THE IDEA

nicotineIn 1998, Joseph Pandolfino founded 22nd Century Limited, LLC (22nd Century) to provide funding to North Carolina State University (NCSU) for a research and development collaboration on nicotine biosynthesis in the tobacco plant. Mr. Pandolfino asked the question: “Since coffee without caffeine and beer without alcohol are commercially available, why aren’t tobacco cigarettes without nicotine a choice for consumers?” Further, he hypothesized: “If it were possible to produce tobacco cigarettes without nicotine, couldn’t smokers use these extraordinary cigarettes to successfully quit smoking?”

A paradox to be sure. Nonetheless, Mr. Pandolfino’s hypothesis stemmed from his careful observation of real smokers. As an importer of tobacco-free herbal cigarettes, Mr. Pandolfino learned that many consumers were using nicotine-free herbal cigarettes to successfully quit smoking. Anecdotal evidence suggested that this approach was particularly effective. The biggest problem with the novel “therapy” was the fact that herbal cigarettes have distinct taste and aroma characteristics which greatly limit their consumer appeal and acceptance.

Indeed, although various processes were developed to improve these nicotine-free herbal cigarettes, it became clear that their peculiar taste and aroma characteristics would never appeal to mainstream smokers. If, on the other hand, a tobacco cigarette without nicotine could be developed, Mr. Pandolfino believed a new cigarette category could prove an attractive product choice to all smokers. With this in mind, Mr. Pandolfino set out to investigate the feasibility of efficiently producing nicotine-free tobacco cigarettes.

Already Philip Morris USA had developed a process to extract nicotine from tobacco; however this process, similar to that of producing decaffeinated coffee, proved very costly. What’s more, these “denicotinized” or “denic” cigarettes (test-marketed from 1989 to 1991) simply did not taste good. Philip Morris concluded that within the denicotinization process, various other tobacco leaf compounds important to tobacco’s taste characteristics were extracted along with the nicotine. Denicotinization tobacco processes are not selective for nicotine and, according to Philip Morris, “resulted in a dramatic change in the taste of the original tobacco” (Philip Morris 1994).

Therefore, Mr. Pandolfino concluded, the key to producing a cigarette with virtually no nicotine – that smokers would find acceptable – is the ability to grow tobacco plants whose intrinsic nicotine content is a tiny fraction of that found in conventional tobacco plants. This conclusion led Mr. Pandolfino on a journey to acquire and develop the know-how and technology, including intellectual property rights, to block nicotine biosynthesis in the tobacco plant through genetic engineering.

THE TECHNOLOGY

To this end, in 1997 Mr. Pandolfino met Dr. Mark Conkling, Director of the Biotechnology Programs at North Carolina State University. Dr. Conkling had recently cloned a key gene in the tobacco plant responsible for nicotine production. Dr. Conkling believed expression of this gene could be blocked to produce tobacco plants with virtually no nicotine. Mr. Pandolfino concurred and the result of their meeting was a successful 5-year research collaboration between 22nd Century and NCSU that resulted in a patented very low nicotine (VLN) tobacco variety (Xie et al. 2004). This became the first genetically modified (GM) tobacco variety deregulated by the Animal Plant & Health Inspection Service (APHIS) of the United States Department of Agriculture (USDA).

ncsu-centennialIn 1999, 22nd Century exclusively sublicensed this proprietary technology and VLN tobacco to Liggett Group, the fifth largest cigarette company in the United States, and shortly thereafter to other subsidiaries of Vector Group Ltd. (Wall Street Journal 2001). In 2003, Vector Tobacco Inc., an affiliate of Liggett Group, marketed in eight U.S. states Quest®, a novel cigarette brand containing 22nd Century’s proprietary tobacco, to gather data for the U.S. Food and Drug Administration (FDA) approval process of Quest® as a smoking cessation aid. Quest® also utilized Mr. Pandolfino’s product concept comprised of a series of cigarettes with the same “tar” yield but progressively reduced nicotine content for use in smoking cessation.

Also in 2003, the USDA, and in 2005, the Plant Breeders’ Rights Office of Canada granted NCSU plant variety protection (PVP) certificates for a VLN tobacco variety developed at NCSU from funding by 22nd Century. 22nd Century has exclusive rights to this VLN tobacco variety. Both the U.S. and Canadian PVP certificates expire in 2023. A PVP certificate is a useful piece of intellectual property since it legally prevents others from growing the protected tobacco variety, and in the case of tobacco, from importing or exporting the subject tobacco leaf.

