Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-10
2002-09-03
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S454000, C514S468000, C514S908000
Reexamination Certificate
active
06444698
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the uses of the chemical compound 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) as a promoter blocker of specific identified cancers in men, specific identified cancers in women, prostate cancers in Black men, and overall cancers in each sex. A large body of significant scientific data on TCDD, including epidemiology studies, was developed as a result of early and continuing regulatory concern about TCDD's persistence in a wide variety of human tissues and its biological activity, often characterized as toxic at very low exposures. U.S. EPA,
Health Assessment Document for Polychlorinated Dibenzo
-
p
-
Dioxins
(1985); U.S. EPA,
Health Assessment Document for
2,3,7,8-
Tetrachloro
-
dibenzo
-
p
-
dioxin
(
TCDD
)
and Related Compounds,
Volumes I, II and III (1994).
A cell which is “initiated” and then “promoted” becomes a cancer cell; once the cell replicates sufficiently, the cancer becomes diagnosable. This two-step cancer creation process, with some mutational involvement but without detailed specifications, has been taught for more than thirty years. A promoter blocker prevents the second, necessary step in the creation of a cancer cell.
TCDD is both a man-made and a naturally occurring chemical. U.S. EPA (1994). It is often a very minor contaminant in the chemical plant production of trichlorophenol, pentachlorophenol, hexachlorphene, and some salts, acids and esters of these compounds. Fingerhout et al.,
Mortality Among U.S. Workers Employed in the Production of Chemicals Contaminated with
2,3,7,8-
Tetrachlorodibenzo
-
p
-
dioxin
(
TCDD
). A NIOSH Report. (1990).
EPA has sought to regulate dioxin as a carcinogen on three occassions. In 1988, it succeeded in characterizing TCDD as a “possible” human carcinogen on the strength of significantly elevated liver cancer incidence in high dose female Sprague-Dawley rats fed TCDD over a lifetime. Kociba et al.,
Toxicol. Appl. Pharmacol.
46, 279-303 (1978). Neither Kociba et al. nor the Agency reported the low dose reduction in each sex—it was significant in the males—and, more importantly, the significant reduction in total cancers in each sex at the low and mid dose TCDD levels of 540 and 5100 parts per trillion (ppt) in liver tissue. Kociba et al. (1978); U.S. EPA (1985); and U.S. EPA (1994).
In 1994, EPA sought to regulate TCDD as a “probable” human carcinogen, using a population of 5280 male workers in 12 chemical plants, each of whom was exposed to contaminant levels of TCDD and some mix of 1000 unidentified other chemicals. Fingerhut et al. (1990). Fingerhut compared the cancer incidence in the plant workers to that expected in a national reference, and EPA concluded all the cancer incidence increases noted by Fingerhut were caused by the TCDD exposure and none were caused by exposures to other chemicals. U.S. EPA (1994). EPA's Science Advisory Board rejected the Agency's TCDD cancer claims. U.S. EPA Science Advisory Board,
Review of Draft Documents: A Second Look at Dioxin
(1995).
Again, in 2000, EPA reworked the criticized sections of its 1994 Report, relying mostly on reshaped and updated epidemiology data to remake its TCDD cancer claims, which the Agency's Science Advisory Board again rejected. U.S. EPA Science Advisory Board,
Review of Draft Documents: A Final Look at Dioxin
(2001).
Four patents have been issued on Beneficial antiestrogenic effects associated with exposure to TCDD-like or related compounds, none on TCDD. Bednarski U.S. Pat. No. 4,745,109; Morgan U.S. Pat. No. 4,732,904; Jones U.S. Pat. No. 4,418,068; and Safe U.S. Pat. No. 5,516,790. Indeed, Safe, whose chemical agents are most structurally similar to TCDD, specifically avoids claims on TCDD. Safe, citing Kociba's high dose female liver cancer data, observed that TCDD was anti-carcinogenic for mammary and uterine cancers, but at a body burden level so high (25,400 ppt) as to be very hepatocarcinogenic, and, therefore, therapeutically without value. The theory behind ass four patents is an anti-estrogenic effect, which is not the basis of this Inventor's claims.
