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 .
Application Status and Election
Claims 1-16 are pending. Applicant’s election without traverse of group I (claims 1-7 is acknowledged. Applicant elects the species of Group A: “inhibiting expression and influencing the protein” and Group B: “siRNA”. Claims 5 and 8-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.
Examination on the merits commences on claims 1-4 and 6-7.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. Specifically, the incorporation by reference statement in the specification filed 12/27/22 is defective because it refers to a file entitled “NewApp_0421350059_SequenceListing.xml” with file size 21KB, which is equivalent to 21588 bytes. However, USPTO records indicate that the file size is actually 21114 bytes.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Warning
Applicant is advised that should claim 2 be found allowable, claim 3 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(b)
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 1-4 and 6-7 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, “administering the composition comprising, as an active ingredient, the inhibitor of the expression,” However, “the composition” that is administered as well as “the inhibitor” of the expression lacks antecedent basis. Therefore, the metes and bounds of the claim is unclear and the claim is indefinite.
Claims 2-4 and 6-7 are also rejected under 35 USC 112 (b) by virtue of their dependency on claim 1 without remedying the indefiniteness.
Claim Rejections - 35 USC § 112(a) – Written DescriptionThe 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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-3 and 6-7 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.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “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 the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
The claims are drawn to a method of treating or alleviating Alzheimer's disease, comprising administering a composition comprising, as an active ingredient, an inhibitor of the expression of the Atlastin 2 (ATL2) protein, to a subject in need thereof. These claims are not limited to any definition of “ATL2 inhibitor” provided in the disclosure. The specification has not adequately described the entire genus of these gene modulators for the following reasons.
Size and Breadth of Genus
The claimed language does not limit the structure of the ATL2 inhibitor, and therefore could encompass any means, directly or indirectly, for inhibiting ATL2. The specification teaches working examples of siRNA therapeutic oligonucleotides within the genus of “ATL2 inhibitors”. However, in the art, other non-nucleic acid agents are known to contribute to the binding and regulation of RNA transcripts as well as regulation at the DNA and transcriptional level which can affect gene expression (See e.g., Cheung, Vivian G., and Richard S. Spielman. "The genetics of variation in gene expression." Nature genetics 32.4 (2002): 522-525.). Additionally, small organic molecules other than small nucleic acids are also known in the art to be able to bind to and regulate RNA transcripts (See e.g., Warner et al., Nature Reviews Drug Discovery (2018), 17: 547-558). As such, the genus of “ATL2 protein expression inhibitors” is extensive and diverse and includes chemical and biological molecules in variable combinations with variable size, structure, and folding patterns such as nucleic acids including shRNA, miRNA, siRNA, dsDNA, short hairpin RNA, or other agents such as proteins, small organic molecules, enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, radiation phototherapy, kinase enzymes, chemical inhibitors, fusion proteins, and monoclonal antibodies, and chromatin modifiers like histone acetyl transferases and deacetylases, as well as epigenetic modifiers like DNA methyltransferases, among others.
Species disclosed in the Specification
Figure 7 and Example 7 from the specification (page 12) teaches siRNA ATL2 inhibitors via quantifying mitochondrial membrane potential in the H4PS1M146vcell line before and after treatment with tetracycline or transfection with ATL2 siRNA. The Specification (pg 16) also teaches ATL2 inhibitors such as the inhibitor of the expression or activity of the ATL2 gene may be one or more selected from the group consisting of microRNA (miRNA), small interference RNA (siRNA), short hairpin RNA (shRNA), a peptide nucleic acid (PNA), an antisense nucleotide, and a ribozyme, which specifically bind to the mRNA of the ATL2 gene and may be the siRNA.
Although the specification discloses potential embodiments of ATL2 inhibitors, the specification fails to sufficiently describe representative species, i.e. structure or secondary structures, for the skilled artisan to predict what other molecules for example can function in ATL2 protein expression inhibition or how the structures relate to the function of inhibiting gene expression.
Species Disclosed in the Art
The genus of “gene inhibitor” and “gene promoter” is diverse in the art and includes biological molecules described in the specification as well as genome editing compositions that knock down or knock out the a gene, including CRISPR-Cas reagents, transcription activator-like effector nuclease (TALEN) reagents, or zinc finger nucleases (ZFN) reagents. Such inhibitors can be used by themselves or in combination for gene inhibition.
Regarding nucleic acids as ATL2 gene inhibitors, Kipnis teaches treating neurodegenerative diseases such as Alzheimer’s with inhibitors including small molecules, antisense nucleic acids, interfering RNA, shRNA, siRNA, aptamers, and ribozymes which can target the Atlastin GTPase2 gene for reduced protein expression of the ATL2 gene ([0019], Table 2, pg 88 line 3, claim 52; Kipnis, J., US-20210311076-A1, published 10/7/21).
