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`The information disclosed herein may be restricted. Unauthorized disclosure may be prohibited by the United States Code Title 35, Sections 122, 181 and 368.
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`FILEDwit: [_] DISK (CRF) Oo FICHEA CD-ROM
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`Applicant: James G. Dobson and Michael F. Ethier
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`Title:
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`TREATMENTOF SKIN WITH ADENOSINE OR ADENOSINE
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`ANALOG
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`Enclosedare the following papers, including those required to receive a filing date
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`under 37 CFR, 1.53(b):
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`bl WASHINGTON, DC
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`In addition to the above-listed pages, the following items are enclosed herewith:
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`e Copies of Petition for Extension of Time, filed in the parent
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`application (to be entered in this application);
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`CERTIFICATE OF MAILING BY EXPRESS MAIL -
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`Express Mail Label No.EL2ZVEA31056US
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`I hereby certify under 37 CFR §1.10 that this correspondence is being
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`deposited with the United States Postal Service as Express Mail Post
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`Office to Addressee with sufficient postage on the date indicated below
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`and is addressed to the Commissioner
`for Patents, Washington,
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`D.C. 20231.
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`FISH & T7HARDSON P.C.
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`Commissioner for Patents
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`September 28, 2000
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`Page 2
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`This application is a continuation (and claims the benefit of priority under 35 USC
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`§120) of U.S. application Serial no. 09/179,006,filed October 26, 1998. The
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`disclosure ofthe prior application is considered part of (and is incorporated by
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`reference in) the disclosure of this application.
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`The presentapplicationis entitled to small entity status. Small entity status from the
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`parentapplicationis still proper. The filing fee has been calculated as follows:
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`Basic filing fee
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`Independentclaimsin excess of 3 times $39
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`$345
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`Under 37 CFR §1.53(d), no filing fee is being paid at this time. Please apply any
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`1050, referencing the attorney docket number shown above.
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`Theprior application is assigned of record to University of Massachusetts,
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`a Massachusetts corporation, by virtue of an assignmentrecord in the U.S. Patent and
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`Trademark Office on January 7, 1999 at Reel/Frame 9690/0305.
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`Please sendall correspondenceto:
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`GARY L. CREASON
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`Fish & Richardson P.C.
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`Boston, MA 02110-2804
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`If this application is found to be incomplete, or if a telephone conference would
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`otherwise be helpful, please call the undersigned at (617) 542-5070. Kindly
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`acknowledgereceipt of this application by returning the enclosed postcard.
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`Respectfully submitted,
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`Pan € batatr
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`Gary L. Creason
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`Reg. No. 34,310
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`Enclosures
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`CFG RHE
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`TREATMENT OF SKIN WITH ADENOSINE OR ADENOSINE ANALOG
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`Abstract of the Disclosure
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`Methods for enhancing the condition of non-diseased .
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`skin by application of compositions containing adenosine or
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`an adenosine analog are disclosed. Also disclosed are
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`methods for increasing DNA synthesis or protein synthesis in
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`dermal cells, and methods for increasing dermal cell size,
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`by application of compositions containing adenosine.
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`227728.B11
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`iO"EeeSe
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`-Attomney’s Docke.
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` 07917-045002 / (UMMC97-32)
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`APPLICATION
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`FOR
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`UNITED STATES LETTERS PATENT
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`TITLE:
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`TREATMENT OF SKIN WITH ADENOSINE OR
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`ADENOSINE ANALOG
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`APPLICANT:
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`James G. Dobson and Michael F. Ethier
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`aeAEi
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`otSe
`OOeee
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`CERTIFICATE OF MAILING BY EXPRESS MAIL
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`Express Mail LabelNo_ EG ZYS43/OS6CUS
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`I hereby certify under 37 CFR §1.10 that this correspondence is being
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`deposited with the United States Postal Service as Express Mail Post
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`Office to Addressee with sufficient postage on the date indicated below
`and is addressed to the Commissioner for Patents, Washington,
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`D.C. 20231.
