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 .
Priority
The instant application claims priority from US provisional application No. 63/141,503,
filed on 01/26/2021.
Claim Status
The Amendment, filed on 04/15/2026, is acknowledged in which:
Claims 2, 5-10, 13, 15, 17-22, 27-32, 35-40, and 43-78 are canceled.
Claims 1, 3, 11, 23-25, and 41 are currently amended.
Claims 4, 12, 14, 16, 26, 33-34, and 42 were previously presented.
Claims 79-80 are new.
Claims 1, 3-4, 11-12, 14, 16, 23-26, 33-34, 41-42, and 79-80 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/02/2026 and 07/30/2026 have been considered by the examiner.
Withdrawn Objections and Rejections
In the office action dated 01/16/2026,
All previous rejections of claims 43 are moot in view of claim cancellation.
Claims 1 and 23 were rejected under 35 U.S.C. 112(b) as indefinite for reciting “decreasing” in relation to disease risk without a standard for ascertaining the requisite degree. Applicants amendment to the claim to recite “delaying the development or reducing the severity” has overcome the rejection and the rejection is withdrawn.
Claims 1, 3, 11-12, 14, 16, 23-26 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 18/157,587 (herein US587). Amendments to the copending application have rendered the rejections moot and the rejections are withdrawn.
The following grounds of rejections are either maintained or necessitated by applicant’s amendment to the claims. Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation
Claims 1 and 23 recite the limitations “delaying the development” and “reducing the severity of” disease. For purposes of examination, these limitations are interpreted as within scope of prevention in view of Feldmen and Jacova (Can J Neurol Sci. 2007;34 Suppl 1:S84-S89) (Abstract) and treatment, respectively.
Claim Rejections - 35 USC § 112(a) (modified)
Claims 1, 3-4, 11-12, 14, 16, 23-26, 33-34, 41-42, and 79-80 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
In making a determination that a disclosure does not satisfy the enablement requirement, the following factors are considered: (A) breadth of the claims, (B) nature of the invention, (C) the state of the prior art, (D) the level of one of ordinary skill, (E) the level of predictability in the art, (F) the amount of direction provided by the inventor, (G) the existence of working examples, and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
Breadth of claims: The breadth of the claimed invention as recited in base claims 1 and 23 encompasses “delaying the development or reducing the severity,” wherein the disease is not Alzheimer’s disease (AD), with an APOE inhibitor treatment comprising inhibitor species listed with or without tailoring said treatment based on the subject’s genotype. While several age-related diseases are disclosed in the specification, these species do not limit the base claims (e.g. cardiovascular disease, diabetes, atherosclerosis, obesity, cancer, infection, immunosenescence, coronary artery disease, and neurological disorders; pg 7-8 spanning ¶) (See In re Van Genus, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993)). Subsequent dependent claims 79 and 80 limit the disease to diabetes or obesity. The specification does not explicitly disclose a definition of regarding the intended scope of “delaying the development or reducing the severity” of age-related disease, though reference is made that any inhibition or delay of the development or severity of any age-related disease is considered to be an inducement of healthy aging (pg 8, lines 19-21). This breadth is not supported in the specification because while the specification provides evidence APOE genotypes are strongly associated with markers of disease risk (i.e. biomarkers as indicated in Examples 2-5), it does not reasonably provide enablement that treating with an APOE inhibitor (e.g. species recited in the instant claims) will delay development (i.e. prevention) or reduce the severity of an age-related disease (excluding AD).
Nature of the invention: Claim 1 is drawn to a method of delaying the development or reducing the severity of at least one age-related disease in a human subject comprising administering an APOE inhibitor [comprising either (i) ASO, siRNA, or shRNA; (ii) Cas protein and gRNA; (iii) soluble LDLR; or (iv) an antibody] to the subject, wherein the subject does not comprise a variant in a non-coding region adjacent to an APOE genomic nucleic acid molecule; and wherein the age-related disease does not comprise AD. Claim 23 is drawn to a method of delaying the development or reducing the severity of at least one age-related disease in a human subject comprising determining whether the subject has a variant in a non-coding region adjacent to and APOE genomic molecule and administering an APOE inhibitor [comprising either (i) ASO, siRNA, or shRNA; (ii) Cas protein and gRNA; (iii) soluble LDLR; or (iv) an antibody] to the subject based on the genotype; and wherein the disease does not comprise AD. Subsequent new dependent claims 79 and 80 limit the age-related disease to diabetes or obesity.
