DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Abate et al. (Bio-catalysed synthesis of optical active Undecavetol enantiomers, Assymetry 16, 2005, 1997-99) (see IDS) further in view of Abate et al. (Lipase-catalysed preparation of enantiomerically enriched odorants, J. Mol. Catal. B 32, 2004, 35-51) (Abate 2d) and Akagi et al. (A general method for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations, Tetrahedron Asymmetry 25, 2014, 1466-77).
Abate, abstract, state:
“Two enantiomers of Undecavertol were prepared by enzymatic methods and their odour properties evaluated.”
“Fragrance materials are employed in a wide range of products ranging from perfumes to skin products such as creams, lotions, detergents and several other personal and household products. Allergic skin reactions to fragrances have been observed in the past by some users, but recently this problem has become very topical and the real size of the problem has yet to be established. . . . According to the proposed Seventh Amendment of the European Cosmetic Directive, which has become effective on March 11,2005, the identity of these compounds in cosmetics should be labelled if they exceed 10 ppm in products intended to remain on the skin, or 100 ppm in products intended to be rinsed off therefrom.” Abate, page 1997, left col.
“In light of these observations, the investigation of the properties of the single enantiomers of chiral odourants is now of primary importance for three main reasons. First of all, as the enantiomers of chiral drugs may have different pharmacological activities and side effects, the enantiomers of chiral fragrances may show different interactions with human beings, not only from an odour
perception point of view. Second, it is necessary to find new odourants to replace the 26 allergenic fragrances. New odour sensations can be developed by preparing new synthetic odourous molecules or investigating the odour response of enantiomers. Finally, if two enantiomers show very different odour thresholds, the most potent one can be employed in commercial formulations in a reduced amount, thus decreasing the quantity of chemicals interacting with human beings.” Abate, page 1997, bridging columns.
Lipase PS-mediated acetylation of (±)-1 (6 days) gave acetate derivative (+)-2 as a 93.5:6.5 mixture of trans- and cis-isomers (GC/MS) (Scheme 1). This latter was hydrolysed by reaction with KOH in methanol, with the corresponding alcohol (+)-1 being obtained as a 96.5:3.5 mixture of trans- and cis-isomers (GC/MS). The enantiomeric excess was evaluated to be 93% by using lanthanide chiral shift reagents.” Abate, page 1998, left col.
That is, with reference to Table 1 and Scheme 1 of Abate, a racemic mixture of 1 (undecavertol) is treated with a lipase such that the R-(+) enantiomer of undecavertol is preferentially acetylated to compound (R)-(+)-2. (R)-(+)-2 is separated from (S)-(-)-1 by column chromatography and enantiomer-enriched (+)-1 ((R)-undecavertol) is then recovered by hydrolysis of (R)-(+)-2 with KOH to recover (+)-1 ((R)-undecavertol) with an apparent enantiomer excess of 93%.
However, Abate does not directly teach an enantiomeric mixture of undecavertol with 94% or 99% enantiomeric excess of (R)-undecavertol.
“Pure materials are novel vis-à-vis less pure or impure materials because there is a difference between pure and impure materials. Therefore, the issue is whether claims to a pure material are nonobvious over the prior art. . . . Purer forms of known products may be patentable, but the mere purity of a product, by itself, does not render the product nonobvious.” MPEP 2144.04(VII). “See also Ex parte Stern, 13 USPQ2d 1379 (Bd. Pat. App. & Inter. 1987) (Claims to interleukin-2 (a protein with a molecular weight of over 12,000) purified to homogeneity were held unpatentable over references which recognized the desirability of purifying interleukin-2 to homogeneity in a view of a reference which taught a method of purifying proteins having molecular weights in excess of 12,000 to homogeneity wherein the prior art method was similar to the method disclosed by appellant for purifying interleukin-2).” MPEP 2144.04(VII)
As in Ex parte Stern, Abate teaches the desirability of purifying (R)-undecavertol to enantiomeric purity, although Abate does not demonstrate (R)-undecavertol purified to enantiomeric excess of 94% or 99%. Abate 2d is cited as reference 3 of Abate. “Nowadays, catalytic enatioselective synthesis is highly preferred in the preparation of enantipure compounds, even if classical resolution via diasteroisomeric salts is still widely employed.” Abate 2d, page 33. “When a really good enzyme is available, the development of a bio catalytic method is generally characterised by lower costs.” Abate, page 33, right col. That is, enzymatic means of producing enantiomerically-enriched mixtures is associated with lower costs relative to other methods; however, other methods including “classical resolution via diastereomeric salts” are still viable.
