CERTIFICATE OF ELECTRONIC TRANSMISSION
`
`I hereby certify that this correspondence, including listed enclosures is
`being electronically transmitted in Portable Document Form (PDF) through
`EFS-Web via Hyper Text Transfer Protocol to the United States Patent and
`Trademark Office's Patent Electronic Business Center on:
`Dated:
`i
`Signed:
`
`‘kw
`
`0'
`
`Attorney DOcket N0’:
`
`1 4-Us
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`Confirmation No.: 4964
`
`Stephen J. BAKER, et al.
`
`Examiner: SHIAO, Rei Tsang
`
`Application No.: 11/357,687
`
`Art Unit: 1626
`
`_
`
`Filed: February 16, 2006
`
`RESPONSE TO FIRST OFFICE ACTION
`
`For: BORON-CONTAINING SMALL
`MOLECULES
`
`Customer No.: 43850
`
`
`
`Commissioner for Patents
`
`P.O. Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`In response to the First Office Action dated August 26, 2008, please enter the
`
`following amendments and remarks.
`
`Amendments to the Claims are reflected in the listing of claims which begins on page 2 of this
`paper.
`
`Remarks/Arguments begin on page 4 of this paper.
`
`Page 1 of 7
`
`CFAD Exhibit 1013
`1
`
`CFAD Exhibit 1013
`
`1
`
`

`
`Appl. No. 11/357,687
`Amendment dated January 23, 2009
`Response to Office Action dated August 26, 2008
`
`PATENT
`
`Amendments to the Claims:
`
`This listing of claims will replace all prior versions, and listings of claims in the application.
`
`Listing of Claims:
`
`1.- 26.
`
`(Cancelled).
`
`1
`
`2
`
`3
`
`4
`
`1
`
`2
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`27.
`
`(Currently arpended) A method of treating or preventing an infection in
`
`an animal, said method comprising administering to the animal a therapeutically effective
`
`amount of l,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable
`
`salt thereof or a prodrug thereof., sufficient to treat said infection.
`
`28.
`
`(Original) The method of claim 27, wherein said infection is a member
`
`selected from a systemic infection, a cutaneous infection, and an ungual or periungual infection.
`
`29.
`
`(Original) The method of claim 27, wherein said infection is a member
`
`selected from chloronychia, paronychias, erysipeloid, onychorrhexis, gonorrhea, swimming-pool
`
`granuloma, larva migrans, leprosy, Orf nodule, milkers' nodules, herpetic whitlow, acute
`
`bacterial perionyxis, chronic perionyxis, sporotrichosis, syphilis, tuberculosis verrucosa cutis,
`
`tularemia, tungiasis, peri- and subungual warts, zona, nail dystrophy (trachyonychia),
`
`dermatological diseases, psoriasis, pustular psoriasis, alopecia aerata, parakeratosis pustulosa,
`
`contact dermatosis, Reiter's syndrome, psoriasiform acral dermatitis, lichen planus, idiopathy
`
`atrophy in the nails, lichin nitidus, lichen striatus, inflammatory linear verrucous epidermal
`
`naevus (IL VEN), alopecia, pemphigus, bullous pemphigoid, acquired epidermolysis bullosa,
`
`10 Darier's disease, pityriasis rubra pilaris, palmoplantar keratoderma, contact eczema, polymorphic
`
`11
`
`12
`
`13
`
`14
`
`erythema, scabies, Bazex syndrome, systemic scleroderma, systemic lupus erythematosus,
`
`chronic lupus erythematosus, dermatomyositus, Sporotrichosis, Mycotic keratitis, Extension
`
`oculomycosis, Endogenous oculomycosis, Lobomycosis, Mycetoma, Piedra, Pityriasis
`
`versicolor, Tinea corporis, Tinea cruris, Tinea pedis, Tinea barbae, Tinea capitis, Tinea nigra,
`
`15 Otomycosis, Tinea favosa, Chromomycosis, and Tinea Imbricata.
`
`Page 2 of7
`
`2
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`

`
`Appl. No. 11/357,687
`Amendment dated January 23, 2009
`Response to Office Action dated August 26, 2008
`
`PATENT
`
`30.
