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PATENT 



Attorney Docket Mo.: 00.22US 

IN THE UNITED STATES PATENT AND TRADEMARK OFFICE 
In re Application of: Maes, et al. 
\J Sena! No, 09/773,351 Group Ait Unit: 1619 

\A Filed:January31,2001 Examiner: Willis, M. 

V^Vj^ Ch0leSter ° 1 Sulfete ^ Amino Su &* Compositions for Enhancement of Stratum Comeum Function 





^\?\ RESPONSE PURSUANT TQ 37 CFR 1.111 

The Assistant Commissioner of Patents and Trademarks 
Washington, D.C. 20231 
Dear Sir: 



In response to the Examiner's Final Action dated December 12, 2001, please enter the following 
amendment and consider the following remarks which are believed to place the application in condition 
for allowance or in better condition for appeal in the event the fmal rejection is maintained. 




CLEAN AMENDMENTS 
Please amend the following claim as follows in its clean form below and as the previous version 
e claim is marked on the attachedjaaae^titied -MARiOm-^ 



(Amended), 
percent chq 



7 




method of claim 16 in which the composition comprises about 0,04 to about 1 .0 
sulfate. 



REMARKS 

L Non-essential Mater ial 

The Examiner has stated in the previous Office Action that an amendment to the disclosure to 
include the material incorporated by reference is required because the incorporation of essential material 
is improper at page 2, second full paragraph. At this cite, il is disclosed that cholesterol sulfate is known 
to retard desquamation in the stratum comeum of the skin in PCT Publication No. WO00/45786. 
Applicants contend that the incorporation by reference of this publication is of non-essential subject 
matter related solely to the background of the invention. As permitted according to the MPEP 608.01(p), 
nonessential subject matter is information referred to for purposes of indicating the background of the 
invention or illustrating the state of the art. The present invention relates to a combination of cholesterol 
sulfate with an cxfoliant, and the application of this combination to the skin is surprisingly effective in 



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strengthening the protective lipid barrier of the stratum coroeum. However, because the present 
invention relates to a mixture of components, the background of each of the components individually is 
provided in the background section of the present specification. Thus, the mention of the PCT 
Publication addressing cholesterol sulfate in die background section is not essential material, and 
Applicants request that this objection be withdrawn. 

n. 35 U.S.C. §112 

The Examiner previously rejected claims 1 2, 1 8, and 20 under section 112. second nara^nh for 
failing to particularly point out and distinctly claim the subject matter of the present invention. The 
Examiner suggested that this rejection can be overcome by adding the phrase "bark extract" to these 
claims. In Applicants' response of October 2, 2001, claims 12 and 20 were amended to add the word 
"extract." Support for these amendments is found in the present specification at page 7, lines 1 to 13. In 
this section of the specification the use of white birch is described and white birch bark extract is also set 
forth as the preferred protease inhibitor. Therefore, as amended, the claims of the present invention 
sufficiently point out and distinctly claim the white birch extract of the present invention, and Applicants 
request mat this rejection be withdrawn. 



The Examiner rejected claim 18 because it is a method claim depending from a composition 
claim. Applicants amend claim 18 herein to correct the inadvertent typographical errors in claim 18, 
including the claim number. Claim 18 should depend from claim 16 which is a method claim. Finally, 
claim 20 was also rejected by the Examiner as a result of typographical errors. Previously, in Applicants 
response of October 2, 2001, claim 20 was amended to remove the duplicate "of the" in the claim. 
Therefore, Applicants request that these rejections be withdrawn. 

The Examiner rejected claim 19 under section 1 12. first paragrap h -far failing to describe subject 
matter such mat one of ordinary skill in the art would be enabled to make and/or use the present 
invention. However, me enablement requirement of §112 has been interpreted to be an objective 
requirement, and therefore, this teaching can be provided through broad terminology or illustrative 
examples. In re Wright, 27 USPQ2d 1510, 1513 (CAFC 1993)(citing In re Marzocchi, 439 F.2d 220, 
223, 169 USPQ 367, 369 (CCPA 1971); In re Wands, 858 F.2d 73 1 , 736-37, 8 USPQ2d 1400, 1404 (Fed. 
Cir. 1988)). Thus, Applicants contend that the term "preventing" as used in claim 19 in connection with 
the description provided in the present specification is sufficient to enable one of ordinary skill in the art 
to make and/or use the present invention. As described at page 3, lines 13 to 15, the ability of the 



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present invention to prevent damage to the skin, especially when such damage is associated with a 
reduction or a loss of skin barrier function, is derived from the reparative and healing properties of the 
skrn. This is further described in the present specification at page 3, lines 26 to 28, wherein it is 
explained that the appearance of fine lines and wrinkles can be prevented by maintaining a thicker 
stratum comeum. This is a key function of the present invention and is based on the logistical behavior 
of the stratum comeum that is readily observed by one of ordinary skill in the art. 

Fine lines and wrinkles that arc present on the surface of thinned skin are part of the process of 
aging and is an expected development especially if there is no treatment applied to the skin to prevent it. 
It well known that youthful skin (e.g. 15 to 25 years of age) has a thicker and suppler consistency than 
older skin (e.g., 30 to 60 years of age). Thus, if the surface thickness can be maintained, the wrinkles 
associated with the thinning of the skin can be prevented. As disclosed in the present specification of 
page 4, lines 14 to 17, the present invention achieves a thicker layer of the stratum comeum while still 
promoting the cycle of removing dead skin cell layers. As a result, moisture is retained, the skin is 
firmer, and the appearance of lines and wrinkles are prevented. Finally, at page 8, lines 2 to 13, of the 
present specification, the method of using the present invention to prevent damage to skin that has 
experienced a reduction or loss m barrier function is provided. In addition, in Example 1 at pages 8 to 
10, the present specification demonstrates an 88 percent barrier repair over a placebo, indicating an 
improvement in the barrier function of the skin and prevention of damage. Therefore, the present 
specification fully enables one of ordinary skill in the art to prevent damage to the skin as described in 
claim 19. 

Applicants also submit herewith several examples of recently issued patents containing claims 
"preventing" various conditions. The first two patents, U.S. Patent Nos. 6,262,050 (copies of cover page 
and columns 7 to 10), and 6,333,042 (copies of cover page and columns 9 to 14), provide examples of 
claims to prevent irritation or skin pain. The third patent, US 6,329,369 ("the '369 patent") (copies of 
cover page and columns 83 and 84) provides an example of the understanding that one of ordinary skill 
in the art has with respect to the reduction of a symptom as being indicative of "preventing " a condition. 
In the present situation, a inverse measurement is made of the damage by measuring the increase in the 
health of the skin based on the increased barrier repair, rather than the decrease in the damage. 
Nonetheless, in either case, i.e., measuring an increase in the positive condition or measuring a decrease 
in the negative condition, the measurement indicates the ability to prevent a symptom. In the case of the 
present invention, the symptom is damage to the skin, especially skin that has experienced a reduction in 



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its protective barrier. One of ordinary skill in the art would understand that an increase in the protective 
barrier correlates to preventing the damaging effects seen on the skin for the reasons explained above, 
and as explained in the present specification. Therefore, Applicants respectfully request that the 
Examiner's rejections based on lack of enablement under 35 U.S.C. § 1 12, first paragraph be withdrawn. 

