Natural Product Innovations: Taxol

Transcription

1 Journal of Intellectual Property Rights Vol 5 July 2000 pp Natural Product Innovations: Taxol M M S Karki National Institute of Science Communication Dr K S Krishnan Marg, New Delhi , and VK Gupta National Institute of Science, Technology and Development Studies Dr K S Krishnan Marg, New Delhi The technological opportunities analysis based on patents has been made in the area of taxol to identify the current status of research efforts and potential commercial use. It indicates the growth of patenting in the area of taxo!. The emerging technological opportunities and directions of research in the field of taxol include focus on the areas like synthesis, extraction and purificaticn or process for production of taxol, its derivatives and analogues; new uses and methods of treatment. This information can be made use of by firms and R&D organizations interested in natural product innovations in the area of taxa!. With its tropical forests and extreme climatic conditions, India has an abundant availability and diversity of biological resources, especially, the plant-based resources. There are increasing opportunities of innovations based on natural products with the developments in biotechnology. This has underscored the importance of identification, extraction, and isolation of active materials from plant sources and the need to focus research efforts on emerging technological opportunities. In this paper, these opportunities have been examined by undertaking an analysis of patenting in the area of taxo!. Data and Methodology The United States of America is one of the leading countries in technological innovations whose market dynamics tend to attract cutting-edge innovations from across the world. A company or an R&D organization believing that it has a first- rate technology, that could earn it global financial returns, would like to have a patent in USA. The US

2 KARKl & GUPTA: NATURAL PRODUCT INNOVATIONS : TAXOL 207 patent database is an important source of information on the patenting activity in the field of research. In the present case, the bibliographic search was made in the US patent database l in the titles of the patents using the following keywords: Taxol or taxoid or taxane or taxotere or paclitaxel or docetaxel or Taxus brevifolia or Taxus baccata or Taxus cuspidata or Taxus. The search lead to a total number of 194 patents. The keywords in the titles of the patents were used to identify the emerging technological opportunities. The abstract and the first page of each of the patents were examined to obtain insights into the inventive activity and the ownership of the patents. What is Taxol Taxol was first isolated in the sixties from the bark of the Pacific Yew (Taxus bre-vi/olia ) by chemists Wall, Wani, and their colleagues working in collaboration with National Cancer Institute, USA and it came into prominence in view of its anti-cancer activity. The taxol is a highly functionalized diterpene amide, a new source of anti-tumour product, active against B16 melanoma, SCRC MX-l, mammary and CX-1colon xenograft. The activity of this chemical in human ovarian cancer was reported in Taxol is a registered trademark of Bristol-Myers Squibb Company. The generic name is paclitaxe!. Taxotere is a registered trademark of Rhone-Poulenc. Its generic name is docetaxei 2,3. The plantations of either Taxus baccata or several ornamental Taxus cultivars have a long-term potential for either direct production of taxol or production of its precursors. In India, T. baccata 1s an evergreen tree found in the temperate Himalayas at altitudes between 1,800 and 3,300 m and in the hills of Meghalaya and Manipur at an altitude of 1,500 m 3. R&D Activity The applied taxol research can broadly be divided into: (i) chemical studies, (ii) biological studies. Chemical studies include synthesis, assays, and structure-activity relationships. Biological studies cover biosynthesis, genetics, tissue culture, and taxol binding site. Understanding of the biosynthetic pathway for taxol in Taxus has many implications for drug production. Progress in taxol biosynthesis has been quite remarkable. The current production method for both taxol and taxotere of isolation of 10-desacetylbaccatin-III (DAB) and conversion by semi-synthesis relies mainly on wild Taxus or Taxus which has been cultivated for ornamental purposes. The total synthesis oftaxol has been a challenging goal to organic chemists since the publication of its structure in The production of taxol and related compounds through semi-synthesis from 10-DAB is now well established. However, none of the route appears to be of commercial interest. There is another approach based on pinene as a starting material, which has not yet been elaborated to the final product. This approach may be of interest to India as pinene - a product of pine tree - is grown in abundance in the country. Recent results have estabi'ished that there is a long term potential in plantation of either Taxus baccata or several ornamental Taxus cultivars, for either direct production of taxol or production of its precursors, or synthesis or semi-synthesis of taxo!. The alternative method of tissue culture is also being tried for the production of taxol precursors.