`
`(Original) The method of claim 27, wherein said infection is
`
`onychomycosis.
`
`31.
`
`(Original) The method of claim 27, wherein said animal is a member
`
`selected from a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit,
`
`cat, chicken and turkey.
`
`32. -39.
`
`(Cancelled).
`
`40.
`
`(Currently amended) The method of claim 30, wherein said
`
`onychomycosis is Tine€l unguium tinea unguium.
`
`41.
`
`(Cancelled).
`
`42.
`
`(Previously presented) The method of claim 27, wherein said animal is a
`
`human.
`
`43.
`
`(New) The method of claim 27, wherein the administering is at a site
`
`1
`
`2
`
`2
`
`3
`
`1
`
`1
`
`2
`
`1
`
`2
`
`1
`
`2 which is a member selected from the skin, nail, hair, hoof and claw.
`
`1
`
`2
`
`1
`
`2
`
`1
`
`2
`
`3
`
`4
`
`1
`
`44.
`
`(New) The method of claim 43, wherein said skin is the skin surrounding
`
`the nail, hair, hoof or claw.
`
`45.
`
`(New) The method of claim 27, wherein said infection is a fungal
`
`infection.
`
`46.
`
`(New) A method of treating onychomycosis in a human, said method
`
`comprising administering to the human a therapeutically effective amount of 1,3-dihydro-5-
`
`fluoro-l-hydroxy-2, 1-benzoxaborole, or a pharmaceutically acceptable salt thereof, sufficient to
`
`treat said onychomycosis.
`
`47.
`
`(New) A method of inhibiting the growth of a fungus in a human, said
`
`2 method comprising administering to the human a therapeutically effective amount of 1,3-
`
`3
`
`dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a pharmaceutically acceptable salt thereof.
`
`Page 3 of7
`
`3
`
`

`
`Appl. No. 11/357,687
`Amendment dated January 23, 2009
`Response to Office Action dated August 26, 2008
`
`PATENT
`
`REMARKS/ARGUMENTS
`
`I. Status ofthe Claims
`
`After entry of this Response, claims 27-31, 40 and 42-47 are pending. Claims 1-
`
`26, 32-39 and 41 are cancelled without prejudice. Claims 43-47 are new. Claims 27-31 and 40
`
`and 42-47 are currently presented. Claim 27 is amended. No new matter has been added.
`
`II. Support for the amended claims and new claims
`
`Claim 27 is amended to add the phrase "sufficient to treat said infection".
`
`Support for this amendment is provided in paragraph 108.
`
`Support for new claim 43 is provided in paragraphs 108 and 109.
`
`Support for new claim 44 is provided in paragraph 109.
`
`Support for new claim 45 is provided in paragraphs 102, 103 and 108-116 and
`
`Fig. 2.
`
`Support for new claim 46 is provided in paragraphs 108, 109 and 258.
`
`Support for new claim 47 is provided in paragraphs 102, 103, 317, 320-323, 324-
`
`334, 335-371, 372-381.
`
`No new matter has been added.
`
`III. Response to the rejections
`35 US. C. § 112, first paragraph. enablement (5.1)
`
`Claims 27-31 and 40-42 are rejected for lacking enablement because the
`
`specification, while being enabling for using the compounds of claim 27 for treating fungal
`
`infections, allegedly does not reasonably provide enablement for using the compounds of claim
`
`27 for preventing infection.
`
`Solely to expedite prosecution, Applicants have amended claim 27 to remove the
`
`phrase 'or preventing'. Applicants reserve the right to pursue this subject matter in another
`
`application, such as a continuation or a divisional.
`
`In light of this amendment, Applicants respectfully request withdrawal of the
`
`rejection.
`
`Page 4 of7
`
`4
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`

`
`Appl. No. 11/357,687
`Amendment dated January 23, 2009
`Response to Office Action dated August 26, 2008
`
`35 USC § 112. first paragraph, enablement (5.2)
`
`PATENT
`
`Claims 27-31and40-42 are rejected for lacking enablement because the
`
`specification, while being enabling for pharmaceutically acceptable salts of the compounds of
`
`claim 27, allegedly does not reasonably provide enablement for prodrugs of the compounds of
`
`claim 27.