in. Non-Obvious 

The Examiner maintains in the final office that Ribier et al. (U.S. Patent No. 5,650,166; "the 
'166 reference") in view of Subbiah (U.S. Patent No. 6,150,381; "the '381 reference") renders claims 1 
to 20 of the present invention obvious under 35 U.S.C. § 103(a) because a mixture includes random 
solutions and vesicles. However, there is no support provided to indicate why or how one of ordinary 
skill in the art would understand that a mixture of the present invention is taught or suggested by a lipid 
vesicle described in the '166 reference. To establish a prima facie case of obviousness based on a 
combination of the content of various references, there must be some teaching, suggestion or motivation 
in the prior art to make the specific combination that was made by the applicant. In re Raynes, 7 F.3d 
1037, 1039, 28 USPQ2d 1630, 1631 (Fed. Cir. 1993); In re Oetiker, 977 F.2d 1443, 1445, 24 USPQ2d 
1443, 1445 (Fed. Cir. 1992). There is no teaching, suggestion or motivation in the art or the knowledge 
of one of ordinary skill in the art to support the assertion that mixing components is equivalent to or 
includes encapsulating components. Moreover, cited '166 reference demonstrates just the opposite: that 
specific processing steps required to make a vesicle distinguish it from a mixture. 

One of ordinary skill in the art understands the difference between a mixture of components, a 
random solution of components, and a vesicle, a discrete arrangement of its components. Evidence of 
this is found in the cited references wherein specific processing steps to make a lipid vesicle are taught 
and/or suggested at column 7, line 42 "A) Production of lipid vesicles containing ASL" to column 8, line 
4 "B) Production of the cosmetic composition.'• The process of making lipid vesicles includes, for 
example, evaporation or co-fusion to achieve encapsulation. This is in stark contrast to the present 
invention of a simple mixture of an effective amount of an exfoliant and cholesterol sulfate. The 
combination of these two components has surprisingly been found to improve and/or protect the barrier 
of the stratum comeum even though the two components have opposite acting activities with respect to 
exfoliation. The present invention is not taught or suggested by the cited references nor would one of 
ordinary skill in the art reasonably expect to achieve the present invention based on the combination of 
the '742 reference and the '381 reference an discussed in further detail below. 



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The '3S1 reference teaches sclareolide-lOce compounds for treating disorders caused by 
microbials such as, for example, bacteria, and one specific disorder is acne. The '381 topical 
formulations containing sclareoiide are generally prepared, according to the <38l referaice, by admixing 
sclareolide in water and at least one organic solvent. Therefore, the '381 reference teaches that 
sclareoiide is an aqueous active. Thus, the combination of the <38I reference with the ■ 166 reference 
fails to teach or suggest the present invention because one of ordinary skill in the art would expect the 
sclareolide disclosed in the '381 reference to be incorporated within the aqueous cavity of the lipid 
vesicles disclosed by the ' 1 66 reference, and therefore, be encapsulated. The * 166 references teaches a 
moisturizing composition which comprises a first and a second dispersion of lipid vesicles. The % 166 
reference discloses at column 3, lines 66 to 67, that the lipid phase of the vesicles is an alkali metal salt 
of cholesterol sulphate. Therefore, the alkali metal salt of cholesterol sulphate is disclosed as part of the 
lipid bilayer which forms the cavity within which an aqueous active, i.e., sclareolide, is encapsulated. 
This is not a mixture of cholesterol sulphate and an exfoliant as is the subject of the present invention, 
and therefore, the combination of the *381 reference and the ' 166 reference fails to teach or suggest the 
present invention- 



In the final action, the Examiner also asserts that the feature of a mixture is not recited in the 
claims nor is it taught in die specification. However, Applicants contend that a mixture is taught both in 
the claims and the specification. First, at page 3, lines 5 to 6, the invention is described as being a 
topically applied composition that is a mixture of an exfoliant and a cholesterol sulfate. Further on page 
3, at lines 18 to 20, the present invention described as a cholesterol sulfate and an exfoliant combined in 
a mixture. Again at page 4, line 25, the components of the mixture are described throughout the 
paragraph. Finally, at page 5, lines 12 to 13, cited by the Examiner, the combination of the two 
components have previously been described as a mixture, as it has been pointed out at pages 3 and 4. 
Thus, the combination refers to the mixture previously mentioned and described in further detail on 
pages 3 and 4. In addition, the "combination 1 ' that can be applied in any type of vehicle refers to the 
mixture previously described in the specification. Further evidence that the reference to a combination 
would be understood as a mixture is found in the following paragraph on page 5, lines 20 to 25, wherein 
the mixture is specifically stated as being used in therapeutic products as well as color cosmetic products. 
Therefore, a mixture is taught in the present specification and one of ordinary skill in the art would 
understand that the teachings in the present specification are to mixtures and not lipid vesicles. 



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In addition to teaching a mixture in the present specification, the claims specifically state a 
mixture. Claims 1, 13, 16 and 19 each describe a composition comprising a mixture of cholesterol 
sulfate and an exfoliant. As previously elaborated upon, the steps taken to make a mixture and the steps 
taken to make a lipid vesicle are vastly different, and the resulting products, i.e, a mixture versus a 
vesicle, are as vastly different as their processing steps. Therefore, the combination of the '1 66 reference 
and the '381 reference fails to teach or suggest the mixture of the present invention and fails to teach or 
suggest the beneficial results derived from the simple mixture of the present invention. Because none of 
the cited references alone nor in combination would lead one of ordinary skill in the art to the 
compositions and methods of the present invention, a prima facie case of obviousness has not been 
established. Applicants request therefore, that the Examiner's rejection under §103 be withdrawn. 

CONCLUSION 

In view of the arguments presented above in the present submission, the claims are believed to be 
in condition for allowance, and issuance of a Notice of Allowance is respectfully solicited. 

Respectfully submitted, 

Dorene M. Price (Reg. No. 43,01 8) 
Estce Lauder Companies 
125 Pinelawn Road 
Melville, NY 11747 
(631) 531-1194 



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MARKED AMENDMENTS 

18 (Amended). The method of claim [1] J6 in which the composition comprises about 0.04 to about 1.0 
percent cholesterol sulfate. 



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(12) Omitted States 

Chow ct aL 



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■■■■■■■iiiiii 

US006329369B1 

(10) Patent No.: US 6,329,369 Bl 
(45) Date of Patent; Dec- 11, 2001 



(54) METHODS OF TREATING PAIN AND 
OTHER CONDITIONS 

(75) iAVentnrs: Ken Chmv, Newport Coast; Daniel W» 
Gil, Corona Del Mar; James A. Burke, 
Santa Ana; Dak A. Harcourt, San 
Clenjcnte; Michael E. Garst, Ncwpnn 
Beach: Larry A. Wheeler, Irvine, all of 
CA (US); Stephcm A. Mnnk, 
NorthviUe, Ml (US) 

(73) Assignee: AlIcrgQb SaJes^ Inc^ Irvine, OA (US) 

( * ) Notice: Subject lo any disclaimer, the term of this 
patent is extended or adjusted under 35 
UJS.ll 154(b) by 0 day*. 

(21) Appl No.: 09/679,919 

(22) Filed: Oct 3, 20H0 

Related VS. Application Data 

(60) Divabq ot application No. U9/32y.75Z filed on Jud. 10. 
1999, now abandoned, which is a eonun initio E-ui-part. of 
appLvutfon No. 09/205,597, lilcd on Det. 4, 1993, now 
abamioned, which in a vcmlinuation-tA-|>afi ol' appticaiioa 
No. 08/985,347, filed ou Dec 4, 1997, now abandon. 

