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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1, 3, and 11-16) in the reply filed on 12/15/2025 is acknowledged. Applicant did not specify that this election was without traverse, however, because no argument was made to the contrary, this election is being interpreted as being without traverse.
Claim Status
Claims 1, 3, 11-16, 23-26, 33, 41-42, and 74-79 are pending.
Claims 23-26, 33, 41-42, and 74-79 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/15/2025.
Claims 1, 3, and 11-16 are being examined on the merits.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted (Figure 1 is in color). Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The disclosure is objected to because of the following informalities: On page 4, lines 28-30, the specification states that the application contains at least one drawing executed in color. However, no petition to include color drawings has been provided, meaning no drawings will be present in color. If a petition is filed with the Office to include colored drawings, this statement can remain. If no petition is filed, it should be removed.
Appropriate correction is required.
The use of the term “Vector NTI” (pg 35, ln 6), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112a – Scope of Enablement
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, and 11-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method of decreasing LDL and/or treating Alzheimer’s disease in a human subject, comprising administering an apolipoprotein E (APOE) inhibitor to the human subject,
wherein the subject is APOE reference or heterozygous for an APOE loss-of-function variant, and
wherein the inhibitor is an antisense nucleic acid molecule, a small interfering RNA, a short hairpin RNA, a soluble receptor for LDL, or an antibody
does not reasonably provide enablement for administering any apolipoprotein E (APOE) inhibitor to any subject to induce healthy aging and/or increase longevity, regardless of the presence or absence of an APOE variant nucleic acid molecule, as is encompassed by the scope of claims 1, 3, and 11-16. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Nature of the invention and breadth of the claims
The invention is in the class of invention which the CAFC has characterized as “the
unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co.,
243 F.3d 1316, 1330 (Fed. Cir. 2001).
The rejected claims are broadly directed to the administration of any kind of APOE inhibitor to any subject regardless of APOE genotype with the aim of “increasing longevity and/or inducing healthy aging”, which the specification defines as “Any inhibition or delay of development or severity of any of the age-related diseases and/or any increase in longevity is considered to be an inducement of healthy aging” (pg 9, ln 22-24). This encompasses the inhibition or delay of any disease related to aging (not just those exemplified in the specification) and any degree of increase in longevity.
Direction provided by the specification and working example
The specification provides working examples in which associations of genetic variants of APOE with various biomarker levels are made using data provided from the UK Biobank study (pg 44). Specifically, the associations of SNPs with the six biomarker traits were conditioned using an APOE genetic variant rs429358 (APOE4 haplotype) that has been heavily associated with risk of developing Alzheimer’s disease in the prior art. The working example defines the SNP rs1065853 as being strongly associated with the traits CYSC, HDL, LDL, and TRIG (pg 45, ln 13-15). Rs1065853 is described as being in high linkage disequilibrium with rs7412, the allele defined by the literature as indicative of the APOE2 haplotype (pg 47, ln 1-5).
No specific associations between this particular genetic variant (as exemplified by SEQ ID NO:2 in claim 16) were made in regards to age (longevity) or Alzheimer’s disease. Other APOE genetic variants were listed as being associated with a protective effect in relation to AD (pg 50-54), but not the specific variant claimed in claim 16. The specification provides putative loss-of-function APOE variants, in combination, as exhibiting a “nominal significance for a protective effect on AD” and LDL lowering effects (pg 50-54, Tables 5-8).
Therefore, the specification provides specific loss-of-function alleles in association with various biomarker levels, LDL lowering, and Alzheimer’s disease (AD), specifically in a human population. The specification does not teach APOE inhibitors being administered to any type of subject (any animal) with any type of APOE genetic background (as encompassed by the claims).
State of the art, level of skill in the art, and level of unpredictability
Because the claims encompass administering APOE inhibitors to any subject with any type of APOE variant (or specifically rs1065853 in the case of claim 16), it is relevant to point out the unpredictability of associating phenotypes with any type of genetic variant and subsequent effect on gene function or expression. For example, specific variants of APOE such as APOE2, while being protective against some forms of age-related diseases (AD), are not protective for others and in fact are associated with increased risk of diseases such as dysbetalipoproteinemia, a condition associated with coronary artery disease (Williams, 2020; pg 1, col 2).
