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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-16 and 39-42, in the reply filed on 03 March 2026 is acknowledged.
Claims 17-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 03 March 2026.
Claim Status
Claims 1-42 are pending, claims 15-16 have been amended, claims 17-38 have been withdrawn, and claims 1-16 and 39-42 have been considered on their merits.
Specification
The disclosure is objected to because of the following informalities: at page 2, lines 14-15 of the specification identifies SEQ ID NO: 2 as an exemplary amino acid sequence, however, this sequence is a nucleic acid sequence. Similarly, at page 4, lines 5-6, the specification identifies the polynucleotides of SEQ ID NO: 3 and amino acid sequence of SEQ ID NO: 4, however, these are amino acid and nucleic acid sequences respectively.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Appropriate correction is required.
Claim Interpretation
Claim 15 includes the limitation “inclusive” at the end of the claim. This limitation is understood to mean the recombinant AAV viral particles copy number includes the beginning and end values of the range.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7-8 and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 depends from claim 5 and recites the limitation “…an AAV serotype capsid”, in the second line of the claim. It is unclear whether the capsid listed in this claim is the same or different than the capsid of claim 5, due to the article “an” preceding AAV serotype capsid.
Claim 8 depends from claim 7 and does not remedy the issue.
Claim 12 recites the limitation, “The recombinant AAV viral particle of claim 10, wherein the recombinant AAV viral particle of claim 1…”. It is unclear how the limitation regarding claim 1 is limiting the claim and is being regarded as a typo. Since claim 12 depends from claim 10, which already comprises the recombinant AAV viral particle of claim 1, the claim is interpreted as the recombinant AAV viral particle of claim 10, wherein the SMN1 transgene is operably linked to the human synapsin 1 gene promoter (SYN).
The language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds". See, e.g., the following decisions: In re Hammack, 427 F 2d. 1378, 1382, 166 USPQ 204, 208 (CCPA 1970); In re Venezia 530 F 2d. 956, 958, 189 USPQ 149, 151 (CCPA 1976); In re Goffe, 526 F 2d. 1393, 1397, 188 USPQ 131, 135 (CCPA 1975); In re Watson, 517 F 2d. 465, 477, 186 USPQ 11, 20 (CCPA 1975); In re Knowlton 481 F 2d. 1357, 1366, 178 USPQ 486, 492 (CCPA 1973).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7-8 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7, which depends from claim 5, requires an AAV capsid from any one phylogenetic Clades A-F. This limitation is broader than the list of capsids found in claim 5, as Clades A-F encompass all AAV capsid serotypes. Dependent claim 8 does not remedy this and thus is included as well.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 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.
Claims 1, 5-7, 10-11, and 13-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shi et al. (Neuromuscular Disorders, Vol. 32, Supplement 1, Page S62, October 2022), hereinafter Shi 2022.
Although Shi 2022 (Neuromuscular Disorders, Vol. 32, Supplement 1, Page S62, October 2022) cited above lists the inventors as three of the six authors of the reference, it is still applicable as prior art under 35 U.S.C. 102(a)(1).
Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection under 35 U.S.C. 102(a)(1) by a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1). Alternatively, applicant may rely on the exception under 35 U.S.C. 102(b)(1)(B) by providing evidence of a prior public disclosure via an affidavit or declaration under 37 CFR 1.130(b).
Regarding claims 1 and 10, Shi 2022 teaches treating mice with spinal muscular atrophy (SMA) comprising injecting SMA mice with AAV9-DLC-i1 (AAV vector comprising DLC1-i1 transgene) (claim 1) together with AAV9-SMN (reads as separate vector) (claim 10) (Abstract).
Regarding claims 5-7, the AAV9 vector of Shi 2022 reads as an AAV9 capsid.
Regarding claim 11, Shi 2022 is silent to the promoters used on the AAV9 vectors, however, the claim allows for the promoter to be the same or different. Therefore, Shi 2022 reads on the limitations of the claim, as promoters would necessarily be present in an expression vector and the promoters could be the same or different.