(51) InL CI. 7 A$1R 31/416-8: A61U 31/4178; 

AG1R 31/538; A61N 9/02; A61N 11/02; 

A61N 27/06 

U.S. CL .„ S14/23G\Sj 514/249; S 14/255; 

514/370; 514/377; 514/392; 514/397; 514/401; 
514/413; 514/415; 514/816; 514/913; Sl4/530^t 

Fteld rtf Search ..... „ 514/249, 377, 

514/413, 415, 255, 816 



(52) 



(58) 



(56) 



Ro fere noes Cited 
U.S. PArtNT DOCUMENT 



Re. 32,400 
4,443,466 
4,496.572 
4^40,705 
5,021,416 
5*034,406 
5,0*^664 
5,077,292 
5,091,52S 
5,112,822 
5,130,441 
5,151,440 
5,151,526 
5,180,721 
5,198,442 
5,215,991 
5.231,096 
S„SS2,403 
5,561,132 
5,580.892 
5,621,113 
5,663,189 
5,750,720 



4/1987 
4/1984 
1/1985 
9/198S 
6/1991 
7/1991 
11/1 <*J1 
12/1991 
2/1992 
5/1992 
7/1992 
9/1992 
9/1992 
1/1993 
3/1993 
6/1993 
7/1993 
9/l9y<> 
10/1996 
12/1996 
4/1997 
9/1997 
5/1998 



Kagabincn el al. , 
Crass ct a). . 
Baifry . 
Glucbowsii . 
GlUehuvndu . 
Gluchowsfei . 
Gluciowski . 
Glucbowski . 
Glucbowikj , 
Glucnowsk; . 
Gluchowski . 
Tfcu ut al. . 
Buifcs d al. . 
Gluchow&ki . 
Burke et aJ. . 
GIuchow%lei . 
Borke et al. . 
Burku el al. . 
Gaffll al. . 
Ooyd et aJ. . 
Maurcr ct al. * 
Boyd, II ct al. . 



0 304 910 
1/242571 
4/267130 
WO 94/07866 
WO 95/16449 
WO 95/19968 
WO 96/01813 
WO 97/0307? 
WO 97/12874 
WO 97/15302 
WO 97/31636 
WO 97/35858 



3/1989 (ElO . 
9/198& (jy). 
9/1992 (JF). 
4/1W4 (WO). 
6/1995 (WO). 
7/199S (WO) . 
1/1996 (WO). 
1/1997 (WO). 
4/1997 (WO). 
5/L997 (WO). 
9/1997 (WO). 
12/1997 (WO). 

OTHHK PUBLICATIONS 



FORKIGN PATENT DOCUMBNTS 
0 194 984 9/1986 (HP) . 



Bylucd et aU 1994, Pharmacol Rev. 46, pp. 121-136, 
International Union of Pharmacology Nomenclature of 
Adrenoceptors". 

Shimtcu el al, 1969, J. Neurocoem. 16, pp. 1609-1619, "A 
Radiosotopic Method For Measuring The Formation of 
Adenosine 3' , 5' -Cyclic Monophosphate in Incubated 
Slices Of Brain". 

Messier ct al, 1995, Pharmacol. Toxicol. 76, pp. 308-311, 
"High Throughput Assays of Cloned Adrenergic, Muscar- 
inic, Neurokinin, and Neurotrophic Receptors in Living 
Mammalian Colls". 

Neve et al, 1992, J. Biol. Cbcm. 267, pp. 25748-25753, 
"Dopamine D2 Receptor Stimulation of Na+/ H+ Exchange 
Assessed by Quantification of Extracellular Acidification". 
Williams el al, 1990, J. Autnrt. Pharmacol, 10, 247. pp. 
109-118, "a 2-adrenoceptor antisecretory responses in the 
rat jejunum". 

Fondacaro ct al. 1988, vol. 247, No. 2, pp. 481-486, "The 
Journal of Pharmacology and Experimental Therapeutics". 
White ct al, 1975, Communications/Synthesis, pp. 602V-3, 
"A Convenient Procedure for the Preparation of 2-cndo-IIy- 
droxy-cis-bkydo pJ.OJoctanc". 

COnklin et al, Nature, 1993, vol. 363» pp. 274-6, "Substi- 
tution of three amino acids swiichcs receptor specrfity of G 
a to thai nf GiCl". 9 
Xchaaf el al, J. Med. Chem. 1983, vol. 26, pp. 328-334, 
"Stmciure-AcoMty Studies of Configurationally Rigid 
Aryl prostaglandins". 

Kihara et al, " Preparation of imidazole derivatives as drugs", 
6001 Chemical Abstracts, Columbus, Ohio, U.S. vol. 1 12 
(Apr. 9, 1996), No. 16, XP-002098179. 
Zhang et al, "Mcdciomidint: Analogs as (^-Adrenergic 
Ligands. 3. Synthesis and Biological Evaluation of a New 
Scries of Mcdctomidine Analogs and Their Potential Bind- 
ing Interactions with CUAdrenoceptors Involving a 'Methyl 
Pocket* J. Med. Cncmc. 1997, 40. pp. 3014-3024. 
Merck Index, Twelfth Edition, p. 1 1 v5, # 71 00 (1996).* 

* cited by ejuum'ncr 

Primary Examiner— ftoyd D. Higei 

(74) Attorney, Agent, or Firm—C&rtQS A. Fisher; Robert J. 

ftaran; Martin A. Vbei 

(57) ABSTRACT 

Methods of treating glaucoma or elevated pressure and other 
diseases with reduced side effects by treating a mammal in 
need thereof an agonist of the alpha 2B or alpha ZB/2C 
adrenejgic receptees). Also described arc compounds hav- 
ing such selective agonist activity, 

17 Claims, No Drawings 



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US 6,329,369 Bl 
83 84 



\V 
\ 




wherein W is a bicyclic radical selected from the group 

consisting Of l0 whcre j n thc d0Ucd hncs rcpfcsent op^ona! doi]b j e R 

is II or lower alkyl; X is S or C{H)R\ wherein R 1 is H or 
lower alkyl or R 1 is absem when X is S or when the bond 
between X and the ring represented by 

iS 




20 » a doable bond; Y is O, N, S, (CR'x)™ Wherein y is an 
wherein R ♦ R% R and R 8 are selected from the group integer of from 1 to 3, — CH=CII— or — Y^-rk— , 
consisting of II and lower afltyl provided that at least one of wherein Y l is O, N or S - x is an integer of 1 ut 3, wfcerein 
R 5 and R a or R s and R* are OCXR^QR^NCR) to form a x is 1 when K 2 , R 3 or R is bound to ao unsaturated carbon 
condensed ring with atom and x is 2 when R 1 . R 3 or R* is bonded to a saturated 

25 carbon atom; K a is II, lower alkyl, halogen, hydroxy or 
lower alkoxy, or oxo; R 3 and R* are, each, H, lower alkyl, 
hydroxy, lower alkoxy, or phenyl or. together, are — (CfR 2 ) 
-YHCOOxK-; -Y^co^y Y 1 -; —(OCR 2 ) 

J0 X)— and — V J — (C(R 2 )x)_ ^-((Xtffry- wherein Z is 
B integer of from 3 to 5, z' is an integer of from 2 to 4 and 

wherein R is H, lower alkyl or oxo and x and y are as defined above, and further either end of each 

of these divalent moicLies optionally attach at either ft* or R 4 




to form the condensed ring structure 




w 
\ 



wherein R 1 " is H, lower alkyl, phenyl or lower alkyl 
substituted phenyl, and Z is O or NIL 40 

9. A process of Claim 8 wherein thc agonist has an cfEcncy 

at least about 0.3 greater at the a2B or 2C adrenoceptor a^d the ring thus formed is totally unsaturated, partially 
subtypes than at the a2A adrenoceptor subtype, and wherein unsaturated, or totally Saturated provided that a ring carbon 
its efficacy at the a2A adrenoceptor subtype is £0.4. nas no more than 4 valences, nitrogen no more than three 

10. A process of claim 9 wherein approximately Q,00l% 4ji a nd O and S have no more than two; or 
to 5% by weight of the agonist is administered topically to 

the mammal in daily or twice daily doses. 

