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`EXHIBIT 3
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`EXHIBIT 3
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`Case 1:17-cv-00868-JFB-SRF Document 13-3 Filed 08/18/17 Page 2 of 8 PageID #: 232
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`(19) United States
`(2) Patent Application Publication (10) Pub. No.: US 2004/0146474 A1
`Galey
`(43) Pub. Date:
`Jul. 29, 2004
`
`US 200401.46474A1
`
`(54) METHOD FOR SOFTENING LINES AND
`RELAXING THE SKIN WITH ADENOSINE
`AND ADENOSINE ANALOGUES
`(75) Inventor: Jean-Baptiste Galey, Aulnay-Sous-Bois
`(FR)
`
`Related U.S. Application Data
`(60) Provisional application No. 60/432,634, filed on Dec.
`12, 2002.
`Foreign Application Priority Data
`
`(30)
`
`Nov. 26, 2002 (FR).............................................. 021.4828
`
`Correspondence Address:
`
`OBLON, SPIVAK, MCCLELLAND, MAIER &
`NEUSTADT, P.C.
`1940 DUKE STREET
`ALEXANDRIA, VA 22314 (US)
`
`-
`
`- -
`
`e
`
`e
`
`Publication Classification
`7
`(51) Int. Cl." .............................. A61K 7/06; A61K 7/11;
`A61K 31/7076
`(52) U.S. Cl. ........................................... 424/70.13; 514/47
`
`(73) Assignee: L’OREAL, Paris (FR)
`(21) Appl. No.:
`10/701,495
`
`(22) Filed:
`
`Nov. 6, 2003
`
`ABSTRACT
`(57)
`The present invention concerns a method for softening lines
`and/or relaxing the skin with adenosine and/or an analogue
`of adenosine.
`
`
`
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`Patent Application Publication
`
`Jul. 29, 2004
`
`US 2004/0146474 A1
`
`
`
`Effect of adenosine on the contraction of equivalent dermis
`
`30 |
`
`|
`
`REFERENCE
`SUBSTANCE
`ADENOSINE
`
`NE
`
`: 3. 0.
`
`2 0.
`
`
`
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`US 2004/0146474 A1
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`Jul. 29, 2004
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`METHOD FOR SOFTENING LINES AND
`RELAXING THE SKIN WITH ADENOSINE AND
`ADENOSINE ANALOGUES
`
`REFERENCE TO PRIOR APPLICATIONS
`[0001] This application claims priority to U.S. provisional
`application 60/432,634 filed Dec. 12, 2002, and to French
`patent application 021.4828 filed Nov. 26, 2002, both incor
`porated herein by reference.
`
`FIELD OF THE INVENTION
`[0002] The present invention relates to a method for
`softening lines and/or relaxing the skin, and/or relaxing
`facial features, comprising topical application to the skin of
`a composition comprising at least one compound selected
`from the group consisting of adenosine and analogues of
`adenosine, in a physiologically acceptable medium. Particu
`lar uses of the invention composition include the decreasing
`of wrinkles, the reduction in laugh lines, the reduction in
`frown lines, etc.
`[0003] It also relates to the use of at least one compound
`as defined above, in a composition suitable for topical
`application to the skin, as an agent intended to soften lines
`and/or relax the skin and/or relax facial features.
`[0004] Additional advantages and other features of the
`present invention will be set forth in part in the description
`that follows and in part will become apparent to those having
`ordinary skill in the art upon examination of the following
`or may be learned from the practice of the present invention.
`The advantages of the present invention may be realized and
`obtained as particularly pointed out in the appended claims.
`As will be realized, the present invention is capable of other
`and different embodiments, and its several details are
`capable of modifications in various obvious respects, all
`without departing from the present invention. The descrip
`tion is to be regarded as illustrative in nature, and not as
`restrictive.
`
`BACKGROUND OF THE INVENTION
`[0005] Women and, increasingly, men have a tendency to
`want to appear young for as long as possible, and so they
`seek to tone down signs of ageing in the skin, primarily
`wrinkles and fine lines. Thus, advertisements and the fashion
`industry promote products intended to keep the skin radiant
`and wrinkle-free, the trade marks of a young skin, for as long
`as possible. Furthermore, physical appearance has an effect
`on psyche and/or morale.
