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 .
Continued Examination 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/05/2026 has been entered.
Response to Amendment
The amendment filed 08/05/2026, amending claim(s) 1 and 62 and cancelling claim(s) 13, 19, 26, 31, 32, 40, 43, 46-48, 50-51, 53-61, and 63-67 is acknowledged.
Claims 1, 21, 22, 24, 35, 36, 44, 45, 52, and 62 are pending and under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/05/2026 is considered by the examiner.
Claim Interpretation
Claim 1 recites “a nucleic acid for expressing a functional frataxin (FXN) protein in the heart”. The examiner notes that the recitation of “for expressing a functional frataxin (FXN) protein in the heart” in the preamble is interpreted as an intended use of the claimed invention and not a limitation of the claimed invention. “For expressing a functional frataxin (FXN) protein in the heart” does not limit the structure of the claimed invention; therefore, it does not provide significance to the claim construction. See MPEP § 2111.02.II.
Claim Rejections - 35 USC § 103- Maintained, modified due to amendments
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.
Claim(s) 1, 21, 44, 45, and 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Voyager (US20180021364A1, published January 25th, 2018) and further in view of McLaughlin (US20170362608A1, published December 21st, 2017) and Venditti (WO2016164642A1, published October 13th, 2016).
Regarding claims 1 and 52, Voyager teaches a nucleic acid, comprising from 5’ to 3’:
a 5’ inverted terminal repeat (ITR);
a promoter;
a transgene sequence encoding the frataxin (FXN) protein;
one or more polyadenylation signals; and
a 3’ ITR [0396].
Voyager teaches SEQ ID NO: 62, which shares 100% identity with instant SEQ ID NO: 19 (SEQ ID NO: 62 is an AAV construct comprising FXN) (claim 21) [0451].
Because Voyager teaches instant SEQ ID NO: 19, representing the nucleic acid sequence of the FXN transgene, Voyager also inherently teaches instant SEQ ID NO: 65, representing the amino acid sequence of the FXN protein (which the transgene sequence comprises).
Additionally, Example 12 of Voyager, which involved delivering AAV constructs comprising FXN to non-human primates then testing FXN expression in various organs, teaches SEQ ID NO: 93 as one of the delivered AAV constructs with successful FXN expression (Group C of Example 12). SEQ ID NO: 93 of Voyager comprises 100% of SEQ ID NO: 19 (and therefore SEQ ID NO: 65), as well as 100% of instant SEQ ID NO: 2 and 95.7% of instant SEQ ID NO: 1 (see comparison in Response to Arguments below).
An Artisan, interested in ITR sequences in engineered polynucleotides, would be aware of McLaughlin for teaching increasing the transduction efficiency and heterologous gene expression of viral particles by altering the Rep nicking sequence found in parvoviral (e.g., AAV) ITR sequences.
McLaughlin also teaches SEQ ID NOs: 67, 73, 70, and 76, which share 100% identity with instant SEQ ID NO: 1, representing a 5’ ITR sequence [0076].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the 5’ ITR sequence taught by McLaughlin for the 5’ ITR sequence in the nucleic acid construct taught by Voyager with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06.
Further, an artisan would have a reasonable expectation for success because replacing one sequence with another has long been done in the molecular biology art and would be routine. One would be motivated to make this substitution because Voyager teaches that the engineered ITR sequences may result in altered Rep binding sequence regions and decreased binding with Rep protein. Voyager teaches that the decrease in Rep binding affects the Rep nicking activity in a manner that promotes the formation of a self-complementary viral genome during replication [0014].
Voyager teaches the EFIα promoter as an option to use in the nucleic acid construct (e.g., [0062, 0063]). Voyager notes promoters specific to the nervous system but does not include EF1-alpha in this list. Additionally, Voyager found that constructs expressing Frataxin driven by a hEF1a promoter results in highest FXN expression in primary fibroblast cells. The presence of a CpG island in the hEF1a promoter promotes FXN expression in all cell types tested compared to CpG-free hEF1a promoter (e.g., [0455]).