11. A process of claim 10 wherein approximately 0.01% 
to 3.0% by weight of the agonist is administered topically to 

the mammal in daily or twice daily doses, 50 . . 

12. A process of claim 8 wherein said agonist has uu ^ / 

detectable activity at the u2A adrenorcccptor subtypes. 

13. A process of claim 8 wherein said agonist has no 

detectable activity at the ct2A and a2C adrenoreceptor wherein W is a bicyclic radical selected from the group 
subtypes. 55 consisting of 

14. A process for administering to a mammal a pharma- 
ceutical composition comprising a therapeutically effective / 
dose nf a compound to treat or prevent a pathological v 
condition selected from the group consisting of muscle 
spasticity; pain; neurodegenerative diseases, spinal ischemia 60 
and stroke; memory and cognition deficits; psychoses, anxi- 
ety and depression; hypertension; congestive heart failure; 
cardiac ischemia and nasal congestion, wherein said com- 
pound has adrenergic activity and is a selective agoaist of 
the a2D or a2B/a2C adrenoceptor receptor subtype(s), said o? 

selective agonist having a structure selected from the group wherein R s , R rt , R 7 and are selected from the group 
consisting of compounds having the formula consisting of II and lower alfcyl provided that at least one of 




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(i2) United States Patent 

be Lachfirriere 



516 531 1340 P. 13 



iHnuinuiuH 

US006262050B1 

(io) Patent No.: US 6,262,050 Bl 
(45) Date of Patent: Jul. 17, 2001 



(54) TOPICAL COMPOSITION CONTAINING 
CAPSAZEPDSfE 

(75) Inventor: Olivier Do Lacharricre, Paris (FR) 

(73) Assignee: S«ciete I'OreaJ S.A., Paris (FR) 

{ * ) Notice: Subject to any disclaimer, the term of this 
patent is extended or adjusted under 35 
U.S.C. 154(b) byOdaySw 

(21) Appl. No.: 09/457,667 

(22) Filed: Dec, 9, 1999 

Related VJS. Application Data 

(63) Coatirtuutfon of application No, OVlttfi^?, filed as appli- 
cation No. PCT/FRQrt/01592 oa Oct. 11, 1996, now PaL N«. 
<J r 04S£S5. 

(30) Fonriga Application Priority Data 

Nov. 6, 1995 (FR) __ „ 95/l3JNo 

(51) Int. CI. 7 _ A0IN 43/46; A61K 31/55 

(52) VS. a „ „. 514/213.01 

(58) Field of S^rch ~ 514/213 



(56) 



References Cited 
PUBLICATIONS 



BRX Pharmacol., vol. 107, No. 2, 1902, pp. 32SU333 
XP000576708, M.N. Perkins "Capsazepine reversal of the 
aotinociwipiivc action of capsaicin io vivo". 

Primary Ex<imin£r—Dviiynz O. Jones 

(74) Attorney, Agent, or Firm — Burn*, Doune, Swccker & 

Mate, L.Li> 



(57) 



ABSTRACT 



A topical Composition containing caps;i2epiiie and particu- 
larly suitable for treating neurogenic skin disorders and 
diseases, especially painful and/or prunginous diseases, as 
well as for treating sensitive skin and eyes, in particular, llie ^ 
uwnposition is useful for preventing and/or COulrulling skin 
and/or eye irritation, itching, erythema and dysesthesia and 
heating of the skin, eyes and mucosa, as well as for reducing 
the irritancy of an active substance having an irritant Side- 
cflfcet. 

9 Claim*, No Drawing* 



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516 531 1340 



P. 14 



-continued 



Folywrhate 60 (V*KCx «J, sole hy 

the Company ICI) 

Stearic Ao'd 

Tiiolbsoolamine 

CBibcmer 

Ucuid fracuuo from tamic butter 

Perfaydnjsqtsileiii! 

Antin«iilnnl 

F/agrantx 

Preservative 

Utter 



US 6,262,050 Bl 



8 



qj- fnr 



1.00 
1.40 

a.70 
o.<o 

tino 

OlOS 

o.s 

OJO 
J00% 



EXAMPLE 6 

Pain-con trol fid, in particular far ihc pain associated with 

shingles 



EXAMPLE 3 



Shampoo 



10 



Capsazfpin; 

HydraxypropyluclluJuat (KDucel H, uulJ 
by Iht Omnpftuy Hurodcs) 
Antioxidant 

I .idocaiac hydrochloride 

lAOpfOpancd 

PlCscrValive 

Water 



qj. for 



OJO 
1D0 

0X5 
2.00 

100% 



EXAMPLE 7 

Face cream for the care of rusacca (oil-in-water emulsion) 



Sodium rn*£dc>uajii buuyl ether arable 
containing 4 ulOl of ethylene oxide, . V U 
urrdet lite name oCTfexapon ASv by Ilanld 
(Anionic aurtaOant) 
Caps&zepiae 

Hj^tttypropylceDtilow (KlUCvl H, sold by 
the Company Hercules) 

Water 



0.02 

1.00 

050 
0.30 
100% 



EXAMP»Jti4 

Anti^wrinltle care cream for the iacc.(oil-in-watCf cmulsiun) 



30 



Cap*fteeplnc 
Glyceryl alette 

Pulywrbnte 60 (TWewi CO, avid by the 

Company ICI) 

Stearic acid 

Mclfonidn^olc 

THetkiftolfl Olloc 

Carhamer 

liquid fraction frum larite huttcf 
Liquid pelroJatum 
AfiLOxiilflJiL 

FrtflCfvntivo 



q.». Cur 



0.25 
2D0 
100 

t.40 
1.00 
0.70 
C.40 
12.00 
12.00 
0.05 
05 

oja 

300% 



Capsazepine 
Glyceryl steonte 

Polywrhme 60 (TVucn 60, sold by the 
Company Id) 
Stearic acid 

5-(n-Od&aoyi)uKcy1tc nctd 

TricUxanoInimne 

C&rfcanjcr 

liquid fraction from JEariLc bullcr 

rerhydmsqunlcnc 

Ar.lioxida.nl 

Fragnoct 

Preservative 

Water 



q.s. Tor 



O.03 
2.00 
1.00 

1.40 
0.50 
0.70 
0.40 

lion 

0.05 
0.5 

o_-?o 
too* 



EXAMPLE 8 

Creara for caring for sensitive skins with respect to simburn 
35 (oil-in-watcr emulsion) or for treating the symptoms relating 
to shingles 



