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Attorney Docket No.: 00.22US 




IN THE UNITED STATES PATENT AND TRADEMARK OFFICE 

In re Application of: Maes, et al. 

Serial No.: 09/773,351 Group Art Unit 1619 

Filed; January 3 1 , 2001 Examiner: Willis, M. 

For: Cholesterol Sulfate and Amino Sugar Compositions for Enhancement of Stratum Comeum Function 

RESPONSE PURSUANT TO 37 CFR LI 11 

The Assistant Commissioner of Patents and Trademarks 
Washington, D.C. 2023 1 
Dear Sir: 

In response to the Final Action of December 12, 2001, and the Advisory Action dated March 26, 
2002, please consider the following remarks regarding the rejections which were maintained therein. The 
Examiner maintained the rejection of claim 19 under section 112, first paragraph for failing to describe 
subject matter such that one of ordinary skill in the art would be enabled to make and/or use the present 
invention. Specifically, the Examiner asserts that the specification lacks enablement for "preventing" 
damage to the skin. The Examiner's position is based on the reasoning that damage to the skin cannot be 
adequately predicted such that it is not possible to determine if damage has been prevented. In addition, in 
response to the submission of other patents using the term "preventing", the Examiner points out that each 
application is examined on its own merits. 

Knowledge of certain factors, such as f for example, chronological aging or overexposure to UV 
radiation based on studies of the changes in the skin subjected to a specific factor makes it possible to 
predict damage to the skin. Thus, while damage to the skin cannot be predicted in its entirety, there are 
specific types of damage that the skin may experience and that are indeed predictable. As an illustration, 
predictability of the damage to the skin is demonstrated in U.S. Patent No. Re. 36,068. In this document, at 
columns 3 to 4, the predictable characteristics of sundamaged and aging skin are described. Similar to Re. 
36,068, Claim 19 does not broadly describe damage to the skin; but rather, addresses a specific type of 
damage. In Claim 19 the damage is that which is associated with a reduction or loss of skin barrier function, 
and the characteristics of this damage are described in the present specification. Specifically, at page \, line 
26 to page 2, line, examples of a compromised skin barrier are provided as being UV-damage, degradation 
of collagen and elastin, and wrinkling and skin atrophy. Therefore, there is an ability based on knowledge in 
the art regarding aging and sundamaged skin to permit with great accuracy the prediction of damage 



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associated with a reduction or loss of skin barrier function. It is important to note that the damage referred 
to in Claim 19 is not open-ended damage to the skin but instead is limited to damage to the skin's protective 
barrier function. 

The Examiner also reasons that "prevention" of a symptom is not the same as a reduction of a 



definition of the word "prevent" as it is defined in the Webster's Encyclopedic Unabridged Dictionary of the 
English Language ("the Dictionary") at page 1 141 means "to keep from occurring/' lliere is no mention of 
a correlation with reducing the thing that is kept from occurring, presumably because they are two different 
words. However, if a condition already exists the fact that it is possible to reduce that condition inherently 
means that it is not occurring any further. One of ordinary skill in the art understands the scope and 
meaning of the word "prevent" as it used in the present invention. Therefore, Applicants request that the 
Examiner's rejections based on lack of enablement under 35 U.S.C. § 1 12, first paragraph be withdrawn. 

The Examiner also maintains in the advisory action 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; u 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. In response to Applicants' previous arguments regarding the teachings of the '166 reference, 
the Examiner points out that the '166 reference teaches the formation of vesicles by mixing. However, the 
second category of vesicles which is taught as being capable of formation by simple stirring does not teach 
or suggest a simple mixture of an exfoliant and cholesterol sulfate which are the actives of the present 
invention. The present invention relates to a mixture of cholesterol sulfate and an exfoliant which can be N- 
acetylglucosamine. Specifically, the 1 166 reference teaches N-acetyl-glucosamine as being an active agent 
with deep down action at column 5, line 67 (i.e., encapsulated in the first category vesicle B) 1 Production of 
vesicles of first category (diffusing deep down)), it is not taught as a second category active for diffusing at 
the surface. Therefore, the teaching of second category vesicles containing surface diffusing actives by 
simple stirring with a lipid system in Table I fails to teach or suggest the present invention because N-acetyl 
glucosamine is not taught in the * 166 as being a surface diffusing active. 

