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
RCE Non-Final Rejection
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/08/2025 has been entered.
Review of Claim Status
Claims 15-17 and 20-35 are currently pending.
No amendments entered.
Claims 15-17 and 20-35 are under examination.
Priority Status
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Examiner Responses to Amendments/Arguments
The issues raised in the Office Action are addressed below:
I. Response to Declaration of Hirofumi Watanabe under CFR 1.132 –-filed 11/06/2025 -
Examiner acknowledges Applicant submission of affidavit under 37 § 1.132.
The declaration under 37 CFR 1.132 filed 11/06/2025 is insufficient to overcome the
rejections as set forth in the last Office action because:
First, the overall research is strengthening plasmalogen levels, especially PlsEtn to aid in memory retention by reducing neuronal cell death and aiding in neuronal signaling pathways – which has been used in the art since 1972 (as evidenced by Debuch & Seng: Ether Lipids Chemistry & Biology, Academic Press).
Plasmalogens are known in the art as endogenous antioxidants, protecting membrane lipids from oxidation due to the enhanced electron density of the vinyl-ether bond (para. [0019] in the Instant Specification), which is vulnerable to cleavage by reactive oxygen species. Reductions in plasmalogens impairs learning and memory, while plasmalogen-rich diets improves these functions. This was done (in the prior arts and Instant Application) through the aquatic invertebrate-derived plasmalogens since most of its constituent fatty acids are omega-3 fatty acids such as DHA, and its structure is similar to that of plasmalogen found in the human brain. In the Instant Specification, the embodiments and figures are geared to plasmalogen analysis as well as the ratio of ethanolamine plasmalogen and memorization ability.
Yamashita teaches (pg. 583, col. 2, hanging para. 2), “PlsEtn bearing DHA levels in RBC were correlated with the levels in the cerebral cortex (Table 7). In our previous study, levels of RBC PlsEtn with DHA were decreased in patients with AD compared to healthy subjects. The levels of RBC PlsEtn having DHA were correlated with the brain volumes of patients with AD and healthy subjects (unpublished observation). The level of RBC PlsEtn with DHA may thus reflect brain condition.”
Both the Instant Application and the prior arts teach to the exact type of plasmalogens, source, and applications in the same field of scope. Also, plasmalogens are essential for brain health, protecting against oxidative stress, modulating membrane fluidity, and supporting neurogenesis and synaptic function. Lowered levels of PlsEtn and PlsCho are consistently associated with cognitive decline and neurodegenerative diseases like Alzheimer's disease (as seen in Yamashita). Evidence in the prior art indicates that plasmalogen is significantly more effective than other phospholipids in inhibiting the aggregation of amyloid beta, which is believed to be the cause of Alzheimer's disease.
Second, Applicant described claimed recitation of Claims 15 and 27 with alleged unexpected results. The prior art though teaches the specified plasmalogens, ranging amounts of the EPA and DHA, method of enhancing memorization, similar source extraction from aquatic invertebrates and also facts which demonstrated in the teachings. It is restated that the elements the Applicant relies on are taught by the prior arts.
Thus, while Applicant asserts that the unexpected results are dissimilar in the light of the prior art, the Examiner disagrees and has explained why these illustrations do read upon the claimed method as shown in the rejection below. In addition, it is also noted that
even if there are slight differences, this would not necessarily render the claims as non-obvious.
Applicant's attention is drawn to MPEP at §2144.05:
"The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages...Where 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."
Third, research studies like Chapman, use MMSE scores to assess cognitive function and track changes over time in relation to conditions like Alzheimer's disease. Chapman’s research focused on the diagnostic accuracy of MMSE and LM cutoff scores used in Alzheimer's disease (AD) clinical trials and diagnostic studies. The study also involved 23,438 subjects with normal cognition (which is a healthy subject), mild cognitive impairment (MCI), and AD dementia, derived from the National Alzheimer’s Coordinating Center database.
Hence, in view of the foregoing when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness. known
II. Claim Rejections 35 USC § 103 –
Claims 15-17, and 20-35 are rejected under 35 U.S.C. 103 as being unpatentable over Yamashita (pub'd: 2017) and in view of Kostetsky (pub'd: 2012) and in further view of KR Chapman ("Mini Mental State Examination and Logical Memory scores for entry into Alzheimer's disease trials" pub'd 02/22/2016).
Claims 27, 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Yamashita in view of Kostetsky and Chapman and in further view of Hoem (US 2015/0164841 Al).
Applicant filed a declaration rebutting the rejection, the Examiner response is located in the Declaration and within the USC § 103 rejection.
III. RCE Non-Final Rejection –
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.
Joint Inventors
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.
