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Patent 2342844 Summary

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(12) Patent Application: (11) CA 2342844
(54) English Title: FREEZE-RESISTANT TOPICAL GERMICIDES AND METHODS RELATED THERETO
(54) French Title: GERMICIDES TOPIQUES RESISTANT AU FROID ET PROCEDES CORRESPONDANTS
Status: Deemed Abandoned and Beyond the Period of Reinstatement - Pending Response to Notice of Disregarded Communication
Bibliographic Data
(51) International Patent Classification (IPC):
  • A01N 37/36 (2006.01)
  • A01N 37/02 (2006.01)
  • A01N 37/10 (2006.01)
  • A01N 59/00 (2006.01)
(72) Inventors :
  • KROSS, ROBERT D. (United States of America)
(73) Owners :
  • ALCIDE CORPORATION
(71) Applicants :
  • ALCIDE CORPORATION (United States of America)
(74) Agent: GOWLING WLG (CANADA) LLP
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 1999-08-31
(87) Open to Public Inspection: 2000-03-16
Availability of licence: N/A
Dedicated to the Public: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US1999/019987
(87) International Publication Number: US1999019987
(85) National Entry: 2001-03-02

(30) Application Priority Data:
Application No. Country/Territory Date
09/146,947 (United States of America) 1998-09-03

Abstracts

English Abstract


A freeze-resistant topical germicide for application to skin, such as the teat
of a dairy cow. The germicide may be a one-part composition or a two-part
system. The one-part disinfecting composition comprises an organic acid
germicide and a non-esterifying antifreeze. The two-part system comprises a
first part and a second part adapted to be mixed to yield the disinfecting
composition. The first part comprises a metal chlorite and a chlorite-stable
antifreeze, and the second part comprises an organic acid germicide and a non-
esterifying antifreeze, or an inorganic acid and either an alcohol or a non-
esterifying antifreeze.


French Abstract

L'invention concerne un germicide topique résistant au froid, à appliquer sur la peau, notamment celle de la mamelle d'une vache laitière. Ce germicide peut être une composition en une partie ou un système en deux parties. La composition désinfectante en une partie comprend un germicide d'acide organique et un antigel non estérifiant. Le système en deux parties comprend une première partie et une seconde partie mélangées afin de produire la composition. La première partie comprend un chlorite métallique et un antigel stable au chlorite, et la seconde partie comprend un germicide d'acide organique et un antigel non estérifiant, ou un acide non organique et un alcool, ou un antigel non estérifiant.

Claims

Note: Claims are shown in the official language in which they were submitted.


17
CLAIMS
I claim:
1. A freeze-resistant aqueous disinfecting composition comprising an
organic acid germicide and a non-esterifying antifreeze, wherein the non-
esterifying
antifreeze contains from 4 to 16 carbon atoms and has no primary carbon atom
bearing a
hydroxyl group.
2. The composition of claim 1 wherein the non esterifying antifreeze is an
ether having at least one ether linkage between two carbon atoms.
3. The composition of claim 1 wherein the non-esterifying antifreeze is an
ether-alcohol having at least one ether linkage between two carbon atoms, and
having at least
one secondary carbon atom bearing a hydroxyl group.
4. The composition of claim 1 wherein the non-esterifying antifreeze is an
ester having at least one ester linkage between two carbon atoms.
5. The composition of claim 1 wherein the non-esterifying antifreeze has
the structure R1-O-CH2-CH(OR2)-R3, wherein R1 is C1-8alkyl, and R2 and R3 are
the same or
different and independently selected from hydrogen or C1-8alkyl, and each
secondary carbon
atom of the C1-8alkyl moiety is optionally substituted with a hydroxyl group.
6. The composition of claim 5 wherein R1 is C1-8alkyl moiety, R2 is
hydrogen, and R3 is C1-8alkyl moiety.
7. The composition of claim 5 wherein R1 is C1-8alkyl moiety, R2 is
hydrogen and R3 is methyl.

18
8. The composition of claim 5 wherein R1, R2-and R3 are C1-8alkyl.
9. The composition of claim 1 wherein the non-esterifying antifreeze has
the structure R4-CH(OR5)-CH2-O-CH2-CH(OR2)-R3, wherein R2, R3, R4 and R5 are
the same
or different and independently selected from hydrogen and C1-8alkyl, and each
secondary
carbon atom of the C1-8alkyl moiety is optionally substituted with a hydroxyl
group.
10. The composition of claim 9 wherein R4 is C1-8alkyl and R5 is hydrogen.
11. The composition of claim 9 wherein R4 is C1-8alkyl and R5 is C1-8alkyl.
12. The composition of claim 5 or 9 wherein at least one oxygen atom is
bound to -CO(C1-8alkyl) to form an ester.
13. The composition of claim 1 wherein the non-esterifying antifreeze is
propylene glycol monomethyl ether having the structure CH3OCH2CH(OH)CH3.
14. The composition of claim 1 wherein the non-esterifying antifreeze is
propylene glycol monoethyl ether having the structure CH3CH2OCH2CH(OH)CH3,
propylene
glycol monopropyl ether having the structure CH3CH2CH2OCH2CH(OH)CH3, or
propylene
glycol monoisopropyl ether having the structure CH3CH(CH3)OCH2CH(OH)CH3.
15. The composition of claim 1 wherein the non-esterifying antifreeze is
dipropylene glycol having the structure CH3CH(OH)CH2OCH2CH(OH)CH3.
16. The composition of claim 1 wherein the non-esterifying antifreeze is
dipropylene glycol methyl ether having the structure
CH3CH(OCH3)CH2OCH2CH(OH)CH3,
dipropylene glycol ethyl ether having the structure
CH3CH(OCH2CH3)CH2OCH2CH(OH)CH3, or dipropylene glycol acetate having the
structure
CH3CH(OCOCH3)CH2OCH2CH(OH)CH3.