Voyager and McLaughlin do not teach a promoter sequence comprising SEQ ID NO: 9.
An Artisan, interested in different types of promoters, would be aware of Venditti for teaching EF-1 alpha as a promoter in a nucleic acid construct to express a transgene.
Venditti teaches SEQ ID NO: 8, which shares 100% identity with instant SEQ ID NO: 9, which represents an EF-1 alpha promoter, in a nucleic acid construct (e.g., AAV vector) [0063] (Fig. 11).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the EF-1 alpha promoter sequence taught by Venditti for the EF-1 alpha in the nucleic acid construct taught by Voyager with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06.
Further, an artisan would have a reasonable expectation for success because replacing one sequence with another has long been done in the molecular biology art and would be routine. One would be motivated to make this substitution because as taught by Venditti and Voyager, the EF-1 alpha promoter sequence is constitutive and can be used in an AAV vector ([e.g., 0147]- Venditti; [0062]- Voyager), and promoted FXN expression in all cell types tested by Voyager.
Regarding claim 44, Voyager teaches a plasmid comprising the nucleic acid of claim 1 [0396].
Regarding claim 45, Voyager teaches a cell comprising the nucleic acids of claim 1 [0390].
Claim(s) 1, 21, 22, 44, 45, and 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Voyager, McLaughlin, and Venditti as applied to claims 1, 21, 44, 45, and 52 above, and further in view of Bauer (Bauer, Asli Petra et al. “The impact of intragenic CpG content on gene expression.” Nucleic acids research vol. 38,12 (2010): 3891-908.).
As shown above, the base claims are obvious over the base art.
Regarding claim 22, Voyager teaches the transgene being codon optimized but does not teach the transgene being CpG optimized [0396]. Voyager also teaches the hEF1a promoter being CpG optimized (e.g., presence of a CpG island in the hEF1a promoter promotes FXN expression in all cell types tested compared to CpG-free hEF1a promoter) (e.g., [0455]).
An Artisan, interested in the impact of CpG content on gene expression, would be aware of Bauer for studying the contribution of intragenic CpG content to expression efficiency in transiently and stably transfected mammalian cells.
Bauer teaches a CpG-depleted variant of a humanized version of green fluorescent protein (GFP) by carefully modulating codon usage (Abstract). Bauer teaches that the altered intragenic CpG content influenced de novo transcriptional activity, thus implying a common transcription-based mechanism of gene regulation via CpGs. (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to apply the teaching of Bauer that CpG content of a gene impacts gene regulation to the nucleic acid construct of Voyager with a reasonable expectation for success. An artisan would have a reasonable expectation for success because CpG optimization is a form of codon optimization, and the transgene of the nucleic acid construct of Voyager can be codon optimized. One would be motivated to apply the teachings of Bauer because as taught by Bauer, optimization of codon usage has therefore substantially encouraged the development of safe lentiviral vectors and highly efficient packaging cell lines for vaccine design (pg. 3892, “Introduction”, para 1), and CpG depleted transgenes (e.g., CpG optimized) not susceptible to methylation have been proven to be beneficial for high and sustained levels of protein expression in vivo (e.g., pg. 3892, col 2, para 1).
Claim(s) 1, 21, 24, 44, 45, and 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Voyager, McLaughlin, and Venditti as applied to claims 1, 21, 44, 45, and 52 above, and further in view of Lundberg (WO2018002783A1, published January 4th, 2018).
As shown above, the base claims are obvious over the base art.
Regarding claim 24, Voyager teaches nucleic acid constructs comprising a full or partial Kozak sequence [0396]. Voyager and McLaughlin do not teach a Kozak sequence at least 95% identical to instant SEQ ID NO: 17.
An Artisan, interested in modulating translation of FXN such as through Kozak sequences, would be aware of Lundberg for teaching sequences used in the gene editing of the FXN gene, such as through Kozak sequences.