40 



4S 



EXAMPLE 5 

Emulsified gel for the care of insect slings (oil-in*water 
emu 



50 



Copsaxepine 
Glyceryl Stttu'AlC 

Polysorbatc 60 (IVoen £0, snld fcy the 

f :ftmp4oy ICI) 

SliAftC fcctd 

rfiycyf/bctinic acid 

Trie(^ncl«imiic 

Carta toer 

Liquid traction from fcorite butter 

SuoiLowET oil 

Antioxidant 

Fragrance 

Preservmjve 



q.*. Cur 



045 
2JX) 
1.00 

1.40 
2.00 
0.70 
0.40 
12.00 
10.00 
0.05 
03 
OJO 
100% 



Cycloawlhiccae 

Puredlin di (sold by the Ccm^y Dia fc -occo) 

PEG-6/F£G-32KJlycol jslearatc (Tcfot:<& 03 iron 

Cjailolcewaa) 

CdpSaicpiDB 

PreaerMiiive 

Fixgranca 

Corbozior 

Crotamiion 

GlyCyiibclinie acid 

Elhyi alcohol 

Trinlhmnl amine 

Vrfeer 



q.#. lor 



3.00 
7.00 
0.3U 



0.35 
0.40 

u.to 

5.U0 
200 
5.00 
0.20 
100% 



Ouular colly fium 



EXAMPLE 9 



Cnpaazepine 




O.03 


Excipient 


qj». for 


100 


Scdittm chloride 




Sodiun ho rate 






Polysorbnta flO 






Boric tcid 






Wmer 







What is claimed is: 

1. A method tot treating cutaneous pain, said method 
comprising ujpicalty applying on effective amount of cap* 



Recdved from < 516 531 1340 > at 3/12/02 2:36:31 PM [Eastern Standard Time] 



MAR-12-2002 15:23 COMPANIES 516 531 1340 P. 15 



US 6,262,050 Bl 

9 , 10 

sazepine to a patient id need of such tnatmcot to prevent V 4. The method according to claim l , wherein capsazepine 
and/or combftt cauocous pain, used in an amount ranging from 0.00000] to 5% by weight 

2. AmctDOdfOr uxattrjg cutaneous and/Of ocular irritation, with respect to the total weight of the composition 
erythemas, pruntus or warming and/or dysacsihctic sensa- 5. The method according to claim 2, wherein capsarepinc 
lions of tbe skin, the eyes Or mucous membranes, said 5 is used in an amount ranging from 0-000001 to 5fl !by weight 
method comprising topically applying ao effective amount /with respect to the total weigh! of the composition 

of capsazepine to a patient in need of such treatment to ✓ 6. The method according to claim 3 t wherein capsazepine 
prevent and/or combai cutaneous acd/or ocular irritation, is used in an amount ranging from 0.000001 to 5% by weight 
erythema, pruritus or warming and/or dysacstkeiic sensa- with respect to the total weight of ihe coniposiUon 
uons of the don or the eyes. 10 7. The method according to claim 4, wherein capsaaepioe 

3. A method for treating symptoms related to shingles, is used in an amount ranging from OOQOOl to 0 5% by 
eczema, sensitive skin or eye*, pnuiginous diseases, weight with respect to the total weight of the compc-friuoa, 
pruritus, herpes atopic or intact dermatitis lichens, 8. Tbe method Jiccurdin K to claim 5, wherein capsazepine 
prurigos, insert slings, rosacea, conjunctivitis or uveitirtcs, is used in an amount ranging from (J.CU001 lo 0.5% by 
said method comprising topically applying an effective 1$ weight wiLh respect to the total weight of tbe composition 
amount of capsazepine to a patient in need of such treatment * 9. The method according to claim 6, wherein capsazepine 
to prevent and/or combat symptoms related to shingle*, \J is used in ao amount ranging from 0.0000.1 to 0.59b by 
eczema, sensitive skin or eyes, pruriginous diseases, weight with respect to the total weight of the composition, 
prontus, herpes, atopic or contact dcrmatiiides, lichens, 

prurigos, insect slings, rosacea, conjunctivitis or uveilides. * * « + * 



Received from < 516 531 1340 > at 3/12/02 2:36:31 PM [Eastern Standard Time] 



MAR-12-2002 15:24 



COMPPNIES 



516 531 1340 P. 16 



(12) Umtnfasdl States Patemit 

De La Charrierc et al. 



USO06333O42B1 

(io) Patent No,: US 6,333,042 Bl 
(45) Date of Patent: *Bcc 25, 2001 



(54) USE OF A SUBSTANCE P ANTAGONIST FN A 
COSMETIC COMPOSITION, AND THE 
COMPOSITION THUS OBTAINED 

(75) Inventors: Olivier De La Charriere, Paris; Uonul 
Breton, Versailles, both of (FR) 

(73) Assignee; Soclctc L'Oreal SA., Paris (PR) 

( * ) Notice; Subject to any disclaimer, foe term of this 
paten! ifr extended or adjusted under 35 
ILS.C. 154(b) by 0 days. 

This patent is subject to a terminal dis- 
claimer. 

(21) Appl. No.: 09/S84>724 

(22) Filed: Jun. 1, 2008 

Related VS. Application Date 

(63) Continuation of application No. 03/881,272, filed on Jud. 
24, 1997, now Pit. No. 6,203^03, whit* is a continuation 
of application No. 08058,562, filed on IV 14, 1994, oc*v 
abandoned. 

(30) Foreign Application Priority Data 

May 5, 1994 (FK) „ „ _..„ 94 (15537 

(51) tot CV A61K 7/00; A61K 7/15; 

A61K 7.16; A61K 7/155; A61K 7/32 

(52) VS. CL .„ 424/401; 424/49; 434/59; 

424/63; 424/76.1; 514/15; 514/210; 514/293; 
514/305; 514/315; 514/41(1; 514/416; 514/422,- 
514/844; 514/845; 514/846; 514/847; 514/848; 

514/880; 514/H81 

(58) Field of Search _ 424/401,49,70.1. 

42450, 63, 76.1, DIG. 1; 514/15, 210, 
293, 305, 315, 410. 416, 422, 844-848, 

tftfn, K«i 

(56) References Cited 

VJS. PATENT DOCUMENTS 

3,266,934 8/1966 Rufes «| nl. . 

3.772.431 11A073 MJlcvv ct aL . 
3,888,976 6/1975 MiUwy el al. . 
4,477,439 10/1984 D'Alelio . 

4.943.432 7/1990 Biener . 
4,980,164 12/1990 Gordon. 
4,986.981 1/1991 Gbo: ct aL . 
5,047,409 9/1991 Di Sohicna ct al. . 
5,079,010 1/199Z Noucref . 
5,091,171 2/1992 Mi ci at . 
5,202,130 4A993 Cram d ol. . 
5.593,992 1/1997 Adaois «t at, . 

5,627,187 5/1997 Kafc „ _ 514/274 

5,658,581 8/1997 dc Lacfaairwre . 

5,679,360 10/1997 dc Ucharrfcrc , 

5,714,155 2/1998 de Ucharricre . 

5,716,625 2/1998 Hahn et aL . 

