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 response to restriction requirement filed on July 16, 2026 have been received and entered. Claims 1-37, 39-47 have been canceled, while claims 48-78 are newly added. Claims 38, 48-78 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 17-37 (group II) in the reply filed on July 16, 2026 is acknowledged. New claims 48-77 read on elected invention.
Claims 78 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 July 16, 2026.
Priority
This application is a divisional of US application no 15/777,456 filed on 05/18/2018 , which is a 371 of PCT/EP2016/078320 filed on11/21/2016, which claims priority from a foreign application EP 15195470.8 filed on 11/19/2015.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/17/2024, 09/09/2025 and 7/16/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 38, 48-76 and 77 are under consideration.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 38 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Gunther et al (US20180037868. EFD 09/18/2015).
Claims are directed 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.
With respect to claims 38, Gunther teaches a vector comprising a nucleic acid sequence coding for humans s-klotho that is operably linked to a promoter (see para.133), wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 3 encoding secreted human klotho protein (see para. 204). It is further disclosed that the promoter is the CMV or EF2 promoter (see para. 66). Gunther contemplated using the construct to overexpress s-KL to improve cognition (see para. 264).
Accordingly, Gunther anticipates claim 38.
Claims 38, 48-49, 66-67, 76 and 77 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kyowa et al (JP2001072607, 3/21/2001, IDS) .
Claims are directed 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.
Claim interpretation: The transition phrase sequence coding for s-KL comprises the nucleic acid of SEQ ID NO:5 is interpreted inclusive or open-ended that does not exclude additional, unrecited sequence. (see MPEP 211.03).
With respect to claims 38, 48, Kyowa teaches a vector comprising a nucleic acid sequence coding for human klotho that is operably linked to a promoter (see para.1, 13, 31), wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 2 that has 100% sequence identity to SEQ ID NO: 5. The term construct for treating or preventing cognitive impairment disease is an intended use recitation and therefore is not given any patentable weight.
Regarding claim 49, Kyowa teaches, wherein the promoter is a constitutive promoter such as a chicken β-actin promoter (see para. 25).
With respect to claim 66, Kyowa teaches that the expression vector comprises a liposome (see para. 12).
Regarding claim 67, Kyowa teaches a pharmaceutical composition comprising an expression vector comprising the gene construct and a pharmaceutically acceptable excipient or carrier such as sterile solution dissolved in water or an aqueous carrier (see para. 10-11, 20).It is further disclosed that the pharmaceutical composition according to item 1, wherein the viral vector is selected from retroviral vectors, adenovirus vectors, adeno-associated (related) virus vectors (see para. 10).
With respect to claims 76-77, Kyowa teaches that the composition, further comprising a sodium citrate (an antioxidant), buffering agents and isotonic agents including sodium chloride, glycine, glucose, or human albumin is used (see para. 20). It is further disclosed that composition, further comprising sodium chloride, potassium chloride, sodium citrate or preservative (see para. 20-21).
Accordingly, Kyowa anticipates claims 38, 48-49, 66-67, 76 and 77.
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.
Claims 38, 48-49, 66, 76 and 77 are rejected under 35 U.S.C. 103 as being unpatentable over Kyowa et al (JP2001072607, 3/21/2001, IDS), Gunther et al (US20180037868. EFD 09/18/2015), as evidenced by Matsumura et al (BBRC, 1998, 242, 626-630).
Claims are directed 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.
The phrase sequence coding for s-KL is interpreted to consist of the nucleic acid of SEQ ID NO: 5 encoding s-kl protien.
Kyowa teaches a vector comprising a nucleic acid sequence coding for human klotho that is operably linked to a promoter (see para.1, 13, 31), wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 2 that has 100% sequence identity to SEQ ID NO: 5.
Regarding claim 49, Kyowa teaches, wherein the promoter is a constitutive promoter such as a chicken β-actin promoter (see para. 25).
With respect to claim 66, Kyowa teaches that the expression vector comprises a liposome (see para. 12). It is further disclosed that the n the viral vector is selected from retroviral vectors, adenovirus vectors, adeno-associated (related) virus vectors (see para. 10).
PNG
media_image1.png
200
400
media_image1.png
Greyscale
PNG
media_image2.png
200
400
media_image2.png
Greyscale
Regarding claim 67, Kyowa teaches a pharmaceutical composition comprising an expression vector comprising the gene construct and a pharmaceutically acceptable excipient or carrier such as sterile solution dissolved in water or an aqueous carrier (see para. 10-11, 20).