19
17. The composition of claim 1 wherein the non-esterifying antifreeze is
present at a concentration ranging from about 10% to about 75% by weight of
the
composition.
18. The composition of claim 1 wherein the non-esterifying antifreeze is
present at a concentration ranging from 15% to 50% by weight of the
composition.
19. The composition of claim 1 wherein the organic acid germicide is an
alpha-hydroxy carboxylic acid having a pKa between about 2.8 and about 4.2.
20. The composition of claim 19 wherein the alpha-hydroxy carboxylic
acid is glycolic acid, lactic acid, malic acid, mandelic acid, citric acid,
tartaric acid, or
mixtures thereof.
21. The composition of claim 1 wherein the organic acid germicide is
formic acid, acetic acid, propionic acid, benzoic acid, caprylic acid, capric
acid,
hydroxybenzoic acid, or mixtures thereof.
22. The composition of claim 1 wherein the organic acid germicide is
present at a concentration between about 0.25% and about 7.5% by weight of the
composition.
23. The composition of claim 1 wherein the organic acid germicide is
present at a concentration between 2% and 5% by weight of the composition.
24. The composition of claim 1 wherein the composition is formulated as a
solution.
25. The composition of claim 1 wherein the composition is formulated as a
cream or gel.

20
26. The composition of claim 1 further comprising a textural modifier, a
surfactant, an odorant, a colorant, or mixtures thereof.
27. A method for disinfecting a substrate, comprising contacting the
substrate with an effective amount of the freeze-resistant aqueous
disinfecting composition of
claim 1.
28. The method of claim 27 wherein the substrate is skin.
29. The method of claim 27 wherein the substrate is a teat of a dairy cow.
30. A two-part freeze-resistant disinfecting system comprising a first part
and a second part adapted to be mixed to yield an aqueous disinfecting
composition, wherein
prior to mixing the first part comprises a metal chlorite and a chlorite-
stable antifreeze, and
the second part comprises (a) an organic acid germicide and a non-esterifying
antifreeze, or
(b) an inorganic acid and either an alcohol or a non-esterifying antifreeze,
wherein each of the
chlorite-stable and non-esterifying antifreezes contain from 4 to 16 carbon
atoms and have no
primary carbon atom bearing a hydroxyl group.
31. The system of claim 30 wherein the metal chlorite is an alkali or
alkaline earth chlorite.
32. The system of claim 30 wherein the metal chlorite is sodium chlorite or
potassium chlorite.
33. The system of claim 30 wherein the metal chlorite is sodium chlorite.
34. The system of claim 30 wherein the metal chlorite is present in the first
part at a concentration such that, when combined with the second part, it is
present within the

21
disinfecting composition at a concentration ranging from about 0.005% to about
1 % by
weight.
35. The system of claim 30 wherein the metal chlorite is present in the first
part at a concentration such that, when combined with the second part, it is
present within the
disinfecting composition at a concentration ranging from 0.05% to 0.5% by
weight.
36. The system of claim 30 wherein the metal chlorite is present in the first
part at a concentration such that, when combined with the second part, it is
present within the
disinfecting composition at an concentration ranging from 0.1 % to 0.4% by
weight.
37. The system of claim 30 wherein the chlorite-stable antifreeze is an
ether having at least one ether linkage between two carbon atoms.
38. The system of claim 30 wherein the chlorite-stable antifreeze is an
ether-alcohol having at least one ether linkage between two carbon atoms, and
having at least
one secondary carbon atom bearing a hydroxyl group.
39. The system of claim 30 wherein the chlorite-stable antifreeze is an
ester having at least one ester linkage between two carbon atoms.
40. The system of claim 30 wherein the chlorite-stable antifreeze has the
structure R1-O-CH2-CH(OR2)-R3, wherein R1 is C1-8alkyl, and R2 and R3 are the
same or
different and independently selected from hydrogen or C1-8alkyl, and each
secondary carbon
atom of the C1-8alkyl moiety is optionally substituted with a hydroxyl group.
41. The system of claim 40 wherein R1 is C1-8alkyl moiety, R2 is hydrogen,
and R3 is C1-8alkyl moiety.

22
42. The system of claim 40 wherein R1 is C1-8alkyl moiety, R2 is hydrogen
and R3 is methyl.
43. The system of claim 40 wherein R1, R2 and R3 are C1-8alkyl.
44. The system of claim 30 wherein the chlorite-stable antifreeze has the
structure R4-CH(OR5)-CH2-O-CH2-CH(OR2)-R3, wherein R2, R3, R4 and R5 are the
same or
different and independently selected from hydrogen and C1-8alkyl, and each
secondary carbon
atom of the C1-8alkyl moiety is optionally substituted with a hydroxyl group.
45. The system of claim 44 wherein R4 is C1-8alkyl and R5 is hydrogen.
46. The system of claim 44 wherein R4 is C1-8alkyl and R5 is C1-8alkyl.
47. The system of claim 40 or 44 wherein at least one oxygen atom is
bound to -CO(C1-8alkyl) to form an ester.
48. The system of claim 30 wherein the chlorite-stable antifreeze is
propylene glycol monomethyl ether having the structure CH3OCH2CH(OH)CH3.
49. The system of claim 30 wherein the chlorite-stable antifreeze is
propylene glycol monoethyl ether having the structure CH3CH2OCH2CH(OH)CH3,
propylene
glycol monopropyl ether having the structure CH3CH2CH2OCH2CH(OH)CH3, or
propylene
glycol monoisopropyl ether having the structure CH3CH(CH3)OCH2CH(OH)CH3.
50. The system of claim 30 wherein the chlorite-stable antifreeze is
dipropylene glycol having the structure CH3CH(OH)CH2OCH2CH(OH)CH3.
51. The system of claim 30 wherein the chlorite-stable antifreeze is
dipropylene glycol methyl ether having the structure
CH3CH(OCH3)CH2OCH2CH(OH)CH3,

23
dipropylene glycol ethyl ether having the structure
CH3CH(OCH2CH3)CH2OCH2CH(OH)CH3, or dipropylene glycol acetate having the
structure
CH3CH(OCOCH3)CH2OCH2CH(OH)CH3.
52. The system of claim 30 wherein the chlorite-stable antifreeze is present
at a concentration ranging from about 10% to about 75% by weight of the first
part.
53. The system of claim 30 wherein the chlorite-stable antifreeze is present
at a concentration ranging from 15% to 50% by weight of the first part.
54. The system of claim 30 wherein the second part comprises the organic
acid and the non-esterifying antifreeze.
55. The system of claim 54 wherein the organic acid and the non-
esterifying antifreeze of the second part is the composition of any one of
claims 1-23.
56. The system of claim 30 wherein the second part comprises the
inorganic acid and either the alcohol or the non-esterifying antifreeze.
57. The system of claim 56 wherein the inorganic acid is selected from
phosphoric acid, monosodium acid phosphate, sulfuric acid, hydrochloric acid,
and sodium
bisulfate.
58. The system of claim 56 wherein the inorganic acid is present in the
second part at a concentration such that, when combined with the first part
and before
reacting therewith, it is present within the disinfecting composition at an
initial concentration
ranging from 0.001 % to 2% by weight.
59. The system of claim 56 wherein the inorganic acid is present in the
second part at a concentration such that, when combined with the first part
and before

