DETAILED ACTION
This office action is in response to applicant’s filing dated November 10, 2025.
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 .
Continued Examination Under 37 CFR 1.114
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 allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). 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, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on November 10, 2025 has been entered.
Status of claims
Claims 1, 8 – 17 and 19 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed November 10, 2025. Acknowledgment is made of Applicant’s cancelation of claims 2 and 18 and addition of a new claim 19.
Priority
The present application was filed on 05/12/2021 and claims the benefit of U.S. Provisional Application No. 63/023698, filed May 12, 2020.
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.
Claims 1 and 8 – 17 are rejected under 35 U.S.C. 103 as being unpatentable over Velazquez et al (Aging Cell. 2019; 18:e13037, hereinafter Velazquez, the reference is of record) in view of Lin et al (Neuron 98, 1141–1154, June 27, 2018, hereinafter Lin, the reference is of record) and Blusztajn et al (Nutrients 2017, 9, 815, hereinafter Blusztajn).
Regarding claims 1 and 12 - 14, drawn to a method of treating a subject for Alzheimer' s disease comprising determining the presence or absence of an ApoE4 gene in a subject and delivering to the subject an effective amount of choline supplementation in the form of choline chloride, if the subject has an ApoE4 gene, wherein the choline supplementation is the only active agent, and wherein the effective amount is an effective daily dose of about 550 mg to 1000 mg, administered to a subject one to three times a day. According to the said method, the effective amount of choline supplementation is an effective amount for decreasing lipid droplet accumulation in the liver of the subject.
Velazquez teaches an effect of choline supplementation throughout life, where the effect of choline supplementation was tested on the APP/PS1 mouse model of AD (page 1, abstract), where mice received choline supplementation in amount of 5.0 g/kg in their daily diet, where choline supplement was administered in the form of choline chloride. (page 2, “results”). Recalculating mice dosage into human equivalent dosage (Nair et al. J Basic Clin Pharm. 2016 Mar;7(2):27-31) choline supplementation was given in the amount 405 mg/kg per day in human equivalent. Velazquez further teaches current established adequate intake level of choline for adult (>19 years of age) women is 425 mg/day and 550 mg/day for adult men, and the tolerable upper limit (TUL) of choline unlikely to cause side effects for adult females and males (>19 years of age) is 3,500 mg/day (page 8, 2nd paragraph). The effective amount of choline taught by Velasquez, overlaps or lies within the ranges of instant claims. MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Summarizing the results of the experiment, Velazquez concludes that “additional dietary choline is a putative treatment option that may prevent AD progression” (page 2, 3rd paragraph).
Velazquez does not teach determining the presence or absence of an ApoE gene in the subject suffering from Alzheimer’s disease.
However, Lin teaches the apolipoprotein E4 (APOE4) variant as a single greatest genetic risk factor for sporadic Alzheimer’s disease (sAD) (page 1142, summary), where sporadic Alzheimer’s disease accounts for more than 90% of the disease cases according to Barykin et al (Front. Genet. 8:58. doi: 10.3389/fgene.2017.00058, reference of record).
Moreover, Blusztajn teaches that dietary choline intake may influence cognitive function in AD patients, and is associated with higher memory performance, and resistance to cognitive decline (abstract). Blusztajn describes the experiment of effects of choline supplementation on APPswe/PS1dE9 (APP.PS1; MGI ID: 3524957) AD mouse model. APP.PS1 mice are characterized by: (1) high production of amyloid Aβ peptides in brain and accumulation of amyloid plaques by 4–6 months of age; (2) cognitive impairments; (3) cholinergic defects; and (4) evidence of abnormal methylation of several genes (page 5, 2.3.5). While the study, described by Blusztajn, used an AD model caused by genes mutated in the familial human disease, the vast majority of AD cases are sporadic, with no known causes (page 6, 1st paragraph). However, subjects with the APOE4 genotype carry the major genetic risk factor for AD, where vulnerability to AD may be modified by early-life choline supplementation (page 8, 1st paragraph).
Thus, since Velazquez teaches delivering an effective amount of choline to the subject with Alzheimer’s disease generically, without identifying presence of ApoE4 allele, Lin and Blusztajn teach presence APOE4 allele as a major genetic factor of development of AD, where choline supplementation intake helps retard the disease progression, a person of ordinary skill in the art would have recognized that determining the presence of E4 allele of the APOE, would be beneficial in targeting a subject with the higher genetic risk factor for developing AD.
Regarding claim 12 limitation, which recites the method “where an effective amount of choline supplementation is an effective amount for decreasing lipid droplet accumulation in the liver of the subject”, Velasquez teaches an amount of choline supplementation which overlaps or falls within the ranges of an effective amount of choline supplementation recited by instant claims, thus amount of choline supplementation taught by prior art is sufficient to decrease lipid droplet accumulation in the liver of the subject as evidenced by instant claim 1.
Regarding claim 14 limitation, which recites the method where an effective amount of choline supplementation is administered to a subject one to three times a day. Velasquez teaches the method, where mice received choline supplementation in amount of 5.0 g/kg in their daily diet, which indicates that mice received and effective amount of choline at least once a day.
