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    Unassociated Document

22nd Century Group, Inc.

8201 Main Street, Suite 6

Williamsville, NY 14221

Tel.: 716-270-1523

June 29, 2011

Mr. John Dana Brown

Attorney-Advisor

UNITED STATES SECURITIES AND

  EXCHANGE COMMISSION

100 F Street, N.E.

Washington. D.C. 20549

Re:

22nd Century Group, Inc. (the “Company”)

Amendment No. 1 (“Amendment No. 1”) to Registration Statement on Form S-1 (the “Form S-1”)

Filed June 7, 2011

File No. 333-173420

Dear Mr. Brown:

The Company received your June 22, 2011 letter (the “June 22 Comment Letter”) containing the comments and questions of the Staff of the SEC regarding Amendment No. 1.  Accompanying this letter is Amendment No. 2 to the Form S-1 (“Amendment No. 2”), which includes revisions in response to the June 22 Comment Letter.  In addition, we discuss the Company’s responses to the June 22 Comment Letter below.  Further, for your convenience, we have restated each of your comments as set forth in the June 22 Comment Letter immediately preceding each of our responses below.

General

1.           We note statements throughout regarding the effectiveness of the products you are developing. Please tell us whether such statements are appropriate given that you have not yet completed the FDA approval process. Additionally please tell us your basis for statements throughout regarding the limited effectiveness or side-effects of competing products.

RESPONSE:  We consider the statements as to the effectiveness of the products we are developing are appropriate, notwithstanding that we have not yet completed the FDA approval process.  We further consider that statements as to the limited effectiveness or side-effects of competing products are likewise appropriate.  Below we describe several trials, studies and articles that substantiate our statements.  Nonetheless, we have removed reference in the Form S-1 to the limited effectiveness of existing FDA-approved smoking cessation products. Please see Prospectus Summary – Our Company – Overview, Page 2 of Amendment No. 2; and Business – Overview, Page 36 of Amendment No. 2.

With respect to the effectiveness of X-22, in comparison to the effectiveness of other products:

The following three smoking cessation Phase II trials, each with different protocols, have been carried out with cigarettes containing our very low nicotine (“VLN”) tobacco:

Hatsukami DK, Kotlyar M, Hertsgaard LA, Zhang Y, Carmella SG, Jensen J, Allen SS, Shields PG, Murphy SE, Stepanov I, Hecht SS. 2010. Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation. Addiction 105:343-355. (Referred to herein as “Hatsukami et al.” and a copy of which is available upon request.)  Please see http://www.ncbi.nlm.nih.gov/pubmed/20078491.

Becker KM, Rose JE, Albino AP. 2008. A randomized trial of nicotine replacement therapy in combination with reduced-nicotine cigarettes for smoking cessation. Nicotine Tob Res 10(7):1139-48.   (Referred to herein as “Becker et al.,” and a copy of which is available upon request.)    Please see http://www.ncbi.nlm.nih.gov/pubmed/18629723.

Rezaishiraz H, Hyland A, Mahoney MC, O’Connor RJ, Cummings KM, 2007. Treating smokers before the quit date: Can nicotine patches and denicotinized cigarettes reduce cravings? Nicotine Tob Res. 9:1139-1146. (Referred to herein as “Rezaishiraz et al.,” and a copy of which is available upon request.)  Please see http://www.ncbi.nlm.nih.gov/pubmed?term=17978987

All three of these studies demonstrated increased quit rates whether VLN cigarettes were used alone (Hatsukami et al.) or used in combination with nicotine replacement therapy, or “NRT” (Becker et al. and Rezaishiraz et al.).  The protocol of the VLN cigarette in the Phase II clinical trial reviewed in Hatsukami et al. is very similar to 22nd Century’s Phase II-B trial.  The treatment consists of six weeks of smoking VLN cigarettes ad libitum (as many as desired) and quitting by the end of treatment period.  The VLN cigarette used in the three clinical trials referred to above and the VLN cigarette being used in 22nd Century’s Phase II-B trial all solely contain 22nd Century’s proprietary VLN tobacco, which has approximately 95% less nicotine compared to tobacco in existing “light” cigarettes.

Dr. Hatsukami, Director of the National Transdisciplinary Tobacco Use Research Center at the University of Minnesota Masonic Comprehensive Cancer Center and one of the nine voting members of the 12-person Tobacco Products Scientific Advisory Committee (TPSAC) at the FDA’s Center for Tobacco Products, has dozens of peer-reviewed publications on smoking cessation/tobacco harm reduction and has received millions of dollars in grants from the U.S. government to conduct smoking cessation and exposure studies. For Dr. Hatsukami’s Curriculum Vitae and more information on TPSAC, please see

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoProductsScientificAdvisoryCommittee/ucm180906.htm

Dr. Hatsukami is currently conducting a follow-up phase II clinical trial with VLN cigarettes supplied by 22nd Century (the results of which are not yet published), entitled “Innovative Interventions for Smoking Cessation.”  There are three arms to the Innovative Interventions for Smoking Cessation clinical trial:  (i) a VLN cigarette by itself, (ii) a nicotine patch (21 mg) by itself, and (iii) both the patch and a VLN cigarette used together. For more information, please see http://clinicaltrials.gov/ct2/show/NCT01050569?term=NCT01050569&rank=1.