24
reacting therewith, it is present within the disinfecting composition at an
initial concentration
ranging from 0.01 % to 1.0% by weight.
60. The system of claim 56 wherein the second part comprises the
inorganic acid and the alcohol.
61. The system of claim 60 wherein the alcohol is a polyol.
62. The system of claim 61 wherein the polyol is glycerine, sorbitol or
propylene glycol.
63. The system of claim 56 wherein the second part comprises the
inorganic acid and the non-esterifying antifreeze.
64. The system of claim 63 wherein the non-esterifying antifreeze is an
ether having at least one ether linkage between two carbon atoms.
65. The system of claim 63 wherein the non-esterifying antifreeze is an
ether-alcohol having at least one ether linkage between two carbon atoms, and
having at least
one secondary carbon atom bearing a hydroxyl group.
66. The system of claim 63 wherein the non-esterifying antifreeze is an
ester having at least one ester linkage between two carbon atoms.
67. The system of claim 63 wherein the non-esterifying antifreeze has the
structure R1-O-CH2-CH(OR2)-R3, wherein R1 is C1-8alkyl, and R2 and R3 are the
same or
different and independently selected from hydrogen or C1-8alkyl, and each
secondary carbon
atom of the C1-8alkyl moiety is optionally substituted with a hydroxyl group.

25
68. The system of claim 67 wherein R1 is C1-8alkyl moiety, R2 is hydrogen,
and R3 is C1-8alkyl moiety.
69. The system of claim 67 wherein R1 is C1-8alkyl moiety, R2 is hydrogen
and R3 is methyl.
70. The system of claim 67 wherein R1, R2 and R3 are C1-8alkyl.
71. The system of claim 63 wherein the non-esterifying antifreeze has the
structure R4-CH(OR5)-CH2-O-CH2-CH(OR2)-R3, wherein R2, R3, R4 and R5 are the
same or
different and independently selected from hydrogen and C1-8alkyl, and each
secondary carbon
atom of the C1-8alkyl moiety is optionally substituted with a hydroxyl group.
72. The system of claim 71 wherein R4 is C1-8alkyl and R5 is hydrogen.
73. The system of claim 71 wherein R4 is C1-8alkyl and R5 is C1-8alkyl.
74. The system of claim 67 or 71 wherein at least one oxygen atom is
bound to -CO(C1-8alkyl) to form an ester.
75. The system of claim 63 wherein the non-esterifying antifreeze is
propylene glycol monomethyl ether having the structure CH30CH2CH(OH)CH3.
76. The system of claim 63 wherein the non-esterifying antifreeze is
propylene glycol monoethyl ether having the structure CH3CH2OCH2CH(OH)CH3,
propylene
glycol monopropyl ether having the structure CH3CH2CH2OCH2CH(OH)CH3, or
propylene
glycol monoisopropyl ether having the structure CH3CH(CH3)OCH2CH(OH)CH3.
77. The system of claim 63 wherein the non-esterifying antifreeze is
dipropylene glycol having the structure CH3CH(OH)CH2OCH2CH(OH)CH3.

26
78. The system of claim 63 wherein the non-esterifying antifreeze is
dipropylene glycol methyl ether having the structure
CH2CH(OCH3)CH2OCH2CH(OH)CH3,
dipropylene glycol ethyl ether having the structure
CH3CH(OCH2CH3)CH2OCH2CH(OH)CH3, or dipropylene glycol acetate having the
structure
CH2CH(OCOCH3)CH2OCH2CH(OH)CH3.
79. The system of claim 63 wherein the alcohol or non-esterifying
antifreeze is present at a concentration ranging from about 10% to about 75%
by weight of
the second part.
80. The system of claim 63 wherein the alcohol or non-esterifying
antifreeze is present at a concentration ranging from 15% to 50% by weight of
the second
part.
81. The system of claim 30 wherein the first part is formulated as a
solution, cream or gel.
82. The system of claim 30 wherein the second part is formulated as a
solution, cream or gel.
83. The system of claim 30 wherein the first part, second part, or both the
first and second parts further comprises a textural modifier, a surfactant, an
odorant, a
colorant, or mixtures thereof.
84. A method for disinfecting a substrate, comprising contacting the
substrate with an effective amount of the disinfecting composition of claim
30.
85. The method of claim 84 wherein the substrate is skin.
86. The method of claim 84 wherein the substrate is a teat of a dairy cow.

Description

Note: Descriptions are shown in the official language in which they were submitted.


CA 02342844 2001-03-02
WO 00/13506 PCT/US99/19987
1
FREEZE-RESISTANT TOPICAL GERMICIDES
AND METHODS RELATED THERETO
TECHNICAL FIELD
The present invention is generally directed to freeze-resistant topical
germicides for application to skin, particularly the teat of a dairy cow,
wherein the
germicide is a one-part disinfecting composition containing an organic acid
germicide
and an non-esterifying antifreeze, or a two-part system comprising a first
part and a
second part adapted to be mixed to yield a disinfecting composition.
BACKGROUND OF THE INVENTION
A constant winter problem on many dairies across the country is
chapping teats, the problem being more severe in the Northern tier of the
United States
and Canada. As temperatures drop, teats become more chapped and cracked. This
generally results in the elevation of the somatic cell counts of the affected
cows, and
often delays the milking process because cows refuse to let down milk when
their teats
1 ~ are irritated. Furthermore, research studies have repeatedly shown that
Staphylococcus
aureus infections of the milk go up dramatically on damaged teats, leading to
an
increase in the number of quarters that are infected with this organism.
Another
problem is that of logistics, where pre- and post-milking teat dips that are
susceptible to
freezing cannot be stored in milking facilities which are exposed to sub-
freezing
ambient temperatures.
Even when the dips are maintained in a non-frozen state, cows that have
been post-dipped must stay protected from freezing temperatures until the teat
dip dries.
This approach is practicable in stanchion barns, but not in milking parlors.
Thus, to
prevent the teat dip from freezing on the teat, some dairymen allow the dip to
remain on
the teat for about 45 seconds after dipping, and then blot off the excess dip
before the
cows go outdoors. Such additional measures, however, are time-consuming and
not
always effective.