As the Examiner points out, at column 8, line 23, of the '166 reference, the production of vesicles of 
the second category (diffusing at the surface) are taught, however, the simple stirring is of the second 
category active into a particular type of lipid system disclosed in Table 1 which will act as the membrane for 
the lipid. Thus, while it appears that the vesicle can be formed by simple stirring according to the '166 
reference in one of the lipid systems of Table 1 7 the vesicle is then added to the cosmetic composition which 



symptom. However, Applicants submit herewith a dictionary definition of the word "prevent." The 



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* also contains first category vesicles. This is evidenced by the section heading B) Production of the cosmetic 
composition. Therefore, there is no teaching of a simple mixture of cholesterol sulfate with N- 
acetylglucosamine in a composition, and thus, no teaching or suggestion of the present invention by the ' 166 
reference. 

Further, the ' 166 reference teaches away from the present invention because the teaching of N- 
acetyl glucosamine in the '166 reference is as a deep down active which is encapsulated according to the 
elaborate process in B) Production of vesicles of first category (diffusing deep down). As previously 
mentioned in the Applicants' Reponse of March 12, 2002, the process of making lipid vesicles taught or 
suggested by the 1 166 reference would not provide motivation to one of ordinary skill in the art to make the 
simple mixture of the present or to achieve the surprising results of the present invention. The '166 
reference demonstrates the exact opposite of the present invention. With respect to N-acetyl glucosamine as 
a deep diffusing active, the '166 reference teaches that co-fusion processing steps are required to make the 
first category vesicle which is distinguishable over a simple mixture. Further, even if a vesicle can be made 
as described in the section for second category vesicles by simple stirring, the second category vesicles are 
still composed of a surface diffusing active encapsulated by a lipid system which is added to a cosmetic. 
The exfoliant, namely N-acetyl glucosamine, of the present invention is not taught in a simple mixture with 
cholesterol sulfate, therefore, the 466 reference, alone or in combination with the '381 reference, fails to 
teach or suggest the present invention. Because neither 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. 43,018) 
Estee Lauder Companies 
125Pinelawn Road 
Melville, NY 11747 
(631) 531-1194 



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United States Patent m 

Kligman 



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iiiiiiiiiiiiiaiiiiiiiii 

USO0RE36068E 

e Patent Number: Re* 36,068 

[451 Reissued Date of Patent: Jan. 26, 1999 



[54] METHODS FOR TREATMENT OF 
S UNDAMAGED HUMAN SKIN WITH 
RETINOIDS 

[76] Inventor: Albert M, Kligman, 238 Oceana Dr., 
Harvey Cedars, N.J. 08008 

[21] Appl. No.: 630,872 
[22] Filed: Apr 2, 1996 

Related VS. Patent Documents 

Reissue of: 

[64] Patent No,: 4,877,805 

Oct 31, 1989 
205,057 
Jun. 3, 1988 



Issued: 
Appl. No.; 
Filed: 
U.S. Applications: 

[63 1 Continuation of Ser. N». HK6 7 596 J Jul. 16, 1986, abandoned, 
which is 3 continuaiion-in-nart of Scr. No. 759,503, Jul. 26, 
196*5, Pat, No. 4,603, 146, which is a continuation of Scr. No. 
610/711, May 16, 19fi4, abandoned, which is a continuation- 
in-part of Sen No. 297,388, Aug. 28, 1981, abandoned. 

[51] Int. CI. 6 A61K 31/20 

[52] U.S. CI 514/381; 514/438; 514/532; 

514/550: 514/617; 51.4/622; 514/725 

[58] Field of Search 514/381. 138, 

514/532, 559, 61 7, 622, 725 

[56] References Cited 

U.S. PATENT DOCUMENTS 



3,729,568 
3,356,934 
3,906,108 
4,247 F 547 
4,396,553 
4,603,146 
4,877,805 
4,888^342 



4/1973 

12/1974 Felty 
9/1975 Fclty. 
1A981 Mart* 
671983 
7/1986 



Marks 5 14/559 

424/62 



514/559 

Klaus 560/456 

Kligman - 514/559 

10/1989 Kligman 514/381 

12/1989 Kligman 514/419 

OTHER PUBLICATIONS 



See Attachment — Part I, Listing of Infumration from Klig- 
man and Brycc File Historic* (3 pages). 
Sec Attachment — Part H„ Record of Interference No. 102, 
638 (22 pages). 

U.S. Scr. No. 297.388 (Abandoned). 

Thomas ct ^Journal of American Academy of Dermatol* 

ogy (May 1981). vol. 4, No. 5, pp. 505-513. 

U.K. 906,000, Sep. 1962. 

U.S. Serial No. 610,711 (Abandoned). 

Kligman el b\., Archives of Dermatology (Oct, 1971), vol 

104, pp. 420 and 421. 

Kligman et al., Archives of Dermatology (Jan., 1975), vol. 
Ill, pp. 40-^S. 