Separation of diastereomers is known in the prior to produce very high enantiomeric purification of secondary alcohol compounds that are similar in structure to undecavertol. Akagi, abstract, teach:
A general method for synthesizing enantiopure (100% ee) aliphatic alcohols with established absolute configurations has been developed and applied to alcohols CH3(CH2)n–CH(OH)–(CH2)mCH3, the enantiomeric discrimination of which is the most difficult, if m = n + 1 and n is large. Racemic saturated alcohols with short chains could be directly enantioresolved as (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid) esters by HPLC on silica gel, and their absolute configurations were simultaneously determined by 1H NMR diamagnetic anisotropy. However, the application of this powerful MαNP ester method to alcohols with long chains was difficult, because of smaller values of the separation factor α. In such cases, the use of the corresponding acetylene alcohol MαNP esters was crucial. Acetylene alcohol MαNP esters were largely separated by HPLC on silica gel, and their absolute configurations were unambiguously determined by 1H NMR as reported in the Part 1 paper. The MαNP esters obtained with established absolute configurations were catalytically hydrogenated to yield saturated alcohol MαNP esters. It was evidenced that no racemization occurred at the stereogenic center of the alcohol moiety during catalytic hydrogenation, by the coinjection of MαNP esters in HPLC. From the MαNP esters obtained, enantiopure (100% ee) aliphatic chain alcohols with established absolute configurations were recovered. Although the [α]D values of these alcohols were too small for the identification of the enantiomers, it was clarified that the analytical HPLC of MαNP esters is useful for identification in most cases.
“It is well known that asymmetric synthesis has been successfully applied to the synthesis of many chiral organic compounds such as bioactive natural products and chiral drugs. However, enantiopure aliphatic compounds such as chiral aliphatic chain alcohols are difficult to obtain by asymmetric reactions or by other enantioresolution methods including chiral HPLC.” Agaki, page 1466, left col.
“In order to solve the above problems, we have developed a method involving (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid 1 (MαNP acid), which is applicable even to aliphatic chain alcohols. The method is outlined as shown in Figure 1: (a) a racemic alcohol (±)-2 is esterified with (S)-(+)-MαNP acid 1 to give a mixture of diastereomeric esters, which are easily separable by HPLC on silica gel.” “The MαNP acid method is useful for the synthesis of enantiopure (100% ee) alcohols with established absolute configurations.” Akagi, page 1466, right col.
Figures 2 and 3 of Akagi shows that racemic secondary alcohols resolved to 100% ee include 2-butanol, 3-hexanol, 4-octanol, and 5-decanol. “It should be emphasized that diastereomeric MαNP esters 12a/12b–15a/15b and 17a/17b were baseline separated,” which are the diasteromeric esters of 2-butanol, 5-decanol and 10-nonacosanol, respectively. Akagi, page 1469, left col. “[I]t was thus possible to discriminate the very small difference between the methyl and ethyl groups. We had thought that when the alkyl chains became longer, the α value would decrease, that is, it was expected that the difference between the ethyl and propyl groups in esters 13a/13b would be smaller than that between the methyl and ethyl groups, and hence the α value would become smaller. However, the opposite was true; α = 1.20 for 3-hexanol MαNP esters 13a/13b. This tendency continued for 4-octanol MαNP esters 14a/14b (α = 1.27), where the propyl and butyl groups were clearly distinguished.” Akagi, pages 1469-70.
