DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s’ amendments to the claims and arguments filed on September 4, 2025 have been received and entered. Claims 17-18, 20-22, 25, 34 have been canceled, while claims 19, 33, 35 have been amended. Claims 37-45 have been newly added that are generally directed to the elected invention.
. Claims 1-16, 19, 23-24, 26-31, 33, 35-44 and 45 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 19-22, 32-35 (group III) in the reply filed on April 11, 2025 was acknowledged.
Claims 1-16, 23-24, 26-31 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 April 11, 2025.
Priority
This application is a 371 of PCT/EP2020/068414 filed on 06/30/2020, which claims priority from a foreign application EP 19382563.5 filed on 07/02/2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/08/2009 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 19, 33, 35, 36-44 and 45 are under consideration.
Maintained-Claim Rejections - 35 USC § 112-Scope of enablement -in modified form
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 19, 33, 35, 36-44 and 45 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 for treating age related dementia in a subject having AD, the method comprising directly administering into CA1 region of the hippocampus of CNS into of the subject, a therapeutically effective amount of AAV2/9 vector comprising a nucleic acid encoding cPLA2e protein comprising amino acid sequence of SEQ ID NO: 1 or 3, wherein said nucleic acid is operably linked to a promoter, and wherein said administration expresses cPLA2e protein in the CA1 region and increases dendritic spine density thereby rescuing the spatial working memory impairment in said subject,
does not reasonably provide enablement for delivering via any parenteral route that includes subcutaneous, intradermal, intramuscular, any other nucleic acid, AAV comprising a nucleic acid encoding any other cytosolic phospholipase A2 epsilon protein, or using nucleotide sequence encoding any protein that is at least 70% identical to SEQ ID NO: 1 or 3. The specification does not enable any person skilled in the art to which it pertains, which it is most nearly connected, to make and use the invention commensurate in scope with these claims. 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 use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
Nature of the Invention:
The claims are directed to a method for treating age-related dementia or Alzheimer's disease in a subject, the method comprising administering a therapeutically effective amount of an adeno-associated virus (AAV) vector comprising any nucleic acid construct comprising any nucleotide sequence encoding a cytosolic phospholipase A2 epsilon (cPLA2e) operably linked to a promote (claim 19)..
Breadth of the claims:
The claims are broadly directed to a method for treating age-related dementia or Alzheimer's disease in a subject, the method comprising administering via any parenteral route a therapeutically effective amount of a AAV encoding a cPLA2e (1) administering a therapeutically effective amount of an AAV of any serotype comprising a nucleic acid encoding any cPLA2e to have an effect on the treatment of c age-related dementia or Alzheimer's disease (3) delivering any AAV encoding any cPLA2e comprising the nucleic acid encoding cPLA2e in any predictable animal model to establish any reasonable correlation of treating age-related dementia or Alzheimer's disease; (4) nexus between cellular pathology associated with age-related dementia or Alzheimer's disease in any subject to the breadth of the claims encompassing cognitive disorder and/or plurality of disease associated with cognitive disorder of different etiology and pathology. The deficiencies were identified by the Office after analysis of the disclosure provided in the instant application. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Guidance of the Specification and The Existence of Working Examples:
The specification discloses cognitive impairment is a condition associated with a large number of brain disorders including dementia associated with aging and/or neurodegenerative diseases such as Alzheimer's disease. The specification further assert that cognitive impairment can be manifest in many ways, e.g., deficits in learning and/or memory including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discrimination learning, decision-making, language retrieval, inhibitory response control, attentional set-shifting, delayed reinforcement learning, reversal learning, the temporal integration of voluntary behavior, and expressing an interest in one's surroundings and self-care. Cognitive impairment may be characterized by progressive loss of memory, cognition, reasoning, executive functioning, planning, judgment and emotional stability (see page 2). Example 1 teaches preparation of AAV2/9-PLA2G4E. Example 2 teaches direct injection of AAV2/9-mPLA2G4E into the CA1 region of the hippocampus of an aged wild type C57BL/6 or APP/PS1 transgenic mouse that exhibits accelerated amyloidosis. The specification teaches testing spatial memory using Morris Water Maze test involving three phases including (i) visible platform phase, (ii) hidden platform phase and (iii) probe trial. Example 3 describes effect of AAV2/9-mPLA2G4E on memory function of APP/PS1 mouse. The results show that treatment with AAV2/9 -mPLA2G4E rescued spatial working memory impairment (fig. 1) and spent more time in the right quadrant than sham injected mouse (see fig. 1b). Example 4 teaches effect of AAV2/9-mPLA2G4E in memory function of elderly wild type mice. Example 5 shows that there is an increase in PLA2G4E in the hippocampus during contextual memory retention, after the retrieval of a consolidated memory. Example 6 shows that the synapse formation and/or stability may be altered upon PLA2G4E knockdown.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The state of the art reported identifying factors responsible for the protection against dementia in a subject is hindered by: i) the genetic diversity of the individuals studied; and iii) the clinical, physical and lifestyle variation among subjects (Caspers et al., 2014, FronL Aging Neurosci. 6, 149). The art teaches central nervous system (CNS) is protected by the blood brain barrier, and this barrier blocks genes from traversing into the CNS if administered outside of the CNS. Puhl reported form of genetic material selected for each application depends on factors such as the desired time frame of gene expression or inhibition and whether the goal is to upregulate or downregulate expression (see page 3, para. 3). The art teaches administering gene delivery systems via intravenous injection into the peripheral vasculature may limit the amount of gene delivered into the CNS. To achieve a therapeutic concentration of administered gene in the CNS, the gene delivery system must be administered at a very high dose. It is known that high amounts of a gene delivery vector in the blood stream, however, may initiate an immune or cytotoxic response (page 3, last para. Puhl et al Brain Res Bull. 2019 150: 216–230). The guidance provided in the specification is limited to a direct injection of AAV2/9-mPLA2G4E into the CA1 region of the hippocampus of an aged wild type C57BL/6 or APP/PS1 transgenic mouse. Maguaire et al (Neurotherapeutics (2014) 11:817–839) report challenges for treating CNS disease involves (i) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier (abstract). Maguaire et al continue to teach that “locale at which a delivery vehicle is administered greatly impacts its ability to transfer its genetic payload to the CNS. Due to the constraints imposed by the blood-brain barrier (BBB), the most common delivery route is direct injection into the target region in the brain, which bypasses this barrier” (see page 818, col. 1, para. 2). Chiorini et al (WO2005/056807) teach “BAAV capsid proteins are distinct from primate and avian AAV capsid proteins and BAAV exhibits a distinct cell tropism, thus making BAAV capsid containing particles suitable for transducing cell types for which primate or avian recombinant AAV particles are unsuited or less well-suited” (see page 6). In the instant case, there is no evidence on record that use of any naked nucleic acid without presence of a promoter, any expression vector, viral vector or host cell comprising the nucleic acid would be predictive of any property of direct delivery by AAV2/9 disclosed in the instant application. Prior to instant invention, Dominguez et al (Human Molecular Genetics, 2011, Vol. 20, No. 4 681–693) teach adeno-associated virus (scAAV9) vectors carrying a codon-optimized SMN1 sequence and a chimeric intron placed downstream of the strong phosphoglycerate kinase (PGK) promoter (SMNopti) to overexpress the human SMN protein in a mouse model of severe SMA (see abstract). It is relevant to note that plasmid expressing hSMN1 has minimal to no expression of SMN1 as compared to plasmid carrying hSMN1 and a chimeric intron placed downstream of the PGK promoter or plasmid carrying the codon optimized SMN sequence and chimeric intron placed downstream of the PGK promoter (see figure 1). Dominguez et al clearly establishes that vector optimization is required prior to delivering AAV9 encoding protein of