CA 02342844 2001-03-02
WO 00/13506 PCT/US99/19987
2
For these reasons, dairymen are advised to stop post-milking dipping
during weather conditions where freezing and chapping are likely to occur.
Since
bacterial transfer and proliferation tend to be lower in colder environments,
dairymen
must balance the potential problems associated with freezing and chapping with
the
potential for elevated somatic cell counts and clinical mastitis, often
choosing to forgo
the use of post-milking dips in freezing weather conditions. Other dairymen
elect to
switch to dips with higher levels of skin softeners and emollients as the
temperatures
drop, while still others elect dry powder dips, which are basically moisture
absorbers
with little antimicrobial effectiveness.
In an attempt to avoid the above problems, freeze-resistant teat dips have
been proposed. For example, a teat-dip composition which freezes below -
20°C is
disclosed in Japanese Patent No. 8175989. The base composition of the dip, as
provided in one example of that document, comprises about 30% each of
propylene
glycol and lactic acid, and 7% sorbitan. Further, a freeze-resistant teat dip,
containing
chlorhexidine disinfectant, and at least 80 wt% of a volatile alcohol, is
disclosed in U.S.
Patent No. 4,434,181.
More recently in the United States, a non-freezing teat dip has been
commercialized which contains, as its base, over 60 wt% of propylene glycol.
The
active germicide in the product is a combination of C8 and C 10 alkanoic
acids. The
shelf life of this product is limited, however, due to tendency of the acid to
react with
the glycol to form esters, which continuously reduces the amount of available
acid in
the formulation and thus the product's effectiveness. For example, periodic
analysis of
such a teat dip indicates a loss of 20% of the acid in only a six-month period
at ambient
conditions, and over a 10% loss of the acid in just one-month at 100°F.
A similar
problem is encountered if one were to introduce glycol-types of antifreeze
into other
acid-containing germicidal teat dips. This includes those dips where the acid
is present
as a buffering agent, such as in iodophor dips where citric acid is used to
maintain a pH
range at which the iodine species are optimally effective (e.g., pH 4-5).
Accordingly there is a need in the art for improved teat dip compositions
which resist freezing in ambient winter conditions, resist reacting with
acidic

CA 02342844 2001-03-02
WO 00/13506 PCTNS99/19987
3
germicides and/or acid buffering agents, and maintain compatibility of the
freeze-
resistant agent with the antimicrobial agent. The present invention fulfills
these needs
and provides further related advantages.
SUMMARY OF THE INVENTION
In brief, the present invention is directed to freeze-resistant topical
germicides for application to, for example, the teat of a dairy cow. Such
compositions
resist freezing in ambient winter conditions, and do not react with organic
acidic
germicides and/or buffering agents. Further, the compositions of this
invention
maintain compatibility between the freeze-resistant and antimicrobial agents.
The topical germicides of this invention may generally be classified as
one-part or two-part formulations. The one-part formulation comprises an
organic acid
germicide and an non-esterifying antifreeze, while the two-part formulation
(hereinafter
referred to as a "system") comprises a first part and a second part adapted to
be mixed to
yield the topical germicide. In the two-part system, the first part comprises
a metal
I S chlorite and a chlorite-stable antifreeze, while the second part comprises
(a) an organic
acid germicide and a non-esterifying antifreeze, or (b) an inorganic acid and
either an
alcohol or a non-esterifying antifreeze.
Accordingly, in one embodiment of this invention, a one-part freeze-
resistant aqueous disinfecting composition is disclosed containing an organic
acid
germicide and an non-esterifying antifreeze, wherein the non-esterifying
antifreeze
contains from 4 to 16 carbon atoms and has no primary carbon atom bearing a
hydroxyl
group. Non-esterifying antifreezes my be an ether having at least one ether
linkage
between two carbon atoms, an ether-alcohol having at least one ether linkage
between
two carbon atoms and with at least one secondary carbon atom bearing a
hydroxyl
group, or an ester having at least one ester linkage between two carbon atoms.
In one aspect of this embodiment, the non-esterifying antifreeze has the
structure R'-O-CHz-CH(OR2)-R3, wherein R' is C,_galkyl, and R2 and R3 are the
same or
different and independently selected from hydrogen or C,_8alkyl, and each
secondary
carbon atom of the C,_galkyl moiety is optionally substituted with a hydroxyl
group.

CA 02342844 2001-03-02
WO 00/13506 PCT/US99/199_87
4
Representative antifreezes include those compounds wherein R' is C~_8alkyl
moiety, Rz
is hydrogen, and R' is C,_galkyl moiety; wherein R' is C,_8alkyl moiety, Rz is
hydrogen
and R3 is methyl; and wherein R', Rz and R3 are C,_8alkyl.
In another aspect of this embodiment, the non-esterifying antifreeze has
the structure R4-CH(ORS)-CHz-O-CHZ-CH(ORZ)-R3, wherein R', R3, R4 and RS are
the
same or different and independently selected from hydrogen and C,_galkyl, and
each
secondary carbon atom of the C,_8alkyl moiety is optionally substituted with a
hydroxyl
group. Representative antifreezes include those compounds wherein R4 is
C,_8alkyl and
RS is hydrogen; and wherein R' is C,_8alkyl and RS is C,_8alkyl.
Non-esterifying antifreezes also include compounds of the above
structures wherein at least one oxygen atom is bound to -CO(C,_salkyl) to form
an ester.
Typical non-esterifying antifreezes of this invention include propylene
glycol monomethyl ether having the structure CH30CHzCH(OH)CH3, propylene
glycol
monoethyl ether having the structure CH,CHzOCHzCH(OH)CH3, propylene glycol
monopropyl ether having the structure CH3CHZCHZOCHZCH(OH)CH3, propylene
glycol monoisopropyl ether having the structure CH,CH(CH3)OCHZCH(OH)CH3,
dipropylene glycol having the structure CH3CH(OH)CHZOCHZCH(OH)CH3,
dipropylene glycol methyl ether having the structure
CH3CH(OCH3)CHZOCHzCH(OH)CH3, dipropylene glycol ethyl ether having the
structure CH3CH(OCHZCH3)CHzOCH2CH(OH)CH3, and dipropylene glycol acetate
having the structure CH3CH(OCOCH3)CHzOCH2CH(OH)CH3.
The non-esterifying antifreeze may be present at a concentration ranging
from about 10% to about 75% by weight of the composition, and typically from
15% to
50% by weight of the composition.
The organic acid germicide may be an alpha-hydroxy carboxylic acid
having a pKa between about 2.8 and about 4.2, such as glycolic acid, lactic
acid, malic
acid, mandelic acid, citric acid, tartaric acid, and mixtures thereof. Other
organic acid
germicides include formic acid, acetic acid, propionic acid, benzoic acid,
caprylic acid,
capric acid, hydroxybenzoic acid, and mixtures thereof.