`[0006] Until now, wrinkles and fine lines have been treated
`using cosmetic products containing active ingredients that
`have an effect on the skin, for example by moisturizing it or
`improving cell renewal, or by encouraging the synthesis of
`collagen from which cutaneous tissue is formed, or by
`preventing its degradation.
`[0007] Although such treatments can have an effect on
`wrinkles and fines lines due to chronological or intrinsic
`ageing, and on those cells due to photo-ageing, they do not
`have any effect on expression lines.
`[0008] Expression lines are produced by mechanisms that
`differ from those generating lines due to ageing.
`
`[0009] More precisely, they are produced by the stress
`exerted on the skin by the facial muscles which produce
`facial expressions. Depending on the shape of the face, the
`frequency of expressions and the existence of any tics, they
`can appear in childhood. Age and some environmental
`factors such as exposure to the sun do not have any effect on
`their genesis but can make them deeper and render them
`permanent.
`[0010] Expression lines are characterized by the presence
`of furrows at the periphery of the orifices, namely the nose
`(nasogenic furrows), the mouth (parabuccal lines and bit
`terness lines) and the eyes (crows feet) around which the
`facial muscles are located, and also between the eyebrows
`(glabellar lines or frown lines) and on the forehead.
`[0011] Until now, the only routine means for dealing with
`expression lines are botulinum toxin, which is injected into
`the glabellar lines (see J. D. Carruthers et al., J. Dermatol.
`Surg. Oncol., 1992, 18, pp 17-21) and degradable collagen
`based, hyalruonic acid-based or polylactic acid-based
`implants.
`[0012] Further, as an alternative to those medical tech
`niques requiring the services of a skilled practician, the
`Applicant has proposed a number of compounds that can
`provide a myorelaxing effect when topically applied to the
`skin and which allow expression lines to be dealt with in a
`different manner. Examples of such compounds that can be
`cited are antagonists for receptors associated with calcium
`channels (French application FR-A-2 793 681), and in
`particular manganese and its salts (FR-A-2 809 005) and
`alverine (FR-A-798 590); and agonists for receptors asso
`ciated with the chlorine channel, including glycine (EP-A-0
`704 210) and certain extracts of Iris pallida (FR-A-2 746
`641).
`[0013] However, there is still a need for effective com
`pounds for relaxing the skin with a view to smoothing or
`toning down expression lines.
`
`BRIEF DESCRIPTION OF THE FIGURE
`[0014] FIG. 1 illustrates the contraction over time of an
`equivalent dermis treated with adenosine.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`[0015] As noted above, the present invention relates to a
`method for softening lines and/or relaxing the skin, and/or
`relaxing facial features, comprising topical application to the
`skin of a composition comprising at least one compound
`selected from the group consisting of adenosine and ana
`logues of adenosine, in a physiologically acceptable
`medium. Particular uses of the invention composition
`include the decreasing of wrinkles, the reduction in laugh
`lines, the reduction in frown lines, etc.
`[0016] The inventor has surprisingly discovered that
`adenosine and its analogues can satisfy the above need for
`effective compounds for relaxing the skin with a view to
`smoothing or toning down expression lines, relaxing the
`skin, relaxing facial features, decreasing wrinkles, reducing
`laugh lines, reducing frown lines, etc. More precisely, the
`inventor has demonstrated that adenosine and its analogues
`can relax the dermal contractile cells which are believed to
`be involved in the genesis of expression lines, etc. It is
`
`
`
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`
`believed that the phenotype of certain fibroblasts located
`along the tension lines created under the effect of contraction
`of facial muscles when making a facial expression is pro
`gressively modified under the effect of said contractions,
`endowing said fibroblasts with particular contractile prop
`erties. Relaxing those cells would thus combat expression
`lines. Of course, the inventor is not bound by any theory of
`operation.
