Food or edible material: processes – compositions – and products – Product for promoting the effect of an alimentary canal...
Reexamination Certificate
2001-10-10
2002-12-10
Hendricks, Keith (Department: 1761)
Food or edible material: processes, compositions, and products
Product for promoting the effect of an alimentary canal...
C426S061000, C426S583000, C424S093400
Reexamination Certificate
active
06491956
ABSTRACT:
FIELD OF THE INVENTION
A nutritional formulation in which non-toxic (to humans) bacteria thrive, is used to prevent and treat gastric disorders associated with
Helicobacter pylori
(also referred to as
H. pylori
) which are believed to be attacked by the non-toxic bacteria. Only particular strains of non-toxic comestible bacteria, when ingested by humans are effective against
H. pylori
. Optionally and preferably, the prophylactic and/or therapeutic effects of the comestible bacteria are boosted with egg yolk containing immunoglubins (antibodies) specific to
H. pylori
antigen (also referred to as “
H. pylori
-antibodies”).
BACKGROUND OF INVENTION
Much has been published regarding
H. pylori
which inhabits the human gastric mucosa. It is a gram-negative spiral rod-shaped bacterium having an outer membrane with four to six polar flagella which are sheathed and have bulbous ends; each
H. pylori
bacterium is about 0.85 &mgr;m (micrometer) in diameter with an average length of 2.9 &mgr;m. Known pathogenic (disease) factors of
H. pylori
are (i) urease (urea aminohydrolase) which is produced by the bacteria to allow it to thrive in a strong acid environment in the range from pH 1-3, (ii) flagella which provide the bacteria with mobility, and (iii) a protein-aceous outer membrane of the cells which membrane helps the cells to stick to the gastric mucosal cells. Survival of
H. pylori
relies upon creation of a relatively non-acidic microenvironment in the vicinity of the bacteria, and a relatively basic microenvironment is provided by the enzyme urease; the more basic the better, and the closer to neutral pH, the more difficult it is for the
H. pylori
to thrive. The ability to command a near-neutral microenvironment is an essential property of bacteria which effectively prevent and treat gastric disorders.
A result of interaction of
H. pylori
on the mucous membrane is the stimulation of numerous cytokines. The predominant immune response to infection is the production of interleukin-8 (IL-8). IL-8-induced neutrophils or macrophages are a direct cause of gastritis. To date, treatment to subdue secretion of gastric acid, for example with H
2
isolator, is deemed unsatisfactory over the long term due to recrudescence which is now countered with medicines which act directly on the
H. pylori
. Presently, trends in the fight against infection by
H. pylori
may be categorized as follows: (a) development of antibiotics showing a direct effect against
H. pylori
, (b) development of vaccines for
H. pylori
, and (c) using anti-
H. pylori
antibodies which allow the live
H. pylori
to be terminated. For prophylaxis, (b) and (c) are preferred.
Bhatia et al in
J. Clin. Microbiol
. 27: 2328-2330, 1989, disclosed that
L. acidophilus
could inhibit the growth of
H. pylori
in vitro, and that this effect was due to lactic acid production. Midolo et al in
J. Appl. Bacteriol
. 79:475-479, 1995, disclosed that
L. casei, L. bulgaticus, Pediococccus pentosaceus
and
Bifidobacterium bifidus
could inhibit the growth of
H. pylori
in vitro, and that this effect was due to organic acids produced by these bacteria. However, as stated in European Patent Application EP 0 877 032 A1 to Kodama et al (hereafter, “the '032 application”), one cannot expect experiments conducted in vitro to be replicated in the stomach. An attempt to use
Lactobacillus salivarius
as a probiotic to inhibit growth of
H. pylori
is reported by Aiba et al in
The Meeting of the
30
th Japan Germ-free Animal Gnotobiology Society
, Program and Abstracts, pp 22, Requested Title 18, “New Attempt for Inhibiting
H. pylori
” (January 1997). They also used anti-
H. pylori
antibodies in the yolks of eggs of hens immunized with formalin-lidlled, whole
H. pylori
cells. In germ-free mice, the effectiveness of the
L. salivarius
was 2 to 3 orders of magnitude greater than that of the antibodies; effectiveness in the environment of the stomach of a mammal such as a normal mouse, or in the pH 1-3 of a human, was not investigated. Though the particular strain of
L. salivarius
was not identified, there is no reason to believe that any lactic acid bacteria will be comparably effective even in a germ-free mouse; data presented below in
FIG. 1
indicate that several species of Lactobacillus show high in vitro activity, but are not as effective in vivo as others with comparably high in vitro activity. Moreover, as also shown in
FIG. 1
, strains which show desirably high in vitro activity, e.g.