interest (SMN) to make and use the invention. The art further teaches intravenous administration of a potentially therapeutic dose of a neurotrophic AAV vector, derived from AAV9 which expressed human SMN under the control of a CB promoter with a cytomegolavirus immediate enhancer, to nonhuman primates and piglets was toxic (Hinderer et al. Hum. Gene Therapy 29(3): 285-298, 2018). Further, Passini et al (Trends in Molecular Medicine, 2011, 17, 5, 259-264) teach that “properties of the viral vector other than dose might also influence survival including regulatory sequences (see page 261, col. 2, para. 1). Therefore, the observations support the stand taken that results obtained in the studies of one disease in a wild type aging mouse or APP/PS1 transgenic mouse exemplified in the specification cannot be predictive of the method of administering via any route using naked nucleic acid encoding PLA2G4E, vector encoding PLA2G4E or virus particle comprising a nucleic acid encoding PLA2G4E for the treatment of genus of diseases associated with cognitive disorders in a subject. In the instant case, the specification fails to demonstrate whether administration of naked DNA or any other vector comprising nucleic acid encoding PLA2G4E without any regulatory sequence would result in PLA2G4E expression for a period to achieve any therapeutic response. The specification does not provide guidance as to how to get RNA polymerase to efficiently prime to a DNA strand that lacks a promoter. Thus, it is clear without any specific guidance of delivering a nucleic acid encoding PLA2G4E that is not linked with any regulatory sequence in a subject and merely a general description of method of delivering nucleic acid encoding a PLA2G4E or exemplifying a role of PLA2G4E in a transgenic mouse model is not enabling commensurate with full scope of the claims, except with a direct injection of AAV2/9 viral vector comprising a regulatory sequence operably linked to a nucleic acid encoding PLA2G4E. It is relevant to note that independent claims do not even require expression of PLA2G4E or PLA2G4E activity in any cell of CNS following administration of nucleic acid, vector, virus or host cell comprising a nucleic acid encoding PLA2G4E (emphasis added). The specification fails to address how to overcome the aforementioned difficulties in the art. Given the breadth of the claims, it is apparent that one of skilled in the art would require the identification and characterization of expression vector, host cell or viral vector and/or its serotype from different species with respect to testing their ability to infect neurons in the CAI region of the hippocampus such that therapeutic protein in expressed in these cells at a therapeutic level in predictable animal model of plurality of disease associated with cognitive disorder of different etiology and pathology to make use of the invention without a reasonable expectation of success. Applicant should note that “case law requires that the disclosure of an application shall inform those skilled in the art how to use applicants’ alleged discovery, not to find out how to use it for themselves.” In re Gardner 166 USPQ 138 (CCPA) 1970. Gene therapy as a broad-based art is clearly unpredictable in terms of achieving levels and duration of expression of a gene of interest, which results in a therapeutic effect. A showing that enough of a nucleic acid encoding PLA2G4E is expressed in the target cell (CA1 region of hippocampus), enough nucleic acid is incorporated into the target cells, that such nucleic acid is properly incorporated into such cells as DNA, enough mRNA is produced therefrom, and enough protein is produced and enhanced PLA2G4E expression have an effect on the target cells ((CA1 region of hippocampus)) and such effect is enough of an effect for a long enough period of time to any diseases associated with cognitive disorders in a subject in a predictable animal model. Absent of any specific dose of vector, virus or naked DNA in a specific volume of liquid suspension that is delivered to maintain an effective concentration of the transgene product at the target site an artisan of skill would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. This is because transport barriers for vector selection, sorting targets to maximize efficiency, characterizing the optimum therapeutic window for treatment, and identifying the best route were known to be critical and unpredictable parameter in achieving more favorable gene therapy outcomes for the treatment of cognitive disorder or diseases associated with cognitive disorders in a subject as supported by the observations in the art record.