`[0017] In the pharmaceutical field, adenosine is adminis
`tered orally or intravenously as a vasodilator and an anti
`arrythmic.
`[0018] In the cosmetics field, it has been suggested, in
`U.S. Pat. No. 6,423,327 and U.S.-2003/044439, that adenos
`ine or an analogue of adenosine be used in a composition
`that is topically applied to the skin to improve skin condition
`and in particular to combat lines, skin laxity, skin dryness
`and pigmentary blemishes. It was indicated that adenosine
`increases the size of fibroblasts and increases the synthesis
`of proteins by fibroblasts.
`[0019] In the same field, documents WO-A-01/43704,
`U.S. Pat. No. 3,978,213, U.S. Pat. No. 5,371,089, German
`patents DE-19545 107 and DE-200 22 691 disclose com
`positions with an anti-ageing effect comprising adenosine or
`an adenosine analogue.
`[0020. None of those documents suggests that adenosine
`could have a relaxing effect on contractile fibroblasts.
`[0021] Thus, the present invention provides a method for
`softening lines and/or relaxing the skin, comprising topical
`application to the skin of a composition comprising at least
`one compound selected from adenosine and an analogue of
`adenosine, in a physiologically acceptable medium.
`[0022] It also concerns the use of at least one compound
`as defined above in a composition adapted for topical
`application to the skin as an agent for softening lines and/or
`relaxing the skin.
`[0023] The present invention further provides a method
`for softening lines and/or relaxing the skin, comprising
`topical application to the skin of an amount of a composition
`comprising at least one compound selected from the group
`consisting of adenosine and analogues of adenosine, in a
`physiologically acceptable medium, effective to provide a
`relaxing effect on contractile fibroblasts.
`[0024] Adenosine analogues that can be used in accor
`dance with the invention and can be cited as particularly
`useful herein include agonists of adenosine receptors and
`compounds increasing intra- or extra-cellular adenosine
`levels.
`[0025] Examples of adenosine analogues include:
`2'-deoxyadenosine; 2',3'-isopropoylidene adenosine; toyoca
`mycin; 1-methyladenosine, N-6-methyladenosine; adenos
`ine N-oxide; 6-methylmercaptopurine riboside; 6-chloropu
`rine riboside; 5'-adenosine monophosphate; 5'-adenosine
`diphosphate and 5'-adenosine triphosphate.
`[0026] Other adenosine analogues include agonists of
`adenosine receptors, including phenylisopropyl adenosine
`(PIA), 1-methylisoguanosine, N°-cyclohexyl adenosine
`(CHA), N°-cyclopenty] adenosine (CPA), 2-chloro-N-6-cy
`clopentyladenosine, 2-chloroadenosine, N°-phenyladenos
`ine, 2-phenylaminoadenosine, MECA, N°-phenethylad
`
`2-p-(2-carboxyethyl)-phenethyl-amino-5'-N
`enosine,
`ethylcarboxamido-adenosine
`(CGS-21680),
`N-ethylcarboxamido-adenosine (NECA), 5'-(N-cyclopro
`pyl)-carboxamidoadenosine, DPMA (PD 129,944) and met
`rifudil.
`[0027] Other adenosine analogues include compounds
`which increase the intracellular concentration of adenosine
`such as erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and
`iodotubercidin.
`[0028] Other adenosine analogues include salts and esters
`of adenosin.
`[0029] Adenosine is preferred for use in the present inven
`tion. It is commercially available in the form of a powder
`from PHARMA WALDHOF.
`[0030] The composition in accordance with the invention
`is preferably intended to be applied to zones of the face or
`forehead marked with expression lines and/or to persons
`having expression lines.
`[0031] The lines concerned are preferably selected from:
`crow’s feet, nasogenic furrows, inter-eyebrow lines and
`forehead lines.
`[0032] The quantity of adenosine and/or adenosine ana
`logue for use in accordance with the invention is a function
`of the desired effect and can thus vary widely. To provide an
`order of magnitude, the composition of the invention can
`comprise 0.001% to 10% by weight, preferably 0.01% to 1%
`by weight of adenosine and/or adenosine analogue with
`respect to the total composition weight.