A. First Rejection –
Claims 15-17, and 20-35 are rejected under 35 U.S.C. 103 as being unpatentable over Yamashita (Lipids. 2017; 52, 7, 575-585; hereinafter “Yamashita”) and in view of Kostetsky (Russ. J. Mar. Biol., 2012,38, 64-71; hereinafter “Kostetsky”) and in further view of KR Chapman, et al in “Mini Mental State Examination and Logical Memory scores for entry into Alzheimer's disease trials” (Alzheimers Res Ther. 2016 Feb 22;8:9; hereinafter “Chapman”).
With respect to Claim 15-17 and 20-35, Yamashita teaches a method for how “oral administration (pg. 575, title) of ethanolamine plasmalogen (PlsEtn) administration affects cognitive deficits and lipid composition in an animal model of Alzheimer’s Disease (AD)” and in so doing, the “administration of ascidian viscera ethanolamine plasmalogen (PIsEtn) into a subject showed reference memory and improved working memory-related learning abilities” (pg. 575, col. 1-2). Yamashita teaches “the maintenance or increase in PlsEtn level, especially that containing Docosahexaenoic acid:22:6n-3 (DHA), in the brain may prevent the pathogenesis and progression of AD via suppression of neuronal apoptosis” (pg. 576, col. 1, para. 3 — col. 2, para 1), which reads on the scope of the claims.
Yamashita continues teaching memory is affected in a learning ability demonstration and administration of ethanolamine glycerophospholipid, EtnGpl. Yamashita also discloses “the numbers of reference memory error (RME) and working memory error (WME) show long- and short-term memory impairments, respectively” (pg. 577, col. 2, para 2). In AD “early stages, patients with AD have problems with short term memory (pg. 577, col. 2, para 2). Both reading on the proficiency memorization in a healthy subject.
However, as AD progresses, patients also show long-term memory loss. AD subjects were evaluated accurately by investigating both RME and WME... Ascidian rat groups were then orally administered ascidian viscera EtnGpl (260 umol EtnGpl/kg BW/day; 209 umol as PlsEtn/kg BW/day)” (pg. 577, col. 2, para 2).
Plasmalogens (glycerophospholipid with a vinyl ether bond at the sn-1 position, different from diacylglycerophospholipids which have a carbonyl group; also seen in the Instant Specification on para. [0019]) help maintain membrane fluidity, lipid raft architecture, and neuron function, in addition to acting as antioxidants by scavenging reactive oxygen species (ROS). PlsEtn is particularly abundant in synaptic membranes. Adequate PlsEtn levels protect proteins and DNA from oxidative damage and maintain membrane fluidity, both crucial for cognition and memory. Boosting PlsEtn-rich plasmalogens improves cognitive markers. Maintaining a high PlsEtn:PlsCho ratio preserves neuronal membrane architecture and signal transduction efficiency.
Yamashita also teaches on pg. 583, col. 2, hanging para. 2, “PlsEtn bearing DHA levels in RBC were correlated with the levels in the cerebral cortex (Table 7). In our previous study, levels of RBC PlsEtn with DHA were decreased in patients with AD compared to healthy subjects. The levels of RBC PlsEtn having DHA were correlated with the brain volumes of patients with AD and healthy subjects (unpublished observation). The level of RBC PlsEtn with DHA may thus reflect brain condition.”
This indicates in the comparison of healthy patients versus those with Alzheimer’s disease studies were done with proper control groups in understanding the administration effects and lipid composition to compare differences in the brain ability of RWE and WME though plasmalogen administration.
Additionally, with respect to Claims 20-24 and 28-30, since the prior art teaches product output, and the claims recite product-by-process language, these claims are therefore obvious. See MPEP 2113, incorporated by reference herein.
MPEP 2113.I:
“[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Yamashita fails to teach for Claims 15 and 27: a mass ratio of ethanolamine plasmalogen to choline plasmalogen comprised; and wherein the healthy subject is a subject with 27 points or more out of 30 points as judged by the Mini-Mental State Examination.