THE RESEARCH

In 2006, Vector Tobacco sponsored a multi-center Phase II smoking-cessation clinical trial to evaluate the effectiveness of Quest® alone or in combination with nicotine replacement therapy (Becker et al. 2008). This trial was performed under Vector’s Investigational New Drug Application (IND) filed with the FDA in 2004. After conveying that it intended to proceed with Phase III clinical trials, Vector Group Ltd. announced that Vector Tobacco was no longer pursuing FDA approval of its smoking cessation aid in development. Accordingly, 22nd Century’s licenses to all affiliates of Vector Group Ltd. were terminated. Subsequently (in 2008) through binding arbitration, 22nd Century obtained rights to use and reference at the FDA all data in Vector’s IND, including all results from the Phase II clinical trial, relating to cigarettes containing 22nd Century’s proprietary tobacco. 22nd Century no longer has any type of relationship with Liggett Group or Vector Tobacco.

NCSUFrom 2005 to 2009, 22nd Century partnered again with NCSU and with other public institutions for further R&D that included the cloning of additional nicotine biosynthesis genes: the Nara Institute of Science and Technology, Nara Japan (NAIST) and the National Research Council of Canada, Plant Biotechnology Institute, Saskatoon Canada (NRC). These contracted R&D partners, NCSU, NAIST and NRC, were first to (i) clone the key nicotine biosynthesis genes and several transcription factor genes that regulate expression of all nicotine biosynthesis genes and (ii) demonstrate biochemical evidence of the function of these genes. The technology and exclusive related patent rights 22nd Century obtained from NAIST and NRC are keystones of 22nd Century’s intellectual property, representing the company’s second-generation technology that has significant advantages over the earlier technology licensed to Liggett Group and Vector Tobacco. Furthermore, 22nd Century’s technology can be employed so that the resulting tobacco plants are not genetically modified (GM).

22nd Century’s model of outsourcing R&D to world-renowned plant biotechnology centers has enabled 22nd Century to maintain strict control of its R&D costs, while providing the company broad access to large public institutions’ infrastructure and transdisciplinary expertise. As a result, 22nd Century has obtained exclusive rights to all key nicotine biosynthesis genes that can be regulated to produce viable commercial products with modified content of nicotine and tobacco-specific nitrosamines (TSNAs).

NAIST assigned various patent families to 22nd Century in 2010, including the NBB technology. Also in 2010, a University of Minnesota clinical trial, led by Dr. Dorothy Hatsukami who is a member of FDA’s Tobacco Products Scientific Advisory Committee known as TPSAC, demonstrated that VLN cigarettes (made exclusively with 22nd Century’s proprietary tobacco) used over a 6-week treatment period are effective for smoking cessation (Hatsukami et al. 2010). 22nd Century also completed development of an improved VLN cigarette to continue clinical trials with the company’s proprietary VLN cigarettes for use in smoking cessation.

A PUBLICLY TRADED COMPANY

XXII Podium Banner2011 was quite an eventful year for the company. In January, 22nd Century became a publicly traded company in conjunction with $5.4 million of private investment. Shares of 22nd Century Group, Inc. are traded under the stock symbol XXII (NYSE MKT:XXII). 22nd Century received FDA clearance for its Investigational New Drug (IND) Application in July and sponsored a Phase II-B clinical trial for its X-22 smoking cessation aid in development, a prescription-based smoking cessation aid consisting of a kit of very low nicotine (VLN) cigarettes. 22nd Century licensed Heracles Pharmaceuticals LLC, its pharmaceutical subsidiary, exclusive worldwide rights to X-22.

Other notable company events that occurred in 2011: 22nd Century entered into a 3-year R&D agreement with University of Virginia, and Goodrich Tobacco Company, LLC, 22nd Century’s tobacco product subsidiary, introduced two super-premium cigarette brands into the U.S. market and delivered more than 9 million SPECTRUM® research cigarettes. SPECTRUM® was developed by 22nd Century for NIDA, a department of the National Institutes of Health (NIH), and is strictly for independent research purposes.

THE PRESENT AND… FUTURE!

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