DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application/Amendments/Claims/RCE under 37 CFR 1.114
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1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 12/22/2025 has been considered.
Claim 2 has been canceled. Claim 1 has been amended. Claims 1, 3-11 and 14-15 are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 62/654,645 and CON of 16/379,440 filed on 4/9/2018 and 4/9/2019, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 4/9/2018.
Withdrawn Rejections
The 35 U.S.C. 103 rejection of claims 1-11 and 14-15 has been withdrawn light of applicants claim amendments which move the limitations of claims 2 into independent claim 1 describing the administration of the recombinant AAV vector to one or more CNS components. All previous 103 rejections have been re-applied in modified form to address applicants claim amendments.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1 and 3-11 are rejected in modified form under 35 U.S.C. 103 as being unpatentable over Ruegsegger et al. "Aberrant association of misfolded SOD1 with Na+/K+ ATPase-α3 impairs its activity and contributes to motor neuron vulnerability in ALS." Acta neuropathologica 131.3 (2016): 427-451 (hereinafter Ruegsegger, reference of record) as evidenced by Masoud et al. "Diagnosis and treatment of alternating hemiplegia of childhood." Current treatment options in neurology 19 (2017): 1-16 (hereinafter Masoud, reference of record) in view of Nathanson et al. "Short promoters in viral vectors drive selective expression in mammalian inhibitory neurons, but do not restrict activity to specific inhibitory cell-types." Frontiers in neural circuits 3 (2009): 19 (hereinafter Nathanson, reference of record), Guhasarkar et al. "A Walk on the Fine Line Between Reward and Risk: AAV-IFNβ Gene Therapy for Glioblastoma: A Dissertation." (2016) (hereinafter Guhasarkar, reference of record) and Gray et al. "Design and construction of functional AAV vectors." Adeno-Associated Virus. Humana Press, 2012. 25-46 (hereinafter Gray, reference of record). This rejection is newly applied to address applicants claim amendments submitted on 12/22/2025. A response to applicant’s traversal follows the reiterated rejection below.
Claim 1: Ruegsegger investigated the aberrant association of misfolded SOD1 with sodium/potassium-transporting ATPase subunit alpha-3 (Na+/K+ ATPase-α3; ATP1A3) and its role in contributing to motor neuron impairment in neurological disorders like amyotrophic lateral sclerosis (ALS) (Ruegsegger, abstract). Ruegsegger describes methods wherein lentiviral or adeno-associated viral (AAV) vectors like AAV6 containing nucleic acids encoding the full length ATP1A3 gene or mutated ATPase-α3 swap protein using a CMV promoter are administered to the central nervous system of diseased model mice, which resulted in a 10% improvement in Na+/K+ ATPase-α3 activity in the case of the mutated ATPase-α3 swap protein compared to the WT controls (Ruegsegger, pg 442 para 3, Fig 7 description, Fig 8, gels shown in Fig a and b). Ruegsegger describes the administration of the ATP1A3 encoding AAV vectors to human lumbar spinal cord samples and specifically mentions intraspinal administration which reads on administration to the cerebrospinal fluid (CSF) as described in newly amended claim 1 (Ruegsegger, pg 429 col 1). It is noted that although the methods of Ruegsegger are directed towards treating ALS via the targeted expression of ATP1A3, AHC is a closely related neurological disease caused by a similar mutation in the ATP1A3 gene. Masoud is provided as evidence showing the commonly known relationship between ATP1A3 mutations and AHC (Masoud, pg 8). Thus, one of ordinary skill would naturally look to apply the methods of Ruegsegger towards treating AHC given that they arise from the same aberrant gene. Ruegsegger does not describe the use of human neuron-specific promoters with a strong bias towards inhibitory neuron (PhSyn).
Claim 4: Ruegsegger describes the administration of the ATP1A3 encoding AAV vectors to human lumbar spinal cord samples (Ruegsegger, pg 429 col 1).
Claims 5: Ruegsegger describes the direct linkage of regulatory sequences such as promoters to ATP1A3 expression (Ruegsegger, abstract).
