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 27, 2025 have been received and entered. Claims 17, 34 and 35 have been amended, while claims 1-16 remain canceled. Claims 17-47 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of species of nucleic acid encoding klotho in the reply filed on May 27, 2025 was acknowledged.
Claims 14-47 drawn to method of using protein were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 May 27, 2025.
Priority
This application is a Continuation of US application no 15/777,456 filed on 05/18/2018 which is a 371 of PCT/EP2016/078320 filed on 11/21/2016, which claims priority from foreign application no EP 15195470 filed on 8 11/19/2015.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/18/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 14-47 are under consideration.
Maintained-Obviousness type Double Patenting
Claims 14- 47 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of USP 12036268. Although the claims at issue are not identical, they are not patentably distinct from each other because claims in both are directed to delivering directly into the central nervous system (CNS), a therapeutically effective amount of an adeno-associated virus (AAV) expression vector with a CNS tropism comprising an expression promoter operatively linked to a nucleic acid encoding an alternative splicing variant of mammalian klotho protein consisting of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 in a pharmaceutically acceptable excipient. As such, the ‘268 claims represent a species of the instant broader claims. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann, 572 F.2d 312, 197 USPQ 5 (CCPA 1978).
Response to arguments
Applicants assert submission of a Terminal Disclaimer to overcome the rejection of record. Applicants’ arguments have been fully considered, but are not found persuasive.
In response it is noted that no terminal disclosure was filed in response to nonfinal office action mailed on June 18, 2025. Therefore, previous rejection of claims 14-47 is maintained for the reasons of record.
Maintained-Claim Rejections - 35 USC § 112-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 14-47 remain 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 the treatment of a cognitive impairment disease in a mammal, said method comprising administering to the mammal, by injecting directly into the central nervous system (CNS) or CSF, a therapeutically effective amount of an adeno-associated virus (AAV) expression vector with a CNS tropism comprising an promoter operatively linked to a nucleic acid encoding an alternative splicing variant of mammalian klotho protein consisting of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 in a pharmaceutically acceptable excipient or carrier, and wherein said mammal is a human, a mouse, a rat, a dog, a goat, or a primate, and wherein said AAV expression vector is serotype AAVrh10, serotype 9 or serotype 8;
does not reasonably provide enablement for using any other AAV vector via any other route for treatment of a cognitive impairment disease in a mammal, improving cognition performance in a mammal or treatment of cognitive decline in a mammal. 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.
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.
Nature of the invention
The claims are directed to a method for the treatment of a cognitive impairment disease in a mammal, improving cognition performance in a mammal or treatment of cognitive decline in a mammal, said method comprising administering to the mammal, by AAV8, AAV9, or AAVrh10 and the administering is by intravenous injection or by intramuscular injection; or AAV expression vector is serotype AAV1-AAV2, AAV4-AAV9, or AAVrh10 and the administering is by injecting directly into the brain or by delivering directly into the CNSa therapeutically effective amount of an adeno-associated virus (AAV) expression vector with a CNS tropism comprising an promoter operatively linked to a nucleic acid encoding an alternative splicing variant of mammalian klotho protein consisting of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 in a pharmaceutically acceptable excipient or carrier, and wherein said mammal is a human, a mouse, a rat, a dog, a goat, or a primate. Dependent claims limit the cognitive impairment disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Multiple Sclerosis, Ataxia telangiectasia, dementia, and craniocerebral or spinal trauma.
