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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/04/2026 has been entered.
Applicant’s amendments to the claims and arguments filed on May 4, 2026 have been received and entered. Claims 17, 34 and 35 have been amended, while claim 48 is newly added. Applicant’s supplemental amendments to the claims filed on June 1, 2026 have been received. Claims 17, 34-35 and 48 have been amended Claims 17-48 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.
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 05/04/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 17-48 are under consideration.
Withdrawn-Obviousness type Double Patenting
Claims 17- 47 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of USP 12036268. In view of Applicants’ terminal disclaimer dated May 4, 2026, the previous rejections are rendered moot and hereby withdrawn.
Maintained &New-Claim Rejections - 35 USC § 112-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 17-48 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 the treatment of a cognitive impairment disease, improving cognition performance or treating cognitive decline in a mammal, said method comprising injecting directly into the brain or into the central nervous system (CNS) of the mammal, 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 or carrier, and wherein said mammal is a human, a mouse, a rat, a dog, a goat, or a primate,
does not reasonably provide enablement for (i) using the AAV vector from different serotype delivered via intravenous route for the treatment of a cognitive impairment disease, improving cognition performance or treating cognitive decline in a mammal or using a nucleic acid encoding any other alternative splicing variant of mammalian klotho protein (claim 48). 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 AAV and the administering is by intravenous injection or 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 any alternative splicing variant of mammalian klotho protein or 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 by intravenous injection a genus of AAV of different serotype 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 and 48);
delivering any AAV comprising a nucleic acid encoding any alternative splicing variant of mammalian klotho protein 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 claim 48;
nexus between cellular pathology associated with (behavior and cognitive tests in 18-month-old mice by intravenous delivering of any AAV encoding s-KL that crosses blood brain barrier to have any effect in region of CNS to have any effect on the disorder of different etiology and pathology by delivering an AAV encoding s-KL or SEQ ID NO: 1 or 2.
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 delivered via intravenous injection other than a direct injection to CNS or brain. 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).
In a post filing art, Zhou (Front. Mol. Neurosci. 2022, 15:988914. 1-13) states “
AAVs are the leading vehicles for delivering gene therapies into the brain, and IV injection is the optimal brain-targeting rAAV injection route because it is minimally invasive, especially when widespread gene therapy is needed in the brain and in some disease conditions in which widely targeting both the CNS and peripheral system is required. However, most rAAVs cannot cross the blood–brain barrier (BBB), and different rAAV stereotypes recognize different cell receptors and thus have different tropisms for distinct tissues and cell types, which causes difficulties in delivering rAAVs into the brain by IV administration. Moreover, the required high concentration of virus vectors, rapid immune responses, immunotoxicity, and potential off-targeting to the peripheral tissues may limit the use of IV for rAAV delivery into the brain.” (see page 2, col. 2, para. 1).
Zhou further states
” IV injection is less invasive and can be used to target widespread areas of the brain; however, the currently used rAAV serotypes lack robust brain tropism and may induce immunotoxicity” (see page 08, col. 2, para. 4)
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).
Claim 48 is directed to administering to the mammal, by injecting directly into the brain, by intravenous injection, or by 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 any alternative splicing variant of mammalian klotho protein in a pharmaceutically acceptable excipient or carrier. The guidance provided in the specification is limited to a direct injection of AAVrh10 vector encoding a secreted (s-KL) Klotho isoform consisting of SE Q ID NO: 1 or 2. It is noted that while instant specification teaches alternative splicing produced a distinct secreted protein consisting of SEQ ID NO:1 or 2, however, post filing art reported summarized by the reference of Mencke (JCI Insight. 2017;2(20):e94375, 1-15) states “
Recent advances in RNA surveillance reveal that premature termination codons, as present in alternative Klotho mRNA (for secreted Klotho), prime mRNAs for degradation by nonsense-mediated mRNA decay (NMD). Disruption of NMD led to accumulation of alternative Klotho mRNA, indicative of normally continuous degradation. RNA IP for NMD core factor UPF1 resulted in enrichment for alternative Klotho mRNA, which was also not associated with polysomes, indicating no active protein translation. Alternative Klotho mRNA transcripts colocalized with some P bodies, where NMD transcripts are degraded. Moreover, we could not detect secreted Klotho in vitro. These results suggest that soluble Klotho is likely cleaved membrane bound Klotho only”(abstract).