Claim 1: Nathanson describes the use of short promoters in transgenic AAV viral vectors which drive selective expression in mammalian inhibitory neurons (Nathanson, abstract). In table 2, Nathanson outlines numerous human neuron-specific promoters with a strong bias towards inhibitory neurons and artificial composite promoters which are compatible with transgenic AAV vectors (Nathanson, Table 2). In particular, Nathanson describes the use of a human synapsin promoter (hSYN) which is a ubiquitous neuronal promoter (Nathanson, pg 12 col 1, pg 10 col 1 and Table 2 row 1). As noted in table 2, AAV-hSYN showed both excitatory and inhibitory neuronal expression. Nathanson outlines transgenic viral construct design and production methods (Nathanson, Materials and Methods, pg 3). Nathanson states that many of these promoters would be useful in constructing transgenic AAV vectors for use in gene therapy against targets with specific expression in neurons (Nathanson, Introduction para 3 and Discussion). Nathanson describes methods for designing constructs which express red or yellow fluorescent protein (YFP and RFP, respectively) reporter constructs in order to examine expression in vivo (Nathanson, Design of Mammalian Reporter constructs and Fig 2).
It would have been prima facie obvious to one of ordinary skill in the art to use a synapsin promoter as described by Nathanson in the AAV construct encoding ATP1A3 as descried by Ruegsegger for the targeted expression of ATP1A3 in neurons of the central nervous system as a treatment for AHC. It would have been a matter of simple substitution of one known promoter element (CMV promoter as described by Ruegsegger) for another (synapsin promoter as described by Nathanson) to obtain predictable results. In particular, one would have been motivated to make this substitution with respect to the synapsin promoter in order to drive ATP1A3 expression in GABAergic inhibitory neurons and minimize off target expression, thus increasing clinical efficacy in treating ATP1A3 related diseases like AHC and ALS. One would have a reasonable expectation of success given the relative interchangeability of different promoters in AAV constructs as shown by Nathanson.
Neither Ruegsegger nor Nathanson describe the use of AAV9 vectors or direct administration into the brain (intracisternal) or spine (intrathecal). Neither Ruegsegger nor Nathanson describe the use of a 3’ UTR rabbit beta-globin polyadenylation (rBGpA) signal sequence.
Claim 1: Guhasarkar describes the systemic infusion of AAV9-IFNβ vectors into the central nervous system as a method for treating highly invasive glioblastoma (Guhasarkar, abstract). Guhasarkar observed efficient transgene expression and high therapeutic efficacy in the central nervous system (Guhasarkar, Fig 4).
Claims 8-10: Guhasarkar describes AAV9 viral constructs carrying a rabbit beta-globin polyadenylation (rBGpA) signal (Guhasarkar, Materials and methods – AAV Vector Design).
Claims 3 and 11: Guhasarkar describes the systemic infusion of single-stranded AAV9 vectors to achieve widespread gene delivery into the CNS of mice, including intracranial administration which reads directly on intracerebroventricular injection (Guhasarkar, pg 1509).
Claims 6-7: Gray describes the routine use of Kozak and 3’-UTR polyadenylation sequence as standard elements in an AAV expression constructs (Gray, Fig 1 and pg 27).
It would have been prima facie obvious to one of ordinary skill in the art to use an AAV9 serotype viral vector as described by Guhasarkar instead of the AAV6 or rAAV2/1 as described by Ruegsegger and Nathanson, respectively, for the delivery of ATP1A3 into the central nervous system. It would have been a matter of simply substituting AAV9 for the AAV6 vector described by Ruegsegger to achieve predictable results. One would be motivated to try an AAV9 serotype with the method for delivering ATP1A3 identified in Ruegsegger since Guhasarkar shows that AAV9 is an effective vector platform for the systemic delivery into the central nervous system. One would have a reasonable expectation of success given the relative similarity between construct designs and methodologies for AAV9, AAV6 or rAAV2/1 serotypes.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art to incorporate a rBGpA regulatory sequence as described by Guhasarkar to create a AAV9/ PhSyn - ATP1A3 cDNA- rBGpA comprising vector for treating AHC. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Guhasarkar shows rBGpA is an effective 3’-UTR sequence for expression in the central nervous system. One would be motivated to make this combination given the relatively small size and proven effectiveness of the 127 bp rBGpA 3’-UTR sequence in AAV9 mediated gene therapy into the central nervous system as shown by Guhasarkar. One would have a reasonable expectation of success given the relative interchangeability of 3’-UTR elements into AAV vector constructs. Furthermore, the inclusion of a Kozak and 3’-UTR polyadenylation sequence are standard elements in an AAV expression construct as shown by Gray (Gray, Fig 1 and pg 27).