`
`Solely to expedite prosecution, Applicants have amended claim 27 to remove the
`
`term 'or a prodrug thereof. Applicants reserve the right to pursue this subject matter in another
`
`application, such as a continuation or a divisional.
`
`In light of this amendment, Applicants respectfully request withdrawal of the
`
`rejection.
`
`35 USC § 103(a)
`
`Over Austin in view of Answers. com
`
`Claims 27-31and40-42 are rejected under 35 U.S.C. § 103(a) as allegedly being
`
`unpatentable over Austin et al., CAPlus Document No. 124:234024 (Accession No.
`
`1996: 181598) or US Patent 5,880, 188 ("Austin") in view of "Fungicide," Answers.com.
`
`Reference to "Answers.com" herein refers to Exhibit A, showing the record accessed December
`
`17, 2008, for "fungicide" on Answers.com.
`
`Austin in view of Answers.com does not teach or suggest the invention as
`
`claimed. Austin states that "The present invention relates to the use of oxaboroles and salts
`
`thereof as industrial biocides ... " Col. 1, lines 6-8. A previous citation in the literature (FR
`
`7329370) "discloses that an oxaborole is ... useful in inhibiting the growth of micro organisms
`
`in aviation fuels." Col. 1, lines 39-45. Austin suggests that the disclosed compounds
`
`"containing an oxaborole ring are particularly effective against ... fungi, especially fungi which
`
`cause degradation of plastics materials." Col. 1, lines 46-50.
`
`Austin contemplates using oxaboroles for "the protection of a medium susceptible
`
`to microbial attack." Col. 1, lines 54 & 55. Examples of a "medium" according to Austin
`
`include "solvent-based paint", col. 5, line 8; "a plastics material", col. 5, line 11; "an aqueous
`
`medium" col. 5, line 15. Austin suggests use of oxaboroles in systems such as
`
`liquid, particularly aqueous, systems such as cooling water liquors,
`paper mill liquors, metal working fluids, geological drilling
`
`Page 5of7
`
`5
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`

`
`Appl. No. 11/357,687
`Amendment dated January 23, 2009
`Response to Office Action dated August 26, 2008
`
`PATENT
`
`lubricants, polymer emulsions and especially surface coating
`compositions such as paints, varnishes and lacquers and more
`especially solid materials such as wood, plastics materials[,]
`leather[, and] plastics materials such as plasticised PVC and
`urethanes [.]
`
`Col. 8, lines 1-10. Further, 5-fluoro substituted benzoxaboroles are taught to provide
`
`"particularly useful effects ... in plastics materials and paint films." Col. 4, lines 50-54. Austin
`
`therefore is specifically directed to industrial uses ofbenzoxaboroles.
`
`In contrast, claim 27 recites a method of treating an infection in an animal
`
`comprising administering to an animal a specific compound recited in the claim. Applicants
`
`submit that one of skill in the art would not presumptively consider a compound to be suitable
`
`for administration to an animal, especially a human, merely because a compound has been shown
`
`to have antifungal effects in paint or aviation fuel. In fact, Answers.com, cited by the Examiner,
`
`teaches away from presuming that any antifungal compound can be administered to an animal.
`
`For example, Answers.com, page 3, states that
`
`Most fungicides can cause acute toxicity, and some cause chronic
`toxicity as well. Hexachlorobenzene, now banned or severely
`restricted in most parts of the world, has been associated with
`human poisoning from contaminated seed grain and poisoning of
`infants from misuse in laundry solutions. Metam sodium and other
`thiocarbanates are skin irritants that can cause reactive airway
`disease at low doses and severe toxicity and even death at high
`doses. The ethylene bis dithiocarbamates (EBCDs) are suspected
`human carcinogens and are tightly regulated in the United States.
