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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 13 February 2026 has been entered.
Applicant’s amendment of 9 January 2026, in which claim 9 has been cancelled, was entered on 11 February 2026 (see advisory action of 11 February 2026).
Claims 1-8, 10-17 are pending in the instant application.
Claims 1-7 13-17 are withdrawn, as being drawn to a non-elected invention.
Claims 8, 10-12 are being examined herein.
Response to arguments of 9 January 2026 and 27 February 2026
In view of Applicant’s amendment of 9 January 2026, all the rejections to claim 9 are herein withdrawn. Claim 9 was cancelled on 9 January 2026.
Applicant’s arguments (Remarks of 9 January 2026, pages 5-7) against the rejection of claims 8, 10-12 under 35 U.S.C. 103 over Uddin, in view of Schulte, have been considered.
Applicant argues (page 6, second paragraph) that claim 8 requires the administration of a single, chemically defined compound of formula (I), and not a complex botanical extract. The examiner encourages the Applicant to further develop this argument, focusing on the complexity of the mixture, the number of compounds present in such botanical extract, citing literature references to support the argument.
Applicant argues (page 6, third paragraph) that Uddin describes biological effects attributed to aqueous extracts of Centella asiatica. Applicant argues that Uddin does not identify the instant compound of formula (I) in the extracts. Applicant argues (page 6, fourth paragraph) that Schulte reports the isolation and structural identification of various polyacetylene compounds from Centella asiatica, but Schulte is entirely silent with respect to Alzheimer’s disease. In response, since Schulte teaches compound V is present in Centella asiatica, and Uddin teaches Centella asiatica is effective to treat AD, a person of ordinary skill in the art would have expected that compound (V) and its isomer, instant compound (I), are both effective to treat AD.
The Declaration under 37 CFR 1.132 signed by Tatsuji Takahashi, co-inventor, submitted on 9 January 2026, is acknowledged and considered.
In the Declaration of 9 January 2026, Applicant choses one particular literature reference in Uddin (Citation nr. 41 in Udin, reference by Kumar et al.) to show that an aqueous extract prepared using the experimental protocol described in that particular reference does not contain araliadiol, the compound of formula (I) in the instant claims.
The examiner acknowledges the data presented in the Declaration using the experimental protocol described in Kumar. Yet, it is noted that the HPLC profiles in the Declaration may be consistent with araliadiol being present in a low concentration below the detection limit at 210 nm. Applicant has not presented for comparison an HPLC profile of a sample containing pure araliadiol. The examiner notes the HPLC profile in Fig. 1 of the instant application seems to incorporate detection at multiple wavelengths, not only at 210 nm. Even under these conditions, the HPLC peak with retention 24 min (which Applicant identifies as araliadiol) is very small. Therefore, one cannot say for sure whether the extract in Kumar does not contain araliadiol, or whether it contains araliadiol in an amount which is below the limit of detection at 210 nm (Applicant has developed the analytical method, therefore Applicant knows what is the detection limit for araliadiol in the method).
Further, Uddin is a review article that cites multiple literature references (beyond Kumar) that teach that Centella asiatica is effective to treat Alzheimer’s disease. While the aqueous extract in Kumar may not contain instant compound of formula (I) (or may contain it in an amount below the detection limit at 210 nm), several other cited references in Uddin point to Centella asiatica (different extracts) being effective to treat AD. Not all extracts reported in the literature cited by Uddin are aqueous extracts identical to that in Kumar. As such, while Applicant’s argument is focused on the Kumar reference and the aqueous extraction method reported by Kumar, Uddin’s teachings are not limited to aqueous extracts of Centella asiatica being effective to treat AD. For example, Uddin reports the use of a methanolic extract of C. asiatica (page 4927, right column, first paragraph). Another reference in Uddin, Wattanathorn (page 4928) uses extract of plant C. asiatica administered to elderly to improve cognition, where the extract contains phenolic compounds such as tannic acid, which are known to be efficiently extracted using mixtures of water and ethanol or methanol.