Yamashita also fails to teach for Claims 20-24 and 28-30: the animal tissue is derived from aquatic invertebrates; the aquatic invertebrates of the phylum Chordata, subphylum Urochordata, class Ascidiacea are aquatic invertebrates of the genus Halocynthia; the genus Halocynthia is ascidian or golden sea squirt;
Kostetsky teaches for Claims 15 and 27: a mass ratio of ethanolamine plasmalogen to choline plasmalogen comprised in the plasmalogen is 7:3 to 9:1 (Pg. 64, col. 2, para. 1; pg. 68, col. 2, para. 2-3; pg. 69, Table 5-Halocynthia roretzi);
Kostetsky further teaches for Claims 20-24 and 28-30:
Claim 20: wherein the animal tissue is derived from aquatic invertebrates (pg. 64, col. 2, para. 1; pg. 68, col. 2, para. 2-3; pg. 69, Table 5-Halocynthia roretzi);
Claims 21 and 28: wherein the aquatic invertebrates are aquatic invertebrates of phylum Chordata, subphylum Urochordata, class Ascidiacea (pg. 64, col. 2, para. 1; pg. 68, col. 2, para. 2-3; pg. 69, Table 5-Halocynthia roretzi);
Claims 22-23 and 29: wherein the aquatic invertebrates of the phylum Chordata, subphylum Urochordata, class Ascidiacea are aquatic invertebrates of the genus Halocynthia (pg. 64, col. 2, para. 1; pg. 68, col. 2, para. 2-3; pg. 69, Table 5-Halocynthia roretzi);
Claims 24 and 30: wherein the aquatic invertebrates of the genus Halocynthia are ascidian or golden sea squirt (pg. 64, col. 2, para. 1; pg. 68, col. 2, para. 2-3; pg. 69, Table 5 - Halocynthia roretzi).
Therefore, it would have been obvious to one of ordinary skill to combine Yamashita with Kostetsky. Yamashita and Kostetsky include relevant data on plasmalogens since combining prior art elements according to known methods yields predictable results. One skilled in the art could have combined the elements by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
With respect to Claims 15 and 27:
Yamashita and Kostetsky, in combination, fail to teach the additional limitation of wherein the healthy subject is a subject with 27 points or more out of 30 points as judged by the Mini-Mental State Examination.
Chapman teaches specific cutoff scores on the Mini Mental State Examination (MMSE) and the Logical Memory (LM) test used to determine inclusion in Alzheimer’s disease (AD) clinical trials and diagnostic studies (abstract). As seen on pg. 4, col. 1, full para. 2, “MMSE cutoffs ranging from 3–14 to >27, but ≤24 and/or ≤26 most commonly defined the clinical spectrum of AD.” In Table 1, on pg. 3, the National Alzheimer’s Coordinating Center (NACC) sample characteristics which has MMSE, mean (SD) for normal cognition at 28.88 (1.41), for mild cognitive impairment at 27.11 (2.43) for Alzheimer’s Disease at 20.92 (5.50) with a ρ value of <0.001.
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According to the Instant Specification, paras. [0063]-[0064], “…the term "healthy" used in the present invention also includes the case where the verbal memorization ability and/or the visual memorization ability is/are lowered due to aging as compared with the young age….. 27 points or more out of 30 points may be judged as a subject having a healthy verbal memorization ability and/or visual memorization ability.” This is understood as the prior art reading on the claims.
Therefore, it would have been obvious to one of ordinary skill to combine Yamashita Kostetsky, with Chapman. In this combination, Yamashita and Kostetsky (according to KSR-Prong A) include applicable data on plasmalogens (both ethanolamine and choline) since combining prior art elements according to known methods yields predictable results. Also, the prior art specifically deals with aquatic invertebrates of the Instant Application with similar methods as seen within the Instant Application. The addition of Chapman to the combination of Yamashita and Kostetsky gives a range that is approved by the National Alzheimer’s Coordinating Center.
One skilled in the art could have combined the elements by known methods with no change in their respective functions, and the combination of Yamashita, Kostetsky, with Chapman, yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
B. Second Rejection -
Claims 27, 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Yamashita in view of Kostetsky and Chapman (seen above in Claims 15-17, 20-32) and in further view of Hoem, et. al US 2015/0164841 A1 (pub’d 06/18/2015; hereinafter “App’841”).
The teachings of Yamashita, Kostetsky and Chapman are disclosed above and at least those teachings are incorporated by reference herein.
The combination of Yamashita, Kostetsky and Chapman teaches a method for how “oral administration (Yamashita; pg. 575, title) of ethanolamine plasmalogen (PlsEtn) administration affects cognitive deficits and lipid composition in an animal model of Alzheimer’s Disease (AD)” and in so doing, the “administration of ascidian viscera ethanolamine plasmalogen (PlsEtn) into a subject showed improved reference memory and working memory-related learning abilities” (Yamashita; pg. 575, col. 1-2).
This combination of Yamashita, Kostetsky, and Chapman, includes teaching a mass ratio of ethanolamine plasmalogen to choline plasmalogen comprised in the plasmalogen is 7:3 to 9:1 (Pg. 64, col. 2, para. 1; pg. 68, col. 2, para. 2-3; pg. 69, Table 5-Halocynthia roretzi) and wherein the healthy subject is a subject with 27 points or more out of 30 points as judged by the Mini-Mental State Examination.