`[0033] The composition of the invention is suitable for
`topical application to the skin and thus it contains a physi
`ologically acceptable medium, i.e. a medium that is com
`patible with the skin. Such media can comprise water,
`C1-C8, preferably C1-C4, alcohols, etc.
`[0034] This composition can be fluid to a greater or lesser
`extent and can have the appearance of a white or coloured
`cream, a pommade, milk, serum, paste or foam. It can also
`be in the form of a solid, in particular in the form of a stick.
`It can be used as a skin care product and/or as a skin makeup
`product.
`[0035] The composition of the invention can be in any
`form, including any of the galenical forms that are normally
`used in the cosmetics field; in particular, it can be in the form
`of an aqueous, possibly gelled solution, a lotion type dis
`persion which may be a two-phased dispersion, an emulsion
`obtained by dispersing an oily phase in an aqueous phase
`(O/W) or vice versa (W/O), a triple emulsion (W/O/W or
`O/W/O) or an ionic and/or nonionic vesicular type disper
`sion. Said compositions are prepared using the usual meth
`ods. Preferably, a composition in the form of an oil-in-water
`emulsion is used in the present invention.
`[0036] When the composition used in the invention is an
`emulsion, the proportion of oily phase can be from 5% to
`80% by weight, preferably 5% to 50% by weight with
`respect to the total composition weight. Oils, emulsifying
`agents and co-emulsifying agents used in the composition in
`the emulsion form are selected from those conventionally
`used in the field under consideration. The emulsifying agent
`and co-emulsifying agent are present in the composition in
`
`
`
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`a proportion of 0.3% to 30% by weight, preferably 0.5% to
`20% by weight with respect to the total composition weight.
`[0037] Oils that can be used in the invention that can be
`cited are hydrocarbons of mineral or synthetic origin (Vase
`line oil, isohexadecane), oils of plant origin (apricot kernel
`oil, the liquid fraction of karite butter oil, avocado, soya oil),
`oils of animal origin (lanolin), synthesized oils (perhy
`drosqualene, pentaerythrity1 tetraoctanoate), silicone oils
`(cyclopentasiloxane and cyclohexasiloxane) and fluorinated
`oils (perfluoropolyethers). It is also possible to use fatty
`alcohols (cetyl alcohol or stearyl alcohol), fatty acids (stearic
`acid) or waxes (carnauba wax, Ozokerite, beeswax) as the
`oily materials.
`[0038] Examples of emulsifying and co-emulsifying
`agents that can be used in the invention that can be cited are
`esters of fatty acids and polyethylene glycol such as PEG
`100 stearate and PEG-20 stearate and esters of fatty acids
`and glycerin such as glyceryl Stearate.
`[0039] The composition of the invention can also contain
`adjuvants, including those that are normal in the cosmetics
`field, such as hydrophilic or lipophilic gelling agents, hydro
`philic or lipophilic active ingredients, preservatives, anti
`oxidants, solvents, perfumes, fillers, filters, pigments, odour
`absorbers and colorants. The quantities of these different
`adjuvants are those that are conventionally used in the field
`under consideration, for example 0.01% to 20% of the total
`composition weight. Depending on their nature, such adju
`vants can be introduced into the oily phase, into the aqueous
`phase or into the lipid vesicles. In all cases, said adjuvants
`and the proportions thereof should be selected so that they
`do not deleteriously affect the desired properties of the
`adenosine/analogue.
`[0040] Particular examples of hydrophilic gelling agents
`that can be cited are carboxyvinyl polymers (carbomers),
`acrylic copolymers such as acrylate/alkylacrylate copoly
`mers, polyacrylamides, polysaccharides, natural gums and
`clays, and examples of lipophilic gelling agents that can be
`cited are modified clays such as bentonites, metal salts of
`fatty acids, hydrophobic silicon and polyethylenes.