The specification contemplated direct injection of AAV2/9-mPLA2G4E into the CA1 region of the hippocampus of a subject (see example 2). The guidance provided in the specification is limited to direct injection of AAV2/9-LA2G4E (cPLA2e) directly into the hippocampus of a transgenic mouse model for AD (AAP/PS1). In the instant case the issues relate to the predictability of animal model with respect to the breadth of claims intended to deliver nucleic acid encoding PLA2G4E, expression vector, virus or host cells comprising a nucleic acid encoding PLA2G4E via any route for treating cognitive disorders and/or diseases associated with cognitive disorders in a subject in need thereof. The specification lacks to establish nexus between cellular pathology associated with changes in dendritic spine density in the subject and treatment of diseases associated with genus of cognitive disorder. The specification contemplates disease includes aging and/or neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis (ALS), psychosis, Parkinson's disease psychosis, Alzheimer's disease psychosis, Lewy-body dementia, prionic neurodegenerative 35 disorders such as Creutzfeld-Jacob disease and kuru disease, corticobasal degeneration, frontotemporal lobar degeneration, multiple sclerosis, normal pressure hydrocephalus, organic chronic brain syndrome, Pick's disease, progressive supranuclear palsy, or senile dementia. Cognitive impairment may also have a congenital basis, e.g., Prader-Willi syndrome, Down Syndrome, Fragile X Syndrome (see page 1 of the specification).. It is emphasized that neurodegenerative disease could be have aggregate of symptoms and signs associated with any other process and constituting together the picture of the disease. In the instant case, the specification only teaches injecting AAV2/9 encoding cPLA2e directly into CA1 region of the hippocampus of the transgenic mice. The effect of AAV2/9-mPLA2G4E on memory function of APP/PS1 mouse was studies. The results show that treatment with AAV2/9 -mPLA2G4E rescued spatial working memory impairment (fig. 1) and spent more time in the right quadrant than sham injected mouse (see fig. 1b). However, it does not detail provide any guidance in terms of its functional involvement in plurality of different neurodegenerative disorder of any other subject nor does it disclose a relationship to a condition associated with genus of neurodegenerative disorder embraced by the breadth of the claims. Prior to instant invention, Weitzer et al (J. Vis. Exp. 2015, (100), e52706 , 1-11) reported that the Morris water maze (MWM) is a commonly used task to assess hippocampal-dependent spatial learning and memory in transgenic mouse models of disease, including Alzheimer's disease. However, the background strain of the mouse model used can have a substantial effect on the observed behavioral phenotype, with some strains exhibiting superior learning ability relative to others (abstract). For example, BALB/c mice exhibit superior performance in learning and memory tasks compared to other strains, such as the C57BU6 (see page 1, last para.). Iqbal et al (J Neural Transm Suppl. 1998; 53:169-80 and Zhang et al Signal Transduction and Targeted Therapy (2024) 9:211, 1-35) describe that Alzheimer disease (AD) has polyetiology. Iqbal et al states “Independent of the etiology the disease is characterized histopathologically by the intraneuronal accumulation of paired helical filaments (PHF), forming neurofibrillary tangles, neuropil threads and dystrophic neurites surrounding the extracellular deposits of beta-amyloid in plaques, the second major lesion. The clinical expression of AD correlates with the presence of neurofibrillary degeneration; beta-amyloid alone does not produce the disease clinically. Therefore, because an artisan does not know any known relationship of plurality of different disease that could be extrapolated to different condition associated with cognitive disorder, an artisan would not know how to treat any condition other than rescuing spatial working memory impairment in subject having AD by direct delivering the AAV2/9 vector encoding PLA2G4E into hippocampus of the CNS of the subject in need thereof. An artisan would have to perform undue experimentation to first establish a nexus between the transgenic animal of the invention with disclosed phenotype and then with a specific disease associated with cognitive disorder and then test various parameters using different type of expression vector and delivery via any route in order to treat cognitive disorder seen in the transgenic animal (APP/PS1) of the invention. In view of foregoing discussion, it is apparent that any difference of symptom seen in the instant transgenic mouse cannot be generally associated with several different complex neurodegenerative diseases that are associated with the cognitive disorder. Therefore, an artisan would not know if delivery via any route to the hippocampus via AAV encoding PLA2G4E would be effective for its intended use in the treatment of diseases associated with cognitive disorder as embraced by the breadth of the claims. Therefore, in absence of additional guidance, the artisan would not find the specification enabling commensurate with the full scope of the claims without an undue amount of experimentation.