With respect to claims 76-77, Kyowa teaches that the composition, further comprising a sodium citrate (an antioxidant), buffering agents and isotonic agents including sodium chloride, glycine, glucose, or human albumin is used (see para. 20). It is further disclosed that composition, further comprising sodium chloride, potassium chloride, sodium citrate or preservative (see para. 20-21).
Kyowa differs from claimed invention by not disclosing the coding sequence of human klotho consisting of SEQ ID No: 5.
Gunther cures the deficiency by disclosing a vector comprising a nucleic acid sequence coding for humans s-klotho that is operably linked to a promoter (see para.133), wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 3 encoding secreted human klotho protein (see para. 204). Gunther teaches using the construct to overexpress s-KL to improve cognition (see para. 264). The coding sequence of human s-KL is further evidenced by Matsumura who teaches nucleotide sequence of the 5'-flanking region of the human kl gene (see fig. 5). The translation initiation site (denoted by boldface ATG) is designated + 1 ATGCCCGCCA GCGCCCCGCC that has 100% sequence identity to nt 1 to nt 20 of the claimed coding sequence of secreted human Kl as set forth in SEQ ID NO: 5.
PNG
media_image3.png
200
400
media_image3.png
Greyscale
Matsumura further teaches nucleotide and amino acid sequences in the vicinity of the internal splice donor site in exon 3 of the human kl gene that has 100% sequence identity to nt 1441-1650 of SEQ ID NO: 5 (see below).
TTTCTAAGCC AGGACAAGAT GTTGTTGCCA AAGTCTTCAG CCTTGTTCTA
CCAAAAGCTG ATAGAGAAAA ATGGCTTCCC TCCTTTACCT GAAAATCAGC
CCCTAGAAGG GACATTTCCC TGTGACTTTG CTTGGGGAGT TGTTGACAAC
TACATTCAAG TAAGTCAGCT GACAAAACCA ATCAGCAGTC TCACCAAGCC
CTATCACTAg
PNG
media_image4.png
200
400
media_image4.png
Greyscale
Matsumura explicitly teaches that the insertion generates an in-frame translation stop codon (denoted by boldface TAG) and the resulting transcript encodes the secreted protein. (see fig. 2).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the construct of Kyowa by substituting coding sequence of klotho with structurally equivalent coding sequence of secreted form of klotho (s-kl) as suggested in Gunther as evidenced by Matsumura, as a matter of design choice, in a method of protecting cells and tissues from oxidative stress, and acts protectively in the context of neurodegenerative diseases such as Alzheimer's Disease (see para. 7 and 9) as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said design choice amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to overexpress the secreted form of Klotho to slow or treat aging related disease (see claims and para. 16). Other limitation of establishing coding sequence of s-kl consisting of SEQ ID NO: 5 would be obvious in view of explicit teaching of Gunther that account for a coding sequence of 1650 nucleotide as set forth above in view of Matsumura showing the translation initiation site starts with ATG and in-frame translation stop codon ends with TAG (see above). One of skill in the art would have been expected to have a reasonable expectation of success in substituting the KL coding sequence with s-KL coding sequence because the art teaches the reported successful use of a vector comprising a nucleic acid sequence coding for humans s-klotho that is operably linked to a promoter as evident from Gunther as evidenced by Matsumura. 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).
Claims 38, 48-49, 52-54, 57-61, 67-70, 76-77 are rejected under 35 U.S.C. 103 as being unpatentable over Kyowa et al (JP2001072607, 3/21/2001, IDS), Gunther et al (US20180037868. EFD 09/18/2015), evidenced by Matsumura et al (BBRC, 1998, 242, 626-630) as applied above for claim 38 and further in view of Hu et al (J Gene Med. 2010, 12(9): 766–778)/Klein et al (Molecular Therapy vol. 16 no. 1, 89–96 2008).
Th teaching of Kyowa, Gunther as evidenced by Matsumura have been described above and relied in same manner here. Gunther teaches secreted Klotho functions as a humoral factor with pleiotropic activities, including suppression of growth factor signaling, suppression of oxidative stress, and regulation of ion channels and transporters (see para. 7). It has been shown that that through the modulation of the cellular response to oxidative stress Klotho also acts protectively in the context of neurodegenerative diseases such as Alzheimer's Disease (see para. 9) Kyowa teaches that the expression vector comprises a liposome (see para. 12). It is further disclosed that the n the viral vector is selected from retroviral vectors, adenovirus vectors, adeno-associated (related) virus vectors (see para. 10).
