DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 71-90 are pending.
Election/Restrictions
Applicant’s election without traverse of group 1 in the reply filed on 07/24/2026 is acknowledged.
Claims 74-82 and 85-90 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/24/2026.
Claims 71-73 and 83-84 are examined.
Claim Rejections - 35 USC § 112
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 71-73, 83-84 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claims 71-73 are directed to nucleic acid based inhibitory molecule for targeting and inhibiting the gene expression of a pathogenic transcript variant of PSEN2, while claims 83 and 84 directed to tagged polynucleotide complementary to a pathogenic transcript variant of PSEN2.
The broad claims encompass the large genus: any reagents that target any pathogenic transcript variant of PSEN2 and inhibit their gene expression. The specification of instant application indicates that reagent comprises any inhibitory nucleic acid molecule.
An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc).
The specification as files failed to provide adequate written description of the claimed genera because it does not provide adequate written description of reagents that target pathogenic transcript variant of PSEN2 and inhibit their gene expression. The written description requirement can be summarized as follows-
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical
properties, by functional characteristics coupled with a known or disclosed correlation between structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within a genus, one must describe a sufficient number of species to reflect the variation within the genus. What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. In an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
The specification as filed disclosed a limited number of pathogenic variants of PSEN2. Paragraph 0010 of the specification discloses exon 9B as transcript variant of PSEN2 and includes the sequences set forth in SEQ ID NOs 2, 3, 4, and 5 for the exon 9B variant. The specification further discloses the pathogenic transcript variant of PSEN2 include a transcript with the inclusion of 77 bp of the intronic sequence prior to exon 6. The 77 bp intronic sequence includes the sequence as set forth in SEQ ID NOs 6 and 7. Table 1 of instant application also discloses two additional PSEN2 variants, K115Efs and N141I. Thus, the specification identifies particular pathogenic variant of PSEN2 but does not provide representative species or common structural characteristics sufficient to support the broad genus encompassed by the claimed invention. The specification of instant application identifies exon 9B, 77 bp of the intronic sequence prior to exon 6, K115Efs and N141I as pathogenic variant of PSEN2. However, the specification provides nucleotide sequence information for only exon 9B (SEQ ID NOs: 2-5) and 77 bp of the intronic sequence prior to exon 6 (SEQ ID NOs: 6-7). For the remaining transcript variant, the specification does not provide sequence information nor fully described structurally. Furthermore, the specification does not provide any other identifying characteristics of the claimed genus except that they are all “pathogenic” and are abnormally spliced transcript that differ from wild-type PSEN2 transcript and can alter PSEN2 function or expression.
The specification as filed discloses a limited number of reagents with generality (e.g., inhibitory nucleic acid molecule) that targets a pathogenic transcript variant of PSEN2 and inhibits their gene expression. For example, paragraph 0011 of instant application discloses antisense oligonucleotides, short hairpin RNA (shRNA), small interfering RNA (siRNA), and/or microRNA (miRNA) as inhibitory nucleic acid molecule that hybridize to a portion of the pathogenic transcript variant of PSEN2. Such a description does not provide any specific structure that would be common among the members of the claimed genus of reagents. Claim 72 of instant application recites reagent has “sufficient complementary” to the pathogenic variant of PSEN2. The specification further defines “sufficient complementarity” functionally as at least 70% sequence complementary (paragraph 0062). For example, an 18-nucleotides miRNA satisfying the 70% complementarity requirement could contain approximately 13 nucleotides complementary, while the remaining 5 nucleotides may vary, thereby encompassing numerous different sequences. The specification as filed, however, does not identify structural features common to the encompassed inhibitory nuclei acid molecules, does not identify which nucleotide position may be varied and which are fixed while retaining inhibitory activity, an does not provide a representative number of sequences across the different class of inhibitory nucleic acids disclosed.
The prior art demonstrates that pathogenic PSEN2 variants encompass a large and structurally diverse genus. For example, Cai et al. 2015 (Clinical interventions in aging, 1163-1172, “Cai”) teaches 38 PSEN2 mutations and reported that only 17 of them were predicted to be disease causing. The reported mutations include structurally different types, including frameshift mutations and numerous nonsynonymous substitutions occurring at different positions of PSEN2 (see table 1). Moreover, different mutations have been reported to produce different biological effects. For example, T122P, N141I, M239I, and M239V, cause an increase in the amount of Aβ peptide whereas T122R, S130L, and M239I were found to alter calcium signaling (see “PSEN2 mutations” section). Furthermore, table 1 of Cai listed multiple biological effects of PSEN2 pathogenic mutations. Similarly, Xiao et al. 2021 (Frontiers in aging neuroscience, 13: 695808, “Xiao”) reported 63 PSEN2 variants, of which 7 and 6 variants were classified as pathogenic and likely pathogenic, respectively (see “PSEN” section under result). Different mutations or variant types were reported by Xiao for pathogenic variants of PSEN2 including missense, splicing, and frameshift (see table 2).
An art by Kole et al. 2012 (Nature reviews Drug discovery, 11:125-140, “Kole”) further demonstrates the RNA-targeting reagents vary in structure and are diverse in structure-function relationship. Kole describes distinct reagents, including siRNAs, antisense oligonucleotides, splice-switching oligonucleotide, translation-suppression oligonucleotides, and external guide sequences and these reagents do not share common structural characteristics. Although these reagents can recognize target through sequence-specific base pairing, they differ in structure, mechanism of action, and the state of gene expression at which they act. For example, siRNA and antisense oligonucleotide can induce enzymatic degradation of target mRNA, whereas splice-switching oligonucleotides acts on pre-mRNA to alter splicing and translation-suppression oligonucleotides inhibit translation process. Table 1 of Kole describes multiple reagents, their mechanism of action, outcome, and state of gene expression at which they act (pre-mRNA or mRNA).
