DETAILED ACTION
Claims 16-19 were/stand cancelled. Claims 1-15 and 20-23 are pending.
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 .
Priority
This application is a 371 of PCT/RU2022/000025 (01/28/2022) and claims priority to RUSSIAN FEDERATION 2021102051 (01/29/2021) as reflected in the filing receipt issued on June 25 2024.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 28 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 8 is objected to because of the following informalities: the recitation “to” is missing between according and claim 5 in line 3. Appropriate correction is required.
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 1-15 and 20-23 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 1 recites the limitation "the SMN1 protein" in 2. There is insufficient antecedent basis for this limitation in the claim. This is the first time SMN1 protein is recited. A isolated nucleic acid does not necessarily contain a microRNA and thus does not provide implicit support.
Claim 1 recites the limitation "the micro RNA miR-23a" in 4. There is insufficient antecedent basis for this limitation in the claim. This is the first time miR-23a is recited. A isolated nucleic acid does not necessarily contain a microRNA and thus does not provide implicit support.
In both instances above, change “the” to “a” would overcome the antecedent basis issue.
Claim 8 as currently written is vague and indefinite. The claim recites an expression vector that comprises “the nucleic acid” which is presumably from claim 1 or the cassette according [to] claim 5. However, the claim only depends from claim 5. Therefore the scope of “the nucleic acid” is unclear.
Claim 9 as currently written is vague and indefinite. The preamble recites AAV9 but the body of the claim merely recites “a capsid”. Therefore, it isn’t clear if the capsid is limited to AAV9.
Claims 10/13 recite the limitation "the AAV9 protein VP1" in line 2. There is insufficient antecedent basis for this limitation in the claim. While the previous claim recites AAV9, this does not provide implicit support for VP1. Therefore, this recitation lacks antecedent basis.
Claims 20-23 as currently written is vague and indefinite. The claim recites “administering..the AAV9-based recombinant virus, presumably from claim 9 but also recites or the composition according to claim 15. The scope of the claim is indefinite as the claim merely depends from claim 15 which clearly is directed to the composition.
Claims 2-7, 11-12, 14-15 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-15 and 20-23 is/are rejected under 35 U.S.C. 103 as being obvious over Madera et al. (RU (2742837 C1) (published February 11 2021 constituting prior art under 102(a)(1))) or in the alternative Madera et al. (USPGPUB No. 20230212699, earliest effective filing date June 2 2020 constituting prior art under 102(a)(2)) in view of Kaifer et al. (Human Molecular Genetics, 2019) as evidenced by GenBank (NR_0356515, 2018).
The applied reference (Madera et al. USPGPUB No. 20230212699) has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) 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 thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
However, the rejection over Madera (RU (2742837 C1) is via the publication date as it is considered an intervening reference). Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Applicant Claims
The instant application claims an isolated nucleic acid for producing a gene therapy viral product, said isolated nucleic acid comprising a nucleic acid that encodes the SMN1 protein (survival motor neuron protein) having the amino acid sequence of SEQ ID NO: 1, and a nucleic acid that encodes the microRNA miR-23a.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Madera et al. (wherein USPGPUB No. 20230212699 is serving as the English Language equivalent and all citations are from that reference) is directed to codon-optimized nucleic acid encoding SMN1 protein. Claimed is a codon-optimized nucleic acid that encodes the SMN1 protein with SEQ ID NO: 1 including the nucleic acid sequence of SEQ ID No: 2 (claim 1). Also claimed is an expression cassette that includes the codon-optimized nucleic acid (claim 2). The expression cassette includes the following elements in the 5′-end to 3′-end direction: a left (first) ITR (inverted terminal repeats); a CMV (cytomegalovirus) enhancer; a CMV (cytomegalovirus) promoter; an intron of the hBG1 gene (hemoglobin subunit gamma 1 gene) the codon-optimized nucleic acid of claim 1; an hGH1 polyadenylation signal (human growth hormone gene polyadenylation signal) a right (second) ITR (claim 3). Taught is administering AAV9-based recombinant vector to deliver the SMN1 gene to target cells. Shown is AAV9-SMN1-GB product, a higher level of SMN1 expression in target cells, which is an important advantage in the treatment of, for example, spinal muscular atrophy (SMA), where the level of SMN1 protein expression defines the type of disease (paragraph 0220).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Madera et al. claims a codon-optimized nucleic acid that encodes the same SMN1 protein, Madera et al. does not teach a nucleic acid comprising both a nucleic acid that encodes the SMN1 protein and a nucleic acid that encodes miR-23a. However, this deficiency is cured by Kaifer et al.