`
`Answers.com, page 4 teaches that "some fungicides are dangerous to human health, such as
`
`vinclozolin, which has now been removed from use [citation to Hrelia et al., The genetic and
`
`non-genetic toxicity of the fungicide Vinclozolin. Mutagenesis 1996, 11, 445-453]." Certain
`
`fungicides, such as captafol, pentachlorophenol, pentachlorophenate sodium, fentin,
`
`cycloheximide, chlorobenzilate, and copper arsenate hydroxide, are banned in Thailand because
`
`of their adverse effects on humans. See http://thailand.ipm-
`
`info.org/pesticides/pesticides _ banned.htm. Thus, the art teaches that compounds that are useful
`
`for killing or inhibiting fungi may also harm animals. Austin, cited by the Examiner, teaches the
`
`use of oxaboroles in treating plastics and materials and in other industrial settings, and there is no
`
`Page 6 of7
`
`6
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`

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`Appl. No. 11/357,687
`Amendment dated January 23, 2009
`Response to Office Action dated August 26, 2008
`
`PATENT
`
`reason why, in view of Answers.com, one of skill in the art would extrapolate such use for
`
`treating animals given the potential harm that may occur.
`
`Answers.com thus does not provide a motivation to modify the teachings of
`
`Austin to use any particular oxaborole to treat an animal, and in fact teaches away from such
`
`modification. The Examiner has not established a prima facie case of obviousness. Withdrawal
`
`of the rejection is therefore respectfully requested.
`
`Double Patenting
`
`The Examiner has provisionally rejected claims 27-31and40-42 as allegedly
`
`being unpatentable over claims 53, 54 and 58 of Application No. 11/505,591 on the ground of
`
`nonstatutory obviousness-type double patenting. Claims 53, 54 and 58 have been canceled in
`
`Application No. 11/505,591, as shown in the accompanying restriction requirement response
`
`filed on December 3, 2008 (Exhibit B). As the claims at issue from Application No. 11/505,591
`
`are no longer pending, Applicants respectfully request withdrawal of the rejection.
`
`CONCLUSION
`
`In view of the foregoing, Applicants believe all claims now pending in this
`
`Application are in condition for allowance. The issuance of a formal Notice of Allowance at an
`
`early date is respectfully requested.
`
`If the Examiner believes a telephone conference would expedite prosecution of
`
`this application, please telephone the undersigned at 415-442-1000.
`
`Respectfully submitted,
`
`Todd Esker
`Reg. No. 46,690
`
`MORGAN, LEWIS & BOCKIUS LLP
`One Market, Spear Street Tower
`San Francisco, CA 94105
`Tel: 415-442-1000
`Fax:415-442-1001
`DB2/2098 l l 66.l
`
`Page 7of7
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`7
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`[Kf! //5f( /
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`8
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`

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`fungicide: Definition from Answers.com
`
`Page 1of7
`
`Answers.com®
`
`fungicide
`
`Dictionary:
`
`fungicide
`
`(fun'j1-sid', fung'gT-) ~~
`n.
`
`A chemical substance that destroys or inhibits the growth of fungi.
`
`fungicidal fun'gi·cid'al (-sid'I) adj.
`fungicidally fun'gi •cid'al • ly. adv.
`
`Encyclopedia of Public Health: Fungicides
`
`Fungicides are a class of pesticides that are marketed specifically for the purpose of killing or
`inhibiting the growth of fungus. Fungus are defined under the Federal Insecticide, Fungicide, and
`Rodenticide Act as "any non-chlorophyllbearing thallophyte (that is, any non-chlorophyllbearing
`plant of a lower order than mosses and
`
`Table 1
`
`Classes of Fungicides, with Examples
`Examples
`Class of Fungicide
`Chloroneb, chlorothalanil, Hexachlorobenzene,
`pentachloronitrobenzene
`Ferbam, metam sodium, thiram, ziram
`
`Substituted Benzenes
`
`Thiocarbamates
`Ethylene Bis Dithiocarbamates
`(EBDC's)
`Thiophthalimides
`Copper compounds
`Organomercury compounds
`Organotin compounds
`Cadmium compounds
`Miscellaneous organic fungicides Benomyl, cyclohexamide, iprodione, metalaxyl, thiabendazole,
`triadimefon
`
`Mancozeb, maneb, nabam, zineb
`
`Captan, captafol, folpet
`
`Ethyl mercury, methyl mercury, phenyl mercuric acetate
`Fentin, triphenyl tin
`
`SOURCE: Courtesy of author.