Robinson et aL, British Journal of Dermatology (1975). vol, 
92, pp. 703-706. 

Kligman el al., Journal of Investigative Dermatology 

(1979), vol 73, pp. 354-358. 

US. Ser. No. 759,505 (Issued as the '146 Patent). 

U.S. 4,603,146. Jul- 1986, 514/559. 

U.S. Ser. No. 886,595 (Abandoned). 

U.K. 1,466,062, Mar. 1977. 

FR 13V30 May, 1972. 

Pawson el al.. Journal of Medicinal Chemistry (1°K2), veil. 
25, pp. 1269-1277. 



Saurat (editor), Symposium Publication— Karger Publishing 
Company (1985) ("Retinoids: New Treads in Research and 
Therapy"). 

Pawson (Deluca et al, editors). Annals of the New York 
Academy of Sciences (1981), veil. 359, pp. 1-13. 
UK 1,335,867, Oct. 1973. 

Sporn et al., 1985 Retinoids, Differentiation Qtut Disease, 
vol. 113, pp. 1-5. 

Elias et al (editors), Topical Retinoids; An Update— Pn> 
ccedings of a Symposium held Apr. 19-20, 1986, pp. 
748-156. 

Bollag (Saurat editor), Retinoids: New Trends in ReseanrJi 
and Therapy (1985), pp. 274-288. 
Spora et al. (editors). The Retinoids (1984), vol. 1, pp. 
393-413; Newton ct al.. Cancer Rcseardx (1980), vol. 40, 
pp. 3413-3425. 

Locligcr ct al„ European Journal of Medicinal Chemistry — ■ 
Chimica Ttierapeutica (Jan .-Feb. 1980), Vol. 15 , No. 1, pp. 
9-15. 

U.S. Ser. No. 228,212 (issued as the F 342 Patent): [no 
additional art cited]. 

U.S. Ser. No. 205,057 (issued as the '805 Patent). 
Saline, Philadelphia Magazine (1980), pp. 102-133. 
Industry Happenings, Drug & Cosmetic, Industries (1985), 
p. 86. ' 

UK 1,239,965. Jul. 1981. 

FR 2,405,068 Oct. 1977. 

German 2,240,187 Feb. 1974. 

BE 877,713 Nov. 1979. 

Mayer et al., Experientia (1978), vol. 34. 

Trown, Cancer Research (1980), vol. 40, p. 212. 

VS. Ser r No. 86,992 (Abandoned). 

VS. Ser. No. 219,616 (Abandoned). 

EPA 253,393, Jan. 1988. 

UK Application 906,000. Sep. 1962. 

U.S. Scr. No. 520.166 (Pending) 1995. 

Declaration of Dr. Graeme Brycc. 

Declaration of Dr, Stanley Shapiro, 1996. 

(List continued on next page.) 

Primary Examiner — James II. Reamer 

Attorney, Agent, or Firm— Sughnic, Mion. Zinn, Macpeak 

& Seas, PLLC 



[57] 



ABSTRACT 



Various effects of photo aging or sundatnage of skip includ- 
ing impairment of differentiation of epidermal epithelial 
cells and loss of collagen hbers, abnormal changes in clastic 
fibers and deterioration of small blood vessels in the dermis 
of the sldn are retarded by applying topically to the epider- 
mis in a maintenance therapy program effective amounts of 
retinoids including retinoid derivatives and stereoisomers 
thereof such that epithelial growths are substantially reduced 
and prevented and the skin substantially regains and main- 
tains its firmness, turgor and elasticity. Moreover with 
persistent treatment dermal blood cells and vessels increase 
and the epidermis and dermis thicken, resulting in improved 
ability of the skin to sense, resist and recover from irritation 
or injury. Further, hyperpigmcntation, lines and wrinkles due 
to aging are reduced and prevented. The treatment is par- 
ticularly useful for human facial skin and preferably applied 
in amounts insufficient to cause excessive irritation. 

U Claims No Drawings 



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* 



Re. 36,068 

1 2 

METHODS FOR TREATMENT OF I L * s ^ own to use certain retinoids, particularly vitamin A 

SUNDAMAGED HUMAN SKIN WITH acid, topically for treatment of acne as set forth in my VS. 