That is, Akagi explains that it is expected that small differences in the two R groups attached to the chiral center of a secondary alcohol would be difficult to resolve by chiral separation of diasteromeric esters of alcohols and larger differences in R groups would be expected to be more easily separated, although good resolution between even small differences (i.e. one methylene group) were observed for many alcohols.
Agaki reports a general method for synthesizing enantiopure (100% ee) aliphatic alcohols. Undecavertol is an aliphatic secondary alcohol. As shown in the structure for undecavertol shown on page 4 of the specification, undecavertol has 11 carbon atoms with two R groups of 5 carbon atoms attached to the chiral center (along with -OH) wherein both R groups have 5 carbon atoms. However, the R groups significantly differ with one R group being a normal chain of 5 carbon atoms and the other chain being branched with an unsaturation. It is noted that Akagi reports that the presence of unsaturation increases the ability to perform enantiomeric purification as described. “[D]iastereomeric MaNP esters of acetylene [C-triple bond unsaturation] alcohols with aliphatic chains can be readily separated by HPLC on silica gel,” as shown in Table 2 of Akagi. Akagi, page 1472, left col. Akagi does not directly discuss alkene R groups; nevertheless, Akagi directly indicates that bigger chemical difference between R groups results in easier separation of enantiomers.
To summarize, Akagi teaches a “a general method for synthesizing enantipure (100% ee) aliphatic alcohols) by reacting a racemic mixture of a chiral secondary alcohol with MaNP acid to form an ester thereof that is a diastereomer (e.g. the S and R configurations of the alcohol reacts to form two diastereomer ester compounds), the two diastereomer esters are separated to enantiomeric purity by chromatography, and then enantiopure S and R alcohol is recovered by hydrolysis of the recovered esters. See Figure 1. Akagi teaches both analytical and preparative HPLC resulting in the production of enantiopure alcohols. “It is noteworthy that the separation factor [Symbol font/0x61] does not change too much between analytical and preparative HPLC.” Agaki, page 1469, left col.
As such, Abate teaches that obtaining purified (R)-undecavertol is desirable including motivation to increase the purity thereof as high as technically possible. “In light of these observations, the investigation of the properties of the single enantiomers of chiral odourants is now of primary importance.” Abate further cites to Abate 2d teaching that resolution with diastereomers is still a viable option to purify chiral fragrance compounds. Akagi teaches a “general method for synthesizing enantiopure (100% ee) aliphatic alcohols” that is taught to have a high likelihood of success when there is a significant chemical difference between the R groups attached to the stereocenter of a secondary alcohol and is surprising successful even wherein such difference is minor, such as a difference of one methylene group for smaller R groups. In view of the above, an ordinarily skilled artisan at the time of filing would have been motivated to prepare 100% enantiomeric excess (ee) (or at least 94% or 99%) (R)-undecavertol by forming two diasteromeric esters of undecavertol and separating such esters via chromatography followed by recovery of the alcohol from the ester to recover 100% or nearly 100% ee (S)- and (R)-undecavertol with a reasonable expectation of success. Again, Akagi teaches “general method for synthesizing enantiopure (100% ee) aliphatic alcohols,” that has an expectation of success in separating undecavertol into separate mixtures of (S)- and (R)-undecavertol due to the significant chemical difference between the two R groups thereof, one R group being a normal aliphatic chain and the other R group being branched and unsaturated. It is noted that the starting undecavertol composition can be either 1) the racemic undecavertol mixture taught by Abate, or 2) the 93% e.e. enantiomeric (R)-undecavertol mixture taught by Abate as a basis for producing enantiopure undecavertol.