Regarding claim 13, Shi 2022 teaches administering the AAV particle of claim 1 to a subject (claim 13(a)) (Abstract). The limitation of claim 13(b) would necessarily be present as a pharmaceutically acceptable excipient for administration would be required for administration.
Regarding claim 14, Shi 2022 teaches administering an AAV particle comprising a SMN1 transgene (Abstract). Shi 2022 is silent to the promoter of said AAV particle expressing the SMN1 transgene, however, this limitation is optional, as such not required by the claim.
Thus, the reference anticipates the subject matter of claims 1, 5-7, 10-11, and 13-14.
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 (i.e., changing from AIA to pre-AIA ) 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2-3, 8-9, 12, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Shi 2022 (Neuromuscular Disorders, Vol. 32, Supplement 1, Page S62, October 2022) as applied to claims 1, 5-7, 10-11, and 13-14 above, and further in view of Nathanson et al. (Neuroscience 161(2): 441-450, 30 June 2009, IDS ref.) as evidenced by Nieuwenhuis et al. (Gene Therapy (2021) 28:56-74).
Shi 2022 anticipate the subject matter of claims 1, 5-7, 10-11, and 13-14, and thus, also render them obvious.
Regarding claims 2, 3, and 12, Shi 2022 is silent to the promoter utilized in the vectors expressing the DLC1-i1 transgene and the SMN1 transgene.
However, Nathanson teaches recombinant AAV vectors for transducing cortical neurons (Abstract). Nathanson teaches viral promoters to include the human synapsin I (hSyn) promoter (claims 2 and 3) (p. 2, Experimental Procedures).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the hSyn promoter of Nathanson with the vectors of Shi 2022 with a reasonable expectation of success because Nathanson teaches it is desirable to have the ability to generate cell type specific expression from viral vectors and the hSyn promoter was demonstrated to express transgenes in neurons (p. 2, Introduction). One would be motivated to utilize the hSyn promoter of Nathanson with the vector of Shi 2022 because the hSyn promoter is effective at expressing transgenes in the corticospinal tract, as evidenced by Nieuwenhuis (Abstract) and Shi 2022 teaches treating mice with spinal muscular atrophy (SMA) by administering AAV9-DLC1-i1 together with AAV9-SMN which resulted in synergistic improvement of their motor activity and lifespan (Abstract). Thus, would be obvious to utilize the hSyn promoter to express both the DLC1-i1 and SMN1 transgene (claim 12).
Regarding claims 8-9, Shi 2022 is silent to the ITR utilized in the vector.
However, Nathanson teaches components of the AAV include AAV2 ITR (p. 2, Experimental Procedures).
It would have been obvious to one of ordinary skill in the art to utilized the AAV2 ITR of Nathanson in the vector of Shi 2022 with a reasonable expectation of success because it is well known in the art to utilize AAV2 ITR in viral gene therapy vectors. One would be motivated to utilized the AAV2 ITR of Nathanson in the vector of Shi 2022 because the vector of Nathanson was able to successfully express transgenes in the targeted cells.
Regarding claim 15, Nathanson teaches the genomic titer of the rAAV2/1-hSyn-RFP in a 1:1 ratio was 8.4 x 1012 (Table 1, row 1), which falls in the range of 2.5 x 1012 and 5 x 1013 genome copies.
Regarding claim 16, Nathanson teaches administering the vector to mice, which are approximately 25 grams (0.025 kg). Therefore, the genomic titer of Nathanson, 8.4 x 1012, when considering the weight of the subject equates to approximately 3.36 x 1014 which is greater than the required at least 5 x 1013.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Shi 2022 (Neuromuscular Disorders, Vol. 32, Supplement 1, Page S62, October 2022) as applied to claims 1, 5-7, 10-11, and 13-14 above, and further in view of Low et al. (Oncogene. 2011 April 21; 30(16): 1923-1935).
Shi 2022 anticipate the subject matter of claims 1, 5-7, 10-11, and 13-14, and thus, also render them obvious.
Regarding claim 4, Shi 2022 teaches the AAV vector comprising DLC1-i1, however, is silent to the sequence of said vector.