CA 02342844 2001-03-02
WO 00/13506 PCT/US99/199$7
The organic acid germicide is present at a concentration between about
0.25% and about 7.5% by weight of the disinfecting composition, and typically
from
2% and 5% by weight of the disinfecting composition.
The disinfecting composition may be formulated as solution, cream or
5 gel, and may include one or more optional components such as a textural
modifier, a
surfactant, an odorant, a colorant, and mixtures thereof.
In another embodiment of this invention, a two-part freeze-resistant
disinfecting system is disclosed comprising a first part and a second part
adapted to be
mixed to yield an aqueous disinfecting composition. The first part, prior to
mixing,
comprises a metal chlorite and a chlorite-stable antifreeze. The second part,
prior to
mixing, comprises (a) an organic acid germicide and a non-esterifying
antifreeze, or (b)
an inorganic acid and either an alcohol or a non-esterifying antifreeze. The
chlorite-
stable and non-esterifying antifreezes contain from 4 to 16 carbon atoms and
have no
primary carbon atom bearing a hydroxyl group.
1 S The metal chlorite of the first part is an alkali or alkaline earth
chlorite,
such as sodium chlorite or potassium chlorite, and is typically sodium
chlorite. The
metal chlorite is present in the first part at a concentration such that, when
combined
with the second part, it is present within the disinfecting composition at a
concentration
ranging from about 0.005% to about 1 % by weight, generally from 0.05% to 0.5%
by
weight, and typically from 0.1 % to 0.4% by weight.
The chlorite-stable antifreeze is as disclosed above with regard to the
non-esterifying antifreeze of the freeze-resistant aqueous disinfecting
composition. The
chlorite-stable antifreeze is present within the first part at a concentration
ranging from
about 10% to about 75% by weight, and typically from 15% to 50% by weight of
the
first part.
In one aspect of the two-part system, the second part comprises an
organic acid and a non-esterifying antifreeze. The organic acid and the non-
esterifying
antifreeze of the second part is as disclosed above with regard to the organic
acid and
the non-esterifying acid of the freeze-resistant aqueous disinfecting
composition. In

CA 02342844 2001-03-02
WO 00/13506 PCT/LTS99/19987
6
other words, the one-part disinfecting composition may be employed as the
second part
of the two-part system.
In another aspect of the two-part system, the second part comprises an
inorganic acid and either an alcohol or a non-esterifying antifreeze.
Representative
inorganic acids include phosphoric acid, monosodium acid phosphate, sulfuric
acid,
hydrochloric acid, or sodium bisulfate. The inorganic acid is present in the
second part
at a concentration such that, when combined with the first part and before
reacting
therewith, it is present within the disinfecting composition at an initial
concentration
ranging from 0.001 % to 2% by weight, and typically from 0.01 % to 1.0% by
weight.
Representative alcohols include polyols, such as glycerine, sorbitol and
propylene glycol, while the non-esterifying antifreeze is as disclosed above
with regard
to the non-esterifying antifreeze of the freeze-resistant aqueous disinfecting
composition. The alcohol or the non-esterifying antifreeze is present within
the second
part at a concentration ranging from about 10% to about 75% by weight, and
typically
from 1 S% to 50% by weight of the second part.
The first and second parts of the two-part freeze resistant system of this
invention may be independently formulated as solutions, creams or gels, and
may
further include one or more optional components such as a textural modifier, a
surfactant, an odorant, a colorant, and mixtures thereof.
In yet a further embodiment, methods are disclosed for disinfecting a
substrate by contacting the substrate with an effective amount of the one-part
freeze-
resistant aqueous disinfecting composition of this inventipn, or the
disinfectant
composition resulting from the combination of the first and second parts of
the two-part
freeze-resistant disinfecting system of this invention. Suitable substrates in
this regard
include skin and, more specifically, the teat of a dairy cow.
These and other aspects of the present invention will be evident upon
reference to the following detailed description.

CA 02342844 2001-03-02
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7
DETAILED DESCRIPTION OF THE INVENTION
Freeze resistance has traditionally been imparted to aqueous systems,
such as radiator coolants, by incorporation therein of such water-soluble
alcohols as
methanol (a mono-hydroxy compound) or glycols (which contain two alcoholic
functions) such as ethylene glycol. Molecules which contain a greater number
of
hydroxyl groups (referred to as "polyols"), such as glycerin and sugars, are
also known
to depress aqueous freezing points. In all cases, the greater the
concentration of
alcoholic solute, the lower the freezing point, with the degree of depression
depending
on the solute. For example, to attain a freezing point of 0°F requires
an aqueous
concentration of methanol of about 28% by weight, about 43% by weight for
glycerin
and about 34% by weight for ethylene glycol.
In order to create a freeze-resistant teat dip formulation, particularly one
which incorporates organic acids as either active ingredients or buffers, the
above
alcohols are not suitable. This is due to esterification of the hydroxyl
moiety by
reaction with the carboxylic acid of the organic acid. For example, the use of
a material
such a.~ propylene glycol to reduce the freezing temperature of a teat dip, in
which
organic acids are either the germicide or the source of buffering, is
counterindicated by
the tendency for the acid to esterify and lose germicidal functionality.
Furthermore, in
such compositions the lower levels of acid which result give rise to higher pH
formulations, so that the remaining acid will tend to exist to a greater
degree in the non-
functioning anionic form.
It has been found that esterification of secondary hydroxyl groups, such
as the hydroxyl at the 2-position of propylene glycol, is less favored due to
both
electronic and steric factors. However, esterification of primary alcohols,
such as the
hydroxyl at the 1-position of propylene-glycol, proceeds at an unacceptably
fast rate.
Thus, in the practice of this invention, a non-esterifying antifreeze is
employed in
combination with one or more organic acids. Such non-esterifying antifreeze
agents
generally contain from 4 to 16 carbon atoms, and contain one or more ether,
secondary
alcohol and/or ester moieties. Such non-esterifying antifreezes do not,
however, contain
any primary carbon bearing a hydoxyl group.