The art further teaches human alternative Klotho mRNA is a target for NMD and does not undergo protein translation, indicating that the supposed kidney-derived secreted Klotho does not exist (see page 11, para. 3) (emphasis added).
The specification fails to recognize any other secreted (s-KL) Klotho isoform other than amino acid of SEQ ID NO: 1 or 2. An artisan would have to perform undue experimentation to revie he presence of premature termination codons in alternative klotho mRNA as observed by Mencke to make and use the nucleic acid encoding any alternative splicing variant of mammalian klotho protein as broadly recited, to make and use the invention, without reasonable expectation of success.
In the instant case, neither specification nor prior art provide evidence of expression of s-KL protein by intravenously delivering AAV vector of any serotype encoding an s-KL other than a direct injection of AAVrh10 encoding s-KL consisting of amino acid sequence of SEQ ID NO: 1 or 2 into CNS at a level sufficient in a 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 via intravenous injection 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 AAV vector comprising a nucleic acid encoding s-KL could delivered via intravenous injection such that 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 intravenously 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. The guidance provided in the specification at best is limited to overexpression of s-KL consisting of amino acid of SEQ ID NO: 1 or 2 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 nucleic acid encoding any 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.
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
To the extent that Applicants’ arguments are pertinent to the standing rejection of claim 17, and the new rejections, they are addressed as follows:
Applicant disagrees with the rejection arguing in part relying on the Rodriguez’s declaration that summarizes the data contained in the specification and in Applicants' companion post-filing, peer-reviewed publication (Massó et al., PLOS One 10(11):1-15 (2015), of record), as well as more recent data obtained from human and non-human primates that confirms the existence of s-KL protein expression and shows that its expression patterns that differ from full length Klotho protein. The declaration further reiterates that his experimental work was the first reported demonstration that 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 (12-month-old) mice.
In his second declaration, Dr. Chillon Rodriguez summarizes the art at the time of filing of the present application with respect to AAV vectors that cross the blood brain barrier (BBB), successfully transduce cells in the CNS, and cause transgene protein expression. Dr. Chillon Rodriguez reiterates that his patent application is the first report that s-KL gene therapy delivers s-KL to the hippocampus and the beneficial results of such AAV vector-delivered s-KL. Dr. Chillon Rodriguez also discusses Applicants' companion post-filing, peer-reviewed publication (Roig-Soriano et al., Aging Cell 21(4):e13581 p. 1-16 (2022) ("Roig-Soriano"), submitted in an Information Disclosure Statement herewith). He explains that the new data reported in Roig- Soriano demonstrates that AAV vectors containing a nucleic acid encoding s-KL delivered to the lateral ventricles travel to the hippocampus and result in s-KL expression, as measured by s-KL mRNA. He explains that this AAV vector, when delivered by intracerebroventricular injection improves cognitive performance associated with aging, including improving working memory and spatial memory in a well-established mouse model of age-related cognitive decline.
Applicants’ arguments have been fully considered, but are not found persuasive.
In response, as stated in previous office action, it is acknowledged that there are many neurotropic AAV serotype that could be delivered directly to the brain or CNS of a subject in need thereof. Therefore, applicant’s amendments to the claims limiting the scope to a direct injection of AAV encoding s-KL consisting of SEQ ID NO: 1 or 2 into the brain or CNS of the subject is enabled as indicated above in scope of enablement rejection.
However, as stated in previous office action, instant specification does not enables using AAV of different serotype derived from different species delivered via intravenous injection correlating the local expression of secreted isoform of klotho, s-KL in any cell of CNS for the 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. Maguaire et al (Neurotherapeutics (2014) 11:817–839, art of record) report challenges for treating CNS disease involves (i) delivery vehicles, (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). The post filing art summarized by the reference of Zhou (Front. Mol. Neurosci. 15:988914. 1-13) states “
AAVs are the leading vehicles for delivering gene therapies into the brain, and IV injection is the optimal brain-targeting rAAV injection route because it is minimally invasive, especially when widespread gene therapy is needed in the brain and in some disease conditions in which widely targeting both the CNS and peripheral system is required. However, most rAAVs cannot cross the blood–brain barrier (BBB), and different rAAV stereotypes recognize different cell receptors and thus have different tropisms for distinct tissues and cell types, which causes difficulties in delivering rAAVs into the brain by IV administration. Moreover, the required high concentration of virus vectors, rapid immune responses, immunotoxicity, and potential off-targeting to the peripheral tissues may limit the use of IV for rAAV delivery into the brain.” (see page 2, col. 2, para. 1).