Breadth of the claims
It is noted that instant rejection is based on three separate issues:
absence of an enabling disclosure for correlating the local expression of secreted isoform of klotho, s-KL in any cell of CNS by delivering directly into the brain, by intramuscular injection, by intravenous injection, or by delivering directly into the CNS, a genus of AAV derived from different species for treatment of a genus of cognitive impairment disease in a mammal, improving cognition performance in a mammal or treatment of cognitive decline in a mammal (claim 1, 34, 35);
delivering any AAV comprising a nucleic acid encoding SEQ ID NO:1 or SEQ ID NOL 2 in any predictable animal model to establish any reasonable correlation of treating any cognitive impairment disease that is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Multiple Sclerosis, Ataxia telangiectasia, dementia, and craniocerebral or spinal trauma. as embraced by the breadth of the claims;
nexus between cellular pathology associated with (behavior and cognitive tests in 18-month-old mice by delivering AAVrh10 encoding s-KL (example 2B-D, 3A-C) to the breadth of he claims encompassing disorder of different etiology and pathology by delivering an AAV encoding SEQ ID NO: 1 or 2; and
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). Wands states at page 1404. 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 secreted Klotho protein improves the learning and memory capabilities of old animals when treated in adulthood. The results disclosed in the instant specification suggest s-KL may have therapeutic potential for dementia. The specification extrapolates this finding to represents a promising new therapeutic approach for neurodegenerative disorders such as Alzheimer's Disease or Multiple Sclerosis among others (see para. 34 of the published application). The specification describes AAV-s-KL (or AAVrh10-s-KL) designates the adeno-associated virus carrying the plasmid with the gene construct coding for s-KL (see Fig. 1). Example 2 of the specification teaches in vivo administration of s-KL vector in old mice. The specification teaches long-term effects of klotho overexpression in the aging CNS in C57BL/6 mice injected at 12 months of age, and tested 6 months later through a battery of tests for behavioral assessment and functional analysis (FIG. 2 and FIG. 3) using an AAVrh10 vector encoding secreted (s-KL) Klotho isoform. The specification discloses intracerebroventricularly injecting AAV vectors to mimic the endogenous production system, in which Klotho produced in the CNS is released into the CSF and distributed throughout the brain. Example 2B shows overexpression of s-KL in the CNS does not affect body weight or sensorimotor skills in old mice. The specification shows s-KL overexpression in the CNS ameliorates age-related motor decline without affecting anxiety-like behavior in old mice by determining locomotion, exploratory activity, emotional and anxiety-like behaviors (see Table 2). Example 2D teaches s-KL overexpression in CNS improves cognitive performance in old mice in two learning and memory tests namely T-maze and Morris Water Maze. These data indicated that an increase in the expression of s-KL in CNS allows improving punctuation in relation to controls. This moreover implies a better working memory, said memory of particular interest in aging people and in Alzheimer's disease. Example 3 teaches sustained overexpression or inhibition of s-KL from 6 to 12 months of age did not affect the reflexes and sensorimotor skills of all groups, the reflexes and sensorimotor skills of all groups were not affected (Table 4). Example 3B show that hippocampal s-KL overexpression results in an increase in horizontal activity and has a mild anxiolytic effect in middle-aged adult mice and improves cognitive performance (see example 3C, table 6). The specification fails to show delivering s-KL directly into CNS by using any other AVV other than AAVrh10 in behavioral improvement following treatment as compared to untreated mouse.
State of the Art and Predictability of the Art and the Amount of Experimentation
Necessary:
The art of gene therapy at the time of the filing of this application was unpredictable wherein any gene was expressed in an individual suffering from cognitive impairment disease in a mammal. While progress has been made in recent years for in vivo gene transfer, vector targeting in vivo to be desired organs continued to be unpredictable and inefficient. For example, numerous factors complicate the gene delivery art that would not have not been shown to be overcome by routine experimentation. For instance, Thomas (Nature review Genetics, 2003 4(5):346-58) states “One of the most important areas for gene-transfer research will be to dissect and understand these vector–host interactions. Monitoring pre-existing immunity to parental wild-type viruses will probably be an important component of patient evaluation in future clinical trials. Rigorous and uniformly recognized standards for measuring vector potency