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Regarding the limited effectiveness of competing products, the Institute of Medicine (the health arm of the National Academy of Sciences), which some consider the highest medical authority in the U.S., in a 2007 report, titled “Ending the Tobacco Problem: A Blueprint for the Nation,” concluded as follows:

The limitations of the pharmacotherapies are that their effectiveness is moderate (achieving cessation rates of 10 to 20%, depending on the population of smokers and whether concomitant behavioral therapies are used) and the fact that many dependent smokers have already tried these therapies and failed to quit smoking when they have used them.  Most studies of re-treatment with the same medication find that cessation rates are very low.

Piper ME, et al also reported (See Table 2 of Piper ME, et al.) point-prevalence abstinence rates during the 8th week of treatment, while the subjects were still on medication, for the three individual treatments (monotherapies) as follows:

40% for the nicotine lozenge,

45% for the nicotine patch, and

40% for Zyban (buproprion), versus 30% for the placebo controls.

Because absolute abstinence rates in smoking cessation trials vary between studies due to a variety of factors, the odds ratios for treatment versus control are usually considered more useful for comparisons. Piper ME et al. shows in Table 3 of that study that for point prevalence abstinence at the 8th week of treatment, odds ratios versus placebos were as follows:

1.57 for the nicotine lozenge,

1.87 for the nicotine patch, and

1.55 for Zyban (buproprion).

An odds ratio of 1 implies that the event is equally likely in both groups. An odds of 1.5 implies than the treatment group has a 50% greater probability to quit versus the placebo group.

In the University of Minnesota study (Hatsukami et al.), the point prevalence abstinence rates at 6 weeks after treatment (patients ceased taking medication 6 weeks previous), were as follows:

47.2% for the very low nicotine (VLN) cigarette (0.05 mg nicotine cigarette),

36.7% for the 4 mg nicotine lozenge, and

23.1% for the intermediate nicotine cigarette (0.3 mg nicotine cigarette).

This corresponds to abstinence odds ratios as follows, showing higher abstinence odds ratios in VLN cigarettes as compared to the nicotine lozenge (both vs. the 0.3 mg cigarette control):

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2.98 for the VLN cigarette, and

1.93 for the nicotine lozenge.

“Varenicline, an ά4β2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Sustained-Release Bupropion and Placebo for Smoking Cessation, A Randomized Controlled Trial,” by David Gonzales, PhD, et. al., Journal of American Medicine, July 5, 2006—Vol 296, No. 1 (a copy of which is available upon request), details a clinical trial of Chantix (varenicline) and Zyban (bupropion), which showed a 44% quit rate of Chantix and 29.5% quit rate of Zyban (both 4-week of continuous abstinence rates) measured during weeks 9 through 12 of the trial, while the subjects were still on medication.  See http://www.ncbi.nlm.nih.gov/pubmed/16820546.

To illustrate relapse rates of patients after stopping Chantix use, “Effect of Maintenance Therapy With Varenicline on Smoking Cessation, A Randomized Controlled Trial,” by Serena Tonstad, MD, PhD et al., Journal of American Medicine, July 5, 2006—Vol 296, No. 1 (a copy of which is available upon request), reported on a study in which subjects initially received 12 weeks of open-label Chantix treatment. In this study, subjects that were abstinent at the end of treatment were randomized to double-blind additional 12 weeks of Chantix or placebo. The study demonstrated that when Chantix was terminated, abstinence declined rapidly (double blind placebo group). For example, at 4 weeks after the end of the initial 12-week Chantix treatment period (week 16), only 68% of those abstinent at week 12 were still abstinent, and at 8 weeks post treatment (week 20), only 55% were still abstinent.  See http://www.ncbi.nlm.nih.gov/pubmed/16820548.

Regarding the side effects of other FDA-approved smoking cessation products, both Chantix® and Zyban® were required by the FDA on July 1, 2009 to add boxed warnings (the most serious warning in prescription drug labeling) to their package inserts.  These warnings highlight that serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt and completed suicide, have been reported in patients taking Chantix® and Zyban®.

o

Please see FDA July 1, 2009 news release: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170100.htm

o

Please see boxed warning on page 1 of Chantix® label:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021928s012s013lbl.pdf

o

Please see boxed warning on page 1 of Zyban® label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020711s032s033lbl.pdf

With respect to the effectiveness of Brand A:

The Hatsukami et al. study also measured exposure of various smoke compounds in smokers from smoking a VLN cigarette containing our proprietary tobacco over a six-week period. Smokers significantly reduced their smoking as compared to their usual brand of cigarettes. Carbon monoxide (CO) levels, an indicator of smoke exposure, significantly decreased from 20 parts per million (baseline) to 15 parts per million. Cotinine, a metabolite and biomarker of nicotine, significantly decreased from 4.2 micrograms/mL (baseline) to 0.2 micrograms/mL. All differences were statistically significant (P<0.05).

