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 .
Status of Application/Amendments/Claims
Applicant’s response filed on 3/13/2026 has been considered. Claims 7, 15 and 27 are amended. Claims 94-96 are newly added. Claims 1-2, 5-40, 74 and 94-96 are pending. Claims 8-14 and 74 are withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-2, 5-7, 15-40 and 94-96 are examined are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 63/271,839 and PRO 63/269,557
filed on 10/26/2021 and 7/27/2022, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 10/26/2021.
Maintained 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 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.
Claims 1-2, 5-6, 15 and 35-40 stand rejected under 35 U.S.C. 103 as being unpatentable over Penfield et al. "Regulated lipid synthesis and LEM2/CHMP7 jointly control nuclear envelope closure." Journal of Cell Biology 219.5 (2020): e201908179 (hereinafter Penfield, reference of record) in view of Eftekharzadeh et al. "Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease." Neuron 99.5 (2018): 925-940 (hereinafter Eftekharzadeh, reference of record). This rejection is maintained with respect to the Office action mailed on 12/15/2025. A response to applicant’s traversal follows the rejection below.
Claims 1, 2, 5, 6, 15 and 39-40: Penfield describes the role of LEMD2 and CHMP7 in regulating the production and remodeling of the nuclear envelope (Penfield, abstract and pg 1-2). Penfield shows that proper LEMD2 function helps maintain a stable and intact nuclear envelope (Penfield, pg 2).
Claims 1, 2, 5, 6, 15 and 39-40: Eftekharzadeh describes how pathological tau proteins interact with components of the nuclear pore complex (NPC), such as Nup98, causing the mislocation of these proteins and a breakdown of nucleocytoplasmic transport (Eftekharzadeh, pg 926). Eftekharzadeh describes how Nup98 mislocalizes from the nuclear membrane to the cytoplasm in neurons with phosphor-tau which contributes to the formation of neurofibrillary tangles (Eftekharzadeh, pg 927 and 929). The interaction of tau with Nup98 causes structural and functional impairments in NPCs, leading to a leaky nuclear envelope and nuclear diffusion barrier (Eftekharzadeh, pg 927 and 928-929).
Claims 35-38: Eftekharzadeh describes assessing one or more signs of tauopathy and tau aggregation by assessing phosphor-tau levels via immunoaffinity purification and immunofluorescence (Eftekharzadeh, pg 931). Eftekharzadeh examines both pre-existing levels of tau aggregation and new aggregate formation in cells, showing predictable methods exist for quantifying the amount of phosphor-tau aggregation which contributes to the formation of neurofibrillary tangles (Eftekharzadeh, pg 927 and 929).
It would have been prima facie obvious to one of ordinary skill in the art to administer LEMD2 to a cell in order to strengthen the nuclear envelope and counteract the effects of tau aggregation on nuclear integrity. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Eftekharzadeh shows that pathological tau proteins interact with components of the NPC causing the mislocation of these proteins and a breakdown of nucleocytoplasmic transport (Eftekharzadeh, pg 926). Thus, one of ordinary skill would have been motivated to make this combination since administering LEMD2 to a cell would help strengthen and maintain a stable and intact nuclear envelope to counteract the negative effects of tau aggregation on nuclear integrity. One would have a reasonable expectation of success given that both the mechanism of LEMD2 and CHMP7 in regulating the production and remodeling of the nuclear envelope is understood and there exists predictable methods using immunoaffinity purification and immunofluorescence to analyze their effects on tau aggregation and the formation of neurofibrillary tangles (Eftekharzadeh, pg pg 927 and 929). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1-2, 5-6, 15 and 35-40 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing that one of ordinary skill in the art would not have been motivated to combine Eftekharzadeh with Penfield since the assumption that administering LEMD2 to a cell would help strengthen and maintain a stable nuclear envelope is not supported. Applicant argues that Penfield generally discloses the role of LEMD2 in nuclear envelope function with conclusions based on LEMD2 loss of function and not artificial expression or overexpression and does not suggest that LEMD2 overexpression would have any beneficial effect on tau aggregation. Applicant argues that administering LEMD2 to a cell to strengthen the nuclear envelope would not be predictable because although Eftekharzadeh may show that pathological tau proteins can affect the NPC, it does not indicate that strengthening and maintaining stable and intact nuclear envelope would have any beneficial impacts on tau pathology.