Taking all together, it would be prima facie obvious to one of ordinary skill in the art before effective filing date of the claimed invention to modify the method of treating a subject with Alzheimer’s disease comprising administering choline chloride taught by Velazquez to further identify the presence of APOE4, since the prior art teaches the presence of APOE4 is known to be a genetic risk factor of developing AD conditions. Thus, resulting in the practice of the method of claims 1 and 12 – 14 with the reasonable expectation of success.
Regarding claims 8 and 9, drawn to a method where the effective amount of choline supplementation is an effective amount for altering phosphatidylcholine (PC) metabolism in the subject, wherein altering PC metabolism in a subject comprises increased expression of one or more of the following genes Pld3, Sipr1 , or Plpp3 in astrocytes.
Lin teaches disfunction of genes in APOE4 astrocytes, such as PLPP3, associated with lipid metabolism. (page 1146, left column, 1st paragraph; Figure 3D).
Blusztajn teaches dietary choline intake in the adult may also influence cognitive function via an effect on PC (phosphatidylcholine) containing eicosapentaenoic and docosahexaenoic acids; polyunsaturated species of PC whose levels are reduced in brains from AD patients. One possible explanation for the effect of concurrent choline intake on cognition in adults lies in its function as a precursor of the phospholipid phosphatidylcholine (PC), a major constituent of all biological membranes, including those in neurons and glial cells. Evidence that phospholipid metabolism is abnormal in AD originated with postmortem brain sample studies dating to the 1980s and 1990s which showed reduced levels of PC in the cerebral cortex of AD patients (page 7, 2nd paragraph).
Velasquez teaches an amount of choline supplementation which overlaps or falls within the ranges of an effective amount of choline supplementation recited by instant claims, thus amount of choline supplementation taught by prior art is sufficient for altering phosphatidylcholine (PC) metabolism in the subject as evidenced by instant claim 1.
Thus, prior art teaches, that regular intake of an effective amount of choline supplies cells with material to build membrane phospholipids (PC), where PC level is reduced in AD patients.
Regarding claims 10 and 11, drawn to a methos where the effective amount of choline supplementation is an effective amount for normalizing microglial activation in the subject, and wherein normalizing microglial activation comprises decreased expression of IL-lb induction following activation with interferon gamma relative to a control.
Velasquez teaches that lifelong Ch+ (choline intake) reduces the levels of activated microglia which are increased in AD, thereby mitigating the detrimental effects of brain inflammation associated with AD-like pathology (page 4, right column, 1st paragraph).
Regarding claim 11 limitation, which recites the method where “normalizing microglial activation comprises decreased expression of IL-lb induction following activation with interferon gamma relative to a control”, the prior art is silent regarding “normalizing microglial activation comprises decreased expression of IL-1b induction following activation with interferon gamma relative to control”. However: “normalizing microglial activation comprises decreased expression of IL-1b induction following activation with interferon. gamma relative to control " will naturally flow from the teachings of (or method made obvious by) the prior art (see above rejection), since the same compound (choline) is being administered to the same subjects (subjects suffering from Alzheimer’s disease). In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
In other words, even though the prior art is silent regarding "normalizing microglial activation comprises decreased expression of IL-1b induction following activation with interferon gamma relative to control ", by practicing the method made obvious by the prior art: "the administration of an effective amount of choline to a patient suffering from Alzheimer’s disease ", one will also be "decreasing expression of IL-1b induction following activation with interferon gamma ", even though the prior art was not aware of it.
Apparently, Applicant has discovered a new property or advantage ("normalizing microglial activation comprising decreased expression of IL-1b induction following activation with interferon gamma ") of the method made obvious by the prior art ("the administration of an effective amount of choline to a subject, having an APOE4 allele and suffering from Alzheimer’s disease ").
MPEP 2145 II states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
Regarding claims 15 - 17, drawn to a method where the choline supplementation is administered to the subject for at least 3 months, at least 6 months or at least 12 months.
Velasquez teaches the method where mice were given choline supplemented diet starting at age 2.5 months until 10 months of age (page 2, “results”, Fig.1). This data indicates that mice were fed choline supplemented diet during 7.5 months, which falls within the claimed range “at least 3 months or at least 6 months”.
Regarding claim 17 limitation, which recites the method where the choline supplementation is administered to the subject for at least 12 months, Velasquez teaches “lifelong choline supplementation”. Since human’s lifespan is considered to be over 70 years, the term “lifelong” falls within the claimed range “at least 12 months. MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Amenta et al (Journal of the Neurological Sciences 322 (2012) 96–101, hereinafter Amenta) in view of Lin et al (Neuron 98, 1141–1154, June 27, 2018) and Blusztajn et al (Nutrients 2017, 9, 815).
Instant claim is drawn to a method of treating a subject for Alzheimer's disease comprising determining the presence or absence of an ApoE4 gene in a subject and delivering an effective amount of choline supplementation and a cholinesterase inhibitor to the subject if the subject has an ApoE4 gene, wherein the choline supplementation and the cholinesterase inhibitor are the only active agents, and wherein the effective amount of choline supplementation is an effective daily dose of about 550 mg to 1000 mg.
