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 .
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 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/14/2025 has been entered.
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 10/14/2025, in which claims 1, 23-25, 33, and 43 are amended; claims 2, 5-10, 13, 15, 17-22, 27-32, 35-40, and 44-78 are canceled, is acknowledged. Claims 1, 3-4, 11-12, 14, 16, 23-26, 33-34, and 41-43 are pending in the instant application and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action dated 08/14/2025,
The objection to the drawings have been withdrawn in view of the amendment filed 08/14/2025.
All previous rejections of claims 74-78 are moot in view of claim cancellation.
All other previously presented rejections under 35 USC 102 or 103 have been overcome by applicant’s amendment to base/independent claims to specify the “disease does not comprise Alzheimer’s disease.” The claims are newly rejected in the instant office action to account for the amended claim limitations.
The following grounds of rejections are either maintained or necessitated by applicant’s amendment to the claims.
New Claim Rejections - 35 USC § 112(b)
Claims 1 and 23 are rejected 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.
The term “decreasing” in relation to disease risk in claims 1 and 23, respectively, is a relative term which renders the claim indefinite. The term “decreasing” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For examination purposes examiner as interpreted this to include instances of disease prevention.
New Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-4, 11-12, 14, 16, 23-26, 33-34, 41-43 are 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 “decreasing the risk of developing at least one age-related disease,” wherein the disease is not Alzheimer’s disease (AD), with an APOE inhibitor treatment (i.e. any agent that inhibits APOE) with or without tailoring said treatment based on the subjects genotype. Age related diseases as defined by the specification are cardiovascular disease, diabetes, atherosclerosis, obesity, cancer, infection, immunosenescence, coronary artery disease, and neurological disorders (such as Alzheimer’s disease) (pg 7-8 spanning ¶). The specification does not explicitly disclose a definition of regarding the intended scope of “decreasing the risk,” 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). As reference is made to inhibition, examiner has interpreted this to include disease prevention. This breadth is not supported in the specification because while the specification provides evidence linking APOE genotype to disease risk it does not reasonably provide enablement that treating with an APOE inhibitor (e.g. species recited in dependent claims 3-4, 11-12, 14, 33, 34, 41-42) will reduce the risk of developing (i.e. prevention) of an age-related disease not AD.
Nature of the invention: Claim 1 is drawn to a method of decreasing the risk of developing at least one age-related disease in a human subject comprising administering an APOE inhibitor 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 decreasing the risk of developing 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 to the subject based on the genotype; and wherein the disease does not comprise AD. Claim 43 is drawn to a method of identifying a subject having an increased risk or decreased risk of developing at least one age-related disease based on the presence or absence of a non-coding variant and administering an APOE inhibitor at dosages based on said risk wherein the disease does not comprise AD.
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 by in linkage disequilibrium with causal genetic SNPs, 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 instead 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, the same does not necessarily hold true in non-AD disorders (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 suggesting rs1065853 may act as a causal variant on the protective e2 haplotype, implying that therapeutic efforts to modify APOE activity should consider the potential effects of rs1065853 on APOE dosage. However, as stated above the specification discloses no guidance or working examples of using the claimed agents to reduce risk of developing an age related disease, wherein the disease is not AD.
Quantity of experimentation needed: Given the above information, it is clear that one of skill in the art would not be enabled to make or use the full scope of the invention as claimed without undue experimentation. As undue experimentation is required, claims 1, 23, and 43 and dependent claims that do not rectify this issue presented within are not fully enabled by the disclosure.
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US18/157,587
Claims 1, 3, 11-12, 14, 16, 23-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 11-14, 23-26, 33, 34, 41 and 42 of copending Application No. 18/157,587 (herein US587). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1, 14, and 16, claim 1 of US587 claims a method of increasing longevity and/or inducing healthy aging with APOE inhibitor. US587 defines any inhibition or delay of development or severity of any age-related disease and/or any increase in longevity is considered to be an inducement of healthy aging (pg 9, lines 22-24). Claim 14 of US587 recites a when a subject is “reference” they are administered an inhibitor at a standard dosage amount. US587 defines “subjects” to include humans (page 6, lines 21-22) and “APOE reference” as SEQ ID NO:1 (human APOE) (US587 specification, page 6, lines 29-30), which does not have non-coding variants (i.e. no SNP according to instant claim 16). Therefore, these claims overlap in scope and are patentably indistinct.
Regarding claims 3, 11, and 12, US587 claims 1 and 14 are patentably indistinct from instant claim 1 as discussed above. Subsequent dependent claims recite identical inhibitors to US587 claims 3, 11 and 12, respectively, and are therefore also patentably indistinct.
Regarding claims 23 and 26, as previously stated US587 defines any inhibition or delay of development or severity of any age-related disease and/or any increase in longevity is considered to be an inducement of healthy aging (pg 9, lines 22-24). US587 claim 23 claims differ from the instant claims as they claim “APOE variant” (genus) rather than non-coding variant adjacent to APOE (species). US587 claim 26 claims the APOE variant comprises a thymine at position 501 in SEQ ID NO:2 (identical to instant claim 26), which is a non-coding variant, therefore these claims overlap in scope and are patentably indistinct. Further, US587 defines “subjects” to include humans (page 6, lines 21-22) and “APOE reference” is defined as SEQ ID NO:1 (human APOE) (US587 specification, page 6, lines 29-30), which does not have non-coding variants. Therefore, the claims overlap in scope and are patentably indistinct.
Regarding claims 24-25, 33, and 41-42, US587 claims 23 is patentably indistinct from instant claim 23 as discussed above (i.e. APOE variant disclosed by US587 is patentably indistinct from the non-coding variant disclosed in the instant claims). Subsequent dependent claims that recite identical administration parameters or inhibitors are therefore also patentably indistinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments - NSDP
Applicant's arguments filed 10/14/2025 have been fully considered but they are not persuasive. As new grounds of rejection are made in view of amendments (i.e. the provisional rejection is not the only remaining rejection as asserted; Remarks pg 16-17), the provisional non-statutory double patenting rejections are maintained (with modifications for claim amendments).
Conclusion
No claims are allowed.
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.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647