State of the prior art and unpredictability: Prior art dictates pleotropic roles of APOE in the brain and in the periphery. Belloy et al. (Neuron. 2019;101(5):820-838) cautions that insights gleaned from genetic association studies should never be a foregone conclusion as many common SNPs that are associated with a given disease may instead be in linkage disequilibrium (LD) with causal genetic SNPs (i.e. correlation not causation), though with regard to APOE4 and AD the general consensus in the field is that the association is mediated by the corresponding amino acid change in the protein itself (pg 821, right column, ¶ 2). With regard to pathology outside the brain, Belloy notes that APOE does not appear to cross the blood-brain barrier, and so peripheral and cerebrospinal fluid pools of APOE are largely considered independent from one another (pg 822, left column, ¶ 2). Belloy teaches APOE genotype is implicated in cardiovascular disease as APOE isoforms show a pronounced, stepwise effect on several, interrelated cardiovascular phenotypes - levels of plasma APOE decrease in a perfect parametric fashion across the six APOE genotypes (Figure 4A) and the reverse is true of LDL levels. However, in contrast to these linear trends, triglyceride levels are parabolic, showing APOE2 carriers and APOE4 carriers are both at increased risk of hypertriglyceridemia. Belloy teaches a small portion of APOE2 homozygotes (in addition to other genetic factors) are prone to severe lipid metabolism disorder, type III hyperlipoproteinemia (OMIM#617347), characterized by extreme elevations in TGs and total cholesterol (defective APOE binding to hepatic lipoprotein receptors) putting them at risk for early coronary artery disease. Therefore, while there is a stepwise association of increasing risk of AD development from E2 > E3 > E4 isoforms and corresponding SNPs the same does not necessarily hold true in non-AD disorders nor to the preventative effects of additional APOE adjacent SNPs (pg 827, left column,¶ 2).
Direction provided by the inventor: The guidance and working examples in the specification is not commensurate with the scope of the claimed invention. Examples and description are limited to genome wide association study analysis and linkage disequilibrium results wherein the biomarker traits were conditioned using an APOE genetic variant (rs429358, marking APOE e4 haplotype). From this data applicant shows LD with an additional SNP rs1065853 to a variant on the protective e2 haplotype (rs7412) and implies that therapeutic efforts to modify APOE activity should consider the potential effects of rs1065853 on APOE dosage. Applicant extrapolates the above findings to the claimed methods of treatment. While the sited treatments, if structurally defined, would be enabled to reduce activity and or levels of APOE (i.e. as taught by US 2023/0357770 A1 (priority to 63/083,006, filed 09/24/2020); WO 2022/066956 A1 as cited in IDS), the claims are not limited using said therapies to strictly APOE-mediated disease, and prior art teaches APOE only reflects part of the pathogenesis of age-related diseases within scope of the instant claims. The specification only supports a correlative relationship between APOE SNPs and risk markers but does not validate an independent causal relationship to age-related diseases (e.g. obesity and diabetes as recited in dependent claims). Moreover, guidance or working examples of using the claimed agents to delay development of an age-related disease is lacking.
Quantity of experimentation needed: Given the above information, it is clear that one of skill in the art would not be enabled to use the full scope of the invention (i.e. including prevention) as claimed without undue experimentation. As undue experimentation is required, claims 1 and 23 and dependent claims that do not rectify this issue are not fully enabled by the disclosure.
Response to Arguments
Applicant's arguments filed 04/15/2026 have been fully considered but they are not persuasive.