Lundberg teaches SEQ ID NO: 16094, representing a FXN gene editing single-molecule gRNA spacer targeting the upstream region of FXN and Exon 1 (Fxn upstream and Exon1_T59), which shares 100% identity with instant SEQ ID NO: 17 (pg. 126, Table 7).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the Kozak sequence taught by Lundberg for the Kozak sequence in the nucleic acid construct taught by Voyager with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06.
Further, an artisan would have a reasonable expectation for success because replacing one sequence with another has long been done in the molecular biology art and would be routine. One would be motivated to make this substitution because as taught by Lundberg, modifications of polynucleotides, including modifications of 5’ UTRs (i.e., Kozak sequences), are well known in the art and are applied to increase translation or stability or to reduce the tendency of the nucleic acid to elicit an innate immune response [000187, 000191].
Claim(s) 1, 21, 35, 36, 44, 45, and 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Voyager, McLaughlin, and Venditti as applied to claims 1, 21, 44, 45, and 52 above, and further in view of Kaczmarczyk (WO2002081632A2, published October 17th, 2002).
As shown above, the base claims are obvious over the base art.
Regarding claims 35 and 36, Voyager teaches the nucleic acid construct comprising chimeric introns [0077; 0080]. Voyager and McLaughlin do not teach the nucleic acid further comprising a chimeric intronic sequence at least 95% identical to instant SEQ ID NO: 15.
An Artisan, interested in intronic sequences, would be aware of Kaczmarczyk for teaching intronic sequences used in transgene expression.
Kaczmarczyk teaches SEQ ID NO: 19, representing a human beta-globin intron from cloning vector pCI (pg. 4; pg. 7-8, “Intron Sequence”, pg. 9 “Intron Sequence”). SEQ ID NO: 19 of Kaczmarczyk shares 100% identity with instant SEQ ID NO: 15. Additionally, Kaczmarczyk teaches that SEQ ID NO: 19 is a nucleic acid sequence for a chimeric intron sequence (Genbank Accession No. U47119) (pg. 4, lines 36-37).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the chimeric intron sequence taught by Kaczmarczyk for the chimeric intron in the nucleic acid construct taught by Voyager with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06.
Further, an artisan would have a reasonable expectation for success because replacing one intron with another has long been done in the molecular biology art and would be routine. One would be motivated to make this substitution because as taught by Kaczmarczyk, the chimeric intron sequence can be used in nucleic acid constructs to express transgenes in eukaryotes (pg. 8, lines 34-38; pg. 41, lines 23- 32; Fig. 5).
Claim(s) 1, 21, 22, 24, 35, 36, 44, 45, 52, and 62 is/are rejected under 35 U.S.C. 103 as being unpatentable over Voyager, McLaughlin, and Venditti as applied to claims 1, 21, 44, 45, and 52 above, and further in view of Bauer, CalTech, Lundberg, Tremblay, Kaczmarczyk, and Sah.
PolyA element of claimed construct:
Firstly, Voyager, McLaughlin, and Vendittii do not teach a human growth hormone (hGH) polyA signal or instant SEQ ID NO: 22, which represents a nucleic acid sequence of an hGH polyA signal.
An artisan, interested in inducible/activity dependent nucleic acid expression, would be aware of CalTech for teaching AAV vectors comprising nucleic acids encoding a polyadenylation site from sources such as human growth hormone.
CalTech teaches SEQ ID NO: 31, representing a human growth hormone polyadenylation site, which shares 100% identity with instant SEQ ID NO: 22 [0018, 0084].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the hGH polyA signal sequence taught by CalTech for the polyA signal sequence in the nucleic acid construct taught by Voyager with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06.
Further, an artisan would have a reasonable expectation for success because replacing one sequence with another has long been done in the molecular biology art and would be routine. One would be motivated to make this substitution because as taught by CalTech, a hGH polyA signal (i.e., instant SEQ ID NO: 22) can be used in an AAV vector activity-dependent expression system [0018] (Fig. 9).