Response to Traversal
Applicant traverses the instant rejection by pointing to the new claim amendments to independent claim 1 which describe directly administering the claimed composition to one or more specific CNS components. Applicant argues that one skilled in the art would not have been motivated to substitute the CMV promoter as disclosed by Ruegsegger with the hSyn promoter disclosed by Nathanson with a reasonable expectation of success in driving the CNS-specific expression of ATP1A3. Applicant argues that Nathanson outlines numerous human neuron-specific promoters with a strong bias towards inhibitory neurons which is not an exhaustive list and describes the unpredictability associated with promoter selection and expression. Applicant states that Ruegsegger discloses the use of a CMV promoter with AAV6 vector to express ATP1A3 that functions as part of a heterotrimeric complex, which is different to that of Nathanson. Thus, one of ordinary skill would not have been motivated to select a human synapsin promoter to combine with an AAV9 vector to arrive at the claimed invention.
This argument has been fully considered but is not found persuasive since Nathanson expressly describes the use of a human synapsin promoter (hSYN) which is a ubiquitous neuronal promoter (Nathanson, pg 12 col 1, pg 10 col 1 and Table 2 row 1). As noted in table 2, AAV-hSYN showed both excitatory and inhibitory neuronal expression. Although it may be true that Nathanson describes other promoters, it is emphasized that nonpreferred and alternative embodiments constitute prior art. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure, see MPEP 2123. The argument is that it would have been a matter of simple substitution of one known promoter element (CMV promoter as described by Ruegsegger) for another (synapsin promoter as described by Nathanson) to obtain predictable results. In particular, one would have been motivated to make this substitution with respect to the synapsin promoter in order to drive ATP1A3 expression in GABAergic inhibitory neurons and minimize off target expression, thus increasing clinical efficacy in treating ATP1A3 related diseases like AHC and ALS. One would have a reasonable expectation of success given the relative interchangeability of different promoters in AAV constructs as shown by Nathanson. Furthermore, with respect to the new claim amendments, it is argued that Ruegsegger describes the administration of the ATP1A3 encoding AAV vectors to human lumbar spinal cord samples and specifically mentions intraspinal administration which reads on administration to the cerebrospinal fluid (CSF) as described in newly amended claim 1 (Ruegsegger, pg 429 col 1). Similarly, Guhasarkar describes the systemic infusion of single-stranded AAV9 vectors to achieve widespread gene delivery into the CNS of mice, including intracranial administration which reads directly on intracerebroventricular injection (Guhasarkar, pg 1509)
Applicant further argues that Guhasarkar does not describe an effective AAV9 vector for delivery into the central nervous system or an AAV9-ATP1A3 construct for delivery into the central nervous system. Applicant argues that the disclosure of Guhasarkar shows peripheral organ transduction to treat glioblastomas and therefore one of ordinary skill in the art would not have a motivation to combine the teachings of the cited prior art. Applicant traverses the instant rejection by pointing to the new claim amendments to independent claim 1 which describe directly administering the claimed composition to one or more specific CNS components.
This argument has been fully considered but is not found persuasive since Fig 4 of Guhasarkar clearly shows efficient transgene expression in the brain (Guhasarkar, Fig 4). Thus, it would have been prima facie obvious to one of ordinary skill in the art to use an AAV9 serotype viral vector as described by Guhasarkar instead of the AAV6 or rAAV2/1 as described by Ruegsegger and Nathanson, respectively, for the delivery of ATP1A3 into the central nervous system. It would have been a matter of simply substituting AAV9 for the AAV6 vector described by Ruegsegger to achieve predictable results. Furthermore, Ruegsegger describes the administration of the ATP1A3 encoding AAV vectors to human lumbar spinal cord samples and specifically mentions intraspinal administration which reads on administration to the cerebrospinal fluid (CSF) as described in newly amended claim 1 (Ruegsegger, pg 429 col 1). One cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references, see MPEP 2145.
Applicant further argues that Ruegsegger only teaches the use of a CMV promoter, which is non-selective and drives a high level of expression in all cell types. Applicant argues that the small size of CMV makes it easy to fit within the viral vector used by Ruegsegger and that the selection of promoters by Nathanson was based on their ability to drive expression of small soluble cytosolic proteins whereas the claimed invention is directed to larger transmembrane proteins.
