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
Applicant's preliminary amendment filed on December 1, 2025 is acknowledged. Claims 2-30 and 32-52 have been canceled. Claims 1 and 31 were amended. Claims 1, 31, and 53-68 are pending.
Election/Restrictions
Upon further consideration, the restriction requirement as set forth in the Office action mailed on October 1, 2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 1, 31, and 53-68 are examined on the merits herein.
Priority
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 14, 2022, June 8, 2025, July 23, 2025, October 3, 2025, December 1, 2025, and February 2, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The information disclosure statement filed June 8, 2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. A copy of EP-0716591A1 and WO 2013/181618A2 was not submitted; therefore, these references were lined through on the IDS.
The information disclosure statement filed July 23, 2025 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. The reference below is in a foreign language and does not include claims in English as indicated; therefore, this reference was lined through on the IDS.
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The information disclosure statement filed July 23, 2025 fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. A copy of the following reference was submitted; however, this reference was not listed on the IDS. In addition, it is noted that this reference is in a foreign language.
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The information disclosure statement filed December 1, 2025 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. The references below are in a foreign language without an English translation; therefore, these references were lined through on the IDS.
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The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings were received on April 14, 2022. These drawings are found acceptable by the examiner.
Specification
The substitute specification filed on September 4, 2025 has been entered.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the abstract is less than 50 words in length. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because of the following informalities:
In the brief description of the figures section, Figure 1 discloses production of inhibitory RNAs from an exemplary target transcript template designated as SEQ ID NOS: 14-18. However, it is unclear which sequences the SEQ ID NOS. correspond to in the figure.
In the brief description of the figures section, Figures 3 and 4 do not refer to “A” and “B” as in the drawings.
In the brief description of the figures section, Figure 6 discloses APOE knock down of expression by four different siRNAs in vitro (SEQ ID NOS: 1-5); however, it is unclear which sequences the SEQ ID NOS. correspond to in the figure.
Page 39, line 8 reads “(red/bold)”; however, the specification does not contain color.
Appropriate correction is required.
Claim Objections
Claims 55 and 64 are objected to because of the following informalities:
Claim 55 recites in part “and the second ITR sequences”. To improve the grammar of the claim, it would be remedial to amend the claim to recite in part “and the second ITR sequence”.
Claim 64 is missing the word “of” before “claim 63”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 66 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 66 recites a pharmaceutical composition comprising the AAV vector of claim 1. The claim does not include any additional or further limitations relative to claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Written Description
Claims 1, 31, and 53-68 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 31, and 53-68 are drawn to the provision of a genus of sequences encoding miRNA defined solely by function to target APOE4. The specification filed on September 4, 2025 states that knockdown with miRNA against all isoforms of endogenous APOE may be accomplished using multiple miRNAs targeting different sections of APOE mRNA thereby enhancing silencing [page 36, second full paragraph]. Thus, the claims encompass a broad genus of sequences encoding miRNA defined solely by function to silence gene expression of APOE4.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
Working example 2 discloses that Figure 6 depicts testing of APOE knockdown efficiency by siRNAs in U87 cells. Four different siRNAs targeting the coding sequence of APOE were generated based on a comparison of multiple siRNA design algorithms. siRNAs were transfected into U87 cells and APOE mRNA copies were quantified by RT-qPCR. The identified sequences were designated as SEQ ID NOS: 1-4, the non-targeting siRNA is SEQ ID NO: 5, and other sequences for siRNAs include SEQ ID NOS: 20-22. Only SEQ ID NO: 2 was converted into a miRNA and a scaffold based on a modified version of miR-155 was employed. For example, for a miR from SEQ ID NO: 2, SEQ ID NOS: 23, 24, or 25 may be employed. On page 38 lines 10-11, the specification envisions that any miRNA backbone may be employed, e.g., miR-21, miR-30, or miR-33.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of a small group of sequences encoding miRNA. The results are not necessarily predictive of other sequences encoding miRNA falling within the broadly claimed genus not limited to any particular structure. Thus, it is impossible for one to extrapolate from the limited examples described herein those sequences encoding miRNA that would necessarily meet the structural/functional characteristics of the rejected claims.
Lam et al. (Molecular Therapy – Nucleic Acids 2015) discloses that siRNAs and miRNAs have similar physicochemical properties but distinct functions. Both are short RNA duplexes that target mRNA(s) to produce a gene silencing effect, yet their mechanisms of action are distinct. As a result, the requirements for sequence design and therapeutic applications of siRNAs and miRNAs are different. On the other hand, for clinical development, the two types of small RNA molecules face a similar set of barriers: poor stability in vivo, delivery challenges and off-target effects [page 1, right column, first full paragraph].