Applicant argues (Remarks of 27 February 2026, page 3, fourth paragraph) that the compound of formula (I), araliadiol, is a polyacetylene compound, which is typically lipophilic and extracted using organic solvents, not aqueous systems. This argument is not persuasive, especially given that Applicant uses an aqueous system, namely aqueous ethanol (Specification, [0017]) to extract the instant compound of formula (I).
Applicant argues (Remarks of 27 February 2026, page 3, 5th paragraph) that neither Uddin nor Schulte identifies instant compound of formula (I), and Schulte identifies compound (V), which is an isomer. In response, since Schulte teaches compound V is present in Centella asiatica, and Uddin teaches Centella asiatica is effective to treat AD, a person of ordinary skill in the art would have expected that compound (V) and its isomer, instant compound (I), are both effective to treat AD.
Applicant argues (page 3, last paragraph, page 4) no motivation to combine Uddin and Schulte to arrive at the instant invention. Applicant argues (page 4, second paragraph) that the botanical extracts in Uddin contain triterpenoids (Asiatic acid, madecassic acid, madecassoside), flavonoids, and other phytochemicals, and there is a “logical gap” between Uddin’s teachings and the instantly claimed method. Applicant argues that a POSITA would understand the reported effects in Uddin are attributable to a complex mixture, not to a single component. Applicant argues that Uddin attributes the neuroprotective effects to triterpenoid compounds.
Applicant argues (page 4, 4th and 5th paragraph) that Schulte is silent regarding treatment of AD, and compound (V) in Schulte is not compound of instant formula (I).
In response, it is maintained that a person of ordinary skill in the art would have been motivated to isolate compound V taught by Schulte (which is an isomer of compound formula (I) in instant claim 8) from an extract of C. asiatica (Gotu kola extract, as in instant claim 10), with the expectation that compound V retains the therapeutic properties of C. asiatica and is effective to treat Alzheimer’s disease. Further, the person of ordinary skill in the art would have been motivated to test an isomer of compound V (Schulte), which is a compound of instant formula (I), in a method of treating Alzheimer’s disease, with a reasonable expectation that said isomer is effective to treat Alzheimer’s disease.
For all the reasons above, the rejection of claims 8, 10-12 under 35 U.S.C. 103 over Uddin, in view of Schulte, is herein maintained.
Applicant is encouraged to focus arguments on the likelihood of success with the instant method- bringing forward literature references showing the complexity of mixtures of compounds present in C. asiatica extracts (known to treat AD); the chemical/structural diversity of compounds; the number of compounds; specifically the number of compounds and their structure already known to be effective, in isolated form, to treat AD; any teachings in the prior art that the combined extract had better anti-AD activity than individual components; the very low content of polyacetylene compounds in C. asiatica extracts, etc. Such arguments will be considered and may help advance prosecution.
Applicant’s arguments against the rejection of claims 8, 11-12 under 35 U.S.C. 103 as over Ma, have been considered.
Applicant argues (Remarks of 9 January 2026, pages 7-10) that there is substantial structural difference between the compounds in Ma and the instant compound of formula (I), and a compound of formula (I) is not a positional isomer, nor a homolog of the Ma compound.
The examiner acknowledges the different position of the double bonds and of the -OH groups in Ma
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wherein R1 is
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m = 6,
versus in instant compound of formula (I)
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, yet the examiner maintains that these compounds are isomers of diacetylene diol, and, as such, are expected to have similar therapeutic effect. Since the compounds in Ma are effective to treat Alzheimer’s disease, an isomer of a compound taught by Ma is also expected to be effective to treat Alzheimer’s disease.
Applicant argues (Remarks of 27 February 2026, pages 5-7) that In re Wilder does not apply; that Ma does not teach a compound where m = 6, let alone an isomer of a hypothetical m=6 compound. In response, Ma teaches a genus of compounds that includes m = 6, effective to treat Alzheimer’s disease. Such a compound m = 6 in the genus of Ma, taught by Ma to be effective against Alzheimer’s disease, is an isomer of instant compound (I).
Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious.