The combination of reference differs from claimed invention by not disclosing expression vector has central nervous system tropism, wherein expression vector is a viral vector selected from an adeno-associated virus (AAV) of serotype AAV8, AAV9, or AAVrh10
However, use of constitutively active promoter with different AAV serotype to express
gene of interest in the brain was routine in art before the effective filing date of the instant invention., Hu et al teach comparing recombinant AAV vectors expressing firefly luciferase driven by a promoter (AAV.CB.LUC) that is packaged with viral capsids AAV 8, 9, and rh10 (see page 767, col. 2, para. 3). Hu et al teach a composition comprising the AAV8, 9 and rh10 vector in a pharmaceutical acceptable carrier (phosphate buffered saline) (see 768, col. 1, para. 1). It is disclosed that AAV9, AAV9 and rh10 transduce neuron in cortex, striatum, hippocampus and thalamus (see page 775, col. 2, last para.). It is further disclosed that AAV rh10 injected intravenously (see page 768, col. 1, para. 2) to the subject provided the greatest level of expression followed by AAV8 and AAV9 as compared to all other serotypes (see page 770, last para. page 771, col. 1, past para.). Likewise, Klein teaches AAV8, AAV9 and AAV10 all are highly efficient for neuronal gene transfer and will be useful for basic proof of concept studies in animal model of neurodegenerative disease (see page 95, col. 1, para. 1).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art
to combine the teachings of prior art to modify the viral vector comprising a nucleic acid sequence which encodes s-kl as disclosed in Gunther, Kyowa to include use constitutive active promoter with different neurotropic AAV serotype such as AAV9, AAV9 or AAVrh10 as disclosed in Hu/ Klein, in order to improve expression of s-kl transgene in the CNS intended to treat or reduce oxidative stress in neurodegenerative disorder, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use constitutive promoter with AAV8, 9 or AVrh.10 vector because this combination explicitly reported (i) the highest levels of transgene expression as compared to the commonly used other AAV serotype (supra). One of skill in the art would have been expected to have a reasonable expectation of success because (i) all the recited elements were known in the art, and hence "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results as evident from the teaching of Gunther and (ii) prior art had successfully reported AAV rh10 provided the greatest level of expression followed by AAV8 and AAV9 as compared to all other serotypes following intravenous injection (see
page 9, last para.). 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).
Claims 38, 48-50, 52-55, 67-71 are rejected under 35 U.S.C. 103 as being unpatentable over Kyowa et al (JP2001072607, 3/21/2001, IDS), Gunther et al (US20180037868. EFD 09/18/2015), Matsumura et al (BBRC, 1998, 242, 626-630), Hu et al (J Gene Med. 2010, 12(9): 766–778)/Klein et al (Molecular Therapy vol. 16 no. 1, 89–96 2008) as applied above and further in view of Doll (Gene Ther 1996 May;3(5):437-47).
The teaching of Kyowa, Gunther, Matsumura Hu/Klein have been described above and relied in same manner here. The combination of references teaches a pharmaceutical composition for treating or preventing a cognitive impairment disease comprising a therapeutically effective amount of the gene construct or an expression vector comprising a nucleic acid sequence coding for a secreted splicing variant of mammal klotho protein (s-KL) operatively linked to a promoter and a pharmaceutically acceptable excipient or carrier. It is noted that nt 1114 -2673 of SEQ ID NO: 4 has 100% sequence identity to s-KL sequence disclosed in Kyowa, Gunther, Matsumura. The combination of references differs from claimed invention by not disclosing use of IECMV promoter.