`[0041] Examples of preservatives that can be cited are
`esters of para-hydroxybenzoic acid, octane-1,2-diol, 3-iodo
`2-propynyl-butylcarbamate, phenoxyethanol and chlorhexi
`dine gluconate.
`[0042] Examples of fillers that can be cited are polyamide
`(Nylon) particles; polymethyl methacrylate microspheres;
`ethylene-acrylate copolymer powders; expanded powders
`such as hollow microspheres and in particular, microspheres
`formed from a terpolymer of vinylidene chloride, acryloni
`trile and methacrylate and sold by Kemanord Plast under the
`trade name EXPANCEL; powders of natural organic mate
`rials such as starch powders, in particular corn starch, wheat
`starch or rice starch, which may or may not be cross-linked,
`such as starch powder cross-linked with octenyl succinate
`anhydride; silicone resin microbeads such as those sold by
`Toshiba Silicone under the trade name TOSPEARL; silica;
`metal oxides such as titanium dioxide or zinc oxide; mica;
`and mixtures thereof.
`[0043] As indicated above, the composition of the inven
`tion can also include UVA and/or UVB filters in the form of
`organic or inorganic compounds, the latter optionally being
`coated to render them hydrophobic.
`[0044] More particularly preferred organic filters are
`selected from the following compounds (cited using the
`
`CTFA nomenclature): Ethylhexyl Salicylate, Ethylhexyl
`Methoxycinnamate, Octocrylene, Phenylbenzimidazole Sul
`fonic Acid, Benzophenone-3, Benzophenone-4, Benzophe
`none-5,4-Methylbenzylidene camphor, Terephthalylidene
`Dicamphor Sulfonic Acid, Disodium Phenyl Dibenzimida
`zole Tetra-sulfonate, 2,4,6-tris-(diisobutyl-4-aminobenzal
`malonate)-s-triazine, Anisotriazine, Ethylhexyl triazone,
`Diethylhexyl Butamido Triazone, Methylene bis-Benzotria
`zolyl Tetramethylbutylphenol, Drometrizole Trisiloxane,
`1,1-dicarboxy-(2,2'-dimethylpropyl)-4,4-diphenylbutadiene
`and mixtures thereof.
`[0045] The inorganic filters are preferably constituted by
`an oxide of zinc, iron, zirconium, cerium and/or titanium
`(amorphous or crystalline in the form of rutile and/or
`anatase), preferably of nanometric dimensions (mean pri
`mary particle size: generally in the range 5 nm to 100 nm,
`preferably in the range 10 nm to 50 nm), optionally coated
`with alumina and/or stearic acid.
`[0046] The invention will now be illustrated by the fol
`lowing non-limiting examples. In said examples, reference
`will be made to the accompanying FIGURE which illus
`trates the contraction over time of an equivalent dermis
`treated with adenosine.
`
`EXAMPLES
`
`Example 1
`
`Determination of Dermo-Relaxant Effect of
`Adenosine
`a) Principle of the Test
`[0047]
`[0048] The principle of this test is to study the relaxing
`effect of adenosine on an equivalent dermis model consti
`tuted by a matrix of collagen seeded with normal human
`fibroblasts.
`[0049] These conditions were intended to imitate in vitro
`the dermal contractile phenomena which occur during facial
`expressions. Under these conditions, cells spontaneously
`express tensile forces which induce retraction of the col
`lagen gel. This results in a reduction in the total surface area
`of the equivalent dermis over time. Measuring that surface
`area allows the relaxation effects of substances that have
`been brought into contact with the equivalent dermis to be
`determined.
`[0050] b) Protocol
`[0051] Two series of 3 attached equivalent dermises con
`taining normal human fibroblasts were prepared: a control
`series with no treatment, and a series treated with adenosine
`(0.01%). The experiment was carried out three times.
`[0052] The skin equivalents were prepared as described by
`Asselineau et al, Exp. Cell. Res., 1985, 159, 536-539;
`Models in Dermatology, 1987, vol 3, pp 1-7, in the following
`proportions:
`
`MEM medium (1.76X) with or
`without adenosine:
`Foetal calf serum:
`NaOH (0.1 N):
`Acetic acid (1/1000):
`Collagen:
`Fibroblasts:
`
`45%
`
`9%
`5%
`4%
`26%
`11%
`
`
`
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`
`[0053] The treated equivalent dermis differed from the
`control equivalent dermis in that 0.01% of adenosine had
`been added.