Obviousness based on similarity of structure and function entails motivation to make claimed compound in expectation that compounds similar in structure will have similar properties. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979) In the cited case law, the claimed and prior art compounds were both directed to heterocyclic carbamoyloximino compounds having pesticidal activity. The only structural difference between the claimed and prior art compounds was that the ring structures of the claimed compounds had two carbon atoms between two sulfur atoms whereas the prior art ring structures had either one or three carbon atoms between two sulfur atoms. The court held that although the prior art compounds were not true homologs or isomers of the claimed compounds, the similarity between the chemical structures and properties is sufficiently close that one of ordinary skill in the art would have been motivated to make the claimed compounds in searching for new pesticides.
For all reasons above, the rejection of claims 8, 11-12 under 35 U.S.C. 103 over Ma is herein maintained and reproduced below.
Claim Rejections- 35 USC 103
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.
Claims 8, 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Uddin et al. (Molecular Neurobiology 2019, 56, 4925-4944, cited in IDS), in view of Schulte et al. (Arch. Pharm. 1973, 306 (3), 197-209, cited in IDS).
Uddin teaches (page 4926, right column, last paragraph) the cognition-enhancing and anti-Alzheimer’s effects of Centella asiatica (C. asiatica). Uddin teaches that C. asiatica is well-known to have the capacity to increase attention span and concentration, revitalize nervous system and the brain and also to combat aging. Uddin teaches that C. asiatica exhibited antioxidant and cognitive-enhancing properties in normal rats. In rats, for 21 days, the effect of an aqueous extract of C. asiatica (i.e., 100, 200, and 300 mg/kg) was estimated in OS induced by streptozotocin (STZ) and cognitive impairment.
Uddin teaches (page 4927, right column, last two paragraphs) the neuroprotective and anti-Alzheimer’s effects of C. asiatica. Uddin teaches the neuroprotective potential of C. asiatica against memory impairment mediated via colchicine and OS in rats; when the extract of C. asiatica was used for chronic oral treatment (i.e., 150 and 300 mg/kg) for 25 days, beginning 4 days prior to administration of colchicine, this considerably (P < 0.05) attenuated memory impairment induced by colchicine and oxidative damage.
Uddin teaches (page 4927, right column, last two paragraphs) that another study in mice examined the neuroprotective potential of C. asiatica aqueous extract in cognitive impairment triggered by scopolamine in mice. Improvement in cognitive impairment mediated by C. asiatica was also compared against a standard drug (i.e., donepezil 50 μg/kg). Conversely, studies conducted in EPM models revealed that C. asiatica considerably (P < 0.001) reduces the retention transfer latency when used at a dose of 300 mg per kg.
Uddin teaches that Soumyanath et al. observed in a study that oral administration of a water extract of C. asiatica attenuated behavioral abnormalities associated with Aβ in Tg2576 mouse, which is a murine model of AD with greater Aβ burden. Water extract also protected MC65 human neuroblastoma cells and SH-SY5Y cells from toxicity triggered by endogenously produced and exogenously introduced Aβ, respectively. In MC65 cells, water extract of C. asiatica reduced the intracellular formation of Aβ aggregates.
Uddin also teaches (Table 2) the neuroprotective effects of asiatic acid, and of madecassoside, which are active ingredients of Centella asiatica and components of the composition in instant claim 8. Uddin teaches (Table 2) that asiatic acid has learning and memory enhancing effect. Uddin teaches (page 4927, right column, second paragraph) that asiatic acid defends neurons from Ab toxicity and is a good candidate as treatment of AD.
Uddin teaches (page 4928, under anti-Alzheimer’s effects in human studies) that in a double-blind, placebo-controlled, randomized study, Wattanathorn et al. examined the C. asiatica effect on cognitive function in 28 healthy elderly subjects who received the extract of the plant once daily for two months at various doses ranging from 750, 500, and 250 mg. The findings revealed that working memory was increased due to the high dose of the plant extract.
Uddin teaches that in a study conducted by Tiwari et al. involving 60 elderly subjects of age group sixty-five and above, a promising improvement was noticed in mild cognitive impairment (MCI) with a dose of 500 mg twice daily for 6 months, aqueous extract of C. asiatica.