RETINOIDS Patt No. 3/729,568. Other known topical uses of vilainiQ A 

acid were reviewed by Thomas, J. R., et al, "The Therapeutic 
Matter enclosed in heavy brackets [ ] appears in the 5 uses of Topical Vitamin A Acid", Journal of American 



in 



original patent but forms no part of this reissue specifi- Academy of Dermatology 4:505-516 (1981) include, 

cation; matter printed in italics indicates the addition* addition to acne treatment, treatment of senile comedones, 

made by reissue. nevus comedonicus, linear verrucous nevus, plantar warts, 

pseud of ollicultis, kcrato acanthoma, Solar keratosis of 

CROSS-REFERENCE TO RELATED 10 extremities, callositcs, keratosis palmaris et plantaris. Dari- 

APPUCATIONS cr's disease, ichthyosis, psoriasis, acanthosis nigricans, 

lichen planus, mulluscuni coulagiosum, reactive perforating 

Ibis application is a continuation of application Ser. No. co iiagt:nu$is, melasma, corneal epithelial abrasion, geo- 

886,595, filed July 16, 1986, now abandoned, which in mm graphic tongue, fojc-Fordyce disease, cutaneous metastatic 

is a continuation-in-part of my VS. Pat. Applicarinn Ser. Mo. ^ mc | annma and keloids or hypertrophic scars. 

759,505 filed July 26, 1985 cndtW, n *^*"£*£ lt is believed that retinoids influence ultrasuuclural and 

mg the EfFccis of Aging of the Skin now U S. Pat, No. KfcnlivB ^ of idermaJ ^ However, these 

4,603 146 which was a conUnaaUon ot appkcaUon Ser No. * of viumin Aacid have generally involved short 

610,711, AW May 16, 1984, now abandoned, which in * flIg ^ ^ ^ conccmmions 

I^^f^TTSf" .f Cr " M retinoic acid are applied (i.e. sufficient to cause significant 

AUg ' 28 h U u U "ru ° n T*Tw oftcD ^^6) in order to obtain a quick 

Me ^/° r L mP T Mgtb l°^ h V therapeutic effect of the particular condition, such as 

Aging Kcurdut , now abandoned. removal of comedones, as oppc^d lo long-term treatment of 

FIELD Of THE INVENTION normal aging or photographing skirt. 

25 My copending application Ser. No. 759,505 discloses 
This invention relates to methods using retinoids to retard methods for treating ^undamaged human skin topically with 
the effects of aging of the skin and generally improve the vitamin A acid in an emollient vehicle iu such amounts as to 
quality of the skin, particularly human facial skin. essentially non-irritaling to the skin. This treatment 

causes the skin, particularly human facial skin, to substan- 
BACKGROUND OP THE INVENTION «0 tkUy cegaill and mamuin its firmness, turgor and elasticity 

Caucasians who have had a good deal of sun exposure in by retarding and reversing the skin's loss of collagen fibers, 

childhood «ill show the following gross cutaneous alter- abnormal changes in elastic fibers, deterioration ot small 

acions in adult life: wrinkling, leathcrincss, yellowing, blood vessels, epidermal atrophy and formation of abnormal 

looseness, roughness, dryness, mottling 3J epithelial growths. 

(hyperpigmeaUtion) and various premalignaot growths " BRIEF SUMMARY Of THE INVENTION 

(often subclinical). These changes arc most prominent in D,UC1 

light-skinned persons who burn easily and tan poorly. The >r DC present invention relates to the use of other retinoids, 
baleful effects of sunlight arc cumulative, increasing wit^ ^ hereinafter defined, in moderating and preventing the 
lime often referred to as "phnLoaging". Although the ana- 



flomic degradation of the skin is most advanced in the 
elderly, the destructive effects of excessive sun exposure arc 



aging changes of the exposed (sundamaged) areas of the 
skin, especially the face. In particular, the methods of the 
present invention retard the effects of photo aging of the skin 



I already evident by the second decade. Serious microscopic} Jj ue lo thinning and abnormal differentiation of the 

^ alterations of the epidermis and dermis occur decades before epidermis, inter alia, la general, the present invention relates 

ihesc become clinically visible. Wrinkling, yellowing, A$ to methods for retarding and reversing the toss of collagen 

leatheriness, loss of elasticity arc very late changes. fibers, abnormal changes in elastic fibers, deterioration of 

Retinoids (e.g. Vitamin A and its derivatives) are sub- small blood vesseLs and formation of abnormal epithelial 

stances which arc known to have a broad spectrum of growths in sundamaged human skin, comprising applying 

biological activity, Most specifically, these substances affect topically to the surface of the skin a composition comprising 

cell growth, differentiation and proliferation. Retinoids 50 effective amounts of a retinoid in an emollient vehicle in a 

affect Ibe differentia lion, maintenance, and proliferation of program of maintenance Ihcrapy, whereby the skin substau- 

many types of cells whether they arc of ectodermal, endo- tially regains and maintains its firmness, turgor and elasticity 

dermal or mesodermal origin; whether they are epithelial, during the therapy, the composition and amounts of retinoid 

fibroblastic or mesenchymal; or whether Lhey are neoplastic, therein being selected so as to provide a sub-irritating dose 

preneoplastic or non-neoplaslic. At present, retinoids have 55 for application. 