Low teaches a sequence of DLC1-i1, which is 100% identical to instant SEQ ID NO: 3. See file us-18-170-296-3.rup, Result 1, in the sequence search results found in the file wrapper.
In regards to SEQ ID NO: 3, Applicant should note that that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
In the instant case, a person of ordinary skill in the art would have been motivated to utilize the amino acid sequence corresponding to DLC1-i1 because Low teaches the sequence with 100% identity and indicates that different DLC1 isoforms may have different functional specialization in cellular homeostasis (p. 7, Discussion).
Furthermore, because, as above, Low teaches the amino acid sequence that is 100% identical to the claim sequence, and Low teaches transfecting cells with DLC1-i1 (p. 6, Results), and because Shi 2022 and Low are in the same technical field of gene therapy, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Shi 2022 (Neuromuscular Disorders, Vol. 32, Supplement 1, Page S62, October 2022) in view of Chauchereau et al. (WO 2011/124669 A1, published 13 October 2011) and Addgene Catalog number: 504465 (see Addgene Catalog) hereinafter Addgene.
The teachings of Shi 2022 have been set forth above.
Regarding claims 39 and 40, while SEQ ID NO: 10 was not known in the prior art, it would be considered obvious to arrive at these sequences considering SEQ ID NO: 2 and 7 were both known in the art and Shi 2022 teaches a vector comprising the DLC1-i1 transgene.
Regarding SEQ ID NO: 10, instant SEQ ID NO: 10 has been identified as the combination of pAAV-hSyn-EGFP (instant SEQ ID NO: 7) and a portion of the cDNA of DLC1-i1 (instant SEQ ID NO: 2). Specifically, inserting nucleic acids 209-4797 of SEQ ID NO: 2 at nucleic acid 646 of SEQ ID NO: 7, equates to SEQ ID NO: 10, absent evidence to the contrary.
Chauchereau teaches SEQ ID NO: 12, which is 100% identical to nucleic acids 209-4797 of instant SEQ ID NO: 2. See sequence search results file us-18-170-296-2.rng, Result 4 in the file wrapper.
Regarding SEQ ID NO: 7, the instant specification has identified the exemplary scaffold vector, pAAV-hSyn-EGFP, Addgene catalog number 504465 which has been available since 17 March 2014.
In regards to SEQ ID NO: 10, the combination of sequences disclosed by Chauchereau and disclosure of Addgene comprise instant SEQ ID NO: 10, Applicant should note that that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
In the instant case, a person of ordinary skill in the art would have been motivated to clone the cDNA corresponding to DLC1-i1 because the combination of sequences taught by Chauchereau and Addgene with 100% identity and Addgene indicates that the plasmid comprises the hSyn promoter which has been identified as a tissue specific promoter for the CNS.
Furthermore, because, as above, Chauchereau and Addgene teach nucleic acid sequences that are 100% identical to the claim sequence, because Shi 2022 teaches a vector expressing the transgene DLC1-i1, and because Shi 2022 and Addgene are in the same technical field of gene therapy, it could have been done with predictable results and a reasonable expectation of success.
Regarding claim 41, Shi 2022 teaches treating mice with spinal muscular atrophy (SMA) comprising injecting SMA mice with AAV9-DLC-i1 (Abstract). The teachings of Shi 2022 would result in a cell comprising the recombinant viral particle of claim 40.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Shi 2022 (Neuromuscular Disorders, Vol. 32, Supplement 1, Page S62, October 2022), Chauchereau et al. (WO 2011/124669 A1, published 13 October 2011), and Addgene Catalog number: 504465 (see Addgene Catalog) hereinafter Addgene as applied to claims 39-41 above, and further in view of Passini et al. (WO 2014/178863 A1, published 06 November 2014).
Regarding claim 42, while SEQ ID NO: 11 was not known in the prior art, it would be considered obvious to arrive at these sequences considering SEQ ID NO: 4 and 7 were both known in the art and Shi 2022 teaches vectors comprising both the DLC1-i1 and SMN1 transgenes.