Kaifer et al. is directed to AAV9-mediated delivery of miR-23a that reduces disease severity in Smn2B/- SMA model mice. Spinal muscular atrophy (SMA) is caused by the homozygous deletion or mutation of survival motor neuron 1 (SMN1) resulting in insufficient levels of the SMN1 protein (page 3199). Recent reports have suggested that miRNA dysregulation contributes to the pathogenic mechanism of SMA. Observed was a significant reduction of miR-23a expression in SMA moto neurons (page 3200, left column). Transfection of synthetic miR-23a into iPSC-derived SMA moto neurons reduced motor neuron death following exposure to SMA astrocyte-condition media. Administration of miR-23a using self-complementary adeno-associated virus serotype I (scAAV9) significantly reduced disease severity, including reduced loss of mono neuron soma area, etc. These results demonstration that modulation of differently regulated miRNA can significantly less the severity of SMA (page 3200, right column).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Madera et al. and Kaifer et al. and utilize a AAV9-mediated delivery system to deliver a nucleic acid that encodes SMN1 as well as miR-23a. One skilled in the art would have been motivated to have both nucleic acids in the AAV9 as both are taught as treating SMA (spinal muscular atrophy). As a general principle it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, the idea of combining them flows logically from their having been individually taught in the prior art. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) MPEP 2144.06. One skilled in the art would have a reasonable expectation of success as both Madera et al. and Kaifer et al. teach delivery to the same patient population AAV9 containing the nucleic acid.
Regarding claims 1-2, as shown below instantly claimed SEQ ID NO: 1 (Qy) and SEQ ID NO: 1 (Db) of Madera et al. have 100% identity:
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Instantly claimed SEQ ID NO: 2 (Qy) and SEQ ID NO: 2 of Madera et al. (Db) have 100% identity:
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Regarding claims 3-4, Kaifer et al. teaches miR-23a. As taught by GenBank, NR-036515 is the RNA sequence harboring miR-23a. This sequence comprises instantly claimed SEQ ID NO: 3 and 4. As shown below instantly claimed SEQ ID NO: 4 (Query) which encompasses SEQ ID No: 3 has 100% identity to the miR-23a gene (sbjct):
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Regarding claims 5-8, Madera et al. expressly claims an expression cassette comprising the SMN1 protein. Specifically, 5′-end to 3′-end direction: a left (first) ITR (inverted terminal repeats); a CMV (cytomegalovirus) enhancer; a CMV (cytomegalovirus) promoter; an intron of the hBG1 gene (hemoglobin subunit gamma 1 gene) the codon-optimized nucleic acid of claim 1; an hGH1 polyadenylation signal (human growth hormone gene polyadenylation signal) a right (second) ITR (claim 3). Madera et al. does not expressly teach this expression cassette comprising the nucleic acid that encodes miR-23a or SV40 promoter and SV40 signal. However, the use of a nucleic acid that encodes miR-23a is obvious for the reasons set forth above. Madera et al. teaches that the recombinant expression of the vectors that carry regulatory sequences that control the expression of the SMN1 gene in a host cell. Promotors and/or enhancers include CMV as well as simian virus 40 (paragraph 0104). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Madera et al. and Kaifer et al. and utilize a SV40 promoter and enhancer with the expression cassette of Madera et al. Since there are two components which need to be expressed (specifically SMN1 and miR-23a), it would have been obvious to utilize the CMV enhancer and promoter for SMN1 and SV40 with miR-23a. Since Madera et al. suggests that both can be utilized there is a reasonable expectation of success. Regarding claim 6, since the combination of Madera et al. and Kaifer et al. suggest all the same components of the expression cassette, the combination also suggest a nucleic acid with SEQ ID NO: 6.
Regarding claims 9-12, Madera et al. expressly claims AAV9 Protein VP1 which has the amino acid sequence of SEQ ID No: 5 (Db) and with one or more point mutations which has shown below as 100% identity with the instantly claimed SEQ ID NO: 7 (Qy) (claim 11):
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Regarding claim 13-14, as set forth above the instantly claimed expression cassette is obvious. The same VP1 AAV9 is taught.
Regarding claim 15, Madera et al. claims a pharmaceutical composition for delivering the SMN1 gene to target cells including the AAV9-based recombinant virus and one or more pharmaceutically acceptable excipients (claim 12).