and concentration also need to be introduced to allow meaningful data comparison across different .. studies” (see page 356, col. 1, para. 2). Phul (Brain Res Bull. 2019; 150: 216–230) emphasizes that it is important to select the optimal route of vector administration (see page). Phul emphasizes use of viral vector raise several issues including possibility of an immune response, broad viral tropism and low production levels of viral vectors. Phul cites Gray et al. who showed that low levels of neutralizing AAV antibody titers in nonhuman primates diminished transduction of CNS cells following intravascular administration. It is disclosed that AAV vectors have a lower immunogenicity compared to others viral vectors. Still, AAV vectors can elicit an immune response in humans and pre-existing antibodies can reduce their efficacy. Phul concludes by stating that “Gene delivery to the CNS, however, is a difficult task. Because of their natural ability to infect host cells, viral delivery systems are studied extensively to deliver genes to the CNS. Although they are useful gene delivery vehicles, views on the use of viral vectors have become less favorable due to their high immunogenicity, broad tropism, and high cost of production” (see pages 3-7). The method disclosed in specification does not provide any specific guidance that sustained expression of s-KL could be achieved by any other vector other than AAVrh10. Furthermore, the state of the prior art effectively summarized by the reference of Shevtsova et al (Exp Physiol. 90.1, 53-59 2005) emphasized that selecting a right vector with an appropriate combination of promoters and serotypes remains an important issue to consider for any gene therapy (pp 58, left column, 2nd paragraph). Barkats et al (USPGPUB 20100240739, dated 09/23/2010) discloses unpredictability in targeting cells of CNS using conventional viral vectors as they do not pass blood brain barrier. It is further disclosed that gene transfer strategies via intrathecal delivery or direct injections of the vectors into the spinal cord parenchyma also failed to produce efficient widespread CNS transduction (see para. 3). 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 BAA V 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). There is no evidence on record that use of any AA viral vector would be predictive of any property of AAVrh10 vector disclosed in the instant application. Mingozzi et al (Nature Review, 2011, 341-355) states “AAV9 is of potential use in gene transfer in the CNS because it appears to have the ability to cross the BBB, a result that was confirmed in small and large experimental animals. However, potential obstacles remain for systemic AAV9 gene transfer targeting the CNS, including the block to transduction posed by humoral immunity, the need for higher vector doses to achieve therapeutic levels of expression in the brain, and the risk of off-target transduction of tissues such as cardiomyocytes. Castle et al (Methods Mol Biol. 2016; 1382: 133–149) reported that “AAVs 2 and 4 typically mediate weaker and less widespread neuronal gene expression. Thus, AAVs 2 and 4 are not recommended for widespread transduction of neurons. AAV2 diffuses less readily through both the brain and spinal cord parenchyma when compared against other serotypes, and therefore mediates transduction over a smaller area. This property can be harnessed for the targeting of small nuclei. The strongest and most widespread neuronal transduction is observed with AAV serotypes 1, 9, and rh.10. Castle states “AAV serotypes 1, 9, and rh.10 are therefore recommended for targeting of neurons via intraparenchymal brain injection” (see page 3, section 3). It is further disclosed that “When the spinal cord is targeted directly via intraparenchymal injection, AAVs 1, 5, and 9 demonstrate the strongest neuronal tropism, while AAVs 2, 6, and 8 demonstrate weaker neuronal tropism” (see page 4, section 5). In the instant case, neither specification nor prior art provide evidence of expression of s-KL protein using any AAV vector other than AAVrh10 at a level sufficient in any predictable animal model of cognitive impairment disorder. 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 AAV vector and/or its serotype from different species with respect to testing their ability to infect neurons such that therapeutic s-KL protein in expressed in these cells at a therapeutic level in predictable animal model of treating a cognitive impairment disease in a mammal, improving cognition performance in a mammal or treatment of cognitive decline in a mammal 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 s-KL is expressed in the target cell, 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 s-KL expression have an effect on the target cells and such effect is enough of an effect for a long enough period of time resulting in improving cognition performance in a mammal in a predictable animal model. Absent of any specific dose or serotype of AAV 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.
