DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 9/30/2025.
Claims 1, 7, 12, 19, 20, 22, 27, 29, 30, 32, 34, 36, 38-41, 43, 45, 50 and 57 are pending.
This application is a 371 filing of PCT/US2020/056156 filed 10/16/2020 which claims the benefit of priority of U.S. Provisional Application No. 62/916,396, filed October 17, 2019.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1, 7, 12, 19, 20, 22, 27, 41, 43, 45, 50 and 57, drawn to a nucleic acid construct comprising a start codon and an intron cassette comprising a cell specific exon, constitutive splice donor site, branch site and constitutive splice acceptor site wherein the exon is out of frame with the start codon and comprises one or more frameshift mutations and is flanked by alternative splice sites) in the reply filed on 9/30/2025 is acknowledged. The traversal is on the grounds that the examiner has not established that a search and examination is made without a serious burden. This is not found persuasive because the instantly filed application was filed under 37 CFR 371. As stated in 1893.03(d), unity of invention (not restriction) practice is applicable in such cases. Search burden is not a criteria in 371 cases. In this case, the inventions listed as Group I-III do not relate to a single general inventive concept because they lack the same or corresponding technical feature.
Hagiwara provided by applicants taught the linked invention linked by the feature of the recited nucleic acid, which is shown by (see US 20130137099, especially 0081 and 0173 (discusses start codons, frameshift mutations in the exon, branch sites are inherent in the intron/exon design) and ¶ 0184 (which shows the two sets of splice sites that function in a cell-specific manner) to lack novelty of inventive step and does not make a contribution over the art.
Because this reference listing was not properly provided, this restriction is non-final.
Claims 29, 30, 32, 34, 36, 39 and 40 are withdrawn from examination as directed to non-elected subject matter.
Information Disclosure Statement
Information disclosure statements filed 11/22/2022 and 12/10/2024 have been identified and the documents considered. The corresponding signed and initialed PTO Form 1449 has been mailed with this action. Initials indicate that the document has been considered even if the reference is lined through.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in ¶ 0097, 0137, 0182, 0192, 0196. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 1 and 7 are objected to because of the following informalities: claim 1 is lacking the term “site” after alternative splice donor in line 9. In claim 7, each of “alternative splice acceptor site” and “cell specific exon sequence” require their own article “the”. These are independent limitations not compound and should individually be preceded by articles. Appropriate correction is required.
Claim Rejections - 35 USC § 112, second paragraph
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.
Claim 1 is unclear as the intron cassette comprises the cell specific exon, a constitutive splice donor site, a branch site and a constitutive acceptor site. Yet, the claim continues that the constitutive splice donor and acceptor sites are outside of the intron cassette as in flanking the intron cassette. It is not clear how the constitutive sites can be internal to the intron cassette and also flank them. The arrangement lacks clarity and as such the metes and bounds of the construct are unclear.
Claims 12 and 50 are unclear in defining the sequence as not having a premature stop codon in a canonically spliced reading frame. A canonically spliced reading frame is the end reading frame after all introns are removed. But, the claim requires simply a cell specific exon sequence. It is noted and expanded below that this reads on a portion of an exon by requiring just a exon sequence which does not require the entire exon. However, to the point of this rejection and considering an entire exon, this is but a portion of the canonically spliced reading frame. Hence, the impact on one exon is unclear.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1, 7, 12, 19, 20, 22, 27, 41, 43, 45, 50 and 57 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicants claim nucleic acid constructs in terms that do not meet the use of the construct in the disclosure. Claim 1 requires that the construct comprise a start codon and an intron cassette. The intron cassette comprises 1) a cell specific exon, 2) a constitutive splice donor site, 3) a branch site, 4) a constitutive splice acceptor site, 5) an alternative splice donor site and 6) an alternative splice acceptor site. The last two flank the exon and the constitutive sites flank the intron cassette. There are many arrangements of these sequences but the disclosure teaches that the functionality of the sequences is to create a system that allows splicing and expression of genes in a cell specific manner. A cell specific exon is one that is included in the mature mRNA in specific cell types but not others through the alternative splicing of the DNA. Hence, the exon and alternative splice sites are cell specific. It is noted that the claims omit an actual full exon by reciting “a cell specific sequence” which entails simply a set of nucleotides. This exacerbates the lack of description set forth below as it creates an even larger genus.
The disclosure teaches the following, the start codon is followed by a constitutive splice donor, a branch comprising sequence, an alternative splice acceptor, an exon, an alternative splice donor site, a branch comprising sequence and a constitutive splice acceptor site. The exon is not positioned such that expression will result, it is out of frame with the start codon. In a specific mammalian cell type, the splicing will remove the exon linking the start to the gene and expression can ensue in the proper vector with a promoter that is either also cell specific or is constitutive. This arrangement is below. It is called SLED (splicing linked expression design).