Quantity of experimentation required
Given the level of unpredictability in terms of associating specific APOE variants with longevity and/or healthy aging in any subject and subsequently administering APOE inhibitors regardless of genotypic background, there would be an undue amount of experimentation required for one skilled in the art to perform the method of treatment as claimed.
Conclusion
After consideration of the teaching of the specification and the specific working examples, considering the breadth of the claims, and the unpredictability in the art, it is the conclusion that an undue and unreasonable amount of experimentation would be required to make and use the invention that is instantly claimed.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, and 11-16 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Freudenberg (Freudenberg et al., US 2022/0233569 A1, EFD of 1/26/2021; cited on IDS of 8/22/2023).
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Claim 1: Freudenberg teaches a method of increasing longevity and/or inducing healthy aging in a subject by administering an APOE inhibitor to the subject (paragraph [0006]).
Claim 3: Freudenberg teaches that the inhibitor of APOE is an antisense nucleic acid molecules, siRNA, or shRNA that hybridizes to an APOE mRNA (paragraph [0030]).
Claim 11: Freudenberg teaches that the APOE inhibitor is a small molecule, such as a soluble receptor for LDL (LDLR; paragraph [0041]).
Claim 12: Freudenberg teaches that the APOE inhibitor is an antibody (paragraph [0041]).
Claim 13: Freudenberg teaches that the method of treatment also comprises detecting the presence or absence of an APOE variant nucleic acid molecule in a biological sample from the subject (paragraph [0042]).
Claim 14 and 15: Freudenberg teaches that subjects that are heterozygous for an APOE variant nucleic acid molecule are administered an APOE inhibitor at a dosage lower than the standard dosage amount. Freudenberg teaches that a standard dosage amount of an inhibitor is administered to subjects that are APOE reference (paragraph [0045]).
Claim 16: Freudenberg teaches that the APOE variant nucleic acid molecule has a nucleotide sequence comprising a thymine at a position corresponding to position 501 according to SEQ ID NO:2. The instant specification defines this variant as rs1065853 (pg 40, ln 10-12). Freudenberg teaches that this variant corresponds to position 501 in the sequence as defined by SEQ ID NO:2 (paragraph [0022 and 0061]).
Claims 1, 3, 11, and 12 are further rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Butovsky (Butovsky et al., US 2017/0334977 A1).
Claim 1: Butovsky teaches treating a neurologic disease by administering an inhibitor of APOE. This reads on inducing healthy aging given that the specification of the instant application states: “Any inhibition or delay of development or severity of any of the age-related diseases and/or any increase in longevity is considered to be an inducement of healthy aging" (Specification, pg 9, ln 22-24).
Claim 3: Butovsky teaches that the APOE inhibitor is an antisense oligonucleotide, small interfering RNA, or shRNA (paragraphs [0009 and 0019]).
Claim 11: Butovsky teaches that the APOE inhibitor is a soluble receptor for LDL (paragraph [0060]).
Claim 12: Butovsky teaches that the APOE inhibitor is an inhibitory antibody (paragraph [0060]).
Claims 1 and 3 are further rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huynh (Huynh et al., Cell Press 2017; cited on IDS of 8/22/2023).
Huynh teaches a method of inhibiting APOE via treatment with an antisense oligonucleotide.
Claim 1: Huynh teaches that the APOE gene (specifically the APOE-e4 allele) is a genetic risk factor for late-onset Alzheimer disease (AD). Huynh teaches modulating/inhibiting plaque formation and toxicity by administering an APOE inhibitor to the subject (Abstract). This reads on inducing healthy aging given that the specification of the instant application states: “Any inhibition or delay of development or severity of any of the age-related diseases and/or any increase in longevity is considered to be an inducement of healthy aging" (Specification, pg 9, ln 22-24). The age-related disease that Huynh teaches inhibiting is AD (Abstract), which is also an example of an age-related disease in the instant specification (pg 9, ln 10).
Claim 3: Huynh teaches that the APOE inhibitor is an antisense oligonucleotide (Abstract).