Although post-filing, Walgrave et al. (Molecular Neurodegeneration 2021) discloses that profiling the impact of miRNA-based multi-targeting therapeutic strategies in Alzheimer’s disease with respect to efficacy and toxicity remains a daunting task, which is reflected by the current sparsity of miRNA therapeutics undergoing clinical trials in AD [page 2, left column, first full paragraph]. Walgrave et al. also discloses that further basic research first, to better characterize how miRNAs target pathways of interest, and second, to systematically map on- and off target toxic effects, is a prerequisite for effective clinical application in AD and other neurodegenerative disorders [page 10, left column, second full paragraph].
Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”). As discussed above, the skilled artisan cannot envision the detailed chemical structure of XBP1 inhibitors and written description requires more than a potential method of obtaining the agents. The compound itself is required. See Fiers v. Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 13 USPQ2d 1016.
Thus, the prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of sequences encoding miRNA that could result in silencing gene expression of APOE4.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 31, and 53-68.
Enablement
Claims 1, 31, and 53-68 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.
There are many factors to be considered when determining whether there is
sufficient evidence to support a determination that a disclosure does not satisfy the
enablement requirement and whether any necessary experimentation is "undue".
These factors include, but are not limited to: (A) The breadth of the claims; (B) The
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. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of claims:
Claims 1 and 54-65 are drawn to an AAV vector comprising a first inverted terminal repeat (ITR) sequence; a nucleic acid sequence encoding at least one APOE4-targeting miRNA; an APOE4-targeting miRNA-resistant nucleic acid sequence encoding an APOE2 polypeptide; and a second ITR sequence.
Claim 31 is drawn to a method to prevent, inhibit, or treat a disease associated with APOE4 expression in a mammal comprising administering to the mammal an effective amount of a composition comprising the AAV vector of claim 1.
Claim 53 is drawn to the AAV vector of claim 1 wherein the nucleic acid sequence encoding at least one APOE4-targeting miRNA comprises a nucleic acid sequence set forth in one or more of SEQ ID NO: 23, 24, or 25.
Claims 66-68 are drawn to a pharmaceutical composition comprising the AAV vector of claim 1.
The broadest reasonable interpretation of claim 1 is that the AAV vector encompasses an AAV vector comprising any nucleic acid sequence encoding any APOE4-targeting miRNA.
The broadest reasonable interpretation of claim 31 is a method to prevent, inhibit, or treat any disease associated with APOE4 expression in a mammal comprising administering to the mammal an effective amount of a composition comprising any nucleic acid sequence encoding any APOE4-targeting miRNA.
Nature of the invention:
The specification filed on September 4, 2025 envisions a method to prevent, inhibit, or treat Alzheimer’s disease in a mammal comprising administering to the mammal an effective amount of a composition comprising the gene therapy vector [page 4, last paragraph]. The specification also envisions a method to prevent, inhibit, or treat a disease associated with APOE4 expression in a mammal comprising administering to the mammal an effective amount of a composition comprising the gene therapy vector [page 5, first full paragraph]. Therefore, the AAV vector comprising any nucleic acid sequence encoding any APOE4-targeting miRNA must be capable of providing a therapeutic outcome for Alzheimer’s disease or any disease associated with APOE4 expression.
Amount of direction provided by the inventor and existence of working
examples:
The specification discloses that adeno-associated virus (AAV) delivery of the human APOE2 gene to murine models of AD expressing human APOE4 demonstrated reduced amyloid-β peptide and amyloid burden. The specification envisions that suppression of APOE4 via delivery of an AAV vector while simultaneously expressing human APOE2 may reduce the risk for Alzheimer’s disease even further. In one embodiment, gene therapy such as AAV therapy is designed to deliver the human APOE2 gene coding sequence and artificial RNAs such as miRNA targeted to the endogenous APOE4. The combination of knockdown of detrimental endogenous APOE4 expression with the expression of the beneficial APOE2 allele may provide enhanced protection from AD development for individuals with homozygous for the APOE4 allele [page 35, last paragraph bridging to page 36]. In one embodiment, siRNA interacts with mRNA to silence translation. To express an siRNA from a DNA sequence, such as a gene therapy expression vector, the targeting sequence must be embedded in a shRNA or miRNA scaffold [page 36, first full paragraph]. Further, the specification envisions that knockdown with miRNA against all isoforms of endogenous APOE may be accomplished using multiple miRNAs targeting different sections of APOE mRNA thereby enhancing silencing. In one embodiment, the vector-derived human APOE2 may contain silent mutations in the coding sequence to prevent silencing [page 36, second full paragraph]. The specification also envisions that the miRNA having the RNAi sequences to inhibit APOE4 expression may be inserted into 5’ non-coding sequences, e.g., an intron, and/or 3’ non-coding sequences. Multiple miRNAs can be placed in tandem for enhanced silencing of APOE4 [Figure 3; page 36, third full paragraph].