Regarding claims 20-23, the active method step in all the claims is administering a therapeutically effective amount or administering the AAV9 based recombinant virus. Madera et al. expressly claims introducing the AAV9 based recombinant virus into one or more target cells reading on claim 22. Madera et al. teaches the therapeutically effective amount refers to the amount being administering during treatment which will relieve to some extent one or more of the symptoms of the disease being treated (paragraph 0070). Kaifer et al. teaches administration of miR-23a using self-complementary adeno-associated virus serotype I (scAAV9) significantly reduced disease severity. Therefore, one skilled in the art would have been motivated to deliver a therapeutically effective amount of the AAV9 with miR-23a and SMN1 protein to a patient with SMA (spinal muscular atrophy) for treatment.
Claims 1-5, 8-9, 15 and 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over Kaifer et al. (Human Molecular Genetics, 2019) as evidenced by GenBank (NR_0356515, 2018) in view of Wilson et al. (USPGPUB No. 20180353624).
Applicant Claims
The instant application claims an isolated nucleic acid for producing a gene therapy viral product, said isolated nucleic acid comprising a nucleic acid that encodes the SMN1 protein (survival motor neuron protein) having the amino acid sequence of SEQ ID NO: 1, and a nucleic acid that encodes the microRNA miR-23a.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Kaifer et al. is directed to AAV9-mediated delivery of miR-23a that reduces disease severity in Smn2B/- SMA model mice. Spinal muscular atrophy (SMA) is caused by the homozygous deletion or mutation of survival motor neuron 1 (SMN1) resulting in insufficient levels of the SMN1 protein (page 3199). Recent reports have suggested that miRNA dysregulation contributes to the pathogenic mechanism of SMA. Observed was a significant reduction of miR-23a expression in SMA moto neurons (page 3200, left column). Transfection of synthetic miR-23a into iPSC-derived SMA moto neurons reduced motor neuron death following exposure to SMA astrocyte-condition media. Administration of miR-23a using self-complementary adeno-associated virus serotype I (scAAV9) significantly reduced disease severity, including reduced loss of mono neuron soma area, etc. These results demonstration that modulation of differently regulated miRNA can significantly less the severity of SMA (page 3200, right column).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Kaifer et al. suggests that SMA results from insufficient levels of SMN1 protein and that miR-23a can be used to reduce severity. Kaifer et al. does not expressly teach administering a nucleic acid which includes a nucleic acid encoding miR-23a and SMN1 protein. However, this deficiency is cured by Wilson et al.
Wilson et al. is directed to adeno-associated viral vectors useful in the treatment of spinal muscular atrophy. Claimed is a recombinant adeno-associated vector comprising a capsid and a vector genome comprising a nucleic acid sequence encoding a functional SMN protein and expression control sequences that direct expression of the SMN sequences in a host cell (claim 1). The nucleic acid sequence encodes SEQ ID NO: 1. Claimed is a method of treating spinal muscular atrophy in a subject comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a viral vector comprising the nucleic acid sequence encoding a functional SMN protein to a subject in need thereof (claim 22). The composition can be administered in combination with another therapy (claim 26). A therapeutically effective dosage is taught (claim 27).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kaifer et al. and Wilson et al. and utilize a AAV9-mediated delivery system to deliver a nucleic acid that encodes SMN1 as well as miR-23a. One skilled in the art would have been motivated to have both nucleic acids in the AAV9 of Kaifer et al. as both are taught as treating SMA (spinal muscular atrophy). As a general principle it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, the idea of combining them flows logically from their having been individually taught in the prior art. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) MPEP 2144.06. One skilled in the art would have a reasonable expectation of success as both Wilson et al. and Kaifer et al. teach delivery to the same patient population a vector containing the nucleic acid. Additionally, Wilson et al. suggest the administration of the SMN protein can be used in combination with another therapy.
Regarding the instantly claimed SEQ ID No: 1, as shown below SEQ ID NO: 1 of Wilson et al. (Db) has 100% identity to instantly claimed SEQ ID NO: 1 (Qy):
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Regarding claim 2, Wilson et al. teaches that the nucleic acid sequencing encoding SMN is the SMN sequence of SEQ ID NO: 2 or at least 70% identify thereof (claim 4) wherein this sequence is a codon optimized sequence. As shown below instantly claimed SEQ ID No: 2 (Qy) has 74.5% identity to SEQ ID No: 2 of Wilson et al.