3 208 J INTELLEC PROP RIGHTS, JULY 2000 The ability to detect and quantitate taxol and other taxanes is one of the important dimensions of the research activity in this area. The research on taxol has progressed at a rather slow pace. There are still constraints I'k' I e Its so I u b'i' I Ity, supp I y, an d toxlclty " The extraction of taxol from its natural source is beset by several problems like low yield of the active principle and non-renewability of the plant source. Since the 1980s, the anti-cancer drug taxol has had a supply problem: its source was the bark of slow growing Pacinc yew trees. As more and more clinical data demonstrated taxol powder against breast, ovarian, and other cancers, medical scientists needed more drug, and a more environmentally friendly source. Besides, its properties like toxicity and less solubility led to the search of similar other less toxic and more soluble anti-cancer compounds. In India, the Regional Research LaboratOlY, Jammu's Palampur Extension Centre, has developed a novel technique for the clonal propagation of Himalayan yew (Taxus baccata). Technologies for the anti-cancer drug taxol and production of rye-ergot have been developed and transferred to industry for commercial exploitation. Technology for the semi-synthetic taxol has been transferred by the Central Institute of Medicinal & Aromatic Plants, Lucknow. The Regional Research Laboratory, J orhat, has also developed the technology of taxol 5,6,7. Patenting Activity Table 1 indicates the growth in patents in the area of taxol. The first patents were taken in Since then, there is a gradual increase in the patenting activity. There are 36 patents in Year Table I-Growth in patents No of patents till 41 2 May, 2000 Technological Trends Table 2 gives the details of patents in the area of taxol according to the technological opportunities.the analysis of patenting activity indicates the technological opportunities and trends in research. There are four major areas of emerging technological importance in the field of taxol resea.. ch. These are: (i) Synthesis, semi-synthesis, preparation, process or production of taxol, its analogues, derivatives, or intermediates The patenting activity in this group focuses upon the preparation or synthesis of the products of taxol, in general. For example, the developments have taken place in total synthesis of taxol or synthesis of taxol or its analogues, and their intermediates with variable A-ring side chain structures and semisynthesis of taxane derivatives using metal alkoxides and oxazinones, production of taxol or taxol like compounds in cell cultures. However, in some of the cases, the

4 KARKI & GUPTA: NATURAL PRODUcr INNOVATIONS: TAXOL 209 Table 2- Technological opportunities/ Research trends S.No. Technological No of opportunities / research patents trends 1 Synthesis/semi- 106 syn thesis/ preparation/ proc ess of production of taxol its derivatives 2 Taxol products- 43 fon11ulation/ compounds/ derivatives/ compositions and intermediates 3 Extraction / isolation / 21 purification 4 New uses/ methods of 16 treatments/ methods of administration / doses 5 Structure - activity 2 relationship 6 Other miscellaneous areas 6 including plant patent or patents on agents for drug resistance invention of the synthesis of products is also associated with invention of the method of use, improved properties of the products, derivatives or intermediates, modified products or method of application, and uses or applications of the products. For example, it includes inventions like preparation of taxol and docetaxel through primary amines, preparation of brominated paclitaxel analogues, water soluble taxol derivatives. (ii)taxol or taxol based products/formulations/ compounds/ derivatives/intermediates/ formulations The patenting activity in this category includes the inventions like novel taxanebased products, taxane or taxol derivatives, derivatives of paclitaxel, brominated paclitaxel analogues, polymer bound paclitaxel derivatives, taxoid based compositions, taxoid intermediates. There are inventions of both product and process patents in some of the cases. The thrust and direction of patenting in other cases is on improved properties like enhancing water solubility of taxol and its derivatives', new structures for polymer - bound paclitaxel derivatives, e n hanced activity, method of treatment, method of administration, or delineating the doses. (iii) Extraction/ isolation/ purification of taxol, its derivatives, analogues or intermediates The patenting activity in this category provides ways and means of obtaining higher yields of the products. The inventions are towards new processes for extraction of taxol and its derivatives or methods of extraction, isolation and purification of taxane derivatives. (iv) New uses/ methods of treatment! methods of administration/ doses There are efforts to concentrate on new uses and methods of treatments based on taxol, its derivatives or analogues. The patenting activity has lead to the developments in selective use of paclitaxel prodrugs, regime for paclitaxel in Kaposi's sarcoma patients, method of treatment for cancer using taxoid onium salt prodrugs and method of treating cancers sensitive to treatment with waler soluble derivatives of taxo!. (v) There were 6 patents in other areas of chemical and biological research. The role of companies is predominant in accelerating the pace of technological devel-

5 210 J INTELLEC PROP RlGHTS, JULY 2000 opment in the area. Rohne-Poulec, Bristol Myers Squibb Company, Scripp's research and Abbott Laboratories are some of the prominent companies engaged in patenting in this area. Most companies are from USA. There are other companies fyom countries like France,Japan, and Italy, which have also taken patents in this field. There were three patents from India including one each by Dr Reddy's Laboratories and CSIR. The contributions have also been made from academic institutions and their independent research foundations, mainly from US universities like University of Florida, and California University. The US government departments like Department of Health have also taken patents in this area. Summary The inventive activity in the area of taxol has been examined based on the patenting activity. It highlights the emerging technological opportunities and research directions in the field of taxo!. References 1 uspto. gov 2 George Gunda I, Chen Thomas T, Ojima Iwao & VyasDolatrai M, Taxane Anticancer Agents-Basic Science and Current Status (American Chemical Society, Washington, DC) Wealth of India CDROM Database (National Institute of Science Communication, New Delhi) Culotta Elizabeth & Koshland( Jr) Daniel E, Science,262 (5142). 1993, CSIR News, 43 (12) 1993, CSIR 2000 : A Profile (Council of Scientific & Industrial Research, New Delhi) 2000,35. 7 CSIR Handbook 1995 (Council of Scientific & Industrial Research, New Delhi) 1995,49.