Claims are also directed to a method that uses a nucleic acid encoding any amino acid sequence having at least 70% sequence identity with the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 3 to treat cognitive disorders and/or diseases associated with cognitive disorders in a subject in need thereof. . The specification contemplated using human cPLA2e isoform 1, or 2 protein fragments, functional protein domains, variants, and homologous proteins (orthologs) are also considered to be within the scope of the cPLA2e of the nucleic acid construct of the invention. It is understood the different embodiments of the cPLA2e have substantially the same cPLA2e activity as human cPLA2e isoform 1 or 2 (see page 7). The specification teaches delivering AAV2/9 vector comprising nucleic acid encoding the PLA2G4E comprising amino acid sequence as set forth in SEQ ID NO:1 or 3. The specification fails to provide any specific guidance of any nucleic acid encoding any amino acid that is at least 70% identical to SEQ ID NO: 1 or 3 and/or functional fragment thereof showing contemplated biological activity. It is emphasized that biological activity of a protein is highly dependent on the overall structure of the protein itself and the primary amino acid sequence determines the conformation of the protein. This is also evidenced by studies of Ngo et al that discloses addition or deletion of amino acid, which are critical to maintain the protein structure/function, will require guidance (Ngo et al., 1994, The protein Folding Problem and Tertiary Structure Prediction, pp492-495). Prior to instant invention, Skolnick et al (Trends in Biotech, 2000,18, 34-39) describing, “..sequence-based methods for function prediction are inadequate because of the multifunctional nature of proteins. However, just knowing the structure of the protein is also insufficient for prediction of multiple functional sites. Structural descriptors for protein functional sites are crucial for unlocking the secrets in both the sequence and structural-genomics projects” (abstract). Skolnick further states that “knowing a protein’s structure does not necessarily tell you its function” and “Because proteins can have similar folds but different functions, determining the structure of a protein may or may not tell you something about its function” (page 36, column 1, box 2). Therefore, it is apparent from the cited art that biological function of a protein was unpredictable from amino acid sequence at the time of the invention and even same short stretch of amino acid sequence could show diverse biological functions while surrounded by different background amino acid sequences. Therefore, considering the unpredictable nature of a sequence of cPLAe containing mutation or a fragment thereof that has at least 70% sequence identity to SEQ ID NO: 1 and 3 the specification as filed fails to support the full scope of invention as claimed. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
Response to arguments
Applicant disagree with the rejection arguing method as amended recites “A method for treating age-related dementia or Alzheimer’s disease in a subject ... comprising ... expressing cPLA2e in the CAI] region of the hippocampus”. Applicant assert that the specification is enabling for “expressing cPLA2e in the CA1 region of the hippocampus. Applicant provide the Osta’s declaration to demonstrate that systemic (for example, intravenous) injection of the therapeutic agent (for example, by inserting a needle into the space behind the eye) of AAVP31-PLA2G4E enhances memory in aged-WT animals and rescues memory deficits in APPNL-F-G mice. The comparative results of the supplemental data in the Declaration support that the claims, as currently amended, are enabled by demonstrating (1) systemic (1.e., intravenous) injection of the claimed therapeutic agent to cPLA2e expression throughout the entire brain rather than being restricted to the hippocampus and (2) the beneficial effects of the systemic administration. For example, beneficial effects were observed in aged WT mice, which showed a significant improvement in memory function and increase in neuronal activity with respect to vehicle treated individuals, and in a further Alzheimer’s disease (AD) in vivo model (for example, APP KI mice). The declaration provides supplementary data show that systemic (i.e., intravenous) injection of the therapeutic agent leads to cPLA2e expression throughout the entire brain rather than being restricted to the hippocampus (Figure 1). Applicant continue to rely on declaration to assert that administration provides AAV9P31 serotype viral particles (for example, the AAV vector has AAV9 ITRs and codes for AAVP31 capsid proteins). A person of ordinary skill in the art would understand that intravenous administration of the AAV gene therapy construct will require that the generated AAV viral particles cross the BBB. AAV viral particles having the ability to transduce cells of the central nervous system (CNS) following systemic injection were already known at the filing date (see, for example, Rincon et al 2018, PMID: 29523880, Gessler et al. 2019, PMID: 30783972; enclosed herein) (also see fig. 4-7 of the declaration). Applicant continue to argue that this vector was shown to be capable of delivering and expressing cPLA2e in the hippocampus (see, for example, the Declaration at §2). Therefore, Applicant submits that the specification as filed and supplementary data presented in the Declaration are enabling for an AAV vector as claimed. Applicants’ arguments have been fully considered, but are not found persuasive.