However, before effective filing date of instant application, use of immediate early CMV promoter in an expression cassette was known in prior art. For instance, Doll supports the teaching of Klein that human cytomegalovirus (CMV) immediate-early promote is strong ubiquitous promoter that function well in multiple cells on transfection and infection by rAAVs (abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art
to combine the teachings of prior art to modify the viral vector comprising a nucleic acid sequence which encodes s-kl as disclosed in Gunther, Kyowa to use ID CMV promoter with AAV as suggested by Doll in view of Klein for different AAV serotype such as AAV9, AAV9 or AAVrh10 as disclosed in Hu/ Klein, in order to improve s-kl transgene expression in the CNS intended to treat or reduce oxidative stress in neurodegenerative disorder, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use IE CMV promoter with AAV including AAV8, 9 or AVrh.10 vector because this combination explicitly reported (i) the high levels of transgene expression as compared to the commonly used other promoter (supra). One of skill in the art would have been expected to have a reasonable expectation of success because (i) all the recited elements were known in the art, and hence "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results as evident from the teaching of Doll and Klein and (ii) prior art had successfully reported IECMV function well with viral vectors. 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)(www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.
pdf).
Claims 38, 65-66 are rejected under 35 U.S.C. 103 as being unpatentable over Kyowa et al (JP2001072607, 3/21/2001, IDS), Gunther et al (US20180037868. EFD 09/18/2015), as evidenced by Matsumura et al (BBRC, 1998, 242, 626-630) as applied above and further in view of Bergen et al (Pharmaceutical Research, Vol. 25, No. 5, 2008. 983-998).
The teaching of Kyowa, Gunther, as evidenced by Matsumura have been described above and relied in same manner here. The combination of references teaches 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, but differs from claimed invention by not disclosing expression vector comprises a lipoplex.
Bergen teaches cationic lipids are among the most efficient nonviral vectors, and have been used extensively to transfect cultured neurons for studies in basic neuroscience. It is disclosed that simple addition of polyanionic nucleic acids to mixtures of cationic lipids or liposomes results in their self-assembly into particles termed lipoplexes (see page 985, col. 1, last para.). Bergen reported intraventricular delivery, lipoplexes containing a reporter gene or heat shock protein HSP70 were infused into the lateral ventricle. Stereological analysis of gene expression after coronal sectioning demonstrated a longitudinal distribution of transgene expression, including expression in neurons as determined by cell morphology and adjacent section staining with NeuN antibodies (see page 993, col. 1, para. 2).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art
to combine the teachings of prior art to modify the vector comprising a nucleic acid sequence which encodes s-kl as disclosed in Gunther, Kyowa to lipoplex as disclosed in Bergen, in order to improve delivery of nucleic acid for a sustained expression of s-kl in the CNS intended to treat or reduce oxidative stress in neurodegenerative disorder, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to lipoplex the vector encodings-kl because direct injection of genes delivered by lipoplexes are expressed in both neurons and glial cells near the injection site (see page 993, col. 1, para. 2). . One of skill in the art would have been expected to have a reasonable expectation of success because (i) all the recited elements were known in the art, and hence "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results as evident from the teaching of Bergen and (ii) prior art had successfully reported direct delivery of nucleic acid lipoplexed enhance gene expression in CNS (see above.). 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.
Claims 38, 48-50, 52-61, 64-65, 67-71, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim of copending Application No. 18773164 in view of Gunther et al (US20180037868) as evidenced by Matsumura et al (BBRC, 1998, 242, 626-630) and Klein et al (Molecular Therapy vol. 16 no. 1, 89–96 2008).
