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 .
Application Status
The amendment filed on 2/02/2026 in response to the non-final action of 12/8/2025 is acknowledged and has been entered. Claims 1-15 are currently pending and under consideration.
Rejections Withdrawn
The rejection of Claim 2 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of Applicants amendments.
Rejections Maintained
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 1-9 and 11-14 remain rejected under 35 U.S.C. 103 as being unpatentable over Oertling et al. (US 9,045,714B2, 2015-06-02) in view of Rearrangement, Aliphatic Claisen. “Aliphatic and Aromatic Claisen Rearrangement.” The Claisen rearrangement: methods and applications 3 (2007):5 referred to herein as Claisen.
Oertling et al. teach compounds of formula (I)
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, wherein R1, R2, R3 and R4, in each case independently of one another, denote hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, acetyl, formyl or cyano which are useful as fragrance or flavoring material (Column 4, lines 20-46). For example, Oertling et al. provide a number of compounds encompassed by a compound of formula (I) including, but not limited to,
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and
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(claim 19 of Oertling et al.) In particular, Oertling et al. provides a general synthesis of the compounds of formula (I) comprising the following steps:
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which involves adding 60.1 g (0.4 mol) of thymol at room temperature to a solution of 52.3 g (80%, 0.4 mol) of prenyl chloride in 250 ml of N-methyl-2-pyrrolidone (NMP). Then 35.2 g of aqueous NaOH (50%, 0.44 mol) is added dropwise slowly with simultaneous ice cooling and on completion of addition it is heated to 40° C. and stirred for 2 hours. Then 250 ml of water is added to the mixture, it is neutralized with 2 M NaOH, and the phases are separated. The aqueous phase is extracted twice with 150 ml MtBE, the organic phases are combined, dried and concentrated by evaporation. The crude product (106 g) is fractionated on a 30 cm Vigreux column under vacuum;
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which involves heating 121.7 g (0.75 mol) of prenyl phenyl ether with 0.84 g (15 mmol, 0.02 eq.) of powdered KOH to 210° C., stirring continuously, and is kept at this temperature for 3 h. During this time, low-boiling fractions that form are removed by means of a water separator. After cooling to room temperature, the mixture is neutralized with saturated NH4Cl solution, MtBE is added, and the phases are separated. The aqueous phase is extracted once with MtBE. The combined organic phases are dried, concentrated by evaporation, and the crude product obtained (106.9 g) is fractionated on a 30 cm Vigreux column under vacuum; and
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which involves adding 2.06 g (26.2 mmol, 1.05 eq.) of acetyl chloride to a solution of 4.00 g (30 mmol, 1.2 eq.) of aluminum chloride in 500 ml of dichloromethane under nitrogen at 0° C. Then 5.46 g of 5-tert.-butyl-2,3,3-trimethyl-2,3-dihydrobenzofuran is added dropwise at 0° C. and stirred for a further three hours. The mixture is poured onto ice, neutralized with 2 M NaOH, extracted once with dichloromethane, and the combined organic phases are dried and concentrated by evaporation. 10 g of ethanol is added to the crude product obtained (6.01 g, 60%), it is refluxed for 10 minutes, and the crystals that precipitate on cooling are filtered off with suction and dried under vacuum; or
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which involves adding 12.6 g of phosphoryl chloride (82.5 mmol, 1.6 eq.) dropwise under nitrogen at room temperature to a solution of 13.5 g (0.1 mol, 2.0 eq.) of N-methylformanilide in 150 ml toluene and is stirred for one hour at this temperature. After adding 10.9 g (50 mmol) of 7-tert.-butyl-2,3,3-trimethyl-2H-benzofuran it is heated to 80° C. and stirred for four hours at this temperature. Then 150 g of a 30% sodium acetate solution is added and it is refluxed for one hour. After cooling to room temperature and adding water and MtBE, the phases are separated, extracted once with MtBE, the organic phases are combined and dried. After concentrating by evaporation, the crude product thus obtained is separated from the bottom fraction by bulb-tube distillation (up to 110° C./0.1 mbar) and then purified by column chromatography (silica gel; cyclohexane/ethyl acetate=40/1). While the prior art does not specifically provide an example where the phenol derivative used in step 1 is a tert-butylphenol, in view of the starting material of step 4, it would reasonably appear that a tert-butylphenol was used as the starting material in step 1.
While the prior art teaches a 3 part synthesis of the compounds of formula I, the prior art does not specifically teach that steps 1 and 2 are performed as a one-pot process. Moreover, the prior art differs from the claimed invention in the temperature of the etherification and Claisen rearrangement/cyclization. Lastly, the prior art does not explicitly teach the production of
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,
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or
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.
Claisen provides a number of examples wherein one-pot synthesis occurred incorporating the Claisen rearrangement. For example, Claisen teaches for the synthesis of the intermediate sesquiterpene (+/-)-ceratopicanol, the secondary alcohol 7 was converted to a new alcohol 8 via one-pot etherification, Claisen rearrangement and reduction with LiAlH4 (page 48, Sulfoxide Elimination, Equation 3.1.6). Moreover, Claisen teaches that a number of vinylation-Claisen rearrangements have been reported as a tandem reaction, wherein allyl vinyl ethers can rearrange without isolation since no additional reagents are required in the thermal Claisen rearrangement (page 71, Section 3.1.7.1)
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the synthesis of the compounds of Formula I of Oertling et al. to combine steps 1 and 2 into a one-pot reaction in view of the teachings of Claisen. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Claisen provides a number of on-pot synthesis incorporation the Claisen rearrangement and specifically comments on how vinylation-Claisen rearrangements have been reported as a tandem reaction since no additional reagents are required in the thermal Claisen rearrangement.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the temperature of Step 1 or Step 2 of Oertling et al.. One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
Lastly, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the starting material of Oertling et al. so as to make compounds having the structures
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,
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, or
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. One would have been motivated to make such a modification with a reasonable expectation of success because: Oertling et al. teaches using t-butylbenzofuran derivative in the formylation reaction Step 4
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. As such, it is reasonable that such intermediate could also be used within the acetylation reaction of step 3 resulting in the claimed compounds.