Zhou further states
” IV injection is less invasive and can be used to target widespread areas of the brain; however, the currently used rAAV serotypes lack robust brain tropism and may induce immunotoxicity” (see page 08, col. 2, para. 4)
In view of foregoing, it is apparent from post filing art that, most rAAVs cannot cross the blood–brain barrier (BBB), and different rAAV stereotypes recognize different cell receptors and thus have different tropisms for distinct tissues and cell types, which causes difficulties in delivering rAAVs into the brain by IV administration. In the instant case, neither specification nor prior art support the breadth of the claims encompassing an intravenous injection of any AAV serotype derived from any species that would cross BBB to infect cells of CNS. Applicant should note that MPEP 2164.05(a) states “ If a publication demonstrates that those of ordinary skill in the art would find that a particular invention was not enabled years after the filing date, the publication would be evidence that the claimed invention was not possible at the time of filing”. See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513-14 (Fed. Cir. 1993).
An artisan would have to perform undue experimentation to identify and characterize AAV vector and/or its serotype from different species with respect to testing their ability to infect neurons via intravenous injection 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 and use of the invention without a reasonable expectation of success.
In response to Applicant’s reliance on declaration and Roig-Soriano et al., Aging Cell 21(4):e13581 p. 1-16 (2022) publication for enabling support, it is noted that publication supports intraventricular administration of AAV vectors expressing secreted and transmembrane Klotho isoforms, rescued accelerated aging phenotype of SAMP8 mice. Roig-Soriano teaches a intracerebroventricular stereotaxic injections of AAV vectors were performed in the right hemisphere at coordinates, −0.2 mm Antero‐posterior, −2 mm Dorso‐ventral, and +1 mm medio‐lateral from bregma (see page 3, col. 1, para. 3, 2.1 and abstract). The results show both AAV9 s-KL and m-KL mediated strong a Klotho expression two months after AAV injection in the different areas analyzed and vector expression was associated with an increase in KL protein in the hippocampus (Figure ld), area of particular interest due to its importance in learning and memory formation. Applicant’s post filing art provide evidence of AAV9 serotype injected directly into brain and not to an intravenous injection as required by the claims. Further, instant specification fails to disclose the method of AAV9 delivery disclosed in Roig-Soriano. Therefore, applicant’s reliance on post filing art is not commensurate with the scope of the claimed invention. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success
New-Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 48 is rejected under 35 U.S.C. 103 as being unpatentable over Dubal (Cell Reports, 7: 1065-1076, 2014, IDS), Dubal (WO2016127097, thereafter referred as Dubal2, IDS), Iida et al (JP2001072607, 3/21/2001) and McCown et al (Brain Research 713 (1996) 99-107).
With respect to claim 48, Dubal discloses a method for improving cognitive function in an individual in need thereof (method of enhancing cognition in humans in need thereof; page 2, second column, second paragraph), thereby improving cognitive function in the individual (improving cognitive function; page 2, second column, second paragraph). KL-VS genetic variant of Klotho is associated with enhanced cognition in three independent human cohorts and in a Meta-Analysis (p 2nd column under results). Dubal further discloses wherein the human has at least normal cognitive function (humans without dementia or cognitive complaints; page 2, second column, third paragraph). Dubal discloses the KL-VS variant significantly increased levels of secreted klotho in the serum (Figure 3A; Table S7) (p 3, 1st column 2nd paragraph). This is further evidenced by Dubal2 who reported KL-VS variant of klotho significantly increased levels of secreted klotho in the serum and Klotho also has a splice variant that results in a 549 amino acid secreted form of the protein that is also functional [0059] to soluble human klotho in mice, transgenic overexpression of klotho extends lifespan and associates with better cognitive functions in the normal and diseased brain [0006], [0007]-[0010], [0059] [0061]. Klotho RNA can also be alternatively spliced and directly secreted into the surrounding fluid (i.e., without forming a transmembrane protein) [0034]. Dubal2 teaches treatment and prevention such that cognition is better than would be expected without treatment (e.g., compared to cognition in the same individual before treatment or compared to cognition in similar non-treated individuals) [0054]. It is further disclosed that a direct delivery of s-KL to CNS is effective at a lower dose (see para. 76). Dubal does not explicitly teach administering a splicing variant of KL to the mammal by injecting into CNS an AAV expression vector comprising a promoter operably linked to a nucleic acid encoding an alternative splicing variant of mammalian klotho protein.