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`“
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`9/156
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`PATENT
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`ATTORNEY DOCKET NO: 07917/045002
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`Field of the Invention
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`This invention relates to dermatology and cell
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`biology.
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`dermis.
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`Background of the Invention
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`Skin includes a surface layer, known as the
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`epidermis, and a deeper connective tissue layer, known as the
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`The epidermis undergoes continuous turnover as the
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`outermost cells are exfoliated and replaced by cells that
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`arise from inner dermal layers.
`The dermis is composed of a
`variety of cell types,
`including fibroblasts.
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`Skin thickness begins to decline in humans after the age
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`of 20 as the dermis becomes thinner and the number of skin
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`fibroblasts declines. As skin ages, or is exposed to UV
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`light and other environmental insults, changes in the
`underlying dermis can lead to the functional and
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`morphological changes associated with damaged skin.
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`Decreases in the abundance and function of products of the
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`fibroblasts, which include collagen and proteoglycans, are
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`believed to play major roles in wrinkled and damaged skin.
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`TREATMENT OF SKIN WITH ADENOSINE OR ADENOSINE ANALOG
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`ask!Statement as to Federally Sponsored Research
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`Work on this invention was supported by funds from
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`the United States government
`(Public Health Service Grants
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`HL-22828 and AG-11491).
`The government therefore has certain
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`rights in this invention.
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`TUNE
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`Summary of the Invention
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`We have discovered that adenosine stimulates DNA
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`synthesis,
`increases protein synthesis, and increases cell
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`size in cultures of -human skin fibroblasts. Based on this
`discovery,
`the invention provides methods and compositions
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`for enhancing the condition of skin.
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`In general,
`the invention provides a method for
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`enhancing the condition of non-diseased skin of a mammal,
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`e.g., a human.
`The method includes topically applying a
`therapeutically effective amount of a composition including
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`adenosine or an adenosine analog to non-diseased skin of the
`mammal .
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`The invention also provides a method for promoting
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`healing of broken, non-diseased skin in a mammal by
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`topically administering a composition including a
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`therapeutically effective amount of adenosine or an
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`adenosine analog to the mammal.
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`Also included in the invention is a method for
`increasing DNA synthesis in a dermal cell of non-diseased
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`skin of a mammal.
`The method includes topically
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`administering a therapeutically effective amount of
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`adenosine or an adenosine analog to a region of non-diseased
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`skin of the mammal containing dermal cell.
`The adenosine is
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`added so that it does not cause proliferation of the dermal
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`cell.
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`The invention also features a method of increasing
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`protein synthesis in a dermal cell of non-diseased skin of a
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`mammal.
`The method includes topically administering a
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`composition including a therapeutically effective amount of
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`adenosine or an adenosine analog to a region of skin of the
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`mammal containing the dermal cell.
`The adenosine or
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`adenosine analog does not cause proliferation of the dermal
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`cell.
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`11/156
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`At,Sh
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`Also provided in the invention is a method of
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`increasing cell size.in a dermal cell in non-diseased skin
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`of a mammal, e.g., a human.
`The method includes topically
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`administering a composition including a therapeutically
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`effective amount of adenosine to a region of skin of the
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`mammal containing the dermal cell, wherein addition of the
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`adenosine does not cause proliferation of the dermal cell,
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`wherein addition of the adenosine does not cause
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`proliferation of the dermal cell.
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`The inventfon also includes a method for enhancing
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`skin condition in a mammal, e.g., a human.
`The method
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`includes providing fibroblasts from the mammal ex vivo,
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`culturing the fibroblasts in the presence of adenosine, and
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`reintroducing the
`fibroblasts into the. mammal.
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`The therapeutically effective amount of adenosine
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`used in the above-described methods is preferably 10° M to
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`10°? M, more preferably 10°* M to 10°° M, and most preferably
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`about 10% M.
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`The composition used in the above-described methods.