The claims are directed to a method for the treatment of a cognitive impairment disease in a mammal, improving cognition performance in a mammal or treatment of cognitive decline in a mammal, said method comprising administering to the mammal, by injecting directly into the brain a therapeutically effective amount of an adeno-associated virus (AAV) expression vector with a CNS tropism comprising an promoter operatively linked to a nucleic acid encoding an alternative splicing variant of mammalian klotho protein consisting of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. Dependent claims limit the cognitive impairment disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Multiple Sclerosis, Ataxia telangiectasia, dementia, and craniocerebral or spinal trauma. The guidance provided in the specification at best is limited to overexpression of s-KL in the CNS ameliorates age-related motor decline without affecting anxiety-like behavior in old mice by determining locomotion, exploratory activity, emotional and anxiety-like behaviors (see Table 2). It is further disclosed that s-KL overexpression in CNS improves cognitive performance in wild type old mice in two learning and memory tests namely T-maze and Morris Water Maze. In the instant case the issues relate to the predictability of animal model with respect to the breadth of claims intended to deliver s-KL for treating any cognitive impairment disease in a mammal subsequently limiting to Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Multiple Sclerosis, Ataxia telangiectasia, dementia, and craniocerebral or spinal trauma. The specification lacks to establish nexus between cellular pathology associated with plurality of cognitive impairment disease in a mammal and therapeutic s-KL level in any cells of CNS for the treatment of said genus of cognitive impairment disease. The specification does not provide any guidance on the resulting outcome in different species of rodent and gender. It is emphasized that cognitive impairment 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 AAVrh10 encoding s-KL directly into CNS. 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.). Bernstein et al (Physiol Behav. 2024 Sep 1:283:114595) in a post filing art reported sex differences in performance on the learning and reversal procedure raise concern for interpretation of behavior differences between sexes due to the attribution of these differences to motor activity rather than cognition (see abstract). Moy et al (Behavioral Brain Research 191 (2008) 118–129) who reported Inbred strain distributions using social choice tasks have shown that levels of social approach and preference are dependent upon genetic background, with some strains (AKR/J, C57BL/6J, C3H/HeJ, FVB/NJ) demonstrating high affiliation, and other strains (A/J, BALB/c, BALB/cByJ, BTBR T + tf/J, 129S1/SvImJ) having low preference or even avoidance (see page 119, col. 1, para. 1). Iqbal et al (J Neural Transm Suppl. 1998; 53:169-80) 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 symptoms that could be extrapolated to different cognitive impairment disease in a mammal, an artisan would not know how to treat plurality of cognitive impairment disease embraced by the breadth of the claim. Furthermore, for an artisan to use or make the instant method for its intended use an artisan would have to determine the specificity of the functional phenotype and if there are any disease or specific conditions associated with this animal model. It is apparent that art suggested strain, gender and breeding specific alteration in neurobehavioral traits. (Emphasis added). It is clear that the effect on behavioral phenotype seen after overexpression of s-KL locus in a C57BL/6 and the phenotype could not be generally extrapolated to any other gender, strain or genetic background. An artisan would have to carry out extensive experimentation to make and use the invention, and such experimentation would have been undue because art of the autism associated cognitive dysfunction in a mammalian model was not routine rather it was unpredictable and specification fails to provide any guidance as to how the claimed mouse and method would have been practiced to achieve a specific phenotype correlating as contemplated in the instant application.
In conclusion, in view of breadth of the claims and absence of adequate showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled for the claimed inventions commensurate with full scope. An artisan of skill would have required undue experimentation to practice the method as claimed because the art of gene delivery intended for treating cognitive impairment disease in a mammal was unpredictable at the time of filing of this application as supported by the observations in the art record.
Response to augments
Applicant disagrees with the rejection arguing the AAV expression vector is serotype AAV8, AAV9, or AAVrh10 and the administering is by intravenous injection or by intramuscular injection; or wherein the AAV expression vector is serotype AAV1-AAV2, AAV4-AAV9, or AAVrh10 and the administering is by injecting directly into the brain or by delivering directly into the CNS. Applicants' priority date reveals members of the AAV genus including specific AAV serotypes that possess the ability to transduce CNS cells which equates to a CNS tropism. A representative selection of the literature showing AAV serotypes with CNS tropisms and delivery into the brain. Applicant provide a representative publication showing AAV serotypes with CNS tropism (see table 1). To the extent that any of these known AAV vectors is not disclosed in the specification, what is known in the art does not need to be described in the application. See, MPEP 2163(II)(A)(2), citing Hybritech, Inc. V. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80 (Fed. Cir. 1986); Capon V. Eshhar, 418 F.3d 1349, 1358 (Fed. Cir. 2005). Therefore, when read in light of the state of the art, the specification would have enabled a person skilled artisan in the art to practice the claimed methods, throughout their full and entire scope, with respect to the recited administration routes of the AAV serotypes. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is acknowledged that there are many neurotropic AAV serotype that could be delivered to CNS of a subject in need thereof. However, as stated in previous office action, the issue is not whether instant specification enables using AAV of different serotype delivered via different route, rather the issue pertains to correlating the local expression of secreted isoform of klotho, s-KL in any cell of CNS by delivering genus of different AAV derived from different species via different route for treatment of a genus of cognitive impairment disease in a mammal, improving cognition performance in a mammal or treatment of cognitive decline in a mammal. The gene therapy in part depends on the robust gene expression in the target cells at appropriate therapeutic level at an appropriate time duration to treat different condition embraced by the breadth of the claim.