Iida discloses [0009] a therapeutically effective dose [JP607 claim 1] of Klotho cDNA is administered to the mammalian subject in need thereof . Iida discloses the Klotho cDNAs have ageing inhibitory activity. Iida discloses the klotho cDNA having SEQ ID NO: 2 [JP claim 3] in a recombinant vector [JP claim 1] is administered to the mammal in a recombinant vector (the claimed “nucleic acid encoding said protein;” claim 17). Iida discloses the recombinant vector can be derived from Parvoviridae ( adenoviral associated vector) (para. 12). Iida discloses administering a recombinant vector comprising the gene sequence encoding SEQ ID NO: 1 (Iida 7 claim 3) to patients (the claimed “wherein the nucleic acid sequences encode the polypeptide of SEQ ID NO:1;” claim 39); that the recombinant vector can be a type 5 adenoviral vector [0013]. Iida discloses administration of the composition in a pharmaceutically carrier [0021]. Iida discloses the formulation can be administered by injection [0022] into a vein claim 17 part 2) or by IM injection ( “intramuscular injection;” claim 17, part 2). McCown teaches advantage of injecting AAV directly into CNS as compared to adenoviral vector. It is disclosed that Adenovirus vectors also have been used to transfer genetic material into the CNS with few signs of neurotoxicity, however, these viral vectors are episo mal, thus transient, and increased titers of these vectors can cause neural damage (see page 99, col. 2, para. 1). The reference shows that vector could transfer an gene of interest (b-galactosidase or a tyrosine hydroxylase gene), and produce sustained expression of the gene product in the CNS with no obvious signs of neuro- toxicity (see page 99, col. 2 to page 100, col. 1, para. 1).
It would have been obvious to one of ordinary skill in the art seeking to overexpress s-KL in the CNS of a subject in need thereof to modify the method of Dubal by directly administering nucleic acid encoding secreted form of klotho (appl SEQ ID NO: 1) as disclosed in Iida, in the method of improving cognitive function in an individual in need thereof, as instantly claimed, with a reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art methods according to known methods to yield predictable results. One of ordinary skill would have been motivated to express klotho protein having SEQ ID NO: 1 because art teaches s-KL has ageing inhibitory activity (see Iida) , while Dubal2 reported use of Klotho and functional variants in preventing or reducing cognitive decline associated with aging in middle aged humans (see para. 89-90). One of ordinary skill would have had a reasonable expectation of success in treating cognitive impairment diseases in a mammal by administering nucleic acid encoding a klotho protein having SEQ ID NO: 1 as prior art successfully reported delivering nucleic acid ncoding s-Kl to have ageing inhibitory activity, while McCown provided reasonable expectation of success in expressing gene of interest by direct delivery of AAV into the CNS. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 48 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 38-44 of copending Application No 18773181. Although the claims at issue are not identical, they are not patentably distinct from each other because claims of instant application explicitly use the AAV vector claimed in ‘181. In the instant case, claim is drawn to a method for the treatment of a cognitive impairment disease in a mammal, comprising administering to the mammal, by injecting directly into the brain, by intravenous injection, or by 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 in a pharmaceutically acceptable excipient or carrier. In contrast, claims in ‘181 application is drawn to a gene construct comprising a nucleic acid sequence coding for a secreted splicing variant of mammal klotho protein (s-KL) operatively linked to an expression promoter for treating or preventing cognitive impairment diseases. Dependent claims limit the a species of promoter, nucleic acid sequence of SEQ ID NOL 38, vector that is neurotropic and wherein expression vector is an adeno-associated virus of serotype AAVrh10. As such, the ‘181 claims represent a species of the instant broader AAV vector encoding s-Kl. 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). The method of claim 48 encompasses the AAV vector specifically recited in ‘181 application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
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/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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