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Furthermore, Hatsukami et al., showed significant reductions in the following biomarkers of tobacco toxins NNAL, NNN, 1-HOP, 3-HPMA and S-PMA. The Brand A cigarette and the VLN cigarette used in Hatsukami et al. solely contain 22nd Century’s proprietary VLN tobacco, which has approximately 95% less nicotine compared to tobacco in existing “light” cigarettes.

With respect to the effectiveness of Brand B:

In the following studies (copies of which are available upon request), nicotine was added to cigarettes by researchers to produce low tar-to-nicotine ratio cigarettes:

o

“Evaluation of a low to middle tar/medium nicotine cigarette designed to maintain nicotine delivery to smoker,” by A.K. Armitage, et al., Psychopharmacology (1988), 6: 447-453. Please see http://www.ncbi.nlm.nih.gov/pubmed/3149764;

o

“Effects of a Nicotine-Enriched Cigarette on Nicotine Titration, Daily Cigarette Consumption, and Levels of Carbon Monoxide, Cotinine, and Nicotine,” by Karl-Olov Fagerstrom, Psychopharmacology (1982) 77: 164-167. Please see http://www.ncbi.nlm.nih.gov/pubmed/6812134; and

o

“The separate effects of tar and nicotine on the cigarette smoking manoeuvre,” by G. Woodman, S. P. Newman, D. Pavia & S. W. Clarke, Eur J Respir Dis (1987) 70, 316-321. Please see http://www.ncbi.nlm.nih.gov/pubmed/3609190.

We are not aware of any study that contradicts the findings of these studies that smokers inhale less smoke, including tar and/or carbon monoxide (CO), with low tar-to-nicotine ratio (≤ 8) cigarettes than they do with conventional cigarettes.  See presentation Joseph Pandolfino gave to the Life Science Research Office (LSRO) regarding this subject: www.xxiicentury.com/news/2005-archive/.

Based on the foregoing and other relevant studies, we do consider our statements in the Form S-1 as to the effectiveness of our products vis-à-vis the effectiveness of other very similar products to be appropriate, notwithstanding that our products have not yet received FDA approval/authorization.

Registration Statement Cover Page

2.           Please revise to indicate the Primary Standard Industrial Classification Code as 2111 or advise.

RESPONSE:  We believe that Primary Standard Industrial Classification Code (“SIC Code”) 5194, which we have consistently used in the past and which relates to tobacco and tobacco products, better describes our business than SIC Code 2111, which is limited to cigarettes only.  As we are engaged in modifying the content of nicotinic alkaloids in tobacco plants and the development of modified risk tobacco products, our products and services are broader than those represented by SIC Code 2111.  Therefore, we have not revised the Form S-1 to indicate the SIC Code that you suggested.

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Prospectus Summary, page 1

Our Company, page 1

Overview, page 1

3. We note your response to our prior comment 33. Please revise to state here that you are currently in default pursuant to the terms of your exclusive world-wide license agreement with North Carolina State University. Please indicate that if NCSU chooses to invoke any right it may have to terminate the License Agreement and you are unable to cure the default, your business would be materially and adversely affected. Please additionally state that if NCSU does not agree to continue to defer payment of the balance, you may not have sufficient funds to pay for the Phase II-B clinical trial for X-22 in full.

RESPONSE:  We have amended the Form S-1 to include the suggested disclosure. Please see Prospectus Summary – Our Company – Overview, Page 1 of Amendment No. 2.

4. We note your response to our prior comment four and reissue in part. Please revise to include your net loss from your most recent interim stub and audited period.

RESPONSE:  We have amended the Form S-1 to include the suggested disclosure. Please see Prospectus Summary – Our Company – Overview, Page 2 of Amendment No. 2.

5. We note your response to our prior comment eight and reissue in part. Please provide support to us for your statement on page 2 that X-22 is the only smoking cessation product that functions exactly like a regular cigarette.

RESPONSE:  We have amended the Form S-1 to remove the statement that X-22 is the only smoking cessation product that functions exactly like a regular cigarette.  Please see Prospectus Summary – Our Company – Overview, Page 2 of Amendment No. 2; and Business – Overview, Page 36 of Amendment No. 2.

6. Please provide support to us that every FDA-approved smoking cessation aid since the establishment of the Fast Track program in 1997 has received the Fast Track designation. Alternatively, please remove this statement.

RESPONSE:  We have amended the Form S-1 to remove the statement that since the establishment of the Fast Track program in 1997 every FDA-approved smoking cessation aid has received the Fast Track designation.

7. Please revise the la