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8
Accordingly, in one embodiment of this invention, a freeze-resistant
aqueous disinfecting composition is disclosed containing an organic acid
germicide and
an non-esterifying antifreeze, wherein the non-esterifying antifreeze contains
from 4 to
16 carbon atoms and has no primary carbon atom bearing a hydroxyl group.
Suitable
non-esterifying antifreezes may be generally characterized as an ether having
at least
one ether linkage between two carbon atoms, an ether-alcohol having at least
one ether
linkage between two carbon atoms and with at least one secondary carbon atom
bearing
a hydroxyl group, ar an ester having at least one ester linkage between two
carbon
atoms.
Representative non-esterifying antifreezes have the structure R'-O-CHZ-
CH(ORZ)-R3, wherein R' is C,_$alkyl, and RZ and R3 are the same or different
and
independently selected from hydrogen or C,_8alkyl, and each secondary carbon
atom of
the C,_~alkyl moiety is optionally substituted with a hydroxyl group. Suitable
compounds are those wherein R' is C,_8alkyl moiety, RZ is hydrogen and R3 is
C,_galkyl
moiety; wherein R' is C,_8alkyl moiety, RZ is hydrogen and R3 is methyl; and
wherein
R', RZ and R3 are C,_8alkyl. In another embodiment, representative non-
esterifying
antifreezes have the structure R~-CH(OR5)-CHZ-O-CHZ-CH(ORZ)-R3, wherein R-',
R3, R'
and RS are the same or different and independently selected from hydrogen and
C,_
8alkyl, and each secondary carbon atom of the C,_8alkyl moiety is optionally
substituted
with a hydroxyl group. Suitable compounds are those wherein R' is C,_galkyl
and RS is
hydrogen; and wherein R4 is C,_8alkyl and RS is C,_8alkyl. Non-esterifying
antifreezes
also include compounds of the above structures wherein at least one oxygen
atom is
bound to -CO(C,_8alkyl) to form an ester.
More specific representative non-esterifying antifreezes of this invention
include (but are not limited to) propylene glycol monomethyl ether (CH3-
OCHZCH(OH)CH3) propylene glycol monoethyl ether (CH3CH,-OCHZCH(OH)CH3),
propylene glycol monopropyl ether (CH,CHzCHz-OCHZCH(OH)CH3), propylene glycol
monoisopropyl ether (CH3CH(CH3)-OCHzCH(OH)CH3), dipropylene glycol
(CH3CH(OH)CHZOCHZCH(OH)CH3), dipropylene glycol methyl ether
(CH3CH(OCH3)CHZOCHZCH(OH)CH3), dipropylene glycol ethyl ether

CA 02342844 2001-03-02
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9
(CH3CH(OCH,CH3)CHZOCHZCH(OH)CH3), and dipropylene glycol acetate
(CH,CH(OCOCH,)CHZOCHzCH(OH)CH3).
Preferred non-esterifying antifreezes are those that are soluble in water at
ambient winter temperatures to at least 1 part by weight of compound per 4
parts of
water. Their concentration should be from about 10% to about 75% by weight,
and
typically from 15% to 50% by weight of the disinfecting composition. The
freezing
point of the disinfecting composition should be at or below 14°F (-
10°C), generally
below about 7°F (-14°C), and typically below about 0°F (-
18°C).
The organic acid germicide may be an alpha-hydroxy carboxylic acid
having a pKa between about 2.8 and about 4.2, such as glycolic acid, lactic
acid, malic
acid, mandelic acid, citric acid, tartaric acid, and mixtures thereof. Other
organic acid
germicides include formic acid, acetic acid, propionic acid, benzoic acid,
caprylic acid,
capric acid, hydroxybenzoic acid, and mixtures thereof. The organic acid
germicide is
present at a concentration between about 0.25% and about 7.5% by weight of the
disinfecting composition, and typically from 2% and 5% by weight of the
disinfecting
composition.
The pH of the mixed disinfecting composition should lie in the range of
about 2 to about 5, and typically from about 2.4 to about 4.5. When organic
acids, such
as citric, are employed primarily as buffering agents, rather than for
germicidal activity,
such as for pH adjustment or iodophor formulations, their level of use is
generally in the
range of about 0.1% to about 1.0%, where the amount utilized depends to a
significant
degree on the chemical characteristics of the specific formulation.
In another embodiment of this invention, a two-part freeze-resistant
disinfecting system is disclosed comprising a first part and a second part
adapted to be
mixed to yield an aqueous disinfecting composition. The first part, prior to
mixing,
comprises a metal chlorite and a chlorite-stable antifreeze. The second part,
prior to
mixing, comprises (a) an organic acid germicide and a non-esterifying
antifreeze, or (b)
an inorganic acid and either an alcohol or a non-esterifying antifreeze. The
chlorite-
stable and non-esterifying antifreezes contain from 4 to 16 carbon atoms and
have no
primary carbon atom bearing a hydroxyl group.

CA 02342844 2001-03-02
WO 00/13506 PCTIUS99/19987
In the two-part system, the metal chlorite of the first part is an alkali or
alkaline earth chlorite, such as sodium chlorite or potassium chlorite, and is
typically
sodium chlorite. The metal chlorite is present in the first part at a
concentration such
that, when combined with the second part, it is present within the
disinfecting
5 composition at a concentration ranging from about 0.005% to about 1 % by
weight,
generally from 0.05% to 0.5% by weight, and typically from 0.1% to 0.4% by
weight of
the disinfecting composition.
The chlorite-stable and non-esterifying antifreezes of the f rst and second
parts, respectively, may be the same or different. Such antifreezes contain
from 4 to 16
10 carbon atoms and have no primary carbon atom bearing a hydroxyl group. In
the case
of the chlorite-stable antifreeze, a primary alcohol will oxidize upon contact
with
chlorite, and is thus to be avoided. The chlorite-stable and non-esterifying
antifreezes
may be an ether having at least one ether linkage between two carbon atoms, an
ether-
alcohol having at least one ether linkage between two carbon atoms and with at
least
one secondary carbon atom bearing a hydroxyl group, or an ester having at
least one
ester linkage between two carbon atoms.
Representative chlorite-stable and non-esterifying antifreezes have the
structure R'-O-CHZ-CH(ORZ)-R3, wherein R' is C,_8alkyl, and RZ and R3 are the
same or
different and independently selected from hydrogen or C,_galkyl, and each
secondary
carbon atom of the C,_8alkyl moiety is optionally substituted with a hydroxyl
group.
Suitable compounds are those wherein R' is C,_8alkyl moiety, RZ is hydrogen
and R' is
C,_8alkyl moiety; wherein R' is C,_8alkyl moiety, Rz is hydrogen and R3 is
methyl; and
wherein R', RZ and R3 are C,_8alkyl. In another embodiment, representative
chlorite-
stable and non-esterifying antifreezes have the structure R4-CH(ORS)-CHZ-O-CHZ-
CH(ORZ)-R3, wherein R2, R', R4 and RS are the same or different and
independently
selected from hydrogen and C,.galkyl, and each secondary carbon atom of the
C,_8alkyl
moiety is optionally substituted with a hydroxyl group. Suitable compounds are
those
wherein R' is C~_8alkyl and RS is hydrogen; and wherein R' is C,_8alkyl and RS
is
C,_8alkyl. Chlorite-stable and non-esterifying antifreezes also include
compounds of the