`[0054] The collagen used was type I collagen (commercial
`solution), but it was also possible to use type III or IV
`collagen. It was extracted from rat tails or calf skin by acid
`hydrolysis and stored in an acidic medium at +4° C.; it
`polymerizes naturally by heating to 37° C. and by reducing
`the acidity. The collagen had been dialyzed against succes
`sive baths of water+acetic acid.
`[0055] The following protocol was employed: the follow
`ing were introduced into a sterile tube: 1.76×MEM medium
`in the presence of additives (glutamine 1%, non essential
`amino acids 1%, sodium pyruvate 1%, fungizone 1% and
`penicillin/streptomycin 1%), foetal calfserum, 0.1 Nisodium
`hydroxide NaOH. Fibroblasts isolated from human skin
`explants were then added in a concentration of 1.4×10° cells
`per ml of culture medium.
`[0056] A 1/1000 vol/vol mixture of collagen in acetic acid
`was then slowly added by pouring it down the tube wall so
`that the appearance of a whitish cloud was observed.
`[0057] The ensemble was then carefully mixed and dis
`tributed into the wells of a 12-well culture plate (Costar,
`reference 3512) in an amount of 0.5 ml of mixture per cm3.
`The culture plate was placed in an incubator at 37°C. with
`5% CO2.
`[0058] Once formed after polymerizing the collagen, the
`equivalent dermises were left adhering to the culture support
`for 3 days then detached from the support so that contraction
`could commence. Said attached equivalent dermises were
`removed from the incubator to record images with a view to
`measuring their surface area at each point of the contraction
`kinetics (0, 4, 8 and 24 hours). They were immediately
`replaced in the incubator between each measuring point.
`[0059] The spontaneous contraction of the treated (with
`adenosine) equivalent dermises and control (no adenosine)
`equivalent dermises was carried out by measuring their
`surface area at different times after the onset of spontaneous
`contraction.
`[0060] To this end, a digital image was acquired for each
`treated or untreated equivalent dermis using a camera (CCD
`Camera—Iris Sony DXC–107P) and the surface area was
`then calculated for each image using an image analysis
`system (Zeiss Axiovision 3.0). This surface area measure
`ment corresponded to a percentage contraction which equals
`the ratio of the surface areas in accordance with the formula:
`% contraction=(Sp—Si)/Spx100
`[0061]
`in which:
`[0062] “Sp” represents the surface area of one well in the
`culture plate; it corresponds to the total surface area of the
`equivalent dermis before contraction;
`[0063] “Si’ represents the surface area of the equiva
`lent dermis at the instanti in the contraction kinetics.
`c) Results
`[0064]
`[0065] As shown in the accompanying FIGURE, the
`degree of contraction of the control equivalent dermis was
`32% four hours after having been detached from its support.
`It increased to 42% after eight hours and reached 54% after
`twenty-four hours.
`
`[0066] Adenosine reduced this contraction percentage by
`6.4% after four hours, 10.5% after eight hours and 12.7%
`after twenty-four hours compared with the control.
`[0067] Thus, this test demonstrates that adenosine causes
`less contraction in an equivalent dermis, and thus has a
`relaxing effect which can be exploited in the preparation of
`compositions with a dermo-relaxant effect. As used herein,
`the relaxing effect is noted any time less contraction is
`observed, including less than 1%, 1%, 3%, 5%, etc.
`Example 2
`Cosmetic Composition
`[0068] This composition was prepared in a manner that
`was conventional for the skilled person. The quantities given
`in this example are indicated as percentages by weight.
