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Attorney Docket No. : 00.22US 



PATENT 



IN THE UNITED STATES PATENT AND TRADEMARK OFFICE 



In re Application of: Maes, et al. 



Serial No.: 09/773,351 



Group Art Unit: 1617 



Filed: January 31, 2001 



Examiner: Jiang, Shaojia A. 



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



U.S. Patent No. 5,650,166 ("the '166 Ribier reference") 

In the Advisory Action, the Examiner finds that Applicants' claims are not limited to a narrow 
combination of NADG and cholesterols but rather to a broad mixture of cholesterol sulfate and an exfoliant. 
The ' 166 Ribier reference cited by the Examiner, however, does not address a mixture of any kind whether it 
be in a narrow or a broad sense. The missing feature pointed out by Applicants between the '166 Ribier 
reference and the present invention is the separation of NADG and cholesterol sulfate by the discrete layers 
of the '166 lipid vesicle. NADG is the exfoliant of focus in Applicants' responses because it is the 
component in the ' 166 Ribier reference cited by the Examiner. 

The Examiner previously asserted that the ' 166 Ribier reference renders the present claims obvious 
because it teaches a composition comprising cholesterol sulfate, see column 3, lines 66 - 67, and N- 
acetylglucosamine (NADG), see column 5, line 67. Applicant's previous argument as summarized by the 
Examiner is that there is no separation or vehicle taught in the '166 Ribier reference for the combination of 
NADG and cholesterol sulfate, and therefore, the '166 Ribier reference fails to teach or suggest a feature of 
the present invention. In response to this, the Examiner noted that it is irrelevant whether the '166 Ribier 
reference teaches or suggest this feature because it is well within the skill of the artisan to incorporate this 
routine skill in the art. Applicants noted that the summary of their argument was not complete. Applicants 
assert that because the two ingredients are used to form, and thus, become part of discrete layers of a lipid 
vesicle, they are not an "integral mixture" as they are in the present invention. Further, while the 
combination of any two ingredients may be routine, in order to be patentable, the combination of the two 
ingredients must not have been taught or suggested to one of ordinary skill in the art. Therefore, this is the 
focus of Applicants' response. 



RESPONSE PURSUANT TO 37 CFR 1.114 



REMARKS 



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The claims of the present invention have been previously amended such that the mixture of 
cholesterol sulfate and exfoliant, for example, NADG, is added to a pharmaceutical or cosmetically 
acceptable vehicle. The mixture of the two ingredients in a vehicle in contrast to the teachings of the '166 
Ribier reference is worthy of note because this is where the difference between the '166 Ribier reference 
and the present invention lies. The '166 reference only discloses the use of cholesterol sulfate to form lipid 
vesicles that can be used to encapsulate NADG. Thus, the two ingredients in the '166 Ribier reference are 
separated by the discrete layers of the vesicle that are formed. The ingredients are separated by virtue of 
their being present in separate and discrete layers of the lipid vesicle. The vesicle is similar to a nut in a 
shell. Like NADG and cholesterol sulfate, the nut and the shell are not mixed. 

Cholesterol sulfate is part of the bilayer of the liposome and resembles the shell of a nut. Inside of 
the shell lies the nut, which resembles NADG inside of the bilayers of the liposome. The important feature 
of this analogy is that the shell and the nut are not mixed just as NADG when it is encapsulated by a lipid 
bilayer containing cholesterol sulfate is not mixed with cholesterol sulfate. To further support the analogy 
Applicants submit herewith a copy of Abraham, et al., "Interaction between corneocytes and stratum 
corneum lipid liposomes in vitro," Biochimica et Biophysica Acta, 1021, pp. 1 19-25 (1990). In the article, 
the authors provide pictures of the liposomes which appear as bubbles. Even in looking at the liposome as a 
bubble or a balloon, it can be seen that cholesterol sulfate is used to make the thin layered wall of the bubble 
or balloon. For decorative purposes some translucent balloons are made to hold items inside. This is similar 
to NADG held inside of a liposome. In each case, a balloon or a nut in a shell, the outer wall is not mixed 
with the content held inside. Likewise, inside of a liposome, NADG is not mixed with cholesterol sulfate. 
Therefore, the arrangement of the components taught in the ' 166 Ribier reference is not the arrangement of 
the present invention, and thus, the present invention is not obvious in light of the '166 Ribier reference. 