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.
In the rejection of claims under 35 USC 103 it is noted that the claims were previously rejected under 35 USC 112a as lacking enablement. In the instant case, while the cited prior art renders obvious a specific embodiment encompassed by the breadth of the rejected claims, the prior art does not provide enablement for the full scope of the claimed subject matter. Nor does the specification particularly contemplate the embodiment set forth in the cited prior art.
Claims 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Huynh (Huynh et al., Cell Press 2017; cited on IDS of 8/22/2023) in view of Williams (Williams et al., Molecular Neurodegeneration 2020; cited on IDS of 3/26/2025).
Huynh teaches the method of claim 1, wherein an APOE inhibitor is administered to a subject to induce healthy aging (to treat Alzheimer Disease; see above for further detail).
Relevant to the instantly rejected claims, Huynh teaches administering APOE inhibitors to subjects with a known genetic background generated through breeding rather than analyzing said subjects for a variant APOE nucleic acid molecule. Additionally, Huynh does not teach administering different dosage amounts to said subjects.
Claim 13: Williams teaches that different APOE isoforms have differential pathogenic effects, with the E4 variants being associated with increased risk of AD, E3 allele being the most common, and the E2 variant being associated with reduced risk of AD (Abstract). Furthermore, Williams teaches that the E4 allele of APOE increases the risk of AD in a dose- and age-dependent manner (pg 1, col 2). Williams teaches that targeting specific therapies to patients stratified for APOE genotype is well-known and leads to better outcomes (pg 4, col 1).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to combine the use of inhibitors to treat AD, as taught by Huynh, with determination of APOE genotype, as taught by Williams. One would be motivated to do so given that Williams teaches that allelic variants of APOE act in a dose-dependent manner, and that stratification of subjects by genotype leads to better treatment outcomes.
Claim 14-15: Williams teaches that haploinsufficiency (reduced expression of functional APOE, regardless of isoform status) is sufficient to reduce Aβ accumulation (pg 4, col 2).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to substitute haploinsufficiency with an inhibitor of APOE, such as an ASO as taught by Huynh, to obtain the predictable result of reducing APOE expression and thus reducing Aβ pathologies associated with unhealthy aging. Additionally, it would be obvious to those skilled in the art that the dosage of the inhibitor would not need to be as high as the standard dosage amount when an allelic variant of APOE that conveys haploinsufficiency is present already (the subject is heterozygous for an APOE variant). One would be motivated to lower the dosage of an APOE inhibitor, when possible, given the teaching by Williams that APOE has a myriad of functions in many different organs throughout the body separate from the central nervous system (pg 2, col 1).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Huynh (Huynh et al., Cell Press 2017; cited on IDS of 8/22/2023) in view of Williams (Williams et al., Molecular Neurodegeneration 2020; cited on IDS of 3/26/2025) as applied to claims 13-15 above, and further in view of Hoekstra (Hoekstra et al., Arterioscler Thromb Vasc Biol 2021; cited on IDS of 3/26/2025).
Huynh in view of Williams teaches administering an APOE inhibitor to subjects and detecting the presence or absence of an APOE variant molecule in a biological sample from said subject.
Huynh in view of Williams does not teach that the APOE variant is rs1065853 (which is the APOE variant as defined by SEQ ID NO:2, cited in the specification of the instant application pg 42, ln 9-10).
Hoekstra teaches detecting the APOE variant rs1065853 and its association with decreased Lp(a) levels (pg 5, paragraph 4 and Table 1).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Huynh in view of Williams, to specifically detect the APOE variant rs1065853, as taught by Hoekstra. One would be motivated to examine this variant given the teaching by Hoekstra that rs1065853 is in high linkage disequilibrium with the apoE2-defining variant rs7412 (pg 6, paragraph 6), which Williams teaches is the “protective” ApoE variant associated with reduced risk of Alzheimer’s disease.
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.
Claims 1, 3, and 11-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 11-12, 14, 16, 23-26, 33, and 41-43 of copending Application No. 17/584,642 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to the same limitations. Any additional limitations of '642 claims are encompassed by the open claim language “comprising” found in the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683