`
`Adenosine
`Stearic acid
`Mixture of glyceryl mono-
`stearate and polyethylene
`glycol stearate (100 OE)
`Polyethylene glycol
`stearate (20 OE)
`Cyclopentadimethylsiloxane
`Fillers
`Vegetable oils
`Synthetic oils
`Preservatives
`Dimethylsiloxane,
`oxyethylenated (16 OE) with
`methoxy extremities
`Silicone gum
`Acrylic copolymer, in
`reverse emulsion (Simulgel
`600 from SEPPIC)
`Stearyl alcohol
`Water
`
`0.10%
`3.00%
`2.50%
`
`1.00%
`
`10.00%
`3.00%
`7.00%
`6.00%
`1.20%
`1.00%
`
`0.20%
`1.70%
`
`1.00%
`qSp
`100%
`
`[0069] This cream was intended for application to the face
`and forehead to soften lines and relax the skin of the face.
`[0070] The above written description of the invention
`provides a manner and process of making and using it such
`that any person skilled in this art is enabled to make and use
`the same, this enablement being provided in particular for
`the subject matter of the appended claims, which make up a
`part of the original description and including a cosmetic
`method for softening lines and/or relaxing the skin, and/or
`for relaxing facial features (“detendre les traits”) comprising
`topical application to the skin of a composition comprising
`at least one compound selected from adenosine and an
`analogue of adenosine, in a physiologically acceptable
`medium. Similarly, the invention composition can decrease
`wrinkles, reduce laugh lines, reduce frown lines, etc.
`[0071] Preferred embodiments of the invention similarly
`fully described and enabled include use of at least one
`compound selected from adenosine and an adenosine ana
`logue in a composition suitable for topical application to the
`skin, as an agent intended to soften lines and/or relax the
`skin, and the use of the invention compositions in an amount
`effective to provide a relaxing effect on contractile fibro
`blasts.
`[0072] As used above, the phrases “selected from the
`group consisting of" and “selected from" include mixtures
`of the specified materials.
`
`
`
`Case 1:17-cv-00868-JFB-SRF Document 13-3 Filed 08/18/17 Page 8 of 8 PageID #: 238
`
`US 2004/0146474 A1
`
`Jul. 29, 2004
`
`[0073] All references, patents, applications, tests, stan
`dards, documents, publications, brochures, texts, articles,
`etc. mentioned herein are incorporated herein by reference.
`Where a numerical limit or range is stated, all values and
`subranges therewithin are specifically included as if explic
`itly written out.
`[0074] The above description is presented to enable a
`person skilled in the art to make and use the invention, and
`is provided in the context of a particular application and its
`requirements. Various modifications to the preferred
`embodiments will be readily apparent to those skilled in the
`art, and the generic principles defined herein may be applied
`to other embodiments and applications without departing
`from the spirit and scope of the invention. Thus, this
`invention is not intended to be limited to the embodiments
`shown, but is to be accorded the widest scope consistent
`with the principles and features disclosed herein.
`1. A method for softening lines and/or relaxing the skin
`and/or relaxing facial features, comprising topically apply
`ing to the skin a composition comprising at least one
`compound selected from the group consisting of adenosine
`and adenosine analogues, in a physiologically acceptable
`medium.
`2. The method according to claim 1, wherein said com
`position comprises an adenosine analogue selected from the
`group consisting of: agonists of adenosine receptors, com
`pounds increasing intra- or extra-cellular adenosine levels,
`and mixtures thereof.
`3. The method according to claim 1, wherein said com
`position comprises at least one adenosine analogue selected
`from the group consisting of: 2'-deoxyadenosine; 2',3'-iso
`propylidene adenosine; toyocamycin; 1-methyladenosine,
`N-6-methyladenosine; adenosine N-oxide; 6-methylmercap
`topurine riboside; 6-chloropurine riboside; 5'-adenosine
`monophosphate; 5'-adenosine diphosphate and 5'-adenosine
`triphosphate; phenylisopropyl adenosine, 1-methylisogua
`nosine, N°-cyclohexyladenosine, N°-cyclopentyladenosine,
`2-chloro-Nº-cyclopentyladenosine,
`2-chloroadenosine,
`N°-phenyladenosine, 2-phenylaminoadenosine, MECA,
`Nº-phenethyladenosine,
`2-p-(2-carboxyethyl)phenethyl
`amino-5'-N-ethylcarboxamidoadenosine, N-ethylcarboxa
`midoadenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine,
`DPMA and metrifudil; erythro-9-(2-hydroxy-3-nonyl)
`adenine and iodotubercidin.