found clinical Utility in the treatment of severe cystic acne, More specifically, the methods comprise the topical appb- 

psor iasis, and other disorders of keratinization. Possible uses cation to the surface of the skin of effective amounts of 

of retinoids are being explored in the prophylaxis and retinoids in a program of main te nance therapy, whereby 

treatment of cancer- For a review c f developments in retin- epithelial neoplasms (basal and squamous cell cancers) and 

oid therapy, see Pawsou, B. A. et at. "Retinoids at the ri0 prc-ncoplastic growths (aclinic keratoses) are substantially 

Threshold; Their Biological Significance and Therapeutic prevented. Also, the skin significantly regains and maintains 

Potential", Journal of Medicinal Chemistry 25:1269-1277 t xs firmness, rurgor and elasticity during the therapy. Efface- 

(1982). menl of fine wrinkles is an important clinical effect. 

The present status of retinoids in research and clinical Generally, the maintenance therapy is begun in adult life 

medicine can be found in the publication of a symposium oS when epithelial growths aud other aging changes begin to 

hcldinCkDeva:J-H.SauraLEojtor,"Rca^oids:New rrends appear cUnically. Pigmentary bblching and mottling are 

in Research and Therapy." Kargcr Publishing Co. (1985). also alleviated. 



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Rc. 36,068 

3 4 

The retinoids may be Applied to the skin in any non-toxic, dermis become thinner with age and the fibrous matrix 

dermatologically acceptable vehicle, preferably a becomes structurally inferior As a rcsuii, there is less bulk 

nonvolatile, emollient or lubricating vehicle, in an amount to protect underlying organs aod therefore more risk ot 

and at a frequency which arc insufficient to cause irritation serious injury. Moreover, when wounds or injuries arc 

of the skin. Generally, the concentrations arc low but may He s sustained, healing of the wounds is much slower in older 

suitably varied depending on the relative strength of Lhe people. 

applied retinoid. The underlying causes of the above gross skin effects may 

be understood more readily from the following discussion of 

DETAILED DESCRIPTION OF THE (hc changes in the epidermis and dermis as aging 

PREFERRED EMBODIMENTS 1n profircss 

The purpose of this invention is to moderate and retard ihe ^ 1. Epidermis 
aging changes in the skin by topical application of retinoids f with increasing age and exposure of a human lo sun and 
beginning in young adult life when aging characters I other environmental traumas, cells divide at a slower rate 
(sundamage) first become evident clinically. Certain aoa^ J (decreased capacity to renew themselves). They show 
tomic alterations can be corrected and at least partially ^marked irregularities in ske, shape and staining properties; 
reversed, accompanied by improvement in the appearance of orderliness (polarity) from below to above is lost. The 
ihe skin. thickness of the epidermis decreases (atrophy). The horny 

The invention accomplishes two goals. First, a prophy- layer which comprises ibe barrier against water loss and 
lactic effect in preventing progression and worsening of the penetration of chemicals becomes abnormal due to the 
damage with the passage of time. Secondly, various abnor- 20 shedding (exfoliation) of cells in large groups or clusters 
xnalities are corrected and modified to the extent Lhat the instead of as individual cells, resulting in roughness, scab' ng 
structure and function of the skip acquires the characteristics and dryness. There is. loss of the orderly transform a ti on of 
of younger (undamaged) skin. living epithelial cells into cornificd dead cells which are 

shed at the surface, that is, differentiation is impaired. 
£&> AGE ASSOCIATED STRUCTURAL CHANGES W /^mat differentiation results in numerous foci of abnor^ 

Although many of the effects of the aging of the human nwl epithelial growths or tumors, the most frequent of which 
skin are the result of underlying structural changes which *re aclinic keratoses. After many years these can transform 
build up over a period of years and can only be detecied into frank skin cancers called basal cell and squamous cell 
histologically prior to young adult life, these changes aad cancers. Pigment producing cells (melanocytes) can also 
effects begin to appear clinically in young adults, namely " become altered, forming flat, dark growths (lentigo 
those between about 20 and 30 years of age, and arc melanoma) which may progress to malignant melanoma, 
generally evident about middle age, namely between about The cells which make up these pcrmahgnant growths are 
35 and 45 years of age, and become more and more evident eliminated by topical application of retinoids, 
and pronounced thereafter, especially in persons excessively 3J 2- Dermis 