Regarding SEQ ID NO: 11, instant SEQ ID NO: 11 has been identified as comprising pAAV-hSyn-EGFP (instant SEQ ID NO: 7) and a portion of the sequence encoding the SMN1 gene (instant SEQ ID NO: 4), absent evidence to the contrary.
Passini teaches SEQ ID NO: 2, which is 100% identical to instant SEQ ID NO: 4. See sequence search results file us-18-170-296-4.rngb, Result 1 in the file wrapper.
In regard to SEQ ID NO: 11, the combination of sequences disclosed by Passini and disclosure of Addgene comprise instant SEQ ID NO: 11, Applicant should note that that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
In the instant case, a person of ordinary skill in the art would have been motivated to clone the cDNA corresponding to SMN1 because the SEQ ID NO: 11 comprises the combination of sequences taught by Passini and Addgene and Addgene indicates that the plasmid comprises the hSyn promoter which has been identified as a tissue specific promoter for the CNS.
Furthermore, because, as above, SEQ ID NO: 11 comprises the combination of sequences of Passini and Addgene, and Shi 2022 teaches a vector expressing the transgene DLC1-i1 and SMN1, and because Shi 2022, Passini, and Addgene are in the same technical field of gene therapy, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 1, 5-7, 10-11, and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (Conference paper Abstract: Elucidating the rold of DLC1 Isoform 1 in Human Motor Neuron Development and Spinal Muscular Atrophy, published 18 June 2021) hereinafter Shi 2021, and further in view of Li et al. (Human Gene Therapy, Volume 34, Numbers 5 and 6, published 10 Feb 2023).
Regarding claim 1, Shi 2021 teaches Deleted in Liver Cancer 1 (DLC1) is the most down-regulated gene in motor neurons (MNs) derived from a spinal muscular atrophy (SMA) patient, wherein knockdown of DLC1-i1 led to a reduction in MN formation, axonal outgrowth and increase apoptosis, whereas overexpression of DLC1-i1 promoted MN differentiation with extensive axonal outgrowth (Abstract). Importantly, SMN knockdown (KD) not only caused MN loss but also intron retention of DLC1-i1, resulting in downregulation of DLC1-i1 expression (Abstract). The teachings of Shi 2021 demonstrate the relationship between the DLC1-i1 gene to the SMN gene as it relates to SMA.
However, Shi 2021 is silent to an AAV viral particle comprising a vector encoding a DLC1-i1 transgene.
Li teaches spinal muscular atrophy (SMA) treatment with AAV9 and SMN1 transgene (Abstract). Li teaches the onasemnogene abeparvovec, brand name Zolgensma®, is an FDA approved treatment for SMA comprising AAV9 mediated gene replacement therapy which creates a copy of the human SMN1 gene under the control of a CBA promoter (Abstract and Table 1). Li teaches AAVs are the first choice for targeting alpha spinal motor neurons in viral gene therapy, specifically AAV9 because it targets the central nervous system (CNS) (p. 184, Gene therapy, 1st column).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the AAV9 vector of Li to express the DLC-i1 gene of Shi 2021 with a reasonable expectation of success because Li teaches AAVs are the first choice for targeting alpha spinal motor neurons in viral gene therapy, specifically AAV9 because it targets the CNS. One would be motivated to utilize the AAV9 vector of Li to express the DLC-i1 gene of Shi 2021 because Shi 2021 teaches Deleted in Liver Cancer 1 (DLC1) is the most down-regulated gene in MNs derived from a spinal muscular atrophy (SMA) patient and the teachings of Shi 2021 demonstrate the relationship between the DLC1-i1 gene to the SMN gene as it relates to SMA, thus making DLC1-i1 an obvious target for gene therapy for treating SMA.
Regarding claims 5-7, Li teaches the AAV9 serotype (claim 5 and 6) was used to deliver the transgene (Abstract). AAV9 belongs to clade F (claim 7), which reads as any one of phylogenetic clades A-F.