Thus, Uddin teaches neuroprotective properties and anti-Alzheimer effect with an extract of C. asiatica (alternative name Gotu kola, as in instant claim 10).
Since Uddin teaches extracts of C. asiatica (Gotu kola) being orally administered to human subjects, Uddin teaches said extracts as a food or drink composition, as in instant claim 11, and as a pharmaceutical product, as in instant claim 12.
Uddin does not teach that the C.asiatica extract comprises compound (I).
Schulte teaches that an extract of Hydrocotyle asiatica (alternative name C. asiatica) comprises compound V (Table 1)
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,
which is an isomer of instant compound of formula (I)
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.
It would have been obvious for a person of ordinary skill in the art to use the teachings of Uddin and Schulte to arrive at the instant invention. The person of ordinary skill in the art would have been motivated to isolate compound V taught by Schulte (which is an isomer of compound formula (I) in instant claim 8) from an extract of C. asiatica (Gotu kola extract, as in instant claim 10), with the expectation that compound V retains the therapeutic properties of C. asiatica and is effective to treat Alzheimer’s disease.
Further, the person of ordinary skill in the art would have been motivated to test an isomer of compound V (Schulte)
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,
which is a compound of instant formula (I),
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, in a method of treating Alzheimer’s disease, with a reasonable expectation that said isomer is effective to treat Alzheimer’s disease.
In the absence of unexpected results, stereoisomers are considered obvious variants of each other. "Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties". In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Further, regarding claims 11, 12, the person of ordinary skill in the art would have prepared a food or drink composition, or a pharmaceutical composition comprising the diacetylene diol compound V (Schulte) or its isomer, instant compound of formula (I), to be administered orally, because Uddin teaches extracts of C. asiatica (Gotu kola) being orally administered to human subjects.
As such, claims 8, 10-12 are rejected as prima facie obvious.
Claims 8, 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (CN 106117015, published 16 November 2016, cited in PTO-892 of 7 May 2025).
Ma teaches (claim 1) a conjugated diacetylene diol compound of formula
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, wherein R1 is, for example,
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m = 1-8, in medicine (as a pharmaceutical product, as in instant claim 12) to prevent or treat nerve cell protecting related diseases (claim 2), such as Alzheimer’s disease (claim 4).
Ma specifically teaches [0053] compound
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(as neuroprotective Fig. 13), which is a homolog m = 1 vs. m = 6 of a diacetylene diol
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wherein R1 is
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m = 6.
Such a diacetylene diol above m = 6 is a compound encompassed by genus in Ma, and is an isomer of a compound of instant formula (I).
Ma does not teach a compound of instant formula (I), nor does he teach a food or drink composition, as in instant claim 11, comprising a compound of instant formula (I), effective to treat Alzheimer’s disease.
It would have been obvious for a person of ordinary skill in the art to use the teachings of Ma to arrive at the instant invention. The person of ordinary skill in the art would have synthesized a diacetylene diol from the genus taught by Ma, which is an isomer of compound formula (I) in instant claim 8, with the expectation that said diacetylene diol has neuroprotective properties and is effective to treat Alzheimer’s disease.
Further, the person of ordinary skill in the art would have been motivated to test an isomer of a diacetylene diol
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wherein R1 is
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m = 6, taught by Ma,
said isomer being a compound of instant formula (I),
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, in a method of treating Alzheimer’s disease, with a reasonable expectation that said isomer is effective to treat Alzheimer’s disease.
In the absence of unexpected results, stereoisomers are considered obvious variants of each other. "Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties". In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Obviousness based on similarity of structure and function entails motivation to make claimed compound in expectation that compounds similar in structure will have similar properties. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979)
Further, regarding claim 11, the person of ordinary skill in the art would have prepared a food or drink composition comprising the diacetylene diol above, to be administered orally, because Ma teaches that the diacetylene diols of the invention are pharmaceutical products, and pharmaceutical products are routinely administered orally.
As such, claims 8, 11-12 are rejected as prima facie obvious.
Conclusion
Claims 8, 10-12 are rejected.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629