exposed to sunlight. The more apparent effects of aging have The cells which make up the fibers of the dermis become 
already been referred to above; aod each is associated with smaller and sparser with increasing age, usually in sundam- 
one or more underlying structural changes in the skin. For aged facial skin. There is a great loss of collagen fibers 
example, blotcliiness or mottling (hyperpigmentation) is due resulting in looseness and easy streichability of the skin; 
to accumulation of melanin in the basal cells of the cpider- ^ elastic fibers become abnormal so lhat the skin docs not 
mis- This happens because ihe reproduction of the cells promptly snap back after being stretched. Since the fibrous 
slows down greatly with aging, allowing them much loogcr components comprise more than 90% of the bulk of skin of 
time to receive melanin from the surrounding pigment- which 95% is collagen, I be degradation of these fibers, 
producing melanocytes. By stimulating the proliferation of especially collagen, is mainly responsible for wrinkling, 
basal cells, pigment retention is prevented. (|5 Uxness and loss of elasticity. 

In addition to obvious cosmetic improvements in the skin,— i Small blood vessels l>ecome thin walled, dilated and often 
there are a number of other changes which are more inipor- j ruptured. Vascular supply thereby hecomes compromised. 

1 'g^^J^^^JZl | BeoeficiMB^orRcUoo.ds^^.KcWUH 

l in the thickness of the skin. Older people have less sensi-^ 0 ™ Prescnt "vennon 

j tivity to pain and a longer response lime Thus, pain due to (a) Increased proliferative activity of epidermal cells. This 

^irritation or injury is not felt as soon or to the same extent results in thickening of the epidermis with correction of 

as in young people wiih the result that superficially roinor^ atrophy. Cell renewal is quickened so that cells divide at a 

f but potentially serious injuries may be sustained without the / fa tc typkal of younger skin. Treatment wiih retinoids in 

\ individual being aware of the injury until serious damagcJ 3S accordance with the invention can double the thickness of 

\ has occurred. the epidermis. The .stimulation of cell growth also results in 

U The surface temperature of the skin in older people is faster wound healing. Experiments have been performed 

loweT than the skin temperature in younger people, so that wherein blisters have been raised and the roofs cut off of ihe 

they ofteo feel cold. This is one reason why the elderly retire skins of individuals of various ages. Healing lakes place in 

to the sun-belt. Anatomically there is a great toss of small 60 2 or 3 weeks in yuuug people, hut lakes much longer in older 

blood vessels so lhat physiologically lhe bluod flow through persons. Application of the retinoid tretinoin, vitamin A acid 

the skin is greatly reduced. The skio becomes paler and or all-trans reticoic acid before raising the blister halves the 

cooler. Furthermore, the decreased blood supply decreases healing time. 

the rate at which irritants and toxins arc cleared from the (p) Correction of abnormalities of differentiation, fcetin- 

skin. Dangerous build-up of toxic agents can result- <6 oids regulate and control the physiologic behavior of epi- 

Still further, the skin of older people is more easily torn Ihelial tissue, assuring ils stability and integrity. They correct 

than that of younger people, since both lhe epidermis and and norraalis* abnormalities of differentiation. In sundam- 



J 



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flPR-12-2002 1?:55 EL COMPANIES 516 531 1340 



Webster's 




English 



The dictionary entries are based on the First Edition of The Random 
House Dictionary of the English Language 



GRAMERCY BOOKS 

NEW YORK / AVENEL, NEW JERSEY 



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ACKNO WIEDG MENTS AND PERMISSION^ 

The -A Dictionary of the English Language' section of .hi. book (Webster** ^ychpe£c Uruibri^e J ^ct^) is based on the first 
edition of The Random House Dictionary of the Mnglish Language, the Unabridged Edition, copyright © 1983. 

Atlas of the World, copyright ffl 1989 by John Bartholomew & Son Limited. Reprintea* by arrangement with John Bartholomew & 
Son Limited. ■ \ ' 

A Manual of Style, copyright © 1986 by Crown Publishers, Inc. Excerpted and reprinted by arrangement with Crown Publihcr*, Inc. 

Krcvisky, Joseph and Jordan L; UnGtld-77te Bad Speller's Dictionary, copyright © 1967, 1963 by Innovation Press* Reprinted by 
arrangement wrt)i Random House, Inc. . ' . , : 

Stein, Jess, &L-Rhymi»g Dictionary, copyright © I960 by Random House, Inc. Reprinted by arrangement with Random Hm*c, Inc. 