Regarding claim 10, Li teaches an AAV9 vector encoding the SMN1 transgene (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the AAV9 vector of Li to express both the DLC-i1 and SMN1 genes of Shi 2021 with a reasonable expectation of success because Li teaches AAVs are the first choice for targeting alpha spinal motor neurons in viral gene therapy, specifically AAV9 because it targets the CNS. One would be motivated to utilize the AAV9 vector of Li to express the DLC-i1 and SMN1 genes suggested by Shi 2021 because Shi 2021 teaches Deleted in Liver Cancer 1 (DLC1) is the most down-regulated gene in MNs derived from a spinal muscular atrophy (SMA) patient and the teachings of Shi 2021 demonstrate the relationship between the DLC1-i1 gene to the SMN gene as it relates to SMA, thus an obvious deliver both transgenes for treating SMA.
Regarding claim 11, Li teaches spinal muscular atrophy (SMA) treatment with AAV9 and SMN1 transgene wherein the SMN1 gene is under the control of a CBA promoter (Abstract and Table 1). Claims 1 and 10 from which claim 11 ultimately depends does not require a specific promoter for the expression of the DLC1-i1 transgene, although, it is understood that for expression of a transgene a promoter would be required. Additionally, the claim allows for the promoter to be the same or different from that of the DLC1-i1 transgene. Therefore, the teachings of Li teach the SMN1 transgene is expressed by a promoter, which read on the limitations of the claim.
Regarding claim 13, Shi 2021 in view of Li teach administering the AAV particle of claim 1 to a subject (claim 13(a)) (Abstract). The limitation of claim 13(b) would necessarily be present as a pharmaceutically acceptable excipient for administration would be required for administration.
Regarding claim 14, Shi 2021 in view of Li teach administering an AAV particle comprising a SMN1 transgene (Abstract). The SMN1 transgene operably linked to a SYN promoter is an optional limitation, as such not required by the claim.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 2-3, 8-9, 12, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Shi 2021 (Conference paper Abstract: Elucidating the rold of DLC1 Isoform 1 in Human Motor Neuron Development and Spinal Muscular Atrophy, published 18 June 2021) in view of Li et al. (Human Gene Therapy, Volume 34, Numbers 5 and 6, published 10 Feb 2023) as applied to claims 1, 5-7, 10-11, and 13-14 above, and further in view of Nathanson et al. (Neuroscience 161(2): 441-450, 30 June 2009, IDS ref.) as evidenced by Nieuwenhuis et al. (Gene Therapy (2021) 28:56-74) and Zolgensma® data sheet (retrieved from www.ema.europa.eu/en/documents/product-information/zolgensma-epar-product-information_en.pdf) hereinafter Zolgensma.
Regarding claims 2-3, and 12, Shi 2021 in view of Li do not teach the transgenes are operably linked to the human Syn promoter, human β-glucuronidase promoter, or the CAG promoter.
However, Nathanson teaches recombinant AAV vectors for transducing cortical neurons (Abstract). Nathanson teaches viral promoters human synapsin I (hSyn) (claims 2, 3, 12) (p. 2, Experimental Procedures).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the promoter of Nathanson with the vectors of Shi 2021 in view of Li with a reasonable expectation of success because Nathanson teaches it is desirable to have the ability to generate cell type specific expression from viral vectors and the hSyn promoter was demonstrated to express transgenes in neurons (p. 2, Introduction). One would be motivated to utilize the promoter of Nathanson with the vectors of Shi 2021 in view of Li because the hSyn promoter is effective at expressing transgenes in the corticospinal tract, as evidenced by Nieuwenhuis (Abstract) and Shi 2021 in view of Li teach treating SMA treatment with AAV9 and SMN1 transgene (claim 12) and also suggest the DLC1-i1 transgene (claims 2 and 3).
Regarding claims 8-9, Shi 2021 in view of Li are silent to the ITR utilized in the vector.
However, Nathanson teaches components of the AAV include AAV2 ITR (p. 2, Experimental Procedures).