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`can include a second agent
`in addition to adenosine.
`The
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`second agent can be, e.g. an agent that promotes binding of
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`adenosine or an adenosine analog to an adenosine receptor,
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`an angiogenic factor such as vascular endothelial cell
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`growth factor (VEGF), basic fibroblast growth factor (BFGF),
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`an agent that itself enhances skin condition, such as
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`tretoinin or another known conditioning agent such as an
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`emollient, a humectant, or an occlusive agent.
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`the
`In preferred embodiments of the invention,
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`adenosine or an adenosine analog does not promote skin cell
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`proliferation.
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`The invention also provides a composition including
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`about 10? M to about 10°? M adenosine and a therapeutically
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`effective amount of an angiogenesis factor.
`In some
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`embodiments,
`M.
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`the composition of the adenosine is about
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`"enhancement of skin condition"
`As. used herein,
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`means a noticeable decrease in the amount of wrinkling,
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`roughness, dryness,
`laxity, sallowness, or pigmentary
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`mottling in skin.
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`As used herein, a "therapeutically effective amount"
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`of adenosine or an adenosine analog means an amount that
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`enhances skin condition when applied to skin.
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`As used henein, "non-diseased skin" means skin free
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`of any proliferative disorder observable by visual
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`inspection.
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`invention advantageously allows for
`The present
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`enhancement of skin condition. This results in skin that
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`shows a less wrinkled,
`rough, or dry complexion.
`For
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`example,
`the invention provides for enhancing the condition
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`of skin damaged due to exposure to the sun or skin whose
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`condition has deteriorated due to normal aging.
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`Unless otherwise defined, all technical and
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`scientific terms used herein have the same meaning as.
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`commonly understood by one of ordinary skill in the art to
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`which this invention belongs. Although methods and
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`materials similar or equivalent to those described herein
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`can be used in the practice or testing of the present
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`invention, suitable methods and materials are described
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`below. All publications, patent applications, patents, and
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`other references mentioned herein are incorporated by
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`reference in their entirety.
`In case of conflict,
`the
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`present specification,
`including definitions, will control.
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`In addition,
`the materials, methods, and examples are
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`illustrative only and not
`intended to be limiting.
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`Other features and advantages of this invention will
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`be apparent from the following description of the preferred .
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`embodiments thereof, and from the claims.
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`Brief Description of the Drawings
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`Figs. 1A and 1B are histograms showing the effect of
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`adenosine on ([*H]thymidine incorporation in cultures of
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`normal human skin (Fig. 1A) and lung fibroblasts (Fig. 1B).
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`After incubation in serum-free medium for 24 hours, cells
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`were exposed to 10°* M adenosine for 18 hours. Medium was
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`replaced with serum-free medium without adenosine, and
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`[7H] thymidine was added. Results are expressed as percent
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`(H]thymidine incorporation compared to control cultures
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`without adenosine and are means + SEM for 4-5 experiments.
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`"*" denotes value was significantly different from control
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`value without adenosine.
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`Figs. 2A and 2B are histograms showing concentration
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`responses of adenosine-stimulated protein synthesis in human >
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`skin fibroblasts from a young (Fig. 2A) and aged (Fig. 2B)
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`donor. Cells were grown to 75% confluence. Medium was then
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`replaced with serum-free medium with or without adenosine.
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`After 48 hours,
`[?H]phenylalanine incorporation was
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`determined as described. Results are expressed as
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`%(37H] phenylalanine incorporation compared to control
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`cultures without adenosine and are means +SEM for 6-25
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`experiments.
`"*" denotes value was significantly different
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`from control value without adenosine.
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`25
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`heSeOo
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`=
`=
`tS
`by
`a
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`Ge
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`Detailed Description
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`The invention is suitable for treating skin of a
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`mammal,
`€.9g.,
`a human, for which promotion of fibroblast-
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`associated dermal functions is desired.