The claim language an “enantiomeric mixture of undecavertol, the mixture having an enantiomeric excess equal to or greater than about 94% [or 99%]” may be interpreted that both enantiomers of undecavertol, R and S, are present even if (S)-undecavertol is present in a very minor amount of less than 1%. “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." MPEP 2144.05(II)(A).
Here, as discussed, Akagi teach an expectation achieving 100% enantiopurity of (S)- and (R)-undecavertol. However, in view of the general conditions taught in the prior art of obtaining chiral alcohols at very high enantiomeric purity, it is not inventive to discover or perform a chromatographic separation that will result in some small amount of contamination of the other enantiomer, i.e. a mixture that is over 99% ee (R)-undecavertol with some very minor amount of (S)-undecavertol. “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
Regarding claims 14 and 15, “The two Undecavertol enantiomers were found to show different odour qualities and strengths. Compound (R)-(+)-1 was the most potent, and showed the best odour profile. It can be used in perfume compositions in half dosage with respect to the racemate.” Abate, page 1998. The preceding is a direct description that enantiomerically-enriched (R)-undecavertol is formulated into a “perfume (i.e. fragrance) composition” that is not neat undecavertol. Any other ingredient that is necessarily and inherently presence in such a perfume composition is within the broadest meaning of a “base material.” Abate directly discusses a “half dosage” of the enantiomerically enriched undecavertol that is a description of mixing any enantiomerically-enriched (R)-undecavertol with the remaining components of the composition (i.e. base material). As such, in forming any perfume composition with an enantiomerically enriched (R)-undecavertol as discussed above, an ordinarily skilled artisan at time of filing would have understood that the same requires mixing enantiomerically enriched (R)-undecavertol and any mixture thereof with a base material to form a perfume composition.
Claim(s) 1-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Abate et al. (Bio-catalysed synthesis of optical active Undecavertol enantiomers, Assymetry 16, 2005, 1997-99) (see IDS) further in view of Abate et al. (Lipase-catalysed preparation of enantiomerically enriched odorants, J. Mol. Catal. B 32, 2004, 35-51) (Abate 2d), Akagi et al. (A general method for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations, Tetrahedron Asymmetry 25, 2014, 1466-77) and Trinh et al. (U.S. 5,849,310 A).
The rejections of claims 1-15 under 35 U.S.C. 103 above are incorporated herein by reference.
As discussed above, claims 14 and 15 are believed to be addressed by Abate.
However, it is further noted that, Trinh, abstract, states:
Personal treatment compositions including cleansing and/or cosmetic compositions are disclosed, the cleansing compositions, for example, comprising from about 0.001% to about 10%, preferably from about 0.005% to about 6%, enduring perfume comprising at least about 70% of enduring perfume ingredients; from about 0.01% to about 95% surfactant system; and the balance carrier. The enduring perfume provides a lasting olfactory sensation thus minimizing the need to use large amounts. Preferred compositions are liquid and comprise water as a carrier.
Table 1 of Trinh provides example perfume compounds that includes undecavertol. Trinh, abstract, further, indicates that perfume ingredients are combined with a surfactant system and water that constitutes a “base material.” As taught by Trinh, it is understood that producing any such composition involves mixing the perfume compound with a base material. For example, Trinh, col. 56, ln. 60 through col. 57, ln. 20, describes forming composing by “thoroughly mixing in the following materials: a) Phenoxyethanol[,] b) Perfume,” wherein the perfume is mixed with base materials including a polymer premix, water, fatty acids, etc. As such, an ordinarily skilled artisan at time of filing would have readily recognized that the employment of undecavertol or any enantiomerically enriched mixture of (R)-undecavertol as discussed above routine requires mixing the same with a base mixture such that an ordinarily skilled artisan at time of filing would have been motivated to do the same to reach the features of claims 14 and 15 with any enantiomerically enriched mixture of (R)-undecavertol as discussed above.
Conclusion
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
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