It would have been obvious to one of ordinary skill in the art to utilized the AAV2 ITR of Nathanson in the vector of Shi 2021 in view of Li with a reasonable expectation of success because it is well known in the art to utilize AAV2 ITR in gene therapy vectors. One would be motivated to utilized the AAV2 ITR of Nathanson in the vector of Shi 2021 in view of Li because the vector of Nathanson was able to successfully express transgenes in the targeted cells.
Regarding claims 15 and 16, Li teaches the onasemnogene abeparvovec, brand name Zolgensma®, wherein the composition comprises 2 x 1013 vector genomes/mL (claim 15) solution for infusion (as evidenced by Zolgensma, p. 2, section 2.2), wherein patients received a dose of nominal 1.1 x 1014 vg/kg onasemnogene abeparvovec (claim 16) (as evidenced by Zolgensma, p. 3, Posology).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Shi 2021 (Conference paper Abstract: Elucidating the rold of DLC1 Isoform 1 in Human Motor Neuron Development and Spinal Muscular Atrophy, published 18 June 2021) in view of Li et al. (Human Gene Therapy, Volume 34, Numbers 5 and 6, published 10 Feb 2023) as applied to claims 1, 5-7, 10-11, and 13-14 above, and further in view of Low et al. (Oncogene. 2011 April 21; 30(16): 1923-1935).
Regarding claim 4, Shi 2021 in view of Li render obvious the recombinant AAV viral particle of claim 1, however, are silent to the sequence of said vector.
Low teaches a sequence of DLC1-i1, which is 100% identical to instant SEQ ID NO: 3. See file us-18-170-296-3.rup, Result 1, in the sequence search results found in the file wrapper.
In regards to SEQ ID NO: 3, Applicant should note that that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
In the instant case, a person of ordinary skill in the art would have been motivated to utilize the amino acid sequence corresponding to DLC1-i1 because Low teaches the sequence with 100% identity and indicates that different DLC1 isoforms may have different functional specialization in cellular homeostasis (p. 7, Discussion).
Furthermore, because, as above, Low teaches an amino acid sequence that is 100% identical to the claim sequence, because Low teaches transfecting cells with DLC1-i1 (p. 6, Results), and because Shi 2021 in view of Li and Low are in the same technical field of gene therapy, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 39-41 are rejected under 35 U.S.C. 103 as being unpatentable Shi 2021 (Conference paper Abstract: Elucidating the rold of DLC1 Isoform 1 in Human Motor Neuron Development and Spinal Muscular Atrophy, published 18 June 2021), in view of Li et al. (Human Gene Therapy, Volume 34, Numbers 5 and 6, published 10 Feb 2023), Chauchereau et al. (WO 2011/124669 A1, published 13 October 2011), and Addgene Catalog number: 504465 (see Addgene Catalog) hereinafter Addgene.
The teachings of Shi 2021 and Li have been set forth above.
Regarding claims 39 and 40, while SEQ ID NO: 10 was not known in the prior art, it would be considered obvious to arrive at these sequences considering SEQ ID NO: 2 and 7 were both known in the art and Shi 2021 in view of Li teaches a vector comprising the DLC1-i1 transgene.
Regarding SEQ ID NO: 10, instant SEQ ID NO: 10 has been identified as the combination of pAAV-hSyn-EGFP (instant SEQ ID NO: 7) and a portion of the cDNA of DLC1-i1 (instant SEQ ID NO: 2). Specifically, inserting nucleic acids 209-4797 of SEQ ID NO: 2 at nucleic acid 646 of SEQ ID NO: 7, equates to SEQ ID NO: 10, absent evidence to the contrary.
Chauchereau teaches SEQ ID NO: 12, which is 100% identical to nucleic acids 209-4797 of instant SEQ ID NO: 2. See sequence search results file us-18-170-296-2.rng, Result 4 in the file wrapper.
Regarding SEQ ID NO: 7, the instant specification has identified the exemplary scaffold vector, pAAV-hSyn-EGFP, Addgene catalog number 504465 which has been available since 17 March 2014.