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Absent this arrangement, the structures as recited will not provide the adequate function as required in the disclosure.
Secondly, to be cell specific as is required in claim 1 but especially in claim 7, the disclosure teaches that the “SLED” requires identification of the cell specific exon to be functional. Applicants provide “[0173] Two proof-of-concept plasmids were generated. First, a plasmid that selectively expresses GFP in neurons and a second plasmid that selectively expresses GFP in photoreceptors”. These sequences are provided on page 56 and shown on the next page. Besides this, there is only guidance on how to identify others. Figure 1 suggests that such exons are limited in cell type to neuronal based on criteria below.
(¶0142) For the first criterion, a splicing event must be above 30 percent spliced in (PSI) in the cell type of interest and near 0 PSI in other non-target cell types that may express a SLED construct.
And those selected were shown in Table 2 wherein only cells associated with neuronal cells are provided. Hence, applicants disclosure only supports neuronal specific exons.
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So, the instant claims lack description for two reasons, first the components as recited do not meet their intended goal as defined by the disclosure. Secondly, the SLED constructs identified that selectively target excitatory and inhibitory cortical and hippocampal neurons, as well as cortical astrocytes and oligodendrocytes are specific to the process applicants have created to identify cell specific exons and suggest that applicants could identify others. However, the instant claims are not drawn to methods of creating or identifying introns that contain exons that are selectively identified in a cell type “cell type exon”. Rather, the claims require an identified cell type exon. To this end, with applicants process, they have only disclosed a neuron specific and a photoreceptor specific exon. Applicants own requirements and criteria demonstrate that this is a limited descriptive element wherein the claims broadly and incompletely claim the inventive elements. The claims lack adequate description to link structure to these required functions. The Court indicated that while applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a precise definition of a representative number of members of the genus, such as by reciting the structure. Structural features that could distinguish the compounds of the claimed genus from others not encompassed by the genus are missing from the disclosure. In this case, there are specific elements referenced but the claims reference these structures with broad generic functional terms that represent a large and diverse genus of elements. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is needed. Since the disclosure fails to describe common attributes or characteristics that identify members of the genera, and because the process demonstrates that the genera does not exist, the claims lack adequate Written Description.
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, 12, 19, 20, 22, 27, 41, 43, 50 and 57 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hagiwara and Takeuchi (US 20130137099) as evidenced by Clancy et al (Nature Education, 2008, pages 1-5).
Hagiwara and Takeuchi teach as construct an alternative splicing reporter system that comprises a start codon (see dot in figure 6 constructs) that also comprise in order, constitutive splice sites flanking the intron cassette, an alternative splice acceptor site a cell specific exon, an alternative donor site wherein the start codon and the cell specific exon are out of frame. Figure 6b demonstrates the cell specificity. This satisfies claims 1, 41 and 43.
As to branch sites, these are inherent in a splicing event and without them splicing does not happen. Hence, even though the term does not appear explicitly it is an inherent part of the splicing mechanism and as the sequences are spliced in Hagiwara, it comprise the branch sequence (as evidenced by Clancy et al, see How splicing occurs).
As to claim 12 and 50, there is no indication that there exists a premature codon, in fact the text teaches the design avoids early premature termination (see e.g. ¶0262).
As to claim 19, 20, 22, 27 and 57, the construct comprises a gene of interest downstream of the intron cassette. The gene encodes a detectable moiety and is part of a vector(see below).
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Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 7, 12, 19, 20, 22, 27, 41, 43, 45, 50 and 57 are rejected under 35 U.S.C. 102(a)(1) unpatentable over Hagiwara and Takeuchi (US 20130137099) as evidenced by Clancy et al (Nature Education, 2008, pages 1-5) in view of Marengo and Garcia-Bianco (US 20130254909).
Similar to Hagiwara and Takeuchi, Marengo and Garcia-Bianco teach as construct an alternative splicing reporter system that demonstrates splicing in a cell specific manner. The disclosure teaches cell specific exons for skeletal muscles (figure 1 and Table 2 thus adding to the teachings of Hagiwara and Takeuchi and providing the teachings relevant for claims 7 and 45.
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to use the cell specific exon of Marengo and Garcia-Bianco in the system of Hagiwara and Takeuchi. Such a modification would have resulted in a method encompassed by claims 7 and 45. As noted above: 1) Both patents teach cell specific splicing wherein the vectors comprise a cell specific exon; 2) Hagiwara and Takeuchi with specificity the components that are claimed but only demonstrate the construct in prostate cells but 3) Marengo and Garcia-Bianco teach the cell specific exon in skeletal muscle cells. Missing from Marengo is the specifics of the construct that are claimed. While believed to be inherent, the description in Hagiwara and Takeuchi provides the exact teachings and hence demonstrates what is known in the art. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the expanded method would allow improved treatment.
Conclusion
No claims allowed.
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/MARIA MARVICH/ Primary Examiner, Art Unit 1634