`For example,
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`A"Eee!aSe
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`anil
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`peteyyaeeeny
`22
`witaeh.
`.Ta
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`in
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`an
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`f£
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`6 ~.
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`promotion of fibroblast-associated functions is desirable
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`enhancing the condition of aged skin, which is associated
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`with a decrease in dermal cell function and is characteri
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`by increased dryness or roughness, or both.
`The method c
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`also be used on subjects having otherwise damaged skin,
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`e.g., wrinkled skin and skin with a non-proliferative
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`The method can may further be used
`disorder.
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`prophylactically on a subject to minimize deterioration °
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`skin condition associated with aging or environmental
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`factors, such as photodamage.
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`Adenosine and suitable adenosine analogs are
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`suitable for use in enhancing skin condition. Adenosine
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`analogs such as adenosine agonists, adenosine receptor
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`agonists, and compounds that increase intracellular or
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`extracellular adenosine levels are suitable for use in the
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`invention:
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`Agonists of adenosine include 2‘ -deoxyadenosine;
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`2',3'-isopropoylidene adenosine;
`toyocamycin; 1-
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`methyladenosine; N-6-methyladenosine; adenosine N-oxide;
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`5
`methylmercaptopurine riboside; 6-chloropurine riboside,
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`adenosine monophosphate, 5’-adenosine diphosphate, or 5’-
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`adenosine triphosphate. Adenosine receptor agonists include
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`phenylisopropyl-adenosine ("PIA"), 1-Methylisoguanosine,
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`ENBA (S(-), N®-Cyclohexyladenosine (CHA), N®-
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`Cyclopentyladenosine (CPA), 2-Chloro-N,-
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`cyclopentyladenosine, 2-chloroadenosine, and adenosine amine
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`(ADAC), all of which are agonists for the adenosine
`congener
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`A, receptor. Other receptor agonists include 2-p-(2-
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`carboxy-ethyl) phenethyl-amino-5’ -N-ethylcarboxamido-
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`adenosine (CGS-21680), N-ethylcarboxamido-adenosine (NECA)
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`and napthyl-substituted aralkoxyadenosine (SHA-082), 5° (N-
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`Cyclopropyl) -carboxamidoadenosine, DPMA (PD 129,944),
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`Metrifudil, which are agonists for the adenosine A,
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`peane
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`<3
`“GeaEke
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`hcsea
`aCSen?
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`receptor. Other adenosine receptor agonists include those
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`which preferentially bind the A, receptor relative to the A,
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`receptor, such as 2-Chloroadenosine, N®°-Phenyladenosine, and
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`N*-Phenylethyladenosine; and those which preferentially bind
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`the A, receptor relative to the A, receptor, such as 2-
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`Phenylaminoadenosine and MECA.’
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`Also suitable for use are compounds that increase
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`intracellular adenosine concentration by inhibiting the
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`cellular uptake of adenosine or the breakdown of adenosine.
`One pathway of adenosine metabolism is the conversion of
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`adenosine to inosine by adenosine deaminase. An example of
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`an adenosine deaminase inhibitor is erythro-9- (2-hydroxy-3-
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`nonyl) adenine ("EHNA"). Adenosine kinase inhibitors can
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`also be used. Adenosine kinase converts adenosine to
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`adenosine monophosphate by adenosine kinase. An example of
`an adenosine kinase inhibitor is iodotubercidin. Other
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`suitable compounds include those that inhibit the
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`dipyridamole-sensitive nucleoside transporter, which exports
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`adenosine from the cytoplasm, and agents that promote: the
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`activity of a 5’-nucleotidase, e.g.,
`the ATP-activated 5’-
`nucleotidase, which forms adenosine.
`Compounds that
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`increase tissue adenosine and ATP levels include acadesine
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`(AICA-riboside), which is described in Gruber et al.,
`Circulation 80:1400-1411 (1989).
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`_ Adenosine can be also be administered with a second
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`compound.