CBA-MVM 5’ UTR intron of claimed construct:
Instant SEQ ID NO: 5 represents a nucleic acid sequence for a CBA-MVM hybrid intron. Voyager teaches that the nucleic acid may comprising an enhancer, including a 5’UTR/intron that is composed of CBA-MVM (i.e., CBA - MVM 5' UTR intron) [0077]. However, Voyager is silent on the sequence of the CBA-MVM enhancer with at least 95% identity to SEQ ID NO: 5.
An Artisan, interested in enhancers used in gene editing systems, would be aware of Tremblay for teaching enhancers, such as a CBA hybrid intron, may be used in gene editing system to modify FXN in a cell.
Tremblay teaches SEQ ID NO: 169, representing a CBA hybrid intron (CBH) (a CBA promoter with a hybrid intron composed of a 5’ donor splice site from the CBA 5’ UTR and 3’ acceptor splice site from MVM, which shares 100% identity with instant SEQ ID NO: 5 (pg. 48).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the enhancer (i.e., CBA-MVM intron) sequence taught by Tremblay for the enhancer (i.e., CBA-MVM intron) in the nucleic acid construct taught by Voyager with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06.
Further, an artisan would have a reasonable expectation for success because replacing one sequence with another has long been done in the molecular biology art and would be routine. One would be motivated to make this substitution because as taught by Tremblay, SEQ ID NO: 169 is used in nucleic acid constructs to effectively edit the FXN gene [0078] (Fig. 17).
Stuffer sequences of claimed construct:
Voyager, McLaughlin, and Vendetti do not teach a nucleic acid sequence comprising a stuffer sequence at least 95% identical to instant SEQ ID NO: 26 (representing a stuffer sequence derived from Alpha-1 Antitrypsin, or A1AT).
An Artisan, interested in stuffer sequences, would be aware of Sah for teaching stuffer sequences used in polynucleotides encoding FXN.
Sah teaches AAV particles comprising a polynucleotides sequence encoding FXN ( Sah claim 1). Although Sah does not teach instant SEQ ID NO: 26, Sah teaches that the viral genomes can contain a stuffer or filler sequence, including alpha-1 antitrypsin (A1AT) sequences, and that any known viral mammalian, or plant sequence may be manipulated for use as a stuffer sequence [0119].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to add the stuff sequence taught by Sah to the nucleic acid construct taught by Voyager to arrive at the claimed invention. One of ordinary skill in the art would understand how to design a stuffer sequence merely using readily available references with which to identify the finite potential options, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success. One would have reasonable expectation for success because including stuffer sequences in vectors are well known in the art in order to maintain optimum vector size, particularly when nucleic acid constructs comprise shorter transgene sequences. It would be only routine experimentation to arrive at an optimal stuffer sequence (i.e., instant SEQ ID NO: 26) to include in a nucleic acid construct.
SEQ ID NO: 32 (sequence of claimed construct):
Regarding claim 62, none of the cited references teach instant SEQ ID NO: 32 (representing a nucleic acid construct comprising ITR, promoter, transgene sequence that encodes FXN protein, and polyA signal). However, as discussed above, Voyager teaches that nucleic acid constructs comprising the FXN transgene were well known in the art before the effective filing date of the current invention. Additionally, McLaughlin, Venditti, and Kaczmarczyk teach that the sequences of components of nucleic acid constructs of the current invention, such as 5’ and 3’ ITRs, a Kozak sequence, and introns were well known in the art before the effective filing date of the current invention. Although no references teach a nucleic acid sequence at least 95% identical to instant SEQ ID NO: 32. Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to combine the teachings of Voyager, McLaughlin, Venditti, Bauer, CalTech, Lundberg, and Kaczmarczyk to arrive at the nucleic acid of the claimed invention (i.e., SEQ ID NO: 32) with a reasonable expectation of success because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” One of ordinary skill in the art would understand how to design nucleic acid sequences comprising previously known transgene, ITR, promoter, and polyA signal sequences, the artisan merely using readily available references with which to identify the finite potential options, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success. As evidenced by the sequence search results, it would be only routine experimentation to determine which specific ITR, enhancer, promoter, etc. sequences to include in the nucleic acid construct, as all these have been well-known and widely used in the prior art.