This argument has been fully considered but is not found persuasive since there is no evidence of inoperability. One of ordinary skill in the art would expect the a synapsin promoter as described by Nathanson to work equally well in the AAV construct encoding ATP1A3 as descried by Ruegsegger for the targeted expression of ATP1A3 in neurons of the central nervous system as a treatment for AHC given its selectivity for neuronal cell expression. Attorney arguments do not replace evidence where evidence is necessary, see MPEP 2145.
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Ruegsegger (supra), Masoud (supra), Nathanson(supra), Guhasarkar (supra) and Gray (supra) as applied to claims 1 and 3-11 above in further view of Doyon et al. WO 2018/039783, published 3/8/2018 (hereinafter Doyon, reference of record). This rejection is newly applied to address applicants claim amendments submitted on 12/22/2025. A response to applicant’s traversal follows the reiterated rejection below.
A description of Ruegsegger, Masoud, Nathanson, Guhasarkar and Gray can be found above. The collection of cited art does not describe a method wherein the an AAV vector comprises SEQ IDs 5-6.
Claim 14: Nathanson outlines numerous human neuron-specific promoters including the use of a human synapsin promoter (hSYN), which is a ubiquitous neuronal promoter (Nathanson, pg 12 col 1, pg 10 col 1 and Table 2 row 1).
Claim 15: Doyon discloses a human ATP1A3 wild-type ORF cDNA and gene delivery methods thereof (Doyon, pg 3 and 62; SEQ ID NO: 461, sequence alignment shown below).
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It is noted that SEQ ID NO 5 corresponds to “PhSyn-ATP1A3 cDNA-rBGpA” and SEQ ID NO 6 corresponds to “ATP1A3 ORF”. Since all of the elements of these sequences were known in the prior art and there exists motivation to combine along with a reasonable expectation of success, is considered prima facie obvious for one of ordinary skill to use an AAV vector comprising one of SEQ IDs 5-6 as a treatment for AHC. Motivation to use different promoters comes from the need to modulate levels of ATP1A3 expression in select tissues of the CNS. There exists a reasonable expectation of success given that all of the elements of these sequences were known individually and combinations thereof flow logically from there having been individually taught in the prior art. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the elected invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the instant rejection by arguing generally that the collection of cited art fails to teach the claimed method. Applicant cites Hunanyan to show evidence of unexpected results wherein “components of the claimed method” are administered directly into the CNS, resulting in a robust CNS-specific expression and minimal peripheral expression (Hunanyan, Fig 4G).
This argument has been fully considered but is not found persuasive since unexpected results are the result of unexpected improved results or a property not taught by the prior art, the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support, see MPEP 716.02(d). Although components of the vector disclosed by Hunanyan may be similar to the claimed invention, the administration conditions and exact vector composition do not appear to be commensurate in scope with the claims.
Nonstatutory 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 Langi, 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 706.02(1)(1) - 706.02(1)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 5-11 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US Patent No. 11,738,093 in view of Masoud (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims would anticipate the instant claims if they were available as prior art. This rejection is newly applied to address applicants claim amendments submitted on 12/22/2025. A response to applicant’s traversal follows the reiterated rejection below.
Claim 1: The patented claims describe a composition comprising a rAAV9 vector encoding a ATP1A3 protein and a promoter specific to the CNS encoded by one of SEQ ID Nos: 3-5 (claim 1). SEQ ID NO 5 from the patented claims corresponds to “PhSyn-ATP1A3 cDNA-rBGpA” which encompasses the AAV vector components of the present invention. Masoud is presented as a reference to show the known linkage between ATP1A3 and methods for treating AHC. Thus, it is considered obvious to apply the composition of the patented claims as a treatment for AHC given the disclosure of Masoud.
Claims 5-11: The patented claims describe the use of rBGpA polyadenylation signals (claims 8-9). The patented claims describe the use of ribosomal binding and Kozak sequences (claims 5 and 6). The patented claims describe the use of single stranded AAV9 genomes (claim 10).
Claim 14: SEQ ID No: 5 is identical to the patented invention wherein SEQ ID NO 5 corresponds to “PhSyn-ATP1A3 cDNA-rBGpA” (Claims 1 and 11-13).
Response to Traversal
Applicant argues that a terminal disclaimer has been provided.
The examiner is unable to locate the referenced terminal disclaimer in the prosecution record. Applicant is advised to resubmit. The rejection is maintained accordingly.
Conclusion
No claims allowed.
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Alexander Nicol
Patent Examiner
Art Unit 1633
/ALEXANDER W NICOL/Examiner, Art Unit 1634
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