January 2015. Accessed May 21, 2017

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741114/#__sec1title

3. HEMP Gazette. The Big List of Cannabis Cannabinoids

4. https://www.forbes.com.mx/140-dias-para-cambiar-a-mexico/

5. https://www.forbes.com.mx/marihuana-vs-hemp-lo-que-tienes-que-conocer/

6. Elie Dolgin.A boosted crop. 29 August 2019. Vol. 572. NATURE S7 – https://www.nature.com/articles/d41586-019-02525-4

7. Jessica L. Parsons, Sara L. Martin, Tracey James, Gregory Golenia, Ekaterina A. Boudko, and Shelley R. Hepworth. Polyploidization for the Genetic Improvement of Cannabis sativa. Front Plant Sci. 2019; 10: 476.

8. S.H. Fox, in Encyclopedia of Movement Disorders, 2010

9. https://patentscope.wipo.int/search/es/search.jsf

10. https://www3.wipo.int/pluto/user/en/

11. https://siga.impi.gob.mx/newSIGA/content/common/principal.jsf

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