Because there are large number of reagents and pathogenic transcript variant of PSEN2 gene with varying structure and function, disclosure of only a limited number of reagents and variants is not reasonably representative of the full scope of the claimed genus. Furthermore, the specification does not identify any common structural or functional characteristics shared across the claimed genus of reagents and pathogenic transcript variant of PSEN2 that would allow and artisan to recognize that the inventors and/or applicant were in possession of the entire claimed genus at the time of filing.
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 71 is 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 71 is directed to a composition comprising a reagent that targets a pathogenic transcript variant of PSEN2. The phrase “thereby inhibiting gene expression” recite a resulting effect of the claimed reagent but it is unclear the phrase merely defines a functional characteristic of the claimed composition, or it requires method to achieve the recited result. Since the claim is directed to a composition but further recites phrase “thereby inhibiting” which indicates a resulting effect of a method, the metes and bound of the claimed composition is unclear.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 71-73 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Mcswiggen (WO2005003350A2, published 13 January 2005).
Mcswiggen teaches compounds, compositions, and methods useful for modulating gene expression of several genes including presenilin 2 (PS-2) by using RNA interference (RNAi) using small nucleic acid molecules (abstract).
Regarding claim 71, Mcswiggen teaches several small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi) against beta-secretase (BACE), amyloid precursor protein (APP), PIN-1, presenillin 1 (PS-1) and/or presenillin 2 (PS-2) gene expression (line 10-17 of page 2). Furthermore, Mcswiggen teaches that the invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions associated with Alzheimer's disease (line 4-6 of page 2).
Mcswiggen teaches that the RNAi embodiments are directed to PS-2 or PSEN2, including mutant genes and splice variants thereof, in the context of proteins associated with Alzhemiers disease (line 10-20 of page 9). Thus, Mcswiggen teaches targeting variant PSEN2 transcript with the disease. Mcswiggen further teaches that these genes are associated with the progression, development, or maintenance of disease, including Alzheimer disease (line 15-20 of page 9). Mcswiggen also teaches small nucleic acid molecules, including siNA, siRNA, dsRNA, miRNA, and shRNA, for modulating PS-2 gene expression ( line 10-17 of page 2), Accoardingly, Mcswiggen teaches a reagent for targeting mutant or splice variant of PSEN2 transcript associated with Alzheimer’s disease and inhibition of PSEN2 gene expression.
Regarding claim 72, Mcswiggen teaches several small nucleic acid molecules, including siNA, siRNA, dsRNA, miRNA, and shRNA, for modulating PS-2 gene expression ( line 10-17 of page 2). Accordingly, Mcswiggen teaches the second alternative of claim 72, wherein the reagent comprise at least one of the inhibitory nucleic acid molecule, a short hairpin RNA (shRNA), a small interfering RNA (siRNA), or a microRNA (miRNA).
Regarding claim 73, Mcswiggen teaches that siNA molecules (reagent) interact with target RNA molecules and down-regulate expression of target gene. Mcswiggen further teaches that the RNA molecule of the invention can be expressed from transcription units inserted into DNA or RNA vectors (line 18-25 of page 83). Mcswiggen expressly teaches that the recombinant vectors can be DNA plasmids or viral vectors and comprise adeno-associated virus, retro virus, adenovirus, or alphavirus (line 18-25 of page 83). Furthermore, Mcswiggen teaches that the antisense region of the PSEN2 siRNA construct comprises a sequence complementary to specific PSEN2 sequences (line 9-17 of page 13).
Claims 83 and 84 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Braggin et al. 2019 (Annals of clinical and translational neurology, 6:761-777, “Braggin”, cited in IDS#6).
Regarding claim 83, Braggin teaches method for analyzing a pathogenic transcript variant, PSEN2 K115Efs*11, which is associated with Alzheimer disease (Abstract and Figure 2B).
Braggin further teaches droplet digital PCR (dPCR) for determining the level of PSEN2 K115Efs*11 transcript. Table 2 of Braggin identifies primers for amplifying PSEN2 K115Efs*11 region and Fig. 2C reports dPCR analysis of cDNA to compare PSEN2 K115Efs*11 transcript copy numbers. Thus, the primers are used to amplify a copy cDNA of the PSEN2 K115Efs*11 mRNA transcript. Braggin, further teaches fluorescent detection of the amplified nucleic-acid produce using the QuantStudio System (see “three-dimensional quant studio dPCR” section of materials and methods).
To further verify that the dPCR primers amplify the exon-containing region of the PSEN2, sequence alignment was performed between the PSEN2 K115Efs*11 dPCR primers as disclosed by Braggin and the human PSEN2 transcript variant 1 (NM_000447.2). The alignment demonstrates 100% identify between the primer and nucleotide 797-817 of NM_000447.2. As shown in the annotated transcript sequence, the nucleotide 797-817 are located within the exon spanning nucleotides 787-925. Thus, the Braggin dPCR antisense primer specifically anneals to an exon sequence of the PSEN2 transcript.
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Regarding claim 84, Braggin teaches that QuantStudio 3D instrument detects the targeted nucleic acid sequence by using FAM dye-labeled probes.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SURAJ SAPKOTA whose telephone number is (571)270-0842. The examiner can normally be reached Monday-Thursday 7am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram R Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Suraj Sapkota
Patent Examiner
AU 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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