Response to Arguments
Applicant's arguments filed 08/05/2026 have been fully considered but they are not persuasive.
The Applicant argues:
“Voyager teaches FXN expression in the central nervous system (CNS) by encapsulation of a FXN transgene construct in an AAV with CNS tropism. At the most, Voyager discusses the possibility that an AAV vector could be used to package a FXN transgene to provide an expression level to the heart (see, e.g., paragraph [0158]). However, Voyager never specifies a transgenic construct that can provide such expression in the heart, among a large number of elements and different combinations explored. Although Voyager, in Example 12, discusses measurement of FXN expression in several tissues including heart after administering different vectors, Voyager does not disclose the vector elements that drive FXN in the heart.”
Firstly, as previously discussed, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, a recitation of the intended use of the claimed invention (i.e., for expressing a functional frataxin (FXN) protein in the heart) must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The Applicant has failed to distinct point out and provide evidence as to why the nucleic acid construct taught by Voyager and McLaughlin would fail to express FXN in the heart.
Further, as noted by the Applicant, Voyager notes that an AAV vector (which would comprise a nucleic acid construct) may be used to provide FXN expression level to the heart. Additionally, Example 12 of Voyager does disclose the vectors used. For example, SEQ ID NO: 93 of Voyager, which was used in Group C of Example 12, comprises SEQ ID NO: 65 (and 19) in its entirety, as well as 100% of SEQ ID NO: 2 and 95.7% of SEQ ID NO: 1:
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Instant SEQ ID NO:1 top, SEQ ID NO: 93 of Voyager bottom
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Instant SEQ ID NO: 2 top, SEQ ID NO: 93 of Voyager bottom
Although Voyager is silent on the resulting FXN expression levels in the heart, absent evidence on the contrary, and given the suggestion of Voyager to use constructs to express FXN in the heart, an artisan would conclude that they can combine the teachings of Voyager and McLaughlin to successfully arrive at the claimed invention structure and its resulting function.
Additionally, the Applicant argues:
“McLaughlin does not cure the deficiency in Voyager. McLaughlin discloses ITRs from numerous AAV serotypes and only suggests that any one of the many ITRs could be combined with any one of the engineered Rep protein binding sites to enhance transduction efficacy. McLaughlin fails to teach use of the AAV2 ITRs for expressing in the heart. A person of ordinary skill in the art would not be motivated to select SEQ ID NOs: 1 and 2 of the many sequences provided in McLaughlin and combine with a transgene from Voyager which expresses frataxin in the CNS, with a reasonable expectation to obtain robust transgene expression in the heart in vivo.”
This argument is not found to be persuasive because as discussed above, Voyager also teaches instant SEQ ID NO: 2, as well as 95.6% of SEQ ID NO: 1 in a construct to express FXN.
Additionally, the claims do not require the ITRs to be derived from AAV2.
In response to the Applicant’s argument that there is no expectation of success because the EF1alpha promoter of Venditti is used for treating cholesterol storage diseases, similar to the response above, a recitation of the intended use of the claimed invention (i.e., what disease/disorder is treated) must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Further, the Applicant fails to provide evidence that the EF1alpha promoter of Venditti would not result in increased expression of FXN.