`
`liverworts), as, for example, rust, smut, mildew, mold, yeast, and bacteria, except those on or in
`
`. http://www.answers.com/fungicide
`
`1/14/2009
`
`9
`
`

`
`fungicide: Definition from Answers.com
`
`Page 2 of 7 '
`
`living man or other animals and those on or in processed food, beverages, or pharmaceuticals."
`Although the United States statutory definition excludes fungi that would grow on food,
`beverages, and pharmaceuticals, biologically these are fungi. Thus, in the United States, products
`designed to kill fungi are regulated by the U.S. Environmental Protection Agency as pesticides
`and/or by the Food and Drug Administration under food and drug law (a chemical may fall under
`the purview of both agencies).
`
`The benefits of fungicide use have been many. In agriculture, fungicides control pests that may
`rob water and nutrients from crop plants or may cause food spoilage as the products are brought
`to market. Fungicides may also prevent the growth of fungi that produce toxins, such as
`aflatoxins. Fungicides also have important industrial applications and are important in preserving
`the purity and safety of certain pharmaceutical agents.
`
`In 1997 there were an estimated $0.8 billion in sales of fungicides in the United States, about 7
`percent of the total pest1cide market. In 1997, worldwide, 5.7 billion pounds of pesticides were
`used, of which 0. 5 billion were fungicides. Of the1 .2 billion pounds of conventional pesticides
`used in the United States in 1997, a total of 81 million pounds of fungicides were used; 79 percent
`of the use was in agriculture. Generally, the United States has experienced a downward trend in
`total fungicide use since 1970.
`
`There are numerous classes of fungicides, with different modes of action as well as different
`potentials for adverse effect on health and the environment (see Table 1 ). Most fungicides can
`cause acute toxicity, and some cause chronic toxicity as well. Hexachlorobenzene, now banned or
`severely restricted in most parts of the world, has been associated with human poisoning from
`contaminated seed grain and poisoning of infants from misuse in laundry solutions. Metam sodium
`and other thiocarbanates are skin irr.itants that can cause reactive airway disease at low doses
`and severe toxicity and even death at high doses. The ethylene bis dithiocarbamates (EBCDs) are
`suspected human carcinogens and are tightly regulated in the United States.
`
`Organic mercurials have caused severe acute and chronic ·toxicity. Worldwide, there have been a
`number of incidents of treated seed grain fed to people, with disastrous consequences in terms of
`acute poisoning and damage to fetuses. Phenyl mercuric acetate is no longer used as a paint
`preservative in the United States because it off-gases elemental mercury into the air, with the
`potential for causing toxicity to young children. Organotin compounds also have serious human
`toxicity and are very toxic to the environment; their use is banned or severely restricted in most
`of the world. Likewise, due to human toxicity concerns, cadmium is no longer used as a fungicide
`in the United States.
`·
`
`(SEE ALSO: Mercury; Pesticides; Toxic Substances Control Act; Toxicology)
`
`Bibliography
`
`Reigart, J. R., and Roberts, J. R. (1999). Recognition and Management of Pesticide Poisoning, 5th
`edition. Washington, DC: U.S. Environmental Protection Agency.
`
`Sine, C., ed. (1998). Farm Chemicals Handbook. Willoughby, OH: Meister.
`
`- LYNN R. GOLDMAN
`
`Britannica Concise Encyclopedia: fungicide
`
`Any mx.i.n used to kill or inhibit growth of fungi (see fung_ys_) that cause economic damage to crop
`
`http://www.answers.com/fungicide
`
`1/14/2009
`
`10
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`

`
`fungicide: Definition from Answers.com
`
`Page 3 of 7 ·
`
`or ornamental plants (including rusts in cereals, blight in potatoes, mildew in fruits) or endanger
`the health of domestic animals or humans. Most are applied as sprays or dusts; seed fungicides are
`applied as a protective coating to seeds before germination. C~ compounds, especially
`copper sulfate mixed with lime and water (Bordeaux mixture), and fil!lfl.lr have Long been used for
`this purpose, but now synthetic organic compounds are commonly used. Many antifungal
`substances occur naturally in plant tissues.