A pair of research papers from DiGiovanni et al. (
Biochem. Biophys. Res. Com.
86, 577-584 (1979);
Polynucl. Aromat. Hydrocarbons: Chem. Biol. Eff. Intl. Symp.
4th (1980)) claim a very high single dose of TCDD significantly reduces an artificially elevated skin cancer incidence in several mice strains, when the YCDD dose is administered one to five days prior to the initiation of those cancers. No reduction in the elevated skin cancer incidence is observed when the TCDD is administered simultaneously with or a day after the skin cancer initiation step. In these papers no claim is made, or should be made by DiGiovanni, that the high level of TCDD administered reduces skin cancer occurence because of an effect on the promotional step in cancer creation. Still, the assertion might be made, by logical extension, that if TCDD is an initiator blocker for mouse skin at high dose, it might also reduce total cancer incidence in man by some other means at high dose. But the multiple step extension (mouse to man; skin to total cancer; and initiation to promotion) from DiGiovanni does not extend well to total cancer incidence in man: for example, Zober et al. (
Int. Arch. Occup. Environ. Health
62, 139-157 (1990)) and Manz et al. (
Lancet
338, 959-964 (1991)) in separate studies of different industrial cohorts observe a total cancer increase rather than the significant decrease expected from the “logical extension”; Steenland et al. (
J. Natl. Cancer Inst.
91, 779-786 (1999)) finds a significant increase in total cancers in the most highly TCDD-exposed members of the NIOSH workforce that Fingerhut et al. reported on in 1990; over twenty years, Bertazzi et al. (
Amer. J. Epidem.
153, 1031-1044 (2001)) finds a significant increase in total cancers among Italian men from Seveso in his pooled two highest exposed cohorts; and Flesch-Janys et al. (
Amer. J. Epidem.
142, 1165-1174 (1995)) reports a significant increase in total cancer mortality among his most highly TCDD-exposed German herbicide chemical plant workers. These studies, individually and collectively, contradict any extension of the high TCDD-based diGiovanni teaching to total cancers in humans. These syudies collectively serve as a barrier to any claims of obviousness from diGiovanni. Further, this Invention is based on low, rather than high, body burden or exposure observations in humans and rats, and predicated on blocking the promotion step in cancer creation rather than the initiation step.
SUMMARY OF THE INVENTION
The proposed use of TCDD as a promoter blocker of cancers is new. TCDD is a well known chemical. In the past it has been manufactured and purified to 99% purity by the Dow Chemical Company. Kociba et al. (1978).
A careful analysis of the Kociba lifetime rodent feeding study shows theat TCDD body burdens of 540 and 5100 ppt are associated with a reduction of cancers at multiple tissue sites and overall in both male and female rats, a highly unusual and unexpected observation which the authors, EPA, and regulated industries failed to note. Kociba et al, (1978); U.S. EPA (1985 and 1994).
In addition to published and unpublished epidemiology data from the NIOSH Report (Fingerhut et al. (1990)), additional NIOSH Life Table records (LT20406 (1990)), and the Steenland et al. article (1999), the Inventor relies on Bertazzi et al.'s (
Epidemiol.
4, 398-406 (1993)) cancer incidence data presentation on a residential population of men and women exposed to the lowest levels of TCDD as a result of a chemical plant explosion near Seveso, Italy, and the Inventor's own analysis of cancer incidence and body burden data in the Operation Ranch Hand (ORH) airmen exposed to TCDD as a result of service in Southeast Asia during the Vietnam War. None of the NIOSH and Seveso papers cited above claim that TCDD acts as an anti-carcinogen. The Air Force Scientists charged with developing the ORH Study also fail to observe TCDD as an anti-carcinogen
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