Applicant states:
“The Office, however, contends that "inhibition" of the development or severity of an age-related disease would include disease prevention. Although Applicant submits that the Office's interpretation is unduly broad, solely to advance prosecution of the present application, Applicant has amended claims 1 and 23 to recite methods of delaying the
development or severity of an age-related disease. Applicant submits that the amended claims are consistent with their broadest reasonable interpretation consistent with the specification" (see, M.P.E.P. §2111 (2024) (emphasis added)” (Remarks, page 8, ¶ 3)
In response to applicant’s argument regarding amendment to claims 1 and 23, while the claims have been amended to remove some ambiguity, “delaying” disease development by broadest reasonable interpretation in view of the instant specification and prior art (as discussed above) still reads on primary prevention.
Applicant states:
“present application discloses that the unexpected discovery of the relationship between a variant in a non-coding region adjacent to an APOE genomic nucleic acid molecule and at least one age-related disease is causal (see, Applicant's specification at page 44, lines 9-11 ("The observation that [the SNP] rs7412 is in near perfect LD with [the SNP] rs1065853 raises the possibility that [the latter] exerts a regulatory contribution to any e2 haplotype effects that are hitherto entirely attributed to the Arg176Cys (rs7412) variant." (Remarks pg 9, ¶ 1)
“…Applicant submits that [the] conclusion of Belloy is speculation at best. Indeed, Belloy teaches nothing that negates Applicant's observation that the SNP rs7412 is in near perfect LD with the SNP rs1065853 which raises the possibility that the latter exerts a regulatory contribution to any e2 haplotype effects that are hitherto entirely attributed to the Arg176Cys (rs7412) variant.” (Remarks, page 9, ¶ 2)
In response to applicant’s argument, Belloy is introduced to address the supposed causative effects of SNPs within scope of any age-related disease. For instance, while APOE rs7412 is protective in AD development (which is excluded from age-related diseases recited in the instant claims), correlation to the identified SNP rs1065853 and APOE inhibition have not been directly attributed to AD disease prevention, nor in the prevention of other age-related diseases within scope of the instant claims as discussed above.
Applicant states:
“…the present application discloses: i) methods of administering APOE inhibitors (see, e.g., Applicant's specification at page 16, lines 18-23); ii) inhibitory nucleic acid molecules that hybridize to an APOE mRNA (see, e.g., Applicant's specification at page 8, line 26, to page 9, line 9); iii) CRISPR/Cas systems (see, e.g., Applicant's specification at page 10, line 8, to page 14, line 10); iv) soluble receptors for LDLR (see, e.g., Applicant's specification at page 14, lines 20-22); v) antibodies configured to bind to APOE (see, e.g., Applicant's specification at page 14, lines 22-27); and vi) amounts of an APOE inhibitor that are lower than a standard dosage amount (see, e.g., Applicant's specification at page 16, lines 1-9). Thus, one skilled in the art would not be required to perform undue experimentation to delay the development or reduce the severity of at least one age-related disease (in addition to AD).” (Remarks, page 10, ¶ 2)
In response to applicant’s argument, the rejection as stated above has been modified to address the scope of enablement: while being enabled for inhibiting APOE, the specification does not provide sufficient enablement for delaying or reducing the severity of age-related disease; and undue experimentation would be required to enable disease prevention for any age-related disease (not AD) using the aforementioned methods as discussed above.
Applicant states:
“Applicant notes that "[c]ompliance with the enablement requirement ... does not turn on whether an example is disclosed" (see, M.P.E.P. §2164.02 (2024) (emphasis added)). Therefore, Applicant was under no obligation to disclose such an example. (Remarks, pg 10, last ¶)
In response to applicant’s argument, the office maintains the test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. The amount of experimentation to make and use the invention and what is reasonable depends on the nature of the invention and underlying art (Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 596, 2023 USPQ2d 602 (2023)). As discussed above, while APOE targeting therapies have reasonable enablement in the prior art for reducing APOE expression and may provide protective effects in the case of AD, applying these findings to alternative age-related disease prevention is unpredictable as taught by Belloy. The office maintains that in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938), as it is not reasonably predictable to extrapolate the finds from one species (e.g. APOE SNPs in AD) to other species encompassed by the generic claim. Due to the lack of guidance or evidence in the specification indicating a preventative effect of any of the recited agents and the complex nature of the invention established by the prior art, undue experimentation would be required to practice the claimed invention in its full scope.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HANNAH SUNSHINE/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
Prosecution Insights