`
`For more information on tuogicid~, visit 8.dtanatca. .. cQm.
`
`Architecture: fungicide
`
`A substance that is poisonous to fungi; retards or prevents the growth of fungi.
`
`Columbia Encyclopedia;. fungicide
`(fUn'jas1d', fling'g0 -), any substance used to destroy fungi. Some fungi are extremely damaging to
`crops (see diseases of plants), and others cause diseases in humans and other animals (see fungal
`infection).
`
`Surface fungicides, which keep harmful fungi from penetrating the tissues of a plant, include
`inorganic and organic compounds. Sulfur compounds, long used on plants, have been
`supplemented for some time by other chemicals, especially by compounds of copper, such as
`Bordeaux mixture. After 1945, organic salts of iron, zinc, and mercury were synthesized as
`fungicides. Most post-1965 fungicides are systemic, acting directly on fungal cells. Antifungal
`drugs, such as miconazole and terbinafine, are used for human fungal infections.
`
`Plant fungicides are usually applied by spraying or dusting, but some types are applied to seeds
`and soil for the destruction of vegetative spores. Fungicides used on wood, including creosote,
`prevent dry rot, and certain compounds are used to make fabrics resistant to mildews. Most
`agricultural fungicides are preventive; those applied after infection are called eradicant, or
`contact, fungicides.
`
`In the United States, fungicides are governed by the 1972 federal Environmental Protection and
`Control Act. They must be registered with the Environmental Protection Agency and must conform
`to specifications. They must control the disease without injuring the plant and must leave no
`poisonous residue on edible crops. Antifungal drugs are approved by the Food and Drug
`Administration.
`
`See also pesticide.
`
`Veterinary Dictionary: fungicide
`
`An agent that destroys fungi.
`
`Gslli1en.er's Dictionary: fungicide
`
`A compound that inhibits the growth of fungal organisms. Fungicides rarely kill fungi and are more
`useful as a preventive than as a cure.
`
`Wikipedja: Fungicide
`
`http://www.answers.com/fungicide
`
`1/14/2009
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`

`
`fungicide: Definition from Answers.com
`
`Page 4of7
`
`Fungicides are ~ll:.al..compounds or biological organisms used to kill or inhibit fungi or fungal
`spores. Fungi are capable of causing serious damage in agriculture, resulting in critical losses of
`~.quality and fl[Qfit. Although similar, oomyc~~ are not fungi. However, they use the same
`mechanisms to infect plants.Ul Consequently, in the study of plant disease (phytopathology),
`chemicals used to control oomycetes are also referred to as fungicides. As well as in agriculture,
`fungicides are used to fight fungal infections in animal tissue.
`
`Fungicides can either be contact or systemic. A contact fungicide kills fungi when sprayed on its
`surface; a systemic fungicide has to be absorbed by the plant.
`
`The majority of fungicides that can be bought retail are sold in a liquid form. The most common
`active ingredient is su..lfur, running at 0.08% for the weaker concentrates, and has high as 0.5% for
`the more potent fungicides. In powdered form, the concentration is usually around 90%, and the
`product is very toxic.
`
`Other active ingredients in different brands include neem oil, rosemary oil, jojoba oil, and the
`bacterium lkKill.Ys subtWs.
`
`Fungicide residues have been found on food for human consumption, mostly from post-harvest
`treatments.C2l Some fungicides are dangerous to human bfilillh, such as vinclozolin, which has now
`been removed from use.Ul
`
`Contents
`
`[bid.el
`
`• 1 Natural fungicides
`• 2 Fungicide resistance
`o 2.1 Fungicide resistance management
`• 3 See also
`• 4 External links
`• 5 References
`
`Natural fungicides
`
`Plants and other organisms over time have developed chemical defenses, (via natural selection),
`which give them an advantage against microorganisms such as fungi. Some of these compounds
`can be used as fungicides.