Working example 2 discloses that Figure 6 depicts testing of APOE knockdown efficiency by siRNAs in U87 cells. Four different siRNAs targeting the coding sequence of APOE were generated based on a comparison of multiple siRNA design algorithms. siRNAs were transfected into U87 cells and APOE mRNA copies were quantified by RT-qPCR. The identified sequences were designated as SEQ ID NOS: 1-4, the non-targeting siRNA is SEQ ID NO: 5, and other sequences for siRNAs include SEQ ID NOS: 20-22. Only SEQ ID NO: 2 was converted into a miRNA and a scaffold based on a modified version of miR-155 was employed. For example, for a miR from SEQ ID NO: 2, SEQ ID NOS: 23, 24, or 25 may be employed. On page 38 lines 10-11, the specification envisions that any miRNA backbone may be employed, e.g., miR-21, miR-30, or miR-33.
State of the prior art, level of predictability in the art, and level of one of
ordinary skill:
Lam et al. (Molecular Therapy – Nucleic Acids 2015) discloses that siRNAs and miRNAs have similar physicochemical properties but distinct functions. Both are short RNA duplexes that target mRNA(s) to produce a gene silencing effect, yet their mechanisms of action are distinct. As a result, the requirements for sequence design and therapeutic applications of siRNAs and miRNAs are different. On the other hand, for clinical development, the two types of small RNA molecules face a similar set of barriers: poor stability in vivo, delivery challenges and off-target effects [page 1, right column, first full paragraph].
Although post-filing, Walgrave et al. (Molecular Neurodegeneration 2021) discloses that profiling the impact of miRNA-based multi-targeting therapeutic strategies in Alzheimer’s disease with respect to efficacy and toxicity remains a daunting task, which is reflected by the current sparsity of miRNA therapeutics undergoing clinical trials in AD [page 2, left column, first full paragraph]. Walgrave et al. also discloses that further basic research first, to better characterize how miRNAs target pathways of interest, and second, to systematically map on- and off target toxic effects, is a prerequisite for effective clinical application in AD and other neurodegenerative disorders [page 10, left column, second full paragraph].
Graham et al. (Annual Review of Medicine 2017) discloses that Alzheimer’s disease (AD) is the primary cause of age-related dementia. Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology [abstract].
Galvin (Journal of the American Geriatrics Society 2017) discloses that ongoing pharmacological trials using anti-amyloid therapies are underway in sporadic and genetic forms of AD, although a large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau. Thus suggesting that prevention studies focusing on risk reduction and lifestyle modification may offer additional benefits [abstract]. Galvin further discloses that an important question is whether AD can be prevented and identified a number of modifiable (e.g., exposures, lifestyle and social habits) and nonmodifiable (e.g., age, sex, genetics) risk factors [page 2128, right column]. A number of prevention studies are ongoing in sporadic and autosomal-dominant forms of AD; however, the results are still pending. Nonetheless, the results from the trials may not be generalizable [page 2129, left column, last paragraph bridging to right column, first paragraph]. Furthermore, Galvin discloses that up to 30% of AD cases may be preventable through modification of risk factors and behavioral changes to mitigate the effect of those risk factors that are not modifiable. A prevention initiative needs to be multimodal and tailored to address individual risks [page 2130, left column, last full paragraph].
Although post-filing, Vitek et al. (Translational Research & Clinical Interventions 2020; reference cited by Applicant) discloses that models reflecting only single aspects of Alzheimer’s disease (AD) pathogenesis do not mimic AD [abstract]. Existing AD animal models have provided important insights into the disease; however, the inability of these models to reflect the entire biology of the disease, much less predict efficacy in clinical trials, has contributed to the high failure rate (99.6%) of AD drugs in clinical development [page 2, left column, second paragraph]. Vitek et al. also discloses that most of the AD mice do not develop neurodegeneration, the models are focused largely on familial AD (FAD) with early onset AD (EOAD) mechanisms, the genetic backgrounds of the mouse strains have not been standardized, and the models incompletely recapitulate the human neuropathology phenotype of typical late-onset Alzheimer’s dementia (LOAD) thus limiting the translatability of findings from transgenic mouse strain to the human disease condition. Further, other limitations of mouse models are expected as a result of their smaller and less-developed prefrontal cortex and a shorter lifespan that may not be useful in studying age-related neurodegenerative diseases such as AD. In addition, there are substantial differences between mouse and human immune systems [page 2, right column, first paragraph]. Vitek et al. also discloses that since no model accurately recapitulates all aspects of AD, a strategically-driven multi-model evaluation strategy incorporating both genetic models and currently available “agnostic” aged animal models of AD-like progression should be considered for drug development to de-risk the transition of pre-clinical drug assets to the clinic [page 9, right column, first full paragraph].
Quantity of experimentation:
In view of the breadth of the claims which embrace an AAV vector comprising any nucleic acid sequence encoding any APOE4-targeting miRNA that must be capable of providing a therapeutic outcome for Alzheimer’s disease or any disease associated with APOE4 expression, the lack of working examples to show any other sequence besides SEQ ID NO: 2 encoding any other APOE4-targeting miRNA besides miR-155, and the failure to provide adequate guidance to overcome the state and level of predictability of the art, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637