CA 02342844 2001-03-02
WO 00/13506 PCTNS99/19987
11
above structures wherein at least one oxygen atom is bound to -CO(C,_galkyl)
to form an
ester.
More specific representative chlorite-stable and non-esterifying
antifreezes of this invention include (but are not limited to) propylene
glycol
monomethyl ether (CH3-OCHZCH(OH)CH3) propylene glycol monoethyl ether
(CH3CHz-OCH,CH(OH)CH3), propylene glycol monopropyl ether (CH3CHzCH2-
OCHZCH(OH)CH3), propylene glycol monoisopropyl ether (CH3CH(CH3)-
OCHZCH(OH)CH3), dipropylene glycol (CH,CH(OH)CH~OCHzCH(OH)CH3),
dipropylene glycol methyl ether (CH3CH(OCH3)CHZOCHzCH(OH)CH3), dipropylene
glycol ethyl ether (CH3CH(OCHzCH3)CHZOCHZCH(OH)CH3), and dipropylene glycol
acetate (CH3CH(OCOCH3)CHZOCHZCH(OH)CH3).
Preferred chlorite-stable and non-esterifying antifreezes are those that are
soluble in water at ambient winter temperatures to at least 1 part by weight
of
compound per 4 parts of water. Their concentration should be from about 10% to
about
75% by weight, and typically from 15% to 50% by weight of the disinfecting
composition. The freezing point of the disinfecting composition should be at
or below
14°F (-10°C), generally below about 7°F (-14°C),
and typically below about 0°F (-
18°C).
In one embodiment of the two-part system of this invention, the second
part comprises an organic acid and a non-esterifying antifreeze. In this
aspect, the
second part may be the freeze-resistant aqueous disinfecting composition as
disclosed
above, containing an organic acid and a non-esterifying antifreeze. Thus, the
organic
acid germicide may be an alpha-hydroxy carboxylic acid having a pKa between
about
2.8 and about 4.2, such as glycolic acid, lactic acid, malic acid, mandelic
acid, citric
acid, tartaric acid, and mixtures thereof. Other organic acid germicides
include formic
acid, acetic acid, propionic acid, benzoic acid, caprylic acid, capric acid,
hydroxybenzoic acid, and mixtures thereof. The organic acid germicide is
present in the
second part such that, following mixture with the first part, it has a
concentration
between about 0.25% and about 7.5% by weight of the disinfecting composition,
and
typically from 2% and 5% by weight of the disinfecting composition. The non-

CA 02342844 2001-03-02
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12
esterifying antifreeze of the second part in this embodiment is as disclosed
above, and is
present at a concentration such that, following mixture with the first part,
it is present at
a concentration from about 10% to about 75% by weight, and typically from 15%
to
50% of the disinfecting composition.
In another embodiment of the two-part system, the second part
comprises an inorganic acid in combination with either an alcohol or a non-
esterifying
antifreeze. The non-esterifying antifreeze of this embodiment is as disclosed
above,
while representative alcohols include polyols, such as glycerine, sorbitol and
propylene
glycol. Representative inorganic acids include phosphoric acid, monosodium
acid
phosphate, sulfuric acid, hydrochloric acid, sodium bisulfate, and mixtures
thereof. The
inorganic acid is present in the second part at a concentration such that,
when combined
with the first part and before reacting therewith, it is present within the
disinfecting
composition at an initial concentration ranging from 0.001 % to 2% by weight,
and
typically from 0.01 % to 1.0% by weight. The alcohol or non-esterifying
antifreeze is
present within the second part at a concentration such that, when combined
with the
first part, it is present in the disinfecting composition at a concentration
from about 10%
to about 75% by weight of the disinfecting composition, and typically from 15%
to 50%
by weight of the disinfecting composition.
Various optional ingredients may be included in the one-part freeze
resistant aqueous disinfecting composition, as well as the first part, second
part, or both
first and second parts of the two-part system. Such ingredients include (but
are not
limited to) wetting agents, textural modifiers, film-forming polymers,
colorants and
mixtures thereof. The wetting agents facilitate contact of the disinfecting
composition
with the skin, and can be selected from those materials recognized to provide
this effect,
in both identity and amount. Textural modifiers are those materials which
primarily
affect the body of the mixed disinfecting composition in terms of retention,
flow and
lubricity. These include thickening agents such as alkyl celluloses, alkoxy
celluloses,
xanthan gum, guar gum, and poiyacrylamide derivatives, of which the polymer of
2-
acrylamido-2-methylpropane sulfonic acid is a preferred example. Other
textural
modifiers include lanolin derivatives, acyl lactylates, polyethylene glycol,
glyceryl

CA 02342844 2001-03-02
WO 00/13506 PCT/US99/19987
13
esters, and mixtures thereof. Film-forming polymers include the above-
referenced
polyacrylamides, as well as the class of polyvinyl alcohols/vinyl acetates)
and
polyvinyl pyrollidone. Colorants are generally selected from the group found
acceptable for use in skin-contacting formulations, and are known to those
skilled in the
art.
In a further embodiment, a method for disinfecting a substrate is
disclosed, wherein the method comprises contacting the substrate with an
effective
amount of the one-part freeze-resistant disinfecting composition of this
invention, or
contacting the substrate with an effective amount of the disinfecting
composition
formed by mixing the two-part disinfecting system of this invention. Suitable
substrates include the skin or tissue of a warm-blooded animal and, in a
preferred
embodiment, the teat of a dairy cow.
In a further aspect of this invention, this invention is directed to a
method for making a disinfecting composition comprising mixing the first part
and the
second part of the two-part disinfecting system, as well as mixing the
respective
compounds to form the first and second parts of the two-part system, and to
form the
one-part disinfectant composition. In one embodiment of the two-part system,
both the
first and second parts are aqueous solutions, creams or gels. In another
embodiment, at
least one of the first or second parts is in a concentrated form, and the
concentrated form
(either solid or liquid) is mixed with the other part and then diluted with
water, or
diluted with water and then mixed with the other part.
The following examples are by way of illustration only, and nothing
therein should be taken as a limitation upon the overall scope of the
invention.
EXAMPLE 1
This Example illustrates the preparation of a freeze-resistant germicidal
formulation that remains free-flowing to below about 10°F (-
12°C). It suppresses the
chapping and cracking of skin to which it is applied, which might otherwise
occur in
sub-freezing temperatures.