`The second compound can enhance the action of
`adenosine or the adenosine analog, e.g., by enhancing
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`binding of adenosine or an adenosine analog to an adenosine
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`receptor. An example of such a compound is PD 81,728, which
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`is described in Kollias-Baker et al. J. Pharmacol. Exp.
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`Ther. 281:761-68. Alternatively,
`the second agent can
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`itself act to enhance skin condition. Examples of these
`types of agents include tretinoin, a recognized skin
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`conditioning agent (see, e.g., Olsen et al., J. Amer. Acad.
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`Dermatol. 37:217-26, 1997), an angiogenic factor such as
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`vascular endothelial cell growth factor (VEGF) or basic
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`fibroblast growth factor (BFGF), or a conditioning agent.
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`"The second compound can also be a conditioning agent
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`such as an emollient, humectant, or occlusive agent.
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`Numerous examples of particular conditioning agents are
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`provided in the CTFA Cosmetic Ingredient Handbook (Cosmetic
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`Toiletries and Fragrances Association, Washington, D.D.,
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`1988). Emollients help to maintain the soft, smooth, and
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`pliable appearance of skin andfunction by remaining on the
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`skin surface or in the stratum corneum to act as lubricants,
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`to reduce flaking, and to improve the skin’s appearance.
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`Examples of emollients include acetyl trioctyl citrate,
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`cetyl alcohol, butyl myristate, cetyl alcohol, and mineral
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`oil.
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`Humectants act to increase the water content of the
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`top layers of the skin. Humectants include, e.g., acetamide
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`MEA, fructose, and xylitol. Occlusive agents inhibit the
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`evaporation of water from skin,
`thereby increasing the water
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`contend of the skin. Acetylated castor oil, mineral oil,
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`and lauryl stearate are examples of occlusive agents.
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`A subject can be treated by applying adenosine or an
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`adenosine analog in a pharmaceutical composition in an
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`effective amount and for a period of time sufficient to
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`improve the condition of the skin.
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`The pharmaceutical composition may be formulated
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`using conventional methods to prepare pharmaceutically
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`useful compositions.
`Such compositions preferably include
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`at least one pharmaceutically acceptable carrier, such as
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`those described in Remington’s Pharmaceutical Sciences (E.W.
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`In addition,
`the compositions preferably include a
`Martin).
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`pharmaceutically acceptable buffer, preferably phosphate
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`- 8 -
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`sungSayHETa"ERSTE,
`cl
`eh
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`AR
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`together with a pharmaceutically acceptable
`buffered saline,
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`compound for adjusting isotonic pressure, such as, for
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`example, sodium chloride, mannitol, or sorbitol.
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`Adenosine or an adenosine agonist can also be
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`provided in carriers and adjuvants such as ion exchangers,
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`alumina, aluminum stearate,
`lecithin, serum proteins, such
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`-as human serum albumin, buffer substances, such as
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`phosphates, glycine, sorbic acid, potassium sorbate, partial
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`glyceride mixtures of saturated vegetable fatty acids,
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`water, salts or. electrolytes, such as protamine sulfate,
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`disodium hydrogen phosphate, potassium hydrogen phosphate,
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`sodium chloride, zinc salts, colloidal silica, magnesium
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`trisilicate, polyvinyl pyrrolidone, cellulose-based
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`substances and polyethylene glycol. Adjuvants for topical
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`or gel base forms of adenosine or adenosine analogs may, for
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`example, be selected from the group consisting of sodium
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`carboxymethylcellulose, polyacrylates, polyoxythylene-
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`polyoxypropylene-block polymers, polyethylene glycol and
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`wood wax alcohols.
`For all administrations, conventional
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`
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`
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`depot forms may be used.
`,
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`The adenosine or adenosine analog-containing
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`compositions may be in any pharmaceutically acceptable
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`dosage form.
`They are preferably applied by topical routes
`
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`
`
`to exert local therapeutic effects.
`For topical
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`the penetration of the adenosine into skin
`applicatio