This argument has been fully considered, but is not found persuasive since Penfield expressly shows that proper LEMD2 function helps maintain a stable and intact nuclear envelope (Penfield, pg 2). Although it is acknowledged that Penfield supports this conclusion with LEMD2 loss of function, the conclusion and mechanistic understanding that Penfield derives from this experiment are important in establishing that proper LEMD2 function helps maintain a stable and intact nuclear envelope and would lead one of ordinary skill to consider its overexpression to strengthen the nuclear envelope and counteract the effects of tau aggregation on nuclear integrity. Furthermore, Eftekharzadeh describes how Nup98 mislocalizes from the nuclear membrane to the cytoplasm in neurons with phosphor-tau which contributes to the formation of neurofibrillary tangles (Eftekharzadeh, pg 927 and 929). The interaction of tau with Nup98 causes structural and functional impairments in NPCs, leading to a leaky nuclear envelope and nuclear diffusion barrier (Eftekharzadeh, pg 927 and 928-929). Thus, it would have been prima facie obvious to one of ordinary skill in the art to administer LEMD2 to a cell in order to strengthen the nuclear envelope and counteract the effects of tau aggregation on nuclear integrity. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Eftekharzadeh shows that pathological tau proteins interact with components of the NPC causing the mislocation of these proteins and a breakdown of nucleocytoplasmic transport (Eftekharzadeh, pg 926). Thus, one of ordinary skill would have been motivated to make this combination since administering LEMD2 to a cell would help strengthen and maintain a stable and intact nuclear envelope to counteract the negative effects of tau aggregation on nuclear integrity.
Applicant further argues that Penfield and Eftekharzadeh in combination would not provide a person of ordinary skill with any reasonable expectation of success because nothing in the cited references suggests a link between proteins involved in maintaining the basic barrier function of the nuclear envelope and tau aggregation. Applicant argues that the LEMD2 loss of function results presented by Penfield would not lead one of ordinary skill to consider its overexpression as a method for inhibiting tau aggregation.
This argument has been fully considered, but is not found persuasive since the results of Penfield show that LEMD2 function helps maintain a stable and intact nuclear envelope (Penfield, pg 2). The LEMD2 loss of function experiments of Penfield provides one of ordinary skill in the art strong foundational support for pursuing LEMD2 protein overexpression as a therapy to counteract the negative effects of tau aggregation on nuclear integrity. The disclosure of Penfield provides strong motivation for one of ordinary skill to pursue such a goal and attorney arguments do not replace evidence where evidence is necessary, see MPEP 2145.
Claims 1-2, 5-6, 15 and 18-40 stand rejected under 35 U.S.C. 103 as being unpatentable over Penfield (supra) and Eftekharzadeh (supra) as applied to claims 1-2, 5-6, 15 and 35-40 above in further view of Feurle et al. "SATB2‐LEMD2 interaction links nuclear shape plasticity to regulation of cognition‐related genes." The EMBO journal 40.3 (2021): e103701 (hereinafter Feurle, reference of record). This rejection is maintained with respect to the Office action mailed on 12/15/2025. A response to applicant’s traversal follows the rejection below.
A description of Penfield and Eftekharzadeh can be found above. Neither Eftekharzadeh nor Penfield describe delivering a LEMD2 AAV expression construct comprising a synapsin-1 promoter or administration via intracranial injection.
Claims 18-27: Feurle describes the functional interaction between the chromosomal scaffolding protein SATB2 and the inner nuclear membrane protein LEMD2 in neurons (Feurle, pg 1). Feurle found that this interaction was critical for the structural plasticity of the nuclear envelope in response to neuronal activity and the regulation of genes linked to human cognitive abilities (Feurle, pg 11). Specifically, Feurle teaches an AAV vector for expressing EGFP and SAB2 transgenes under the control of a neuron-specific human synapsin (hSyn) promoter (Feurle, pg 13). Feurle does not expressly describe the use of this expression construct for expressing LEMD2.
Claims 28-33: Feurle describes the in vivo expression of these AAV vectors in mammalian mouse primary hippocampal or cortical neurons (Feurle, pg 13).
Claim 34: Feurle describes transducing primary hippocampal or cortical neurons with the AAV vectors using bilateral stereotaxic injections into the dorsal hippocampus (Feurle, pg 13).
It would have been prima facie obvious to one of ordinary skill in the art to deliver an AAV vector expressing LEMD2 under the control of a synapsin-1 promoter to the cortical neurons of a subject in order to strengthen the nuclear envelope and counteract the effects of tau aggregation as a treatment for Alzheimer’s disease. It would have been a matter of simple substitution of one known transgene for another to obtain predictable results for one of ordinary skill to express LEMD2 in the AAV vectors described by Feurle. One of ordinary skill would have been motivated to make this substitution given that LEMD2 expression would help strengthen and maintain a stable and intact nuclear envelope to counteract the negative effects of tau aggregation on nuclear integrity. One would have a reasonable expectation of success given that the hSyn promoter and administration route via intracranial injection would drive strong expression into cortical neurons where tau aggregation is most prominent. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1-2, 5-6, 15 and 18-40 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicants’ arguments are traversed above. No specific arguments can be found with respect to the present rejection.