5,788,956 8/1998 De Licharriun: et al 424/65 

5,803,095 9 A 998 De Ucharriwe et al 132/204 

5317,666 1Q/1998 Kite _„ 514/274 

5,851,556 12/1998 Drctoa ct al 424/639 

5,853,024 1/1999 Dc Luehamerc ct al _ &W1H 

5,850,168 2/1999 De J.^charriere et al. _ 424/639 



5,900,257 5/1999 Breton et al 424/639 

5,972,892 10/1999 Dc Laddrriere ct aL 514/15 

ri/)34,256 3/2000 Carter ctal 549/456 

FOREIGN PATENT DOCUMENTS 



3320539 Al 
3338957 

3627746 Al 
0280992 
0297062 
0217975 

0299457 A2 
0360390 
0401503 
0429366 
0439640 
045989ft 

0461526 A2 
052280ft 
0514273 
0520555 

0522808 A2 
0528495 
0*45478 
05S6929 
061257,*! 

0668075 A2 
5394 

2271774 
63-56206 
83/01252 
87/01935 

91/18899 
93/01165 
93/01159 
93/01160 
93/01 16« 
93/01 J 70 
V3/U4U40 
93/1 40fU 
96/19181 
96/19182 
96/19183 
96/19184 
96/19228 
97/15276 



12/1983 
5A985 
2/19S8 
7/1990 

4/1987 
1/1989 
3/1990 
4/1990 
5/1991 
8/1991 
12/1991 
12/199 J 
7/1992 
11/1992 
12/1992 
1/1993 
2/1993 
6/1993 
3/1994 
8/1994 
8/1995 
10/1967 
6/1978 
4/1994 
U/L99S 
4/1963 
1CV1986 
5/1990 
12/1991 
7/1992 
1/1993 
1/1993 
1/1993 
1A993 
3/1993 
7/1993 
6/1996 
6/1996 
6/1996 
6/1996 
6/1996 
5/1997 



(DE). 
(DE). 
(TWO. 
(DE). 
(DE). 
(FT). 
(EIO. 
(HP). 

m - 

(CP). 
(EP). 
(FP). 
(EP). 
(EP). 
(LP). 
(EP) - 
(EP). 

(ISP). 
(KM). 
(RK). 
(EP). 
(FR). 
(FR). 
(GB) . 
(IF). 
(WO). 
(WO), 
(wo). 
(WO). 
(WO). 
(WO). 
(WO). 
(WO). 

(WO). 

(WO). 
(WO). 
(WO). 
(WO). 
(WO). 
(WO). 
(WO). 
(WO). 



OTHtLR PUBLICATIONS 

RajadhyakstKU Chemical Abstracts, vol 107, 1987, No. 
2232S1. 

Pi Seta icna, Chemical A bstracts. vol. 106, 1 987, No. 107768. 
Smilb et al, ChetnicalAbstractx, vol. 114, 1991, No. 206554. 

(List continued on next page.) 

Primary £xn/ii//Mr^-Gollatfliidi S. Kishnre 

(74) Attorney, Agent, or Firm— Burns, Doane, Swecker & 

Mathis. L.L.P. 



(57) 



ABSTRACT 



A substance P antagonist is used in a cosmctii; composition 
tn treat sensitive skin. More specifically, a cosmetic com- 
position containing a substance P antagonist is used to 
prevent and/or combat skin irritations, desquamation, / 
erylhermas, sensations of dysestocsia/overbealing, nr pruri- 
tus uf the skin. 

180 Claims, No Dm wings 



Received from < 516 531 1340 > at 3/1 2102 2:36:31 M [Eastern Standard Time] 



MAR-12-2002 15:24 



9 



COMPANIES 



516 531 1340 P. 17 



EXAMPLES 



Shampoo 



US 6,333,042 B1 

10 

EXAMPLE 12 
Anti-Solar Erythenw Cream (OU-iuAvaler Emulsion) 



Secdide 

Ilydioxyprapy Iccllul cue 

(KteccJ U, sold by the Hercules Cbmpady) 

Prewrvalivo 
Water 



0.00.1 
J -00 

0.30 

<pp ion* 



EXAMPLE 9 

Emulsified Gel To Fight Insect Slings (Oil-in-water 
Emulsion) 



15 



spantide Q 


0.25 


Glycerol steams 


2JX) 


Polysorbate &> 




(T»-«n W «4d by the JC1 Company) 




Stearic acid 


1.40 


Olycyrrhetinic auk] 


2.00 


TrielhanolamuM 


0.70 


Gubomcr 


0.40 


Liquid focljra of lean la m »l butler 


J2J00 


Sunfbwc / uil 


J 0H0 


Antioxidant 


o.ns 


HttUmt 


0.50 


Preservative 









CycJomeibfcooe 


.V0f) 


PurceMlfl oil 


TOO 


(acid hy the Dragoccn Cntnpi>ny) 


PF.rVli/pEG-32/Gtycera! $tea>*tc 


0.30 


flfcfotM ® cold by OftMtbno) 




spantide II 


ao2 


Preservative 


030 


Perfume 


0.40 


Caibanwr 


o.<w 




5.00 


Oiycynhetinic arid 


100 


Ethyl alcohol 


5.00 


Triethftaoliaiise 


0.20 


WliCr 


qsp, 100% 



25 



3U 



EXAMPLE 10 



Pain-Fighting (jcl 



Spantide II 

Hydroxy propylcelluJosc 

Coined tU add by the Heicn|«* Company) 

Antioxidant 

Lidocaioo ehlaxhydmte 

Iaoprapanol 

Preservative 

Water 



OA* 
1.00 

U.U5 
2.00 
40.00 
030 
q*p 100% 



EXAMPLE 11 
Anti-Acne Rosacea Face Cretin (Oil- in -water Emulsion) 



Spentidc u 


0.25 


(rlyticroJ atearate 


2.00 


Poly soibaia 60 


3.00 


(TUcca 60 sold by tfee IGt Oumpany) 




Stearic acid 


1.60 


Metronidazole 


LOO 


Trieth^jolamiR* 


0.7G 


Carbomsr 


0.40 


Liquid ftftcdoa uf kaiile nul butter 


12.00 


MueHne oU 


12j00 


Antioxidant 


0.05 


Perfume 


0.50 


PTEjervniivc 


030 


Water 


qsp lOOCn 



Wbai is claimed is; 

1. A topically applicable cosmetic composition which is 
adapted for use in a cosmetic regimen tUat Comprises topical 
application of Raid composition to at least one of the akin, 
hair, or mucous membranes, which composition comprises: 

(1) an amount of al least one irritant substance sufficient 
to elicit an irritant side eHect tn a user having sensitive 
skin when utilized in a topical cosmetic regimen that 
docs not include the use of a substance P antagonist. 
Wherein said irritant substance is an active agent ia Said 
topical cosmetic regimen; 

(2) an amount of at least one substance P antagonisl . 
sufficient to prevent or alleviate Said irritation when v 
said composition is utilized in a topical cosmetic regi- 
men on a user having sensitive skin, wherein said 
substance P antagonist is a substance which possesses 

at least one of Ihe following characteristics: 
35 (i) it elicits a pharmacological response in at least one 
of the following tests: 

(a) it reduces the extravasation of plasma through too 
vascular wall cavscd by capsaicin or antidromic 
nerve excitation; and 
40 (b) it inhibits the contraction of Smooth muscle 

induced by substance P; add 

(3) a cosmetically acceptable medium. 