In response to Applicant’s argument that instant disclosure and the Osta’s declaration provide adequate guidance enabling for “expressing cPLA2e in the CA1 region of the hippocampus” is found not fully persuasive. It should be noted that claims continue to read on delivering AAV of any serotype comprising a nucleic acid encoding any cPLA2e via any parenteral route that includes subcutaneous, intradermal, intramuscular to make and use the invention. The guidance provided in the specification is limited to direct injection of AAV2/9-mPLA2G4E into the CA1 region of the hippocampus of an aged wild type C57BL/6 or APP/PS1 transgenic mouse that exhibits accelerated amyloidosis. The previous office action indicated that claims are enabled for a direct injection of AAV2/9-mPLA2G4E into the CA1 region of the hippocampus of an aged wild type C57BL/6 or APP/PS1 transgenic mouse that exhibits accelerated amyloidosis. The art teaches administering gene delivery systems via intravenous injection into the peripheral vasculature may limit the effective amounts of gene delivered into the CNS. To achieve a therapeutic concentration of administered gene in the CNS, the gene delivery system must be administered at a very high dose. It is known that high amounts of a gene delivery vector in the blood stream, however, it is known to initiate an immune or cytotoxic response (page 3, last para. Puhl et al Brain Res Bull. 2019 150: 216–230). In the instant case, neither specification nor prior art provided adequate guidance of delivering AAV of any serotype via any parenteral route that includes subcutaneous, intradermal, intramuscular. While it is known in prior art that intravenous injection of AAV9 crosses the BBB, however, AAV2/9 systemic distribution also makes it challenging to be specifically contained expression in a small, critical area like the CA1 region in a without potential off-target effects or overexpression in other tissues. There is no evidence on record that intravenous injection or intradermal or intramuscular injection of AAV of any serotype enables the method as claimed. One of ordinary skill in the art would have to perform undue experimentation to first characterize of AAV of different serotype from different species with respect to testing their ability to infect neurons in the CAI region of the hippocampus such that therapeutic protein in expressed in these cells at a therapeutic level in predictable animal model of age-related dementia in a subject having AD, to make use of the invention without a reasonable expectation of success.