CA 02342844 2001-03-02
WO 00/13506 PC'T/US99/19987
14
Stir O.SO gms of Natrosol 2SOMBR thickener into 2S gms of propylene
glycol monomethyl ether, and then add O.S gms of Triton X-100 and 0.25 gms of
Pluronic L-31 surfactants. Thereafter, dissolve the following three acid
germicides into
the mixture: 2 gms of mandelic acid, 0.2 gms of benzoic acid and 2 gms of
propionic
S acid. Finally, dissolve 0.1 gms of citral odorant into the glycol ether mix.
While
stirring, add O.OS mgs of FD&C Yellow #S and O.OOOOS gms of FD&C Yellow #33,
followed by a quantity of water necessary to bring the weight of the mixture
to 100
gms. Continue stirring until the thickener is fully dissolved. The viscosity
of this
formula is about S7S centipoise, when measured with a Brookfield RVF
viscometer,
using Spindle #3 at 20 rpm.
The gold-colored formulation, which has a citrus odor, can kill
approximately 104 logarithms of the microbial pathogen Staphylococcus aureus
deposited onto a simulated cow teat after 1 minute of contact. The residual
germicide
on the teat surface can also destroy at least 102 logarithms of the
environmental
1 S pathogen Streptococcus uberis 12 hours after deposition onto the teat
following a
30 minute contact.
EXAMPLE 2
The above Example 1 is repeated, using 3S gms of propylene glycol
monomethyl ether, 0.1 gms of methyl salicylate in place of the citral, and
0.00065 gms
of methylene blue in place of the yellow and red colorants. The blue
formulation thus
prepared has a wintergreen odor, remains liquid to below about 0°F (-
18°C), and has a
viscosity of 30S cps.
2S EXAMPLE 3
This example illustrates the use of the present invention in a two part
chlorous acid-forming germicidal barrier teat dip, in which both parts, as
well as the
mixed formulation, remain fluid to a temperature below 0°F.
A first thickened liquid is prepared by mixing the following ingredients:
Coamedia brand poly (sulfonic acid), 16% solid 16.00%

CA 02342844 2001-03-02
WO 00/13506 PCT/US99/19987
1S
Sodium hydroxide, 1N 16.00%
Sodium dodecylbenzene sulfonate 1.80%
Sodium chlorite O.SO%
Dipropylene glycol 32.00%
S Hi-Sil T-600 (Silica) 2.50%
Water q.s.
A second thickened liquid is prepared by mixing the following
ingredients:
Malic acid 4.2%
Natrosol 2S0 MBR 1.00%
Dipropylene glycol monomethyl ether 35.00%
Sodium benzoate 0.04%
Poloxamer 188 0.40%
FD&C Yellow #S 0.20%
1S Water q,s,
The two thickened liquids are blended, preferably within two hours
before application. The resulting liquid remains fluid on the cow's teats
throughout the
intermilking period, preventing chapping and cracking, while providing
continuous
antimicrobial activity to suppress mastitis formation.
EXAMPLE 4
This example illustrates the use of the present invention in a freeze-
resistant topical germicide which contains a film-forming agent and which
remains fluid
to below 0°F.
2S Disperse 2 gms of polyvinyl alcohol), PVA-2408 into 6S gms of
dipropylene glycol monomethyl ether, followed by the addition of 1 gms each of
the
germicidal agents caprylic acid, malic acid and glyceryl monolaurate. After
the latter
are dissolved, add 0.075 gms of methyl salicylate, stir and add 0.0001 gms of
FD&C
Blue #1 and O.OS gms of FD&C Yellow #S followed by sufficient water to take
the

CA 02342844 2001-03-02
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16
weight of the mixture to 100 gms. Continue stirring until the PVA is fully
dissolved
and the mixture becomes uniform.
From the foregoing it will be appreciated that, although specific
embodiments of the invention have been described herein for purposes of
illustration,
various modifications may be made without deviating from the spirit and scope
of the
invention. Accordingly, the invention is not limited except as by the appended
claims.

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Administrative Status

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Event History

Description Date
Application Not Reinstated by Deadline 2003-09-02
Time Limit for Reversal Expired 2003-09-02
Deemed Abandoned - Failure to Respond to Maintenance Fee Notice 2002-09-03
Inactive: Cover page published 2001-05-28
Inactive: First IPC assigned 2001-05-18
Letter Sent 2001-05-08
Inactive: Notice - National entry - No RFE 2001-05-08
Application Received - PCT 2001-05-04
Application Published (Open to Public Inspection) 2000-03-16

Abandonment History

Abandonment Date Reason Reinstatement Date
2002-09-03

Maintenance Fee

The last payment was received on 2001-08-30

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  • the late payment fee; or
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Please refer to the CIPO Patent Fees web page to see all current fee amounts.

Fee History

Fee Type Anniversary Year Due Date Paid Date
Registration of a document 2001-03-02
Basic national fee - standard 2001-03-02
MF (application, 2nd anniv.) - standard 02 2001-08-31 2001-08-30
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
ALCIDE CORPORATION
Past Owners on Record
ROBERT D. KROSS
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Description 2001-03-01 16 795
Abstract 2001-03-01 1 49
Claims 2001-03-01 10 355
Reminder of maintenance fee due 2001-05-07 1 111
Notice of National Entry 2001-05-07 1 193
Courtesy - Certificate of registration (related document(s)) 2001-05-07 1 113
Courtesy - Abandonment Letter (Maintenance Fee) 2002-09-30 1 182
PCT 2001-03-01 14 501