`
`• Tea tree oil
`• CinnamaldehycleW
`• Cinnamon essential oil!Sl
`• Jojoba oil is fungicide, and can be used for controlling ~.I6l
`• Neem oil
`• &>semary oil
`
`Whole live or dead organisms that are efficient at killing or inhibiting fungi can sometimes be
`used as fungicides:
`
`• The bacterium Bacillus subtilis
`• KfilQ (powdered dried kelp is fed to cattle to protect them from fungi in grass)
`
`http://www.answers.com/fungicide
`
`1/14/2009
`
`12
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`

`
`fungicide: Definition from Answers.com
`
`Page 5 of 7
`
`Fungicide resistance
`
`Pathogens respond to the use of fungicides by evolving resistance. In the field several mechanisms
`of resistance have been identified. The evolution of fungicide resistance can be gradual or
`sudden. In qualitative or discrete resistance a mutation (normally to a single gene) produces a
`~of a fungus with a high degree of resistance. Such resistant varieties also tend to show
`stability, persisting after the fungicide has been removed from the market. For example .s.ugar:
`bm leaf blotch remains resistant to ~ years after they were no longer used for control of
`the disease. This is because such mutations often have a high selection pres.s.u.re when the
`fungicide is used, but there is low selection pressure to remove them in the absence of the
`fungicide.
`
`In instances where resistance occurs more gradually a shift in sensitivity in the pathogen to the
`fungicide can be seen. Such resistance is polygenic - an accumulation of many mutation in
`different genes each having a small additive effect. This type of resistance is known as
`quantitative or continuous resistance. In this kind of resistance the pathogen population will
`revert back to a sensitive state if the fungicide is no longer applied.
`
`Little is known about how variations in fungicide treatment affect the selection pressure to evolve
`resistance to that fungicide. Evidence shows that the doses that provide the most control of the
`disease also provide the largest selection pressure to acquire resistance, and that lower doses
`decreased the selection pressure.CZl
`
`In some cases when a pathogen evolves resistance to one fungicide it automatically obtains
`resistance to others - a phenomenon known as cross resistance. These additional fungicides are
`normally of the same chemical family or have the same mode of action, or can be detoxified by
`the same mechanism. Sometimes negative cross resistance occurs, where resistance to on·e
`chemical class of fungicides leads to an increase in sensitivity to a different chemical class of
`fungicides. This has been seen with carbendazim and diethofencarb.
`
`There are also recorded incidences of pathogens evolving multiple drug resistance - resistance to
`two chemically different fungicides by separate mutation events. For example Botrytis cinerea is
`resistant to both azoles and dicarboximide fungicides.
`
`There are several routes by which pathogens can evolve fungicide resistance. The most common
`mechanism appears to be alternation of the target site, particular as a defence against single site
`of action fungicides. For example l3_l_ack_5.igfilQka, an economically important pathogen of banana,
`is resistant to the Q.Q!. fungicides, due to a single nucleotide change resulting one amino acid
`(glycine) being replaced by another (alanine) in the target protein of the Qol fungicides,
`cytochrome b.00 This presumably disrupts the binding of the fungicide to the protein, rendering
`the fungicide ineffective.
`
`Upregulation of target genes can also render the fungicide ineffective. This is seen in DMI
`resistant strains of venturia jnaequatis)2l
`
`Resistance to fungicides can also be developed by efficient efflux of the fungicide out of the cell.
`Septoria tritici has developed multiple drug resistance using this mechanism. The pathogen had 5
`ABC type transporters with overlapping substrate specificities that together work to effectively
`pump toxic chemicals out of the ceu.L10J
`
`In addiction to the mechanisms outlined above, fungi may also develop .!I!.etab.Qlic pathways that
`circumvent the target protein, or acquire enzymes that enable metabolism of the fungicide to a
`harmless substance.
`
`http://www.answers.com/fungicide
`
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`
`fungicide: Definition from Answers.com
`
`Page 6 of 7
`
`Fungicide resistance management
`
`The fungicide resistance action committee (FRAC) has seven~l recommended practices to try to
`avoid the development of fungicide resistance, especially in at-risk fungicides including
`Strobilurins such as azoxYstrobin.