Applicant’s reliance on using different publication showing AAV genus including specific AAV serotypes that possess the ability to transduce CNS cells is not found fully persuasive because Griffey (Molecular Therapy, 2006, 538-47 , cited by applicant) explicitly states direct injection of AAV2 PPT1 resulted in no significant decrease in seizure frequency nor an increase in longevity. The publication emphasizes higher levels or a broader distribution of PPT1 expression, or both, will be required for more complete correction of this neurodegenerative disease (see abstract). The study cited by applicant suggests mere delivery of AAV2 encoding s-KL to CNS is not sufficient to treatment of a genus of cognitive impairment disease in a mammal as there is no evidence on record that a sufficient level of s-KL could be expressed in the relevant cells of hippocampus to have any significant effect in the mammal in need thereof. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. Further, Mason (Molecular Therp, 2019, 18, 715-724, IDS, cited by applicant) also reported “which vector performs best depend upon the area being injected (see page 721, col. 1, last para.) within the CNS and cell type being targeted (see page 721, col. 2, para. 1). In the instant case, specification acknowledge that there is much efficiency of AAV transduction in older compared to younger brains (see example 3). The specification further explicitly teaches:
“AAV was specifically injected into the hippocampus. The main reasons were (i) the klotho gene is abundantly expressed in hippocampus; (ii) hippocampus is involved in learning and memory processes; and (iii) in mice, the hippocampus develops structurally until 12 months of age, later undergoing age-dependent functional decline” (emphasis added).
In view of foregoing disclosure, it is apparent from the teaching of prior art made of record by applicant that one of ordinary skill in the art would conclude that a direct inject to hippocampus region in a subject would be enabling for many of the AAV serotype. The claims as amended do not even require expression of s-KL in any cell of any region of CNS and therefore a showing that enough of a nucleic acid encoding s-KL is expressed in the target cell, 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 s-KL expression have an effect on the target cells and such effect is enough of an effect for a long enough period of time resulting in improving cognition performance in a mammal in a predictable animal model. Further, it is emphasized that an intramuscular injection into CNS primarily targets the injected muscle tissue and associated motor neurons in the spinal cord and brainstem that may have some usefulness in treating motor neuron related disease. However, there is no evidence on record or any nexus between an intramuscular injection of AAV8, AAV9 or AAVrh10 that would effectively target the hippocampus region of CNS for over expression of s-KL to improve cognition in any mammalian subject. In fact, Maguaire teaches that “local 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). Examiner would acknowledge that an intraparenchymal injection directly into the hippocampus is the most effective way to ensure high and localized expression, as AAV 1, 2, 5, 8, and 9 as they have all shown robust expression when injected directly into the hippocampus. Absent of any specific site of and directly injecting into any site of CNS to maintain an effective concentration of the transgene product at the target site in hippocampus region of CNS, an artisan of skill would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
On page 10 of the applicant’s argument, applicant provide a number of publications (Borde et al , Webster et al , Yang et al and Loone et al ) that are art recognized model in recognized models in the sense that tests and tasks given to mice can measure their memory and cognitive abilities, and that the results of in these mouse models of neurological disease reasonably correlate to human diseases recited in the present claims. This response is accompanied a copy of the declaration under 37 C.F.R. § 1.132 by named co-inventor Dr. Miguel Chillon Rodriguez submitted on September 25, 2023 in parent patent application 15/777,456 (now U.S. Patent 12,036,268). It is probative with respect to the issues raised in the rejection at hand. Applicants’ arguments have been fully considered, but are not found persuasive.