Cholesterol sulfate is taught at column 3, lines 57 to 67, of the '166 Ribier reference as being an 
additive to the lipid membrane of the vesicle. Further, one of the actives contained within the lipid vesicle 
with deep down action are taught at column 5, lines 59 to 67, to include inter alia, NADG. Thus, there is no 
mixing of these ingredients as they are in the present invention by adding them in combination to a vehicle. 
Unlike the present invention, the '166 Ribier vesicles contain these two ingredients in separate and distinct 
layers and the vehicle containing them in separate layers is added to a medium as taught at column 8, lines 
32 to 35. This is in contrast to adding the ingredients themselves directly to a vehicle. This is especially the 
case for N-acetylglucosamine (NADG) as the '166 reference fails to teach or suggest adding the NADG 
directly to a vehicle because it teaches that the NADG is contained within the lipid vesicle. Therefore, even 



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though the vesicle is added to a vehicle, because the NADG is inside the vesicle, there is no teaching in the 
6 166 Ribier reference where NADG, per se, is added directly to the vehicle. 

The Examiner finds that the addition of a mixture of NADG and cholesterol sulfate to a vehicle is 
considered to be well within the skill of the ordinary artisan. However, the addition of many mixtures to a 
vehicle have been found patentable because as it pertains to obviousness, an inventive concept is patentable 
if it is not taught or suggested by a cited prior art reference or known generally. Thus, while Applicants 
refrain from comment regarding the general task of adding a mixture to a vehicle, attention is given to the 
issue with respect to the present inventive concept, namely, whether one of ordinary skill in the art was in 
possession of the addition of a mixture of the exfoliant and cholesterol sulfate to a vehicle. A pplicants 
assert that the '166 Ribier reference demonstrates that the addition of the specific combination of NADG 
and cholesterol sulfate to a vehicle was not in the possession of one of ordinary skill in the art as it merely 
suggests that the cholesterol sulfate is useful in the lipid bilayer of a vesicle holding NADG inside of it. 
None of the cited prior art references teach or suggest adding a combination of the exfoliant and cholesterol 
sulfate as a mixture directly to a vehicle. Thus, the '166 Ribier reference fails to teach the exfoliant added 
directly to the vehicle, and therefore, there is no teaching or suggestion of the mixture of cholesterol sulfate 
and the exfoliant like that of the present invention. 

In the present submission, Applicants amend the claims of the present invention such that the 
addition of the mixture of cholesterol sulfate and an exfoliant is made integrally into the composition. 
Support for this amendment is found in the present specification at page 4, lines 22 to 24, wherein the 
compositions of the present invention are described as achieving integrated results between the two 
components that possess opposite activity. Heretofore, as indicated by the cited references, they have been 
kept separated by the bilayers of a lipid vesicle. Further, as amended, the claims of the present invention are 
more distinguishable than before from the teachings of the ' 166 Ribier reference. The ' 166 Ribier reference 
teaches a lipid vesicle which has NADG in one bilayer and cholesterol sulfate in another bilayer. The test 
for obviousness is whether the claimed invention as a whole, in light of all the teachings of the references in 
their entireties, would have been obvious to one of ordinary skill in the art at the time the invention was 
made. 35 U.S.C. §103; Connell et al. v. Sears, Roebuck & Co., 220 USPQ 193, 199 (1983). Because there 
is no integration of these two compounds taught or suggested by the '166 Ribier reference, the present 
invention, where the exfoliant and the cholesterol sulfate are integrally added to the composition is not 
obvious. Applicants request that the rejection of the claims based on the 4 166 Ribier reference be 
withdrawn. 