Amenta teaches multicenter, randomized, placebo-controlled, double-blind clinical trial ASCOMALVA, where 183 subjects with AD (105 female and 78 male), aged between 56 and 91 years (average 75) were recruited The study protocol includes the treatment of patients with cholinesterase inhibitor (donepezil 10 mg/day) + precursor cholinergic (choline alphoscerate 1200 mg/day) (treatment group) or donepezil+ placebo (control group) for 24 months starting from enrolment in the study (page 97, “methods”). The amount 1200mg/day, taught by prior art, is close to the claimed range daily dose of about 550 mg to 1000 mg. MPEP 2144.05.I. states: […]a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%).
Amenta does not teach determining the presence or absence of an ApoE gene in the subject suffering from Alzheimer’s disease.
However, Lin teaches the apolipoprotein E4 (APOE4) variant as a single greatest genetic risk factor for sporadic Alzheimer’s disease (sAD) (page 1142, summary), where sporadic Alzheimer’s disease accounts for more than 90% of the disease cases according to Barykin et al (Front. Genet. 8:58. doi: 10.3389/fgene.2017.00058, reference of record).
Moreover, Blusztajn teaches that dietary choline intake may influence cognitive function in AD patients, and is associated with higher memory performance, and resistance to cognitive decline (abstract). Blusztajn describes the experiment of effects of choline supplementation on APPswe/PS1dE9 (APP.PS1; MGI ID: 3524957) AD mouse model. APP.PS1 mice are characterized by: (1) high production of amyloid Aβ peptides in brain and accumulation of amyloid plaques by 4–6 months of age; (2) cognitive impairments; (3) cholinergic defects; and (4) evidence of abnormal methylation of several genes (page 5, 2.3.5). While the study, described by Blusztajn, used an AD model caused by genes mutated in the familial human disease, the vast majority of AD cases are sporadic, with no known causes (page 6, 1st paragraph). However, subjects with the APOE4 genotype carry the major genetic risk factor for AD, where vulnerability to AD may be modified by early-life choline supplementation (page 8, 1st paragraph).
Thus, since Amenta teaches delivering an effective amount of choline and cholinesterase inhibitor to the subject with Alzheimer’s disease generically, without identifying presence of ApoE4 allele, Lin and Blusztajn teach presence of APOE4 allele as a major genetic factor of developing AD, where choline supplementation intake helps retard the disease progression, a person of ordinary skill in the art would have recognized that determining the presence of E4 allele of the APOE, would be beneficial in targeting a subject with the higher genetic risk factor for developing AD.
Taking all together, it would be prima facie obvious to one of ordinary skill in the art before effective filing date of the claimed invention to modify the method of treating a subject with Alzheimer’s disease comprising administering choline supplementation and the cholinesterase inhibitor taught by Amenta to further identify the presence of APOE4, since the prior art teaches the presence of APOE4 is known to be a genetic risk factor of developing AD conditions. Thus, resulting in the practice of the method of claim 19 with the reasonable expectation of success.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
- In view of amended claim1, now reciting "wherein the choline supplementation is the only active agent" and "wherein the effective amount is an effective daily dose of about 550 mg to 1000 mg.", claim 1 as amended explicitly excludes administration of active agents other than choline supplementation, whereas Wurtman describes a method for treating Alzheimer's disease by administering to the patient an omega-3-fatty acid or metabolic precursor thereof, there is no suggestion in Wurtman that choline, alone, without the omega-3-fatty acid would be useful for treating Alzheimer's disease;
- Wurtman does not teach or suggest the limitation “wherein the subject has an ApoE4 gene”, and wherein the effective amount is an effective daily dose of about 550 mg to 1000 mg; Lin does not cure the deficit;
- In view of amended independent claim 1, Velasquez does not cure the deficit of claim14 limitations, which depends on claim1;
- claim 18, earlier rejected under 35 USC 103 as being unpatentable over Wurtman, in view of Lin and Gervais is now canceled;
- newly added claim 19 is not obvious in view of Wurtman and Lin as neither of them teach the limitation "consisting essentially of delivering an effective amount of choline supplementation and a cholinesterase inhibitor to the subject if the subject has an ApoE4 gene, wherein the choline supplementation and the cholinesterase inhibitor are the only active agents, and wherein the effective amount of choline supplementation is an effective daily dose of about 550 mg to 1000 mg." Gervais does not cure this deficit.
Examiner’s response:
Applicant's arguments have been fully considered, and found persuasive, that Wurtman, Lin and Gervais do not teach all the limitations of amended claims and newly added claim 19. However, the instant invention is considered obvious in view of Velazquez, Lin and Blusztajn as applied to claims 1 and 8 – 17 and in view of Amenta, Lin and Blusztajn as applied to claim 19 (see the rejection section above).
Conclusion
Claims 1, 8 – 17 and 19 are rejected. No claim is allowed.
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/E.V.V./ Examiner, Art Unit 1691
/SAVITHA M RAO/ Primary Examiner, Art Unit 1691