`4. The method according to claim 1, wherein the compo
`sition comprises 0.01% to 1% by weight of adenosine and/or
`adenosine analogue with respect to the total composition
`weight.
`5. The method according to claim 2, wherein the compo
`sition comprises 0.01% to 1% by weight of adenosine and/or
`adenosine analogue with respect to the total composition
`weight.
`6. The method according to claim 3, wherein the compo
`sition comprises 0.01% to 1% by weight of adenosine and/or
`adenosine analogue with respect to the total composition
`weight.
`7. The method of claim 1, wherein the composition is
`applied to one or more zones of the face or forehead marked
`with expression lines and/or to persons having expression
`lines.
`8. The method of claim 1, wherein said composition
`comprises adenosine.
`
`9. The method of claim 4, wherein said composition
`comprises adenosine.
`10. The method according to claim 1, comprising topi
`cally applying to the skin an amount of said composition
`effective to provide a relaxing effect on contractile fibro
`blasts.
`11. The method according to claim 10, wherein said
`composition comprises an adenosine analogue selected from
`the group consisting of: agonists of adenosine receptors,
`compounds increasing intra- or extra-cellular adenosine
`levels, and mixtures thereof.
`12. The method according to claim 10, wherein said
`composition comprises at least one adenosine analogue
`selected from the group consisting of 2'-deoxyadenosine;
`2',3'-isopropylidene adenosine; toyocamycin; 1-methylad
`enosine, N-6-methyladenosine; adenosine N-oxide; 6-meth
`ylmercaptopurine riboside; 6-chloropurine riboside; 5'-ad
`enosine monophosphate; 5'-adenosine diphosphate and
`5'-adenosine triphosphate; phenylisopropyl adenosine,
`1-methylisoguanosine, N°-cyclohexyladenosine, N°-cyclo
`pentyladenosine,
`2-chloro-Nº-cyclopentyladenosine,
`2-chloroadenosine, N°-phenyladenosine, 2-phenylaminoad
`enosine, MECA, N°-phenethyladenosine, 2-p-(2-carboxy
`ethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine,
`N-ethylcarboxamidoadenosine,
`5'-(N-cyclopropyl)-car
`boxamidoadenosine, DPMA and metrifudil; erythro-9-(2
`hydroxy-3-nonyl) adenine and iodotubercidin.
`13. The method according to claim 10, wherein the
`composition comprises 0.01% to 1% by weight of adenosine
`and/or adenosine analogue with respect to the total compo
`sition weight.
`14. The method according to claim 11, wherein the
`composition comprises 0.01% to 1% by weight of adenosine
`and/or adenosine analogue with respect to the total compo
`sition weight.
`15. The method according to claim 12, wherein the
`composition comprises 0.01% to 1% by weight of adenosine
`and/or adenosine analogue with respect to the total compo
`sition weight.
`16. The method of claim 10, wherein the composition is
`applied to one or more zones of the face or forehead marked
`with expression lines and/or to persons having expression
`lines.
`17. The method of claim 10, wherein said composition
`comprises adenosine.
`18. The method of claim 13, wherein said composition
`comprises adenosine.
`19. The method of claim 1, wherein said composition
`comprises adenosine and at least one adenosine analogue.
`20. The method of claim 10, wherein said composition
`comprises adenosine and at least one adenosine analogue.
`21. The method of claim 1, comprising topically applying
`to the skin an effective amount of said composition to
`decrease wrinkles and/or reduce laugh lines and/or reduce
`frown lines.
`22. The method of claim 8, comprising topically applying
`to the skin an effective amount of said composition to
`decrease wrinkles and/or reduce laugh lines and/or reduce
`frown lines.
`
`