2. A topically applicable cosmetic composition which is 
adapted for use in a cosmetic regimen that comprises topical 
45 application of said composition to at least one of the skin, 
hair, or mucous membranes, which composition comprises: 
0) an amount of at least one irritant substance suHknent 
to elicit an irritant side effect to a user having sensitive 
Skin when utilized in a topical cosmetic regimen that 
50 docs not include the use of a substance P antagonist, 
wherein said irritant substance is an active agent in said 
topical cosmetic regimen; 
(2) an amount of al least one .substance P antagonist 
sufficient In prevenl or alleviate said irritation when K/ - 
ss said composition is utilized in a topical cosmetic regi- 
men on a user having sensitive skin, wherein said 
substance P antagonist is a substance which possesses 
at least one of the following characteristics: 
(i) it exhibits a selective affinity for the NK, receptors 
60 on the tachykinins; and 

(u) it elicits a pharmacological response in at least one 
Of the following tests: 

(a) it reduces the extravasation of plasma through the 
vascular wall caused by capsaicin or antidromic 

65 nerve excitation; and 

(b) it inhibits the contraction of smooth muscle 
ipduevd by substance P; and 



Received from< 516 531 1340 > at 3112/02 2:36:31 FM [Eastern Standard Time] 



ML COMPPNIES 



.MPR-12-2002 15:25 (JB- COMPPNIES W 516 531 1340 P. 18 



11 



US 6,333,042 Bl 



15 



(3) a cosmetically acceptable medium; 
wherein said topical jy applicable cosmetic composition 
comprises a galenic formulation which is a solution or 
dispersion formulated as a lotion or scrum, microgranulale 
dispersion, vesicular ionic or non-ionic dispersion, alcoholic 
Or hydroalcoholic aqueous Solution, cream, gel, oil-in- Water 
ur waier*h>Ofl emulsion, foam, aerosol, soKd or paste. 

3. A topically applicable cosmetic composition which is 
adapted for use in a cosmetic regimen that comprises topical 
application Of said composition to at least One of the skin, 
hair, or mucous membranes, which composition comprises: 

(1) an amount of at least one irritant substance sufficient 
to elicit an irritant side effect to a user having sensitive 
skin when utilized in a topical cosmetic regimen that 
does cot include the use of a substance P antagonist, 
and wherein said irritant substance is an active agent in 
said topical cosmetic regimen; 

(2) an amount of at least one substance P antagonist 
sufficient to prevent or alleviate said irritation when s/ 
said composition is utilized in a topical cosmetic rcgi- 
men on a user having sensilive skin, wherein said 
substance P antagonist is a substance which possesses 
at Least one of the following characteristics: 
(i) it elicit* a pharmacological response in at least one 

of the following tests: 

(a) it reduces the extravasation of plasma through the 
vascular wall caused by capsaicin or antidromic 
nerve excitation; and 

(b) it inhibits the contraction of smooth muscle 
induced by substance P; and 

(3) a cosmetically acceptable medium; 
wherein said topically applicable cosmetic composition suit- 
able for use in a cosmetic regimen is selected from the group 
consisting ofa hair care composition, skin Care composition, 
cleansing composition, fiunscreen composition, and a mouth 
care composition. 

4. A topically applicable cosmetic composition which is 
adapted for use in a cosmetic regimen that comprises topical 
application of said composition to at least one of the skin, 
hair, or mucous membranes, which composition comprises: w 

(1) an amount of at least one irritant substance sufficient 
to elicit an irritant side eifcet to a user having sensilive 
skin when utilized in a topical cosmetic regimen that 
does not include the use of a substance P antagonist, 
and wherein said irritant .substance is an active agent in 4S 
said topical cosmetic regimeo; 

(2) an amount of at least One substance P antagonist 
sufficient to prevent or alleviate said irritation when >/ / 
Said composition is Utilised in a topical cosmetic regi- 
men on a user having sensitive skin, wherein Said 
substance P antagonist is a substance which possesses 
at least one of the following characteristics: 

(i) it exhibits a selective affinily for the NK, receptors 
On the tachykinin^; and 

(ii) it elicits a pharmacological response in at least one 
of the following tests; 

(a) it reduces the extravasation Of plasma through (be 
vascular wall caused by capsaicin or antidromic 
nerve excitation; ami 

(b) iL inhibits the contraction of smooth muscle 
induced by substance P; and 

(3) a cosmetically acceptable medium; 
wherein said topically applicable cosmetic composition suit- 
able for use in a cosmetic regimen is selected from the group 
consisting of a hair care composition, skin caic composition, 65 
cleansing composition, sunscreen composition, and a mouth 
care composition. 



12 



50 



«0 



5. A topically applicable cosmetic composition which is 
adapted for use in a cosmetic regimen that comprises topical 
application of said composition to at least one of the skin, 
hair, or mucous membranes, which composition comprises: 

(1) an amount of at least one irritant substance sufficient 
to elicit an irritant side eiTect to a user having sensitive 
skin when utilized in a topical cosmetic regimen that 
docs not include the use of a substance P antagonist, 
wherein said irritant substance is an active agent in said 
topical cosmetic regimen; 

(2) an amount of at least one substance P antagonist y 
sufficient to prevent or alleviate said irritation when v 
said composition is utilized in a topical cosmetic regi- 
men 00 a user having sensitive skin, wherein said 
substance P antagonist is a substance which possesses 
at least one of the following characteristics: 
(i) it elicits a pharmacological response in at least ODC 

Of the following tests: 

(a) ii reduces the extravasation of plasma through the 
vascular wall caused hy capsaicin or antidromic 
nerve excitation; and 

(b) it inhibits the contraction of smooth muscle 
induced by substance P; and 

(3) a cosmetically acceptable medium; 
wherein said topically applicable cosmetic composition 
comprises a galenic formulation which is a solution or 
dispersion formulated as a lotion or scrum, micrngjanulate 
dispersion, vesicular ionic or non-ionic dispersion, alcoholic 

^ Or hydroalcoholic aqueous solution, cream, gel. oil-in-water 
or wator-io-oiJ emulsion, foam, aerosol, solid or paste, 

6. A topically applicable cosmetic composition which is 
adapted for use in a cosmetic regimen that comprises topical 
application of said composition to at least one of the skin, 
hair, or raucous membranes, which composition comprises: 

(1) an amount of at least one irritant substance sufficient 
to elicit an irritant side effect to a user having reactive 
skin when utilized in a topical cosmetic regimen that 
does not include the use Of a substance P antagonist, 
wherein Said irritant substance is an active agent in said 
topical cusmetfc regimen; 

(2) an amount of at least one substance P antagonist / 
sufficient to prevent or alleviate said irritation when ^ 
said composition w utilized in a topical cosmetic regi- 
men on a user having reactive skin, wherein said 
substance P antagonist is a substance which possesses 
at least one of the following characteristics: 
(i) il elicits a pharmacological response in at least one 

of the following tests: 

(a) it reduces the extravasation of plasma through the 
vascular wall caused by capsaicin or antidromic 
nerve excitation; and 

(b) it inhibits the contraction of smooth muscle 
induced by substance P; and 

(3) a cosmetically acceptable medium, 

7. A topically applicable cosmetic composition which is 
adapted for use in a cosmetic regimen that comprises topical 
application of said composition to at least one of the skin, 
hair, or mucous membranes, which composition comprises: 