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kaifer et al. and Wilson et al. and utilize a codon optimize sequence to arrive at a SMN1 protein. One skilled in the art would have been motivated to utilize a codon optimized sequence as Wilson et al. expressly teaches using a codon optimized sequence. Since the scope of the codon optimized sequences in Wilson et al. has at least 70% identity with SEQ ID NO: 2 and the instantly claimed sequence has 74.5% identity with SEQ ID No: 2, one skilled in the art would have a reasonable expectation at arriving at instantly claimed SEQ ID NO: 2.
Regarding claims 3-4, Kaifer et al. teaches miR-23a. As taught by GenBank, NR-036515 is the RNA sequence harboring miR-23a. This sequence comprises instantly claimed SEQ ID NO: 3 and 4. As shown below instantly claimed SEQ ID NO: 4 (Query) which encompasses SEQ ID No: 3 has 100% identity to the miR-23a gene (sbjct):
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Regarding claims 5 and 8-9, Wilson et al. teaches expression cassettes comprising the hSMN1 nucleic acid is provided. Expression cassette refers to a nucleic acid molecule which comprising the hSMN1 sequence, promoter and other regulatory sequences which cassette may be packaged into the capsid of a viral vector (paragraph 0034). it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kaifer et al. and Wilson et al. and utilize an expression cassette in order to package the nucleic acid sequences into the vector as taught by Wilson et al. Since Kaifer et al. teaches incorporation in a AAV, one skilled in the art would have a reasonable expectation of success.
Regarding claims 15 and 20-23, Wilson et al. claims a method of treating spinal muscular atrophy in a subject comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a viral vector comprising the nucleic acid sequence encoding a functional SMN protein to a subject in need thereof (claim 22). A therapeutically effective dosage is taught (claim 27). The active method step in all the claims is administering a therapeutically effective amount or administering the AAV9 based recombinant virus. Kaifer et al. teaches administration of miR-23a using self-complementary adeno-associated virus serotype I (scAAV9) significantly reduced disease severity. Therefore, one skilled in the art would have been motivated to deliver a therapeutically effective amount of the AAV9 with miR-23a and SMN1 protein to a patient with SMA (spinal muscular atrophy) for treatment.
Claims 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Kaifer et al. as evidenced by GenBank in view of Wilson et al. as applied to claims 1-5, 8-9, 15 and 20-23 above and in further view of Muramatsu (USPGPUB No. 20130224836)
Applicant Claims
The instant application claims the capsid comprises the AAV9 protein VP1.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Kaifer et al. and Wilson et al. are set forth above. Kaifer et al. teaches miR-23a for treating SMA. Wilson et al. teaches that previous studies involving administration of an adeno-associated virus to the CNS (central nervous system) in SMA-mouse models demonstrated expression of SMN in the spinal cord (paragraph 0003).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Kaifer et al. teaches a AAV9, Kaifer et al. does not expressly teach VP1 or VP1 of seq ID NO: 7. However, this deficiency is cured by Muramatsu.
Muramatsu is directed to adeno-associated virus virion for gene transfer to nervous system cells. Taught is the construction of a recombinant adeno-associated virus virion capable of transferring a gene to a nervous system cell by modifying a wild type capsid protein by using the resultant configuration in combination with a recombinant AAV genome (paragraph 0012). Taught are including capsid protein capable of forming a capsomere (e.g. at least one of VP1, VP2 and VP3) (paragraph 0063). VP1 amino acid sequences (SEQ ID No: 2, 4 or 6) are taught (paragraph 0066). The rAAV virion of the present invention can target nerve cells containing in brains, spinal cords (paragraph 0066). Claimed is a recombinant adeno-associated virus virion comprising a capsomere comprising a protein comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID No: 2, 4 or 6 and a polynucleotide packaged in said capsomere (claim 1). Point mutations, specifically tyrosine residents are substituted (claim 2). AAV9 is specifically taught (paragraph 0079). Examples show that the vector was able to pass through the blood-brain barrier through peripheral administration to transfer the gene to nervous system cells in the brain and spinal cord with high efficiency (paragraph 0152).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kaifer et al., Wilson et al. and Muramatsu and utilize a recombinant adeno-associated virus virion (AAV) comprising a capsomere of SEQ ID NO: 6 or a mutation (specifically tyrosine substitutions) to deliver the SMN1 protein and miR-23a. One skilled in the art would have been motivated to utilize the AAV of Muramatsu as it is specifically taught as allowing for gene transfer to nervous system cells. Since Kaifer et al. and Wilson et al. suggest treatment of SMA and Wilson et al. teaches an adeno-associated virus to the CNS (central nervous system) in SMA-mouse models demonstrated expression of SMN in the spinal cord, one skilled in the art would have been motivated to utilize the AAV of Muramatsu as it has been shown to allow gene transfer into nerve cells.