`
`Products should not be used in isolation but rather as mixture, or alternate sprays, with another
`fungicide with a different mechanism of action. The likelihood of the pathogen developing
`resistance is greatly decreased by the fact that any resistant isolates to one fungicide will
`hopefully be killed by the other - in other words two mutations would be required rather than just
`one. The effectiveness of this technique can be demonstrated by Metalaxyl. When used as the
`sole product in !rfilanQ to control potato blight (Phytophthora jnfestans) resistance developed
`within one growing season. However in countries like the UK where it was only ever marketed as a
`mixture resistance problems were not seen.
`
`Fungicides should only be applied when absolutely.necessary, especially if they are in an at-risk
`group. Lowering the amount of fungicide in the environment lowers the selection pressure for
`resistance to develop.
`
`Manufacturers' ~-should always be followed. These doses are normally designed to give the
`right balance between controlling the disease and limiting the risk of resistance development.
`Higher doses increase the selection pressure for single site mutations that confer resistance, as all
`strains but those that carry the mutation will be eliminated, and thus the resistant strain will
`propagate. Lower doses greatly increase the risk of polygenic resistance, as strains that are
`slightly less sensitive to the fungicide may survive.
`
`It is also recommended that where possible fungicides are only used in a protective manner,
`rather than to try to cure already infected crops. Far fewer fungicides have curative/eradicative
`ability than protectant. Thus fungicide preparations advertised as having curative action may only
`have one active chemical; a single fungicide acting in isolation increases the risk of fungicide
`resistance.
`
`It is better to use an integrative pest management approach to disease control, rather than
`relying on fungicides alone. This involves the use of resistant varieties and hygienic practises,
`such as the removal of potato discard piles and stubble on which the pathogen can overwinter,
`greatly reduce the titre of the pathogen and thus the risk of fungicide resistance development.
`
`See also
`
`·~_g
`• List of fungicides
`• Pesticide application
`• Phytopathology
`• Plant disease forecasting
`
`External links
`
`• B!ogicide Resistance Action Group
`• General Pesticide Information - National Pesticide Information Center
`
`References
`
`http://www.answers.com/fungicide
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`1/14/2009
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`. ·fungicide: Definition from Answers.com
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`Page 7 of 7
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`This article needs additional citations for verification.
`Please help improve this article by adding reliable references. Unsourced material may be challens.ed. and
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`: Latijnhouwers M, de Wit PJ, Govers F. Oomycetes and fungi: similar weaponry to attack
`plants. Trends in Microbiology Volume 11 462·469
`: Pesticide Chemistry and Bioscience edited by G.T Brooks and T.R Roberts. 1999.
`Published by the Royal Society of Chemistry
`: Hrelia et al. 1996 ·The genetic and non-genetic toxicity of the fungicide Vinclozolin.
`Mutagenesis Volume 11 445·453
`: "Cinnanialdehyde Use". PAN Pesticides Database. Retrieved on 2007-10-23.
`: Lopez P, Sanchez C, Batlle R, Nerin C (August 2005). "Solid· and vapor-phase
`antimicrobial activities of six essential oils: susceptibility of selected foodborne bacterial
`and fungal strains". J. Agric. Food Chem. 53 (17): 6939-46. d.Qi:10.1021 /jf050709y. EMl.Q
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`: !JS.patent 6174920 Method of controlling powdery mildew infections of plants using
`jojoba wax
`: Metcalfe, R.J. et al. (2000) The effect of dose and mobility on the strength of selection
`for DMI fungicide resistance in inoculated field experiments. Plant Pathology 49: 546·557
`: Sierotzki, Helge (2000) Mode of resistance to respiration inhibitors at the cytochrome bc1
`enzyme complex of Mycosphaerella fijiensis field isolates Pest Management Science
`56:833-841
`: Schnabel, G., and Jones, A. L. 2001. The 14a-demethylase (CYP51A1) gene is
`overexpressed in V. inaequaUs strains resistant to myclobutanil. Phytopathology 91:102·
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`: Zwiers, L. H. et al. (2003) ABC transporters of the wheat pathogen Mycosphaerella
`graminicola function as protectants against biotic and xenobiotic toxic compounds
`Molecular Genetics and Genomics 269:499·507
`
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