As an initial matter, none of the cited publication of Borde et al , Webster et al , Yang et al and Lione are made of record as part of IDS as argued by applicant. It is emphasized that previous office action did not raise an issue with respect to open filed test or MWM spatial memory test to measure memory and/or cognition. In fact, prior art of record summarized by the teaching of Weitzer et al (J. Vis. Exp. 2015, (100), e52706, 1-11) acknowledges that the Morris water maze (MWM) is a commonly used task to assess hippocampal-dependent spatial learning and memory in mouse models of disease, including Alzheimer's disease. However, the issue pertains to 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.) (emphasis added). Bernstein et al (Physiol Behav. 2024 Sep 1:283:114595) in a post filing art reported sex differences in performance on the learning and reversal procedure raise concern for interpretation of behavior differences between sexes due to the attribution of these differences to motor activity rather than cognition (see abstract). Moy et al (Behavioral Brain Research 191 (2008) 118–129) who reported inbred strain distributions using social choice tasks have shown that levels of social approach and preference are dependent upon genetic background, with some strains (AKR/J, C57BL/6J, C3H/HeJ, FVB/NJ) demonstrating high affiliation, and other strains (A/J, BALB/c, BALB/cByJ, BTBR T + tf/J, 129S1/SvImJ) having low preference or even avoidance (see page 119, col. 1, para. 1). The guidance provided in the instant application is limited to long-term effects of klotho overexpression in the aging CNS in C57BL/6 mice injected at 12 months of age (middle-aged, N=10), and tested 6 months later. It is apparent that art suggested strain, gender and breeding specific alteration in neurobehavioral traits. (Emphasis added). It is clear that the effect on behavioral phenotype seen after overexpression of s-KL in a C57BL/6 could not be generally extrapolated to any other gender, strain or genetic background. Applicant has not provided any contrary argument and/or evidence to support that results obtained in c57/bl mouse could be extended to other gender, strain or genetic background. An artisan would have to carry out extensive experimentation to make and use the invention, a, without reasonable expectation of success. Should applicant provide a copy of the Rodriguez’s declaration filed in parent application ‘456, instant rejection pertaining to this issue would be overcome.
On pages 10-11 of the applicant’s argument, applicant in part rely on the Rodriguez’s declaration filed in parent application ‘456 to support data contained in the instant specification to confirm the existence of s-KL protein expression shows that its expression patterns differ from full length Klotho protein and overexpression of s-KL (by way of gene therapy) improved short- and long- term spatial learning and memory in older (18-month-old) mice, and improved learning and long-term working memory in middle-aged. Applicant continue to argues that decreasing levels of s-KL in brain tissue correlate with Alzheimer's disease progression as discussed, the Rodriguez’s declaration.
Applicants’ arguments this response is accompanied by the Rodriguez’s declaration are not found persuasive because there is no declaration filed in response to previous non-final office action. As stated in the previous office action, Applicant's arguments and reliance on arguments filed during the prosecution of the prior applications that relied in part on declaration filed under 37 CFR 1.130, 1.131 and 1.132,do not automatically become a part of this application. Where it is desired to rely on an earlier-filed affidavit or declaration, the applicant should make the remarks of record in this application and include a copy of the original affidavit or declaration filed in the prior application (see MPEP 201.06(c) IX). In the instant case, the Rodriguez’s declaration filed in parent application ‘456 is missing in the instant application. Therefore, instant rejection is maintained for the reasons of record.
Conclusion
No claims allowed.
The closest prior art of Dubal (Cell Reports, 7: 1065-1076, 2014) and Dubal (WO Publication No. 2016127097) teach splicing forms that are different than the splicing forms recited in the instant claims and there is no motivation and/or suggestion to use nucleic acid encoding SEQ IDNO: 1 or 2 in the method as claimed. Further, prior art including JP 2001 072607-A (JP607) fails to teach or suggest treating a cognitive impairment disease, improving cognition performance or method for treatment of cognitive decline in a mammal by administering a therapeutically effective amount of an adeno- associated virus expression vector with a CNS tropism comprising an expression promoter operatively linked to a nucleic acid encoding an alternative splicing variant of mammalian klotho protein consisting of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. Accordingly, claims are free of prior art.
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