Regarding the instant claimed SEQ ID NO: 7 as shown below, SEQ ID NO: 6 of Muramatsu (Db) has 100% identity to instantly claimed SEQ ID NO: 7:
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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 1-5, 8-12, 15 and 20-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 18000612 (USPGPUB No. 20230212609) in view of Kaifer et al. as evidenced by Genbank. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant application claims an isolated nucleic acid for producing a gene therapy viral product, said isolated nucleic acid comprising a nucleic acid that encodes the SMN1 protein (survival motor neuron protein) having the amino acid sequence of SEQ ID NO: 1, and a nucleic acid that encodes the microRNA miR-23a.
Copending ‘612 claims a codon-optimized nucleic acid that encodes the SMN1 protein with SEQ ID NO: 1 including the nucleic acid of SEQ ID NO: 2 (claim 1).
Copending ‘612 does not claim a nucleic acid encoding both a nucleic acid that encodes the SMN1 protein and a nucleic acid that encodes miR-23a. However, this defiance is cured by Kaifer et al.
Kaifer et al. is directed to AAV9-mediated delivery of miR-23a that reduces disease severity in Smn2B/- SMA model mice. Spinal muscular atrophy (SMA) is caused by the homozygous deletion or mutation of survival motor neuron 1 (SMN1) resulting in insufficient levels of the SMN1 protein (page 3199). Recent reports have suggested that miRNA dysregulation contributes to the pathogenic mechanism of SMA. Observed was a significant reduction of miR-23a expression in SMA moto neurons (page 3200, left column). Transfection of synthetic miR-23a into iPSC-derived SMA moto neurons reduced motor neuron death following exposure to SMA astrocyte-condition media. Administration of miR-23a using self-complementary adeno-associated virus serotype I (scAAV9) significantly reduced disease severity, including reduced loss of mono neuron soma area, etc. These results demonstration that modulation of differently regulated miRNA can significantly less the severity of SMA (page 3200, right column).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Copending ‘612 and Kaifer et al. and utilize a AAV9-mediated delivery system to deliver a nucleic acid that encodes SMN1 as well as miR-23a. One skilled in the art would have been motivated to have both nucleic acids in the AAV9 as both are taught as treating SMA (spinal muscular atrophy). As a general principle it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, the idea of combining them flows logically from their having been individually taught in the prior art. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) MPEP 2144.06. One skilled in the art would have a reasonable expectation of success as both Copending ‘612 and Kaifer et al. teach delivery to the same patient population AAV9 containing the nucleic acid.
Regarding claims 1-2, as shown below instantly claimed SEQ ID NO: 1 (Qy) and SEQ ID NO: 1 (Db) of Copending ‘612 have 100% identity:
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Instantly claimed SEQ ID NO: 2 (Qy) and SEQ ID NO: 2 of Copending ‘612. (Db) have 100% identity:
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Regarding claims 3-4, Kaifer et al. teaches miR-23a. As taught by GenBank, NR-036515 is the RNA sequence harboring miR-23a. This sequence comprises instantly claimed SEQ ID NO: 3 and 4. As shown below instantly claimed SEQ ID NO: 4 (Query) which encompasses SEQ ID No: 3 has 100% identity to the miR-23a gene (sbjct):
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Regarding claims 5 and 8, Copending ‘612 claims an expression cassette comprising the SMN1 protein (claim 3).
Regarding claims 9-12, Copending ‘612 claims AAV9 Protein VP1 which has the amino acid sequence of SEQ ID No: 5 (Db) and with one or more point mutations which has shown below as 100% identity with the instantly claimed SEQ ID NO: 7 (Qy) (claim 11):
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Regarding claim 15, Copending ‘612 claims a pharmaceutical composition for delivering the SMN1 gene to target cells including the AAV9-based recombinant virus and one or more pharmaceutically acceptable excipients (claim 12).
Regarding claims 20-23, the active method step in all the claims is administering a therapeutically effective amount or administering the AAV9 based recombinant virus. Copending ‘612 expressly claims introducing the AAV9 based recombinant virus into one or more target cells reading on claim 22. Kaifer et al. teaches administration of miR-23a using self-complementary adeno-associated virus serotype I (scAAV9) significantly reduced disease severity. Therefore, one skilled in the art would have been motivated to deliver a therapeutically effective amount of the AAV9 with miR-23a and SMN1 protein to a patient with SMA (spinal muscular atrophy) for treatment.