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U.S. Patent Nos. 5.650.166. 6.159.381. and 5,702,691 ("three references") 

The Examiner finds that Claims 10-12 and 20 are not patentable over the combination of three 
references (individually referred to as the * 166, the '381, and the '691 references") for reasons of record 
stated in the Office Action of November 5, 2002. Further, the Examiner claims that the motivation to 
combine the three references is provided sufficiently in the Office Action of November 5, 2002. However, 
in Applicants' previous response it was pointed out that neither of the additional references remedied the 
defect of the '166 Ribier reference in that each failed to teach or suggest the addition of the NADG directly 
to a vehicle because the '166 Ribier reference merely taught how to incorporate NADG inside of a lipid 
vesicle, and then subsequently to incorporate the vesicle containing NADG into a vehicle. Applicants 
comment further herein on the motivation presented in the Office Action of November 5, 2002. The 
Examiner finds that motivation stems from the benefit of anti-inflammatory properties as those taught in the 
'691 reference and the anti-acne properties as taught in the '381 reference in a cosmetic formulation. The 
missing ingredients according to the Examiner have art recognized suitability in cosmetic formulations. 
Therefore, the Examiner concludes that the selection of known materials based on their suitability for their 
intended uses is prima facie obvious. However, the arrangement of the materials in the '166 Ribier 
reference is different than the arrangement in the present invention, and therefore, the '166 Ribier reference 
fails to teach or suggest the present invention, and the '381 and the '691 references fail to remedy this 
defect. 

As discussed above the cholesterol sulfate of the '166 Ribier reference is taught as part of the 
membrane of the lipid vesicle that holds the deep down active agent, NADG, contained within the vesicle. 
This is different than a simple mixture of the exfoliant with cholesterol sulfate like that of the present 
invention. Thus, the arrangement of NADG in the ' 166 Ribier reference as an active encapsulated in a lipid 
vesicle is different than the mixture of NADG with cholesterol sulfate for three reasons. First, the '166 
Ribier reference fails to place in possession of one of ordinary skill in the art the mixture of NADG and 
cholesterol sulfate integrally into a composition. While the cholesterol sulfate is part of the membrane of 
the lipid vesicle it is not mixed with NADG as it remains a separate entity inside of the membrane layers of 
the lipid vesicle. Second, while the NADG is encapsulated inside of the membrane layers it is not directly 
added to a vehicle because the NADG remains protected from the vehicle by virtue of its presence inside of 
the membrane layers. Third, because of the first two reasons, there is no integration between NADG and 
cholesterol sulfate in the '166 Ribier reference. 

As found by the US Supreme Court in United States v. Adams et aL 9 148 USPQ 479, 482-84 (US 
SupCt 1966), the case of Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) 



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is inapposite in a situation where the subject matter of the prior art is a completely different design type. In 
Adams, magnesium in place of zinc and copper as a substitute for silver was found not to be a mere 
equivalent substitution in batteries the design of which between that of the prior art and the invention at 
issue were of a completely different type. Adams, at 483. As in Adams, the design and arrangement of 
cholesterol sulfate in a membrane layer of a lipid vesicle encapsulating NADG is completely different than 
the type of design and arrangement of the present invention whereby cholesterol sulfate is simply combined 
with NADG and as a mixture are added directly to a vehicle. T hus, because the mixture of cholesterol 
sulfate and NADG is not taught or suggested by the '166 Ribier reference, the ' 166 Ribier reference fails to 
render the present invention obvious. Further, the '381 and the '691 references fail to teach or suggest the 
direct addition of an integral mixture of the exfoliant and cholesterol sulfate to a vehicle because the 
Examiner in the Office Action of November 5, 2002 notes that the '381 reference teaches the use of 
sclareolide in topical formulations particularly for acne, and the '691 reference teaches that white birch 
extract is a known anti-inflammatory agent. The teachings of the '381 and the '691 references fail to 
remedy the defect of the ' 166 Ribier reference, and therefore, the combination of the cited references fail to 
establish a prima facie case of obviousness. Applicants respectfully request that the rejection of the claims 
under the three references be withdrawn. 