(1) an amount of at least one irritant substance sufficient 
in elicit an irritant side effect to a user having reactive 
Skin when utilized in a topical cosmetic regimen that 
does not include the use of a substance P antagonist, 
wherein said irritant substance is an active agent in said 
topical cosmetic regimen; 

(2) an amount of at least one substance P antagonist s 
sufficient tn prevent ur alleviate said irritation when v 



AS 



Received from < 516 531 1340 > at 3/12(02 2:36:31 PM [Eastern Standard Time] 



^MAR-12-2002 15:25 



COMPANIES 



516 531 1340 P. 19 



13 



US 6,333,042 Bl 



said composition is utilized in a topical cosmetic regi- 
men on a user having reactive skin, wherein said 
substance P antagonist is a substance which possesses 
at least one of the following characteristic*: 
(0 it exhibits a selective affinity fox the NK 3 receptors 

on ihc tachykinins; and 
(ii) il elicits a pharmacological response in at least one 

Of the following testa: 

(a) it reduces the extravasation of plasma through the 
vascular wall caused by capsaicin or antidromic 
nerve excitation; and 

(b) it inhibits the contraction or smooth mu.se! c 
induced by substance P; and 

(3) a cosmetically acceptable medium; 
wherein said topically applicable cosmetic composition 
comprises a galenic formulation which is a solution or 
dispersion formulated as a lotion or Serum, microgranulate 
dispersion, vesicular ionic or non -ionic dispersion, alcoholic 
or hydroaicoholie aqueous solution, cream, gel, oil-in-watcr 
or water-in-oil emulsion, foam, aerosol, solid or paste, 

£. A topically applicable cosmetic composition which is 
adapted for use in a cosmetic regimen thai comprises topical 
application of said composition to at least one of the skio, 
hair, or mucous membranes, which composition comprises: 

(1) an amount of at least one irritant substance sufficient 
to elicit an irritant side effect to a user having reactive 
skin when Utilized in a topical cosmetic regimen that 
does not include toe use of a substance P antagonist* 
and wherein said irritant substance is an active agent in 
said topical cosmetic rejjimen; 

(2) an amount of at least one substance P antagonist / 
sufficient to prevent or alleviate said irritation wheW 
.said composition is utiliy^d in a topical cosmetic regi- 
men on a user haviog reactive skin, wherein said 
substance p antagonist is a substance which possesses 
at least one of the following characteristics: 
(i) it elicits a pharmacological response in ai least one 

of the following tests: 

(a) il reduces the extravasation of plasma through the 
vascular wall causwl by capsaicin or antidromic 
nerve excitation; and 

(b) it inhibits the contraction of Smooth muscle 
induced by substance P; and 

(3) a cosmetically acceptable medium; 



14 



(ii) ft elicits a pharmacological response in at least one 
of the following tests; 

(a) it reduces the extravasation of plasma through the 
vascular wall caused by capsaicin or antidromic 

5 nerve excitation; and 

(b) it inhibits the contraction of smooth muscle 
induced by substance P; and 

(3) a cosmetically acceptable medium; 
wherein said topically applicable cosmetic composition suit- 
10 able far use in a cosmetic regimen is selected from the group 
consisting of a hair care composition, *k\rt care composition, 
cleansing composition, sunscreen composition and a mouth 
care composition, 

10, A topically applicable cosmetic composition which is 
, s . adapted for use in a cosmetic regimen that comprises topical 
application of said composition to at least one of the skin, 
hair, or mucous rncmbraneS;, which composition comprises: 

(1) an amount of at least one irritant substance Sufficient 
!o elicit an irritant side effect to a user having reactive 

2D skin when utilized in a topical cosmetic regimen that 
docs nor include the use of a substance P antagonist, 
wherein said irritant substaflce is an active agent in Said 
topical cosmetic regimen; 

(2) an amount of at least one substance P antagonist > 
sufficient lo prevent or alleviate said irritation when v 
said composition is utilized in a topical cosmetic regi- 
men on a user having reactive skin, wherein said 
substance p antagonist is a substance which possesses 
at least one of the following characteristics: 
(i) it elicits a pharmacological response in at least one 

Of the fallowing tests: 

(a) il reduces the extravasation of plasma through the 
vascular wall Caused by capsaicin or antidromic 

- nerve excitation; and 

(b) it inhibits the enn traction of Smooth muscle 
induced by substance P; and 

(3) a cosmetically acceptable medium; 
wherein said topically applicable cosmetic composition 
comprises a galenic formulation which is a solution or 

40 dispersion formulated as a lotion or scrum, microgranulate 
dispersion, vesicular tonic or Don-ionic dispersion, alcoholic 
or nydroaknholjc aqueous solution, cream, gel, oil-in-waier 
or water-in-oil emulsion, foam, aerosol, solid or paste. 
11. The composition of claim 3„ wherein said hair care 



25 



30 



35 



able for use m a cosmetic regmten is selected from the £roirD ^ a JT™ „„=..„ 1 ~! , - 



able for use in a cosmetic rcghnen is selected from the group 
consisting Of a hair care composition, skin care composition, 
cleansing composition, sunscreen composition and a mouth 
care composition. 

9. A topically applicable cosmetic composition which is 
adapted for use in a cosmetic regimen that comprises topical 
application of said composition to at least one of the skin, 
Hajr, or mucous membranes, which Composition comprises: 

(1) an amount of at least one irritant substance sufficient 
to elicit an irritant side effect to a user having reactive 55 
skin when utilized in a topical cosmetic regimen that 
does not include the use of a substance P antagonist, 
and wherein said irritant substance is an aedve agent in 
said topical cosmetic regimen; 

(2) an amount of at least one substance P antagonist fry 
sufficient lo prevem or alleviate Said irritation whenv 
said composition is utilized to a topical cosmetic regi- 
men on a user having reactive skin, wherein Said 
substance P antagonist is a substAQCC which possesses 
at least one of the following characteristics: 
(i) it exhibits a selective affinity for the NK 2 receptors 

on the tachykinins; and 



shampoo, setting lotion, treatment lotion, hair cream, hair 
gel, cob ring composition, restructuring lotion, permanent 
composition, anti-hair loss lotion and anti-hair loss gel. 
1-2. The composition of claim 4, wherein said hair care 
so composition is selected from the group consisting of a 
shampoo, setting lotion, treatment lotion, hair cream, hair 
gel, coloring coinposilinn, restructuring lotion, permanent 
composition, ami -hair loss lotion and anti-hair loss gel. 

13. The composition of claim 3, wherein said hair care 
composition is in a galenic form selected from the group 
consisting of a cream, gel, emulsion, foam and aerosol. 

14. 'The composition of claim 4, wherein said hair care 
composition is in 4 galenic form selected from the group 
consisting of a cream, gel, cmuJstOu, foam and aerosol 

15. Tbe composition of claim 3, wherein said cosmetic 
composition is a cleansing cream, skin protecting or skin 
treatment cream, make-up removal cream, foundation 
cream, sunscreen composition, liquid foundation, make-up 
removal lotion, protective or sldn care lotion, slrin Care geL 

<S5 skin care foam, bath preparation, deodorant composition, 
after-shave gel or lotiou, depiUtnry cream, composition for 
alleviating insect sting, soap or cleansing bar. 



Received from<516 531 1340 > at 3/1^02 2:36:31 PM [Eastern Standard Time] 



TOTAL P. 19