In regards to SEQ ID NO: 10, the combination of sequences disclosed by Chauchereau and disclosure of Addgene comprise instant SEQ ID NO: 10, Applicant should note that that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
In the instant case, a person of ordinary skill in the art would have been motivated to clone the cDNA corresponding to DLC1-i1 because the combination of sequences taught by Chauchereau and Addgene with 100% identity and Addgene indicates that the plasmid comprises the hSyn promoter which has been identified as a tissue specific promoter for the CNS.
Furthermore, because, as above, Chauchereau and Addgene teaches nucleic acid sequences that are 100% identical to the claim sequence, because Shi 2021 in view of Li teaches a vector expressing the transgene DLC1-i1, and because Shi 2021 in view of Li and Addgene are in the same technical field of gene therapy, it could have been done with predictable results and a reasonable expectation of success.
Regarding claim 41, Li teaches spinal muscular atrophy (SMA) treatment with AAV9 and SMN1 transgene (Abstract). The teachings of Li would result in a cell comprising the recombinant viral particle of claim 40.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable Shi 2021 (Conference paper Abstract: Elucidating the rold of DLC1 Isoform 1 in Human Motor Neuron Development and Spinal Muscular Atrophy, published 18 June 2021) in view of Li et al. (Human Gene Therapy, Volume 34, Numbers 5 and 6, published 10 Feb 2023), Chauchereau et al. (WO 2011/124669 A1, published 13 October 2011), and Addgene Catalog number: 504465 (see Addgene Catalog) hereinafter Addgene, as applied to claims 39-41 above, and further in view of and further in view of Passini et al. (WO 2014/178863 A1, published 06 November 2014).
Regarding claim 42, while SEQ ID NO: 11 was not known in the prior art, it would be considered obvious to arrive at these sequences considering SEQ ID NO: 4 and 7 were both known in the art and Shi 2021 in view of Li teaches vectors comprising both the DLC1-i1 and SMN1 transgenes.
Regarding SEQ ID NO: 11, instant SEQ ID NO: 11 has been identified as comprising pAAV-hSyn-EGFP (instant SEQ ID NO: 7) and a portion of the sequence encoding the SMN1 gene (instant SEQ ID NO: 4), absent evidence to the contrary.
Passini teaches SEQ ID NO: 2, which is 100% identical to instant SEQ ID NO: 4. See sequence search results file us-18-170-296-4.rngb, Result 1 in the file wrapper.
In regard to SEQ ID NO: 11, the combination of sequences disclosed by Passini and disclosure of Addgene comprise instant SEQ ID NO: 11, Applicant should note that that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
In the instant case, a person of ordinary skill in the art would have been motivated to clone the cDNA corresponding to SMN1 because the SEQ ID NO: 11 comprises the combination of sequences taught by Passini and Addgene and Addgene indicates that the plasmid comprises the hSyn promoter which has been identified as a tissue specific promoter for the CNS.
Furthermore, because, as above, SEQ ID NO: 11 comprises the combination of sequences of Passini and Addgene, the teachings of Shi 2021 suggest vectors expressing the transgenes DLC1-i1 and SMN1, and because Li, Passini, and Addgene are in the same technical field of gene therapy, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Relevant prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Pattali et al. (Gene Therapy (2019) 26:287-295).
Pattali teaches AAV9 was employed as a vehicle for one-time administration of the SMN gene. Pattali teaches for virus-mediated gene therapy, the AAV can deliver the transgene of choice as well as achieve a stable, robust, and extensive transduction of desired tissues with no pathogenicity or immunogenicity. Pattali teaches AAV9 was found to have the highest tropism for the CNS. Pattali teaches modified the scAAV9-SMN vectors by codon optimization and delivered them to SMA mice and in addition to regulating the SMN gene, several studies using AAV9 to regulate other therapeutic target genes showed mitigated SMA symptoms and effectively extended lifespan of mouse models. Pattali teaches combinatorial therapeutic studies demonstrate targeting SMN and SMN-independent pathways can be a potential option for SMA. Pattali teaches a clinical study was conducted wherein scAAV9-SMN was administered intravenously as a single dose to 15 type-1 SMA patients.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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