The Applicant argues:
“Bauer teaches CpG content optimization for augmented gene expression. Applicant submits that Bauer does not cure the deficiencies of Voyager and McLaughlin. Bauer simply investigates the impact of CpG intronic content on the expression of a GFP reporter. According to Bauer, the degree of effect of CpG optimization on gene expression for a select gene is unpredictable (see, e.g., Figure 3). Furthermore, Bauer primarily demonstrates the importance of CpGs in introns by removing CpGs in entirety. A person of ordinary skill in the art would understand that the manner and degree of CpG optimization for a gene require specific designs. A person of ordinary skill in the art would not be to optimize CpGs in the FXN transgene with the teachings by Bauer.”
This argument is not convincing because the claims do not require a specific manner and degree of CpG optimization, nor a specific design. The claim generically recites “CpG optimized”, thus teachings of Bauer read on the claim language. Bauer teaching that reduction in protein expression is associated with CpG depletion by creating a CpG-depleted variant of a humanized version of GFP (e.g., a transgene), transfecting the variant into CHO 293 cells, which then resulted in significantly decreased GFP reporter activity and detectable protein amounts (e.g., Abstracts) provides an artisan sufficient knowledge on how to modify the nucleic acid construct of Voyager to be “CpG optimized”. Additionally, Bauer teaches CpG depleted transgenes (e.g., CpG optimized) not susceptible to methylation have been proven to be beneficial for high and sustained levels of protein expression in vivo (e.g., 3892, col 2, para 1). Additionally, Voyager teaches codon-optimizing the FXN transgene (but is not specific to the type of optimization), such as Example 11, and how optimization can affect expression levels of the transgene. The Applicant fails to provide objective evidence that CpG optimizing the transgene constitutes undue experimentation in view of the prior art.
The Applicant argues:
“Lundberg provides no teaching for inclusion of an AAV2 ITR sequence to a FXN transgene to drive FXN expression in the heart. SEQ ID NO: 16094 in Lundberg represents a FXN gene editing single-molecule gRNA spacer targeting the upstream region of FXN and Exon 1. While SEQ ID NO: 16094 of Lundberg contains a sequence that shares identity with SEQ ID NO: 17 recited in claim 24, a person of ordinary skill in the art would not be motivated to choose one of the 192 guide RNAs for use as a Kozak sequence as there is no discussion in Lundberg for such use. Thus, the inclusion of SEQ ID NO: 17 into the claimed nucleic acid is not obvious in view of Voyager, McLaughlin, and Lundberg.”
Firstly, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., inclusion of an AAV2 ITR sequence to a FXN transgene) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Additionally, as previously stated, Kozak sequences are typically found upstream of the start codon, which is often located within the first exon (exon 1) of a gene (and Lundberg teaches that SEQ ID NO: 16094 represents a gRNA targeting the upstream region of FXN and Exon 1). Thus, an artisan may come to the conclusion that the SEQ ID NO taught by Lundberg could successfully be substituted into Voyager.
In response to applicant's arguments against CalTech, Tremblay, Kaczmarczyk, and Sah, that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., AAV2 ITR sequences) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to applicant's argument that the nucleic acid construct resulting from the combined teachings of Voyager, McLaughlin, Venditti, CalTech, Bauer, Lundberg, Tremblay, Kaczmarczyk, and Sah would not drive the expression of FXN in the heart, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The Applicant has not provided evidence that the nucleic acid construct taught by the prior art would not be able to express FXN in the heart (e.g., if the nucleic acid construct taught by the prior art and claimed invention share the same structure, why would they not have the same function?).
Further, the cited references demonstrate all components of the claimed nucleic acid construct were previously known in the art. The Applicant fails to distinctly point out or provide evidence as to why it would be undue experimentation, for example, for an artisan to arrive at the claimed invention in view of the prior art (e.g., it is typical in the art to create constructs from various known ITRs, polyA tails, etc. to express a transgene of choice and routine to swap out ITR sequences, for example, to modulate gene expression- why would an artisan be unable to do so for this specific construct when all components are known in the art?).
In response to applicant's argument that the claimed nucleic acid increases FXN expression in heart tissue and extends mouse survival, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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