The rejection is maintained accordingly.
Claims 1-2, 5-7, 15-40 and 94-95 are rejected under 35 U.S.C. 103 as being unpatentable over Penfield (supra), Eftekharzadeh (supra) and Feurle (supra) as applied to claims 1-2, 5-6, 15 and 35-40 above in further view of Cooper et al. US 2007/0072175, published 3/29/2007 (hereinafter Cooper, reference of record). This rejection is maintained with respect to the Office action mailed on 12/15/2025 and newly applied to claims 94-95. A response to applicant’s traversal follows the rejection below.
A description of Penfield, Eftekharzadeh and Feurleet can be found above. Neither Eftekharzadeh, Feurleet nor Penfield describe delivering a codon optimized human LEMD2 comprising SEQ ID NO: 1, cDNA or mRNA of LEMD2.
Claims 7 and 94-95: As stated in the claim interpretation section, claim 7 describes the LEMD2 which is encoded by SEQ ID NO: 1. As shown by Cooper in the sequence search results below, a polynucleotide sequence with 100% sequence similarity to the codon optimized amino acid sequence disclosed in SEQ ID NO: 1 is known in the art (Cooper, claim 18; SEQ ID NO: 48448). Briefly, Cooper discloses nucleotide arrays for detecting changes in gene expression upon administration of a therapeutic agent (Cooper, abstract).
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Claims 16 and 17: Cooper discloses methods and embodiments wherein cDNA and mRNA used, showing that it is trivial to convert from a known nucleotides sequence to an amino acid sequence, cDNA sequence or mRNA sequence (Cooper, para 40).
It would have been prima facie obvious to one of ordinary skill in the art to deliver an AAV vector expressing LEMD2 as disclosed in SEQ ID NO: 1, a cDNA or mRNA sequence thereof in order to strengthen the nuclear envelope and counteract the effects of tau aggregation as a treatment for Alzheimer’s disease. It would have been a matter of combining prior art elements according to known methods to yield predictable results since the nucleotide sequence of LEMD2 is known in the art and there are predictable methods to generate cDNA and mRNA sequences thereof. One of ordinary skill would have been motivated to make this combination since delivering mRNA provides transient expression, cDNA would facilitate cloning the gene into expression vectors and AAV vectors would allow for long-term expression and efficient tissue targeting. One would have a reasonable expectation of success given that the sequence of human LEMD2 is known in the art and there exists predictable methods for converting known nucleotides sequence to an amino acid sequence, cDNA sequence or mRNA sequence (Cooper, para 40). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1-2, 5-7, 15-40 and 94-95 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicants’ arguments are traversed above. No specific arguments can be found with respect to the present rejection.
The rejection is maintained accordingly.
New Claim Rejections - 35 USC § 103
Claims 1-2, 5-7, 15-40 and 94-96 are newly rejected under 35 U.S.C. 103 as being unpatentable over Penfield (supra), Eftekharzadeh (supra), Feurleet (supra) and Cooper (supra) as applied to claims 1-2, 5-7, 15-40 and 94-95 above in further view of Chan et al. "Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems." Nature neuroscience 20.8 (2017): 1172-1179 (hereinafter Chan). This rejection is newly applied to address applicants’ amendments on 3/13/2026.
A description of Penfield, Eftekharzadeh, Feurleet and Cooper can be found above. The collection of cited art does not describe an AAV vector that is a AAV PHP.eB (AAV9 serotype variant).
Claim 96: However, AAV PHP.eB vectors are frequently used for gene delivery into neuronal tissue due to their ability to cross the blood-brain barrier and achieve widespread transduction into the CNS as shown by Chan. For example, Chan describes AAV PHP.eB vectors which transduce 69% of cortical and 55% of striated neurons (Chan, abstract and Fig 1).
It would have been prima facie obvious to one of ordinary skill in the art to select a AAV PHP.eB type vector in order to deliver LEMD2 to strengthen the nuclear envelope and counteract the effects of tau aggregation as a treatment for Alzheimer’s disease. It would have been a matter of combining prior art elements according to known methods to yield predictable results since AAV PHP.eB vectors have the ability to cross the blood-brain barrier and achieve widespread transduction into the CNS as shown by Chan. One would have a reasonable expectation of success given that there are well known protocols and predictable methods described in Chan for transduction into the CNS with high transduction efficiencies into cortical and striated neurons. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Conclusion
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 extension fee 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 Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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