Regarding general nucleic acids gene modulators, Wang teaches that the ability to predict nucleic acid hybridization (i.e., via “rational design”) is generally limited to the use of unmodified nucleic acids, and that many broadly employed chemical modifications to DNA and RNA have not been included in predictive models (pg. 2, para. 1 and pg. 14, para. 1; Wang et al., 2022, PLOS ONE, 17(5), e0268575). Wang teaches thermodynamic models of hybridization for nucleic acid molecules with phosphorothioate linkages, where each linkage modification decreases duplex stability (pg. 13, para. 4) Wang teaches that backbone and sugar ring modifications, in conjunctions with nucleotide sequence, would likely require a combinatorially large (and synthetically intractable) set of duplexes to fully characterize (pg. 13, para. 3). Therefore, it is unpredictable that nucleic acid hybridization without a rational design incorporating thermodynamics, phosphorothioate linkages or backbone/sugar ring modifications would successfully promote nucleic acid binding.
Regarding such non-nucleic acid based inhibitors, given the lack of structure-function relationship in proteins, the skilled artisan could not predictably design a protein that would bind to a particular RNA transcript for RNA mediated gene expression inhibition. This is evidenced by Hentz (Hentz et al., Nature Reviews Molecular Biology (2018), 19: 327-341) and Warner, cited above. Hentz teaches RNA-binding proteins (RBP) can interact with RNA through defined RNA-binding domains to regulate RNA metabolism and function, establishing a functional crosstalk between proteins and RNA (Fig. 1 pg 328). However, Hentz teaches that binding of RBPs to RNA constantly changes, where the composition of RNA interactomes is context-dependent, responds to stimuli, and has regulation of binding activity by multiple agents (pg 331 co 2 para 2). Hentz teaches long non-coding RNAs lncRNAs are currently assumed to participate in the recruitment of transcription factors or chromatin-modifying complexes ---or inhibit protein complexes, however, these functions break with convention by indicating that RNAs may regulate RBP function rather than be regulated by RBPs (Fig. 1b pg 328). Given this dynamic regulation of functional crosstalk between proteins and RNA with context dependent response to stimuli, it is not predictable that a person of ordinary skill in the art could design any inhibitor to bind a particular ATL2 mRNA transcript for the purpose of gene expression inhibition without knowledge of that structure function relationship.
Given that the prior art establishes there is substantial variation within the genus ATL2 inhibitors, Applicant fails to adequately describe a sufficient variety of species to reflect the variation within the genus. Furthermore, the description of a representative number of species from the specification is not representative of the entire genus. Given the lack of guidance in the art and specification regarding common structural characteristics shared by members of the genus and lack of predictability of undefined nucleic acids, proteins, and small molecules as sufficiently inhibiting gene expression, the ATL2 inhibitors in the specification disclosure are not sufficient to show that the Applicant was in possession of all such at the time the invention was filed. However, given evidence in the art and specification regarding oligonucleotides siRNA ATL2 inhibitors, Examiner interprets these as sufficiently predictable ATL2 inhibitors within Applicant’s written description.
Dependent claims
Other than claim 4 which recites the elected species of siRNA ATL2 protein expression inhibitor, the dependent claims of claim 1 do not further limit the genus of ATL2 inhibitors so as to resolve the issues above, and therefore lack adequate written description for the reason outlined for claim 1.
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.
Claim(s) 1-4 and 6-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kipnis (Kipnis, J., US-20210311076-A1, published 10/7/21), claim 2 and 3 as evidenced by GenBankATL2 (GenBankATL2, atlastin-2 isoform 5 [Homo sapiens], accession NP_001317388 XP_011531321, https://www.ncbi.nlm.nih.gov/protein/1060099103?sat=49&satkey=12143486, retrieved 12/29/25, revision 10/11/20, printed as pg 1/2 to 2/2), claims 6 and 7 as evidenced by Liang (Liang, Jin Rui, et al. "Atlastins remodel the endoplasmic reticulum for selective autophagy." Journal of Cell Biology 217.10 (2018): 3354-3367) and Ferro (Ferro-Novick, Susan, Fulvio Reggiori, and Jeffrey L. Brodsky. "ER-phagy, ER homeostasis, and ER quality control: implications for disease." Trends in biochemical sciences 46.8 (2021): 630-639.)
Regarding claim 1, Kipnis teaches a method of diagnosing and treating neurodegenerative disorders, specifically Alzheimer’s disease (abstract) by detecting and/or inhibiting an upregulated target gene (claim 1 and [0006]), specifically Alzheimer’s disease (claim 66 and [0021]), where the fold change of the upregulated target gene relative to control is measured (Table 2). Kipnis teaches wherein the agent or inhibitor targets the upregulated Atlastin GTPase2 gene (ATL2) from Table 2 (pg 88 line 3, claim 52).
Regarding claims 2 and 3, Kipnis is silent as to the sequence of the ATL2 gene being inhibited, however, GenBankATL2 teaches instant SEQ ID NO: 1 sequence is the ATL2 gene in homo sapiens (pg 1-2).
Regarding claim 4, Kipnis teaches wherein the agent or inhibitor for treating the neurodegenerative disease is an siRNA for the upregulated target Atlastin GTPase2 gene (ATL2) gene from Table 2 (pg 88 line 3, claim 52).
Regarding claim 6, Kipnis is silent as to the influence of target ATL2 gene expression inhibition on the co-localization of endoplasmic reticulum (ER) binding with mitochondria, however this co-localization would be expected absent evidence to the contrary, particularly given the integral