Chapman teaches specific cutoff scores on the Mini Mental State Examination (MMSE) and the Logical Memory (LM) test used to determine inclusion in Alzheimer’s disease (AD) clinical trials and diagnostic studies (abstract). As seen on pg. 4, col. 1, full para. 2, “MMSE cutoffs ranging from 3–14 to >27, but ≤24 and/or ≤26 most commonly defined the clinical spectrum of AD.” In Table 1, on pg. 3, the National Alzheimer’s Coordinating Center (NACC) sample characteristics which has MMSE, mean (SD) for normal cognition at 28.88 (1.41), for mild cognitive impairment at 27.11 (2.43) for Alzheimer’s Disease at 20.92 (5.50) with a ρ value of <0.001.
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According to the Instant Specification, paras. [0063]-[0064], “…the term "healthy" used in the present invention also includes the case where the verbal memorization ability and/or the visual memorization ability is/are lowered due to aging as compared with the young age….. 27 points or more out of 30 points may be judged as a subject having a healthy verbal memorization ability and/or visual memorization ability.” This is understood as the prior art reading on the claims.
Therefore, it would have been obvious to one of ordinary skill to combine Yamashita Kostetsky, and Chapman. Yamashita and Kostetsky include relevant data on plasmalogens since combining prior art elements according to known methods yields predictable results and Chapman gives a range that is approved by the National Alzheimer’s Coordinating Center. One skilled in the art could have combined the elements by known methods with no change in their respective functions, and the combination of Yamashita Kostetsky, and Chapman yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
The combination of Yamashita, Kostetsky and Chapman fails to teach wherein the purified plasmalogen is soluble in a mixed solution of 95% ethanol and 5% water; is included in an enteric coated soft capsule; said purified plasminogen also contains fatty acid triglyceride and vitamin E are included in an enteric coated soft capsule.
With respect to Claims 33, 34 and 35, App’841 teaches:
Claim 33: wherein the plasmalogen (“phospholipid” compositions defined as a phosphatide such as lecithin, cephalin, phosphatidyl serine or plasmalogen; para. [0016]) is a purified plasmalogen that is soluble in a mixed solution of 95% ethanol and 5% water (in some embodiments, the ratio of polar solvent, for example ethanol, to water is taught from 1:1 to 1:5, as well as 1:1 to 100:1, 2:1 to 100:1, 2:1 to 20:1, 3:1 to 20:1, 4:1 to 20:1, 5:1 to 20:1, or 10:1 to 20:1; para. [0039]);
Claim 34: wherein said plasminogen is included in an enteric coated soft capsule;
Claim 35: wherein said purified plasminogen also contains fatty acid triglyceride (omega-3, 6 and astaxanthin; paras [0016]-[0019]) and vitamin E (para. [0034]) are included in an enteric coated soft capsule (para. [0028]).
Additionally, with respect to the range of Claims 27 and 33, the combination of Yamashita, Kostetsky and Chapman fails to teach App’841’s overlapping ratio range of polar solvent to water in various ranges. However, for a ratio of 95:5 of ethanol to water, it would be equivalent to 19:1. As such, the ratio of 19:1 overlaps with the 2:1 to 20:1, 3:1 to 20:1, 4:1 to 20:1, 5:1 to 20:1, or 10:1 to 20:1. This indicates that the range of 95:5 (19:1) overlaps. According to MPEP 2144.05.I:
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Therefore, it would have been obvious to one of ordinary skill to combine Yamashita, Kostetsky, Chapman with App’841. Yamashita, Kostetsky, and Chapman include evidence on plasmalogens, varying ratio concentrations, relation to the MMSE (indicated above) and ways to purify those plasmalogens. Since combining prior art elements with known methods yields predictable results and known results, one skilled in the art would expect with no change in their respective functions, the combination yielded nothing more than predictable results to one of ordinary skill. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
One would be motivated with the success of Yamashita, Kostetsky and Chapman’s work since the plasmalogens of the prior art as well as the source of the aquatic invertebrate is similar to the Instant Application. It is also known the sources used have established biologically active substances.
It would therefore have been obvious to combine Yamashita, Kostetsky, Chapman with App’841 for the reason that processing phospholipids from marine oil concentrates is established in the art, as well as methods of extraction from marine specimens. The combination with Hoem teaches the use of designing a formulation in which one can orally administer as individualized treatment, as seen in App’841. MPEP 2144.05 (incorporated by reference herein).
One skilled in the art could also apply KSR-Prong B and substitute krill oil for one of the Instant Application plasmalogens as well. One skilled in the art would expect success because the pieces of art relate to compositions containing plasmalogens (krill oil also contains an ethanolamine plasmalogen), have a similar utility of how plasmalogen administration
affects cognitive deficits (working memory/reference) and its lipid composition.
Conclusion
Claims 15-17, and 20-35 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Josmalen M. Ramos-Lewis whose telephone number is (571)272-0084. The examiner can normally be reached M-F 9:30-5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached on (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621