Webster* Crossword Puzzle Dictionary, edition, copyright © 1963 by Fawatt Publications, Inc. and copyright © 1964 b r 
Ottenhcimer Publishers, Inc. Reprinted by arrangement with Ottenheimer publishers, Inc. 

Copyright © 1989 by dilrthhim Press, Ltd. 
■ AU rights reserved. 

TrJs^edmonispUbfeh^ . •/ - 

Inc., a Random House Company, 40 Engelhard Avenue, Avencl, New Jersey 07G0L 

Printed and Bound in the United States of America 

Library of Congress Cataloging-in-Pubrication Data . •-/••> 
Webster's encyclopedic unabridged dictionary of the English language. 1 
1. English language — Dictionaries, 

PEI625.W46 1989 'p. .: / ; 

423— dcl9 89-3785 f ; 

CIP 

ISBNO-51^6878l-X ' . 

15 1A 13 12 11 10 9 8 



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See 




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•^TeLto or £«nr brfbrttand or In <ui- 
Tanie. Also, provtte. [rs»- + '»™»J 
Mm*.* wife TC?° a "^^?' *&: l «. e ^Sf-f r «5Srt 

atruiv. to pro*- 4* ■ lf 2 J ww ' J S-- ■ « 

^PTeArfcoaa.ry. ado. — ™*wl-oa*-na««,, n - 
^-Byo. 1, earlier. 

1. later. _ _ „1. p^. question 



*?TT«teVw»t* to P« eonunon. extend** See corral -Antl.roro. 

^JT Wafc). 1819-1001. Bcw WJSSSi. a- anticipatory. t< ^ P;«W«tt- (fl. 
Sta SostH Africa. S?flSmflM) coming before, pn>. of pro*™^ 

? HSr a trial to atmpliry /Srev/Tn^ni). pre-«*«..lence Cpd v5fl/y9P*). ft 
fcrt'oBd ■^^E rt fi^ t S vWlrnt-ly. art. 



18A2. 



Pr^voRt iurR vSO. ft. Mar-c*I (HUB BOKJ 

iMy.adP. - 1607-1763. W noreWft . vlfiyr 

rter to «w*vo i^ vv — - nrovenlent grace', dWiw grace operating on tne ppe .yu e (prS'vySa'O. n. t -rod, -m-m». 
trial. -Sfl- 2. of or pertaining ^ ^^™^p^ to Its fcrnlna to Ck^L prew(pr«©),ft. a t»y'a iftVBU nam*. t . 

£0- ^_:T^^^^ HeS^ n. ft ^ nam., form of 

Praw. aIspT Prew'ltt, Pratt, Praitt. 

shortening and alter, of oratfdept) + -y*J , 

mt4i « i m axtlm&l hanccd or seised for foon. 

thS ^icftltn of an enemy, » *wtodlpr, \ a 




-tUrse. n.. pi. 
1* Dleainjf or attract^ w 
>Tin rfWcfa way. as by d-dlcacy, 



«• ^ 8 —id: this U o P«to 
— Tat: This 



or 
i roper 



-S2f9. 10. moderately: tfjjj 
fell irattn: very: TAe wind tttew W 

gSl tomalrtpretty: Improve the 



rl*. To HIKBnt* u bo Keep wjr ^70^-- 

nrbantt a 1 "action; t*> WndV tfn proirew of an **P. 
T^^* to ti. mate dlf'lralt thB^morvcmeiit 



SBmS foL Dy "uiy. to v^Uy em*«l] 
, a room. [ME P^P^yJ?^ 



elf kt.a« /-^i fi. 1. one who or that w 



ty ontJtlf "Z^TZJ^V.nr /JvMi/tar) n. 1. onfi who or that whJcfc 

derlT- of P*ft a inck wile: P»vento. 2. £W^ 0 J3fL£y runnlaa or »*aadlpB 
l23 1 prtftrA*, ^«mi£r trlc&| JJ^J"* b °/ a ^^ Q r ^™On< s^ll from JiWn* 

tea; 1.*—^ OTjsS^r 8rt ^ 



JBflmy, » iwuiuivr, » ■ * or 

Hta. a."*o le5« or habit of praylaa: ^jrf ' •/| r Si 0 J_ 

SSrV/iorW fJmi Pray «p<ni iA« CM® y«y « < of < 
L pra«4a booty, prey] — p»y'«Tt n. . 

Ste cJ-SaSi/Hector. Polyxena, «^ ™»V other* 
^ii^W faring the capture of Troy. 2, the 
■rr&Bdsou or Kins Priam- : 
Pri a nW (prl/e BOd). Cto. Afsth- any of tne 60 
sjd0 of Priam, 



i^or Balm an-' 

^^'tn^'typo" °f: 

,1, a crlap, dry lm»**«*»»» jTm~~ r 
t or sflcft. salted on^tbo^outsWo. 



q). n. German name of Prwla- gSfviirr + -mO — pro ^"tl»«-ly. oJ«. — .v. ^ 



[PaiAP(*ra) + • . 