In response to applicant’s argument and reliance on Osta’s declaration demonstrates that systemic (for example, intravenous) injection of the therapeutic agent (for example, by inserting a needle into the space behind the eye) of AAVP31-PLA2G4E enhances memory in aged-WT animals and rescues memory deficits in APPNL-F-G mice is not found persuasive. In the instant case, applicant’s argument and evidence is not commensurate with the scope of the claims. Firstly, claims 19, 33, 35, 36-44 and 45 are not limited to intravenous injection of AAVP31 serotype encoding PLA2G4E. Further, MPEP2164.05 states “To overcome a prima facie case of lack of enablement, applicant must present argument and/or evidence that the disclosure would have enabled one of ordinary skill in the art to make and use the claimed invention at the time of filing. This does not preclude applicant from providing a declaration after the filing date which demonstrates that the claimed invention works. However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art at the time of filing. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must reasonably enable the full scope of the claimed invention. See Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021). In the instant case, declaration explicitly uses intravenous delivery of AAVP31-PLA2G4E. The AAV9P31 is an engineered adeno-associated virus (AAV) capsid variant, derived from AAV9, designed for efficient gene delivery directly to the central nervous system (CNS) by crossing the blood-brain barrier (BBB) after intravenous injection is not even disclosed in instant specification. Zhang (PLoS Pathog . 2024 Feb 5;20(2):e1011953.1-20, cited as evidence in response to declaration without relying on the rejection) teaches AAV9P31 has a unique peptide insertion (WPTSYDA in loop VIII) to bind to its receptor, carbonic anhydrase IV (Car4), allowing for a normal transport system into the brain, outperforming earlier versions like AAV9. Likewise, Rinson pertains to use of another newly engineered capsid, AAV-PHP.B that is reported to cross the BBB at even higher efficiency. None of the claims under consideration limit the viral vector to be AAV-PHP.B or AAVP31. Gessler teaches use of AAV9 to deliver gene of interest across BBB, however, Gessler is silent on expressing gene of interest in CAI region as required by the claim. There is no evidence on record and/or declaration that results disclosed in the declaration could not be extended to any other serotype delivered via any parenteral route. An artisan would have to perform undue experimentation to make and use the invention without reasonable expectation of success.
On page 17-18 of the applicant’s argument, applicant assert that different embodiments of the cPLA2e have substantially the same cPLA2e activity as human cPLA2e isoform 1 or 2 and amended to claim 19 is commensurate with the scope that is supported by the specification. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that the specification contemplated using human cPLA2e isoform 1, or 2 protein fragments, functional protein domains, variants, and homologous proteins (orthologs) are also considered to be within the scope of the cPLA2e of the nucleic acid construct of the invention. In this regard, previous office action explicitly stated that specification teaches delivering AAV2/9 vector comprising nucleic acid encoding the PLA2G4E comprising the amino acid sequence of SEQ ID NO:1 or 3. The specification fails to provide any specific guidance of any nucleic acid encoding any amino acid that is at least 70% identical to SEQ ID NO: 1 or 3 and/or functional fragment thereof showing contemplated biological activity. The art teaches biological function of a protein was unpredictable from amino acid sequence at the time of the invention and even same short stretch of amino acid sequence could show diverse biological functions while surrounded by different background amino acid sequences. The specification fails to provide any protein fragments, functional protein domains, variants of cPLA2e. It is evident form a post published article shows in most cases different isoforms likely have unique functions or regulatory mechanisms (see Vitting-Seerup NAR Genomics and Bioinformatics, 2023, 5, 1–9, cited as evidence without relying on the rejection). Therefore, considering the unpredictable nature of a sequence of cPLAe isoform, fragment or variant containing mutation or a fragment thereof that has at least 70% sequence identity to SEQ ID NO: 1 and 3 the specification as filed fails to support the full scope of invention as claimed. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants’ arguments are not compelling and do not overcome the rejection of record.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 19-22, 32-35 were rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Shayman et al (US20120121571, dated 5/17/2012) as evidenced by Peretti (Psychother Psychosom 2012;81:276-285) and Morgan (Semin Immunopathol (2018) 40:113–124). In view of applicant’s amendment to claim 19 limiting the scope to a method of treating age-related dementia or Alzheimer’s disease by expressing cPLA2e in the CA1 region of hippocampus obviates the basis of the rejection. Applicant’s argument that prior art neither teaches nor suggests expressing cPLA2e in the CA1 region of hippocampus to treat any condition is found persuasive. Therefore, previous rejection of claims 19-22, 32-35 are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. 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.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632