U.S. Patent Nos. 5.925.364 and 5,41 1.742 ("the two references") 

The third obviousness rejection is based on two references (individually referred to as the '364 
Ribier and the '742 references"). Specifically, the Examiner rejects Claims 1, 3 - 4, 6 - 9, 1 1 and 18 under 
35 U.S.C. 103(a) as being unpatentable over the '364 Ribier reference in view of the '742 reference. 
Applicants assert that the argument applied to the ' 364 Ribier reference previously in their Response of 
February 5, 2003 applies herein because of the oily globules coated with a lamellar liquid crystal coating in 
the '364 Ribier reference, and the similarity with the lipid vesicles of the '166 Ribier reference. 
Specifically, the '364 Ribier reference discloses an emulsion composition that has oily globules with a 
lamellar liquid crystal coating dispersed in an aqueous phase. Like that of the '166 Ribier reference, the 
composition as described in the claims can include materials such as alkali metal salts of cholesteryl 
sulphate as the ionic amphiphilic lipid as one of the layers coating an active (i.e., similar to the membrane 
layers of the '166 Ribier vesicles). Therefore, the oily globules of the '364 Ribier reference, like that of the 
'166 Ribier reference, fails to teach or suggest the integral mixture of the exfoliant and cholesterol sulfate in 
the present invention. 

According to the Examiner, the '364 Ribier reference in combination with the '742 reference is 
obvious to one of ordinary skill in the art. The '364 Ribier compositions can contain as a fatty substance, a 



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keratolytic agent. One of the many keratolytic agents listed is retinol and salicylic acid which the Examiner 
notes a re known exfoliants. Motivation is, according to the Examiner, based in using the fatty acid and 
cholesterol of the '364 Ribier reference since fatty acids are known to be used in cosmetic compositions for 
treating skin. Further, the Examiner notes that cholesterol is a well known ingredient in a cosmetic. 
Therefore, according to the Examiner, one of ordinary skill in the art would reasonably expect that a 
combination of the '364 Ribier compositions with the '742 compositions would be useful for the same 
purpose, treating skin, and would improve the therapeutic effect of treating the skin. Applicants assert that 
the basis of motivation to combine the references is misplaced because the combination of the '364 Ribier 
and the '742 references does not render the present invention. 

Both the '364 Ribier reference and the '742 reference disclose lipid vesicle/lamellar systems. Thus, 
neither reference alone or in combination teaches or suggests the mixture of NADG and cholesterol sulfate 
like that of the present invention for the reasons presented above with respect to the '166 Ribier reference. 
Basically, the lipid vesicles/lamellar systems separate the NADG (exfoliant) from the cholesterol sulfate 
because the cholesterol sulfate is part of the membrane layer of the vesicle or lamellar system. As it is noted 
by the Examiner in the present action both the '364 Ribier reference and the '742 reference disclose metal 
salts of cholesterol sulphate. There is a basic reason why both references make such a disclosure - namely 
both references disclose lipid vesicle/lamellar systems whereby the layers of the vesicle or lamellar system 
contains cholesterol sulfate. The capsule formed by the membrane holds within it an active which can 
include an exfoliant. However, one of ordinary skill in the art would not find a disclosure of encapsulating 
an exfoliant within a lipid vesicle to be a teaching of an integral mixture of the exfoliant with cholesterol 
sulfate found in the membrane layer of the vesicle. Thus, Applicants assert that the scope of the '364 Ribier 
and the '742 references is to be interpreted in view of how one of ordinary skill in the art would make such 
an interpretation. Evidence of this interpretation is found in the cited references wherein it is disclosed that 
the cholesterol sulfate is part of the membrane forming the vesicle and the exfoliant is an active 
encapsulated therein. 

See column 4, lines 42 - 50, of the '364 Ribier reference "[w]hen the compositions 
according to the invention are used for cosmetic treatment ... the active agent contained 
in the oily phase is . . . keratolytic agents. The oily phase of the '364 Ribier reference is 
coated with a lamellar liquid crystal coating that can contain cholesterol sulfate 
derivatives. See column 3, line 36 to column 4, line 15, of the '364 Ribier reference 
"[t]he coating ... of the oily globules preferably requires the use of a total amount of 
hydrophilic surface-active agent, of lipophilic surface-active agent and of ionic 
amphiphilic lipid ..." and "[t]he ionic amphiphilic lipid used within the context of the 
present invention is . . . metal salts of cholesteryl sulphate. . ." 