Although the claims at issue are not identical, they are not patentably distinct from each other because the gene construct claimed in the instant application is explicitly used in the method claimed in ‘164. For instance, claims in the instant application is directed 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, wherein the nucleic acid sequence coding for s-KL comprises the nucleic acid sequence of SEQ ID NO: 5. Claim 52 is directed to an expression vector comprising the gene construct of claim 38, wherein said expression vector has central nervous system tropism. Dependent claims limit the expression vector is a viral vector that is an adeno-associated virus (AAV) of serotype AAV8, AAV9, or AAVrh10. Claim 61 is directed toa n expression vector comprising the gene construct according to claim 38, wherein said expression vector comprises a lipoplex or comprises a liposome. Claim 67 is directed to a pharmaceutical composition for treating or preventing a cognitive impairment disease comprising a therapeutically effective amount of the gene construct of claim 38 or an expression vector comprising the gene construct and a pharmaceutically acceptable excipient or carrier, wherein herein said expression vector has central nervous system tropism and wherein the expression vector is an AAV of serotype AAV8, AAV9, or AAVrh10. In contrast, claims in ‘164 are directed 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 intramuscular injection, 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 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. Claims are also directed to method for the treatment of a cognitive impairment disease in a mammal, comprising administering to the mammal, by injecting directly into the brain, by intramuscular injection, 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. The “164 application differs from claimed invention by not disclosing that SEQ ID NO: 1or 2is encoded by SEQ ID NO: 5 or the neurotropic AAV is selected from AAV8, AAV9 or AAVrh10. However, Gunther cures the deficiency by disclosing a vector comprising a nucleic acid sequence coding for humans s-klotho that is operably linked to a promoter (see para.133), wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 3 encoding secreted human klotho protein (see para. 204). Gunther teaches using the construct to overexpress s-KL to improve cognition (see para. 264). The coding sequence of human s-KL is further evidenced by Matsumura who teaches nucleotide sequence of the 5'-flanking region of the human kl gene (see fig. 5). The translation initiation site (denoted by boldface ATG) is designated + 1 ATGCCCGCCA GCGCCCCGCC that has 100% sequence identity to nt 1 to nt 20 of the claimed coding sequence of secreted human Kl as set forth in SEQ ID NO: 5. Klein teaches AAV8, AAV9 and AAV10 all are highly efficient for neuronal gene transfer and will be useful for basic proof of concept studies in animal model of neurodegenerative disease (see page 95, col. 1, para. 1). Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of ‘161 to modify the AAV comprising a nucleic acid sequence which encodes s-kl as disclosed in Gunther, Kyowa s-Kl to include use constitutive active promoter with different neurotropic AAV serotype such as AAV9, AAV9 or AAVrh10 as disclosed in Klein, in order to improve sustained expression of s-kl transgene expression in the CNS intended to treat or reduce oxidative stress in neurodegenerative disorder, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant. The method of claim 48 that uses a AAA comprising an expression promoter operably linked to a promoter encoding s-kl as recited in claims 48 is encompassed by the gene construct or AAV vector specifically claimed in the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 38, 65-67, 76-77, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim of copending Application No. 18773164 in view of Kyowa et al (JP2001072607, 3/21/2001, IDS) and Bergen et al (Pharmaceutical Research, Vol. 25, No. 5, 2008. 983-998).
Although the claims at issue are not identical, they are not patentably distinct from each other because the gene construct claimed in the instant application is explicitly used in the method claimed in ‘164. For instance, claims in the instant application is directed 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. Claims 65-66 are drawn to expression vector of claim 38 comprising lipoplex or a liposome or a nanoparticle. Claim 67 is directed to a pharmaceutical composition for treating or preventing a cognitive impairment disease comprising a therapeutically effective amount of the gene construct of claim 38 or an expression vector comprising the gene construct and a pharmaceutically acceptable excipient or carrier. The pharmaceutical composition further comprising an antioxidant, a buffer, a bacteriostat, a solute, or a combination of two or more thereof or suspending agent, a solubilizer, a thickening agent, a stabilizer, a preservative, or a combination of two or more thereof. In contrast, claims in ‘164 are directed to a method that uses 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. The ‘164 differs from claimed invention by not specifying pharmaceutical carrier or using lipoplex or liposome for delivery. However, before the effective filing date of instant application, Kyowa teaches that the expression vector comprises a liposome (see para. 12). Bergen teaches simple addition of polyanionic nucleic acids to mixtures of cationic lipids or liposomes results in their self-assembly into particles termed lipoplex. Kyowa teaches that the pharmaceutical composition comprising the vector could further include a sodium citrate (an antioxidant), buffering agents and isotonic agents including sodium chloride, glycine, glucose, or human albumin is used (see para. 20). It is further disclosed that composition, further comprising sodium chloride, potassium chloride, sodium citrate or preservative (see para. 20-21). Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of ‘164 to modify the vector comprising a nucleic acid sequence which encodes s-kl to include pharmaceutical carrier as disclosed in Kyowa or encapsule in liposome or lipoplex as disclosed in Bergen, in order to improve expression of s-kl transgene in the CNS intended to treat or reduce oxidative stress in neurodegenerative disorder, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Objections
Claims 56, 62-64, 72-75 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 56, 62-64, 72-75 are free of prior art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. GenBank accession no KT600161.1 cloning vector backbone and Xba1 restriction sequence site teaches 100% sequence identity to major part of the remining portion of vector backbone set forth in SEQ ID NO: 4, however, there is no motivation to choose additional element set forth in SEQ ID NO: 4. Therefore, SEQ ID NOL 4 is free of prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
Prosecution Insights