In response to this rejection Applicants assert that the cited teachings of Claisen do not teach or suggest the substitutions to Oertling asserted in the Office action. In particular, Applicants contend that U.S. Courts have held that the chemical arts are unpredictable and sesquiterpene (+/1)-ceratopicanol synthesis cited in the Office action (from Claisen) is not in any way related to the compounds in the claims and therefore, a person of skill in the (unpredictable chemical arts) would not have combined these two teachings and arrived at the claimed invention citing a passage from Anacor Pharmaceuticals, Inc. v. Iancu, 889 F.3d 1372, 1385 (Fed. Cir. 2018) (citing: Eisai Co. Ltd. v. Dr. Reddy's Laboratories, Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2008) “"[O]ur cases recognize that the chemical arts are unpredictable and that similar structures do not always result in similar properties.". Thus, Applicants contend that the Office Action has not alleged or shown that there is structural and functional similarity between Oertling and Claisen and a person of skill in the art would not have been able to predict that combining Oertling and Claisen would have achieved the claimed invention with a reasonable expectation of success. Applicants further contend that it is unpredictable as to whether a multi-step synthetic strategy can or will be successful if performed in a one-pot strategy, wherein one of the many disadvantages of one-pot reactions is the additional byproducts are frequently formed, which can only be separated with losses in yield. Thus, Applicants assert that the use of a one-pot reaction strategy cannot be generalized and to every target compound simply because the one-pot principle has been successfully applied to a different target compound.
These are arguments have been carefully considered, but are not found persuasive.
In response to applicant's argument that sesquiterpene (+/1)-ceratopicanol synthesis cited in the Office action (from Claisen) is not in any way related to the compounds in the claims, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As depicted or noted above, Oertling et al. teach a vinylation-Claisen rearrangement in Step 2. Claisen provides a number of examples wherein one-pot synthesis occurred incorporating the Claisen rearrangement. Moreover, as noted in the preface of Claisen, the thermal rearrangement of aromatic and aliphatic allyl vinyl ethers was first published in 1912 by Ludwig Claisen. As such, the primary focus of the obviousness rejection revolves around a well-known chemical transformation and not the specific compound used. Regarding Applicants contention of the unpredictability in chemical arts, it is recognized, as stated previously, the thermal rearrangement of aromatic and aliphatic allyl vinyl ethers was first published in 1912 by Ludwig Claisen. As such, there is a reasonable expectation that the Claisen rearrangement will occur in a one pot synthesis. Moreover, the two cases provided by Applicants appear to focus on the unpredictability in biological activity of chemical compounds and not related to the synthesis. Again, as noted above, the Claisen rearrangement is a known chemical transformation. Lastly, regarding Applicants contention that one-pot synthesis are unpredictable because of the additional byproducts frequently formed, which can only be separated with losses in yield. The examiner recognizes that Claisen teaches that a number of vinylation-Claisen rearrangements have been reported as a tandem reaction, wherein allyl vinyl ethers can rearrange without isolation since no additional reagents are required in the thermal Claisen rearrangement (page 71, Section 3.1.7.1). As such, this appears to infer that there is a reasonable expectation of success that a one-pot reaction would be successful.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oertling et al. (US 9,045,714B2, 2015-06-02) in view of Rearrangement, Aliphatic Claisen. “Aliphatic and Aromatic Claisen Rearrangement.” The Claisen rearrangement: methods and applications 3 (2007):5 referred to herein as Claisen, as applied above to claims 1-9 and 11-14, in further view of M.P. Neves et al. (European Journal of Medicinal Chemistry, 2011; 46 (6): 2562-2574, IDS).
The combination of Oertling et al. and Claisen, as discussed above and incorporated herein, suggest a two-step process for the synthesis of compounds having the generic structure
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, wherein the first step involves etherification using a halogenated prenyl and NaOH as a base, followed by a Claisen rearrangement/cyclization in a one-pot reaction.
The combination does not specifically teach that the etherification utilizes a base such as K2CO3 (potassium carbonate).
M.P. Neves et al. describes the prenylation of baicalein by convention heating, wherein a mixture of baicalein, prenyl bromide and anhydrous K2CO3 in anhydrous acetone was refluxed at 65oC for 8 h (see page 2570, section 6.2).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute NaOH used in the etherification of Oertling et al. for K2CO3 in view of the teachings of M.P. Neves et al. . One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-M.P.Neves et al. teach that K2CO3 can also be used as a base in etherification.
In response to this rejection, Applicants contend that Neves does not cure the deficiencies of Oertling and Claisen, and therefore, claim 10 is not obvious.
These arguments have been carefully considered, but are not found persuasive for the reasons set forth above.
Conclusion
Therefore, No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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BRANDON J. FETTEROLF, PHD
Primary Patent Examiner
Art Unit 1626
/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626