L. casei
HY2743 and
L. plantarum
HY2207 are found to be far from equally effective in vivo.
In the prior art there are taught many immunization schedules under which growth of anti-
H. pylori
antibodies can be stimulated, most relevant among which are the disclosures of Japanese Patent Application Kokai No. 4-275232 to Takahashi et al, which discloses antibodies obtained in eggs of hens immunized against
H. pylori
whole cells as an antigen; and, the disclosure of the '032 application which discloses antibodies obtained in eggs of hens immunized against (i) flagella of
H. pylori
separated from the rest of the cells; and (ii) urease of
H. pylori
separated from the rest of the cells, these being pathogenic factors associated with
H. pylori
. Antibodies obtained from either (i) or (ii), by themselves, had no noticeable effect on the number of cells in the stomach of five mice; however, (i) and (ii) in combination eliminated the
H. pylori
cells from the stomachs of 5 out of 5 mice. (see Table 2 in the '032 application).
Takahashi et al teach the use of a solution of shattered or comminuted
H. pylori
as antigen, but the beneficial effects are relatively small because the solution additionally contains many other different proteins which appear to dilute, if not diminish or negate, the ability of the antigen to generate effective antibodies.
Furthermore, Kodama et al teach that either the anti-urease antibodies or the anti-flagella antibodies, or both together, may be used in combination with at least one organism selected from the group consisting of lactic acid bacteria, Enterococci, yeasts and Bacillus to inhibit the growth of
H. pylori
in the stomach, teaching that the presence of any live organism unexpectedly enhances the effectiveness of the antibodies, though the live organism, by itself, was ineffective in the environment of the stomach. In particular, Kodama states that
L. acidophilus, L. casei, L. bulgaricus, Pediococcus pentosaceus
and
Bifidobacterium bifidus
were all reported to inhibit growth of
H. pylori
in vitro purportedly due to organic acids produced by these bacteria, but such effectiveness was of no help to assess the effect in the stomach. Evidence of the synergistic effect of anti-urease antibodies and
Lactobacillus acidophilus
administered in combination orally to
H. pylori
-infected mice is presented in Table 3 of EP '032. Note however, that only one-half of the population of
L. acidophilus
is found after 14 days. Without considering the propriety of extrapolating those results to all live organisms tested, it is evident from results presented in Table 3 that one particular strain of
L. acidophilus
showed a synergistic effect with
H. pylori
-urease. However, one skilled in the art is unable, without undue experimentation, to reproduce the effect reported, because it is not reasonably possible to find the single strain among all the known strains of
L. acidophilus
which produces the synergistic result.
Confirmation of the ineffectiveness of the live organism, by itself, is stated as follows: “
L. acidophilus
alone was almost the same as that of the control group, and there was no significant difference between the two groups, as shown in Table 3. Also, gastritis conditions were observed and
L. acidophilus
had no efficacy on suppressing gastritis.” (see page 10, lines 49-52). The tests were performed on hairless mice (NS:Hr/ICR) having a high sensitivity to
H. pylori
infection. Such mice do not have the normal flora found in a BALB/c mouse which provides a bet
Baek Young Jin
Heo Cheol Seong
Kim Hyung Soo
Lee Jeong Jun
Hendricks Keith
Korea Yakult Co. Ltd.
Lobo Alfred D.
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