X. Pa/h*/- -conthmoiifl 



KM-*: 



(ttrXfe'pV- 
pt paflam- 



? fa A?^&vyrfl. t» b* or prove t^^^n^cr jwchbtric andwedlcal care ftt-ft-pnB rprl a'P»)j «j 

*\ iSavS or taKencB (naaally fot by _ p J~r nmve t ftW / B r^u, that part of ofUcB practice lt c&. My**- a gud of 
^SSXJ SSm^ £ »ST^SpS ^«Ad5SS aSd Sevent future diaap- ^ P^g^Pf^ 

^ domln&nt; Tin out; To oXM }J^J« SLtSeS? or controversy. ' ^"^O' ^S 11 ^ Ta 



•JL; pL «U 

iff* a#. 

• adj. 



I view 

p re 'tr»n- « c r*p ^tian, rv, ■ 
pf*'tran4*l*fto'. -Ut-od. 

-laft-lklff. 
pro'trawlfttion. «, 
pro/trana-miM^BieB, n, • ■ . . 
Bro/traa^-mic/, fl.C, -tnit-ted, 

-mit-tinff. 

-»/te«D*'pnrf. ff. - ■ , i 
a /ffan»-par>tA/tton, ft. 



aealx 




nelonging 



-tak-on, -tak-ln*. 

pre'oXtc'. oX. -nlt-ed. -nlt-lntf 
PTO-n^cMK^a-ble. a4j. 
Pr*/o-d>U-sa^tlon. n. ' 

pre-va^oato, fl.t., -oa 
•«as*lng. .> 
"Dxa^va-ca'tlon^rt., adj. 



ai OJ., 



pre-VBr / alan. n. 
pre*««r / t«'brBl» t 
pro-w^to, tv. pL 
.toed, -to*«Bf 

pre/vlc^to/rl^O^, adj. 
pre»wlg/l.lane«, nj , 

' -lat.teg. 
Bn/vl^la/tlsn, n. 

pro'vU-l-bU/l-ry» n. ' 



trying. 



-tijLt'tatf. • - 

pre^vaa>cl*na / tv i n. n. 

pre-valld- «^.; 
pre'va'Ud/My, n. 
pTe>«ol.n>«'Uoa, b. 
pre<val^Be, o.f. . -aod, -P^mtf; n 
pxe^ar-l'a^Uon, n. 
pT «^Vttg*e.fca/t!on. n. 
irr*< 0 «n^ferau P^f- 
pr».vcn/toxet o., -tnred, 
-tnr*buf. 
pT«-«or^bal, odf. 

Dr^^or'i-ry 7 . -ftcd. -fy-lng. y« > -— d t 



pr**cr6»>al, ad?. 
pra'-Trl-dao/dji* 
pra^rro/enat, odi. 
pra-ory/, f Jt,, -tried, 
pra-TnAtor, adj. 
pro'trin.pan'lc. aOj. 
pra-^^phoW* 
PTa^y-P^0T«ph/l.c*X adj 

pro-cyr'an-ny. n. 

prro-om/bo»aal. 0(H. 
pPD/un^er'atand', f- 
— tabbing 



prtj-vlat-tor, n. 
pr^yogno/, n. 
prcvold/. ttJ. 
pro.vold/anca, rt. - 
vrv^ro-U/Uoa-aL adj. 
pr^/.VoUstead^ n. 
pra'vol-an'i**''* 
pr«-voteS, ^foi-ed, 

_uot>lnjr> 
pra'wum'.^* 



pr«.war^rant. n.. rJ. 
pvo.waah^ n., *X 

pr«>w«l«h' r OA 
p r o^ w Pcomg, n,, V-t~ ■ 

-CTJOl.tP*- 

prv*viu/inir, adj.; -ty, ox/p.; 

-o«»«. ft. " " j i 

pr».wlre<. eX, -wired, • ■ 

.wtr-iptf. - • 

pr««vtn^l*»»t 
prw'vlt/napa. a w 0.1. 
pro-world^UusH, n. 

M.woc^ah&i °-. -*biped or 
' -shipped. ~»hlp-ln* or 

*«n|p«>plnC> 
px«-wor^thi4y, 
pr».wor<tni<afliiB. ft- " 
pra-ww/thy* a<fj. * 
pr«.woond/, n.. t.t. 



TOTAL P. 14