Claims 6-7 and 13-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 18000612 in view of Kaifer et al. as evidenced by Genbank as applied to claims 1-5, 8-12, 15 and 20-23 above and in further view of Enenkel (US Patent No. 8466271). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant application claims an expression cassette comprising the following elements in the 5'-end to 3'-end direction: a left-hand (first) ITR (inverted terminal repeats); a CMV (cytomegalovirus) enhancer; a CMV (cytomegalovirus) promoter; an intron of the hBG1 gene (hemoglobin subunit gamma 1 gene); a nucleic acid that encodes the SMN1 protein; an hGH1 polyadenylation signal (human growth hormone gene polyadenylation signal); an SV4o promoter (simian virus 40 promoter);a nucleic acid that encodes the microRNA miR-23a;an SV4o polyadenylation signal (simian virus 40 polyadenylation signal), and a right-hand (second) ITR.
The teachings of copending ‘612 are set forth above. Copending ‘612 claims an expression cassette including the following elements in the 5′-end to 3′-end direction: a left (first) ITR (inverted terminal repeats); a CMV (cytomegalovirus) enhancer;
a CMV (cytomegalovirus) promoter; an intron of the hBG1 gene (hemoglobin subunit gamma 1 gene) the codon-optimized nucleic acid of claim 1; an hGH1 polyadenylation signal (human growth hormone gene polyadenylation signal); a right (second) ITR.
Copending ‘612 does not expressly claims SV40 promoter or SV40 polyadenylation signal. However, this deficiency is cured by Enenkel.
Enenkel is directed to regulatory elements. Expression of the recombinant protein requires an expression vector encoding the desired gene of interest. Gene expression is related on transcription and translational levels. Strong promoters and enhancer improve the efficiency with which protein encoding genes are transcribed. Examples of these are CMV, SV40 etc. (column 1, lines 28-40). These include a polyadenylation signal (column 2, lines 1-20).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Copending ‘612 and Kaifer et al. and Enenkel and utilize a SV40 promoter and enhancer with the expression cassette of copending ‘612. Since the combination of copending ‘612 and Kaifer et al. would be designed to express two different species, namely SMN1 and miR-23a, one skilled in the art would have been motivated to utilize the CMV promoter for SMN1 and the SV40 promoter for miR-23a. One skilled in the art would have been motivated to utilize the different promoters and enhancer in order to control expression of the resulting SMN1 and miR-23a. Regarding claim 6, the use of a nucleic acid encoding miR-23a and SV40 promoter and enhancer would result in the nucleic acid with SEQ ID NO: 6.
Regarding claim 13-14, as set forth above the instantly claimed expression cassette is obvious. The same VP1 AAV9 is taught.
Data in the Specification
The instant specification, example 4, is purported to teach the synergistic effect of SMN1 and miR-23a in treating animals of SMA mouse model. The specification teaches that the SMA phenotype was most corrected in the group injected with the virus AAV9-SMN1-miR-23a. This result was significantly different from the group injected with the virus AAV9-SMN1. It is stated that this result shows the synergistic effect of SMN1 and miR-23a. However, the examiner cannot agree. Where the combined action of two or more agents is greater than the sum of the action of one of the agents used alone, “synergy” according to the legally accepted definition exists. In re Kollman, 201 USPQ 193 (CCPA 1979). Claims drawn to (unexpectedly) synergistic combinations of known ingredients must be factually supported by data commensurate in scope with the claims. See, In re Kollman, 201 USPQ 193 (C.C.P.A. 1979). (The court affirming a 103 rejection of a claim containing the word “synergistic”, because the claims were not commensurate in scope with the showing of unexpected results, other than at 1:1 ratio for certain specific combinations).
The instant specification merely compares the results of AAV9-SMN1 and AAV-SMNI-miR-23a. But never shows the effect with AAV9-miR-23a. As set forth above synergy is wherein the combined action of two or more agents is greater than the sum of the action of the of the agents used alone. In order to establish that the combination is synergistic, the data must show the results of the individual agent alone in order to determine if the combined effect is greater than the additive effect. This is especially true in light of Kaifer et al. which specifically teaches that AAV9-mediated delivery of miR-23a reduces disease severity in SMA model mice.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636