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In the same fashion, see column 3, line 64 to column 6, line 20, of the '742 reference 
"the constituent lipid phase of the membranes of the vesicles of the dispersion comprises, 
in a known manner, at least one amphiphilic lipid . . . cholesterol sulphate. . . " And, see 
column 3, lines 1 to 8, "[t]he subject of the invention is therefore a composition for the 
treatment of acne by topical application containing . . . vesicles of amphiphilic lipid(s) 
consisting of a lipid phase membrane encapsulating an aqueous phase E, the lipid phase 
containing as additive a charged lipid . . . [containing] at least one salicylic acid 
derivative of formula: ..." 

Clearly, it can be seen from the inventions described by both the '364 Ribier reference and the '742 
reference that these descriptions both relate to lipid vesicles/ lamellar systems like that of the '166 Ribier 
reference. Therefore, the combination of these references for reasons stated above, fail to teach or suggest 
an integral mixture of exfoliant and cholesterol sulfate as in the present invention. 

Finally, even if the interpretation of one of ordinary skill in the art were that a lipid vesicle 
containing cholesterol sulfate in the membrane layer and NADG encapsulated therein was equivalent to the 
integral mixture of the present invention, Applicants assert that it would be rebutted by the surprising results 
of the present invention. The Examiner notes in the Advisory Action and the Final Office Action that the 
Example in the present specification does not provide clear and convincing evidence of nonobviousness or 
unexpected results over the cited prior art because there is no direct comparison of the same. However, as 
Applicants have pointed out in the present response, the two systems are not the same and there is no reason 
to believe that the integral mixture of the ingredients of the present invention directly in a vehicle would 
necessitate a comparison with a lipid vesicle as these are two completely different systems and different 
arrangements of the components. To support this fact, Applicants submit herewith a copy of an article, 
Bouwstra et al., "Cholesterol sulfate and calcium affect stratum corneum lipid organization over a wide 
temperature range" Journal of Lipid Research, vol. 40, 2303-3212 (Dec. 1999). In the article, the authors 
note that reduced levels of cholesterol sulfate contribute to desquamation, thus indicating that the presence 
of cholesterol sulfate would maintain the integrity of the stratum corneum and prevent desquamation. 
Therefore, one of ordinary skill in the art would expect a combination of cholesterol sulfate and an exfoliant 
to have no effect on the surface on the skin because while the exfoliant would contribute to desquamation, 
the cholesterol sulfate would act to prevent desquamation. 

The present invention is based on the finding that two ingredients, the cholesterol sulfate and the 
exfoliant, although they have opposing activities , when added as a mixture to a pharmaceutical or cosmetic 
vehicle, do not neutralize one another's activities, but rather their activity occurs in tandem, and can improve 
or maintain a healthy skin barrier. This benefit cannot even be addressed with the cited references because 
these two materials are not in fact mixed. Rather, they are separated such that one, the cholesterol sulfate, is 



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part of a protective membrane that encases the other, the NADG. The whole point of the lipid 
vesicles/lamellar systems of the cited references is to protect and prevent the active inside from integrating 
with anything else. Thus, a comparison of this kind would be futile. Finally, Applicants point out that the 
burden to provide evidence of unexpected results does not pass from the Examiner to Applicants until a 
prima facie case of obviousness has been made. 



The present invention, as amended, is an integral mixture of an exfoliant and a cholesterol sulfate 
that is not taught or suggested by the cited references describing lipid vesicles having one bilayer containing 
N-acetyl D-glucosamine, and another bilayer containing cholesterol sulfate as the component are arranged 
differently. 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. 
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. 



CONCLUSION 



Respectfully submitted, 





Dorene M. Price (Reg. No. 43,018) 
Estee Lauder Companies 
125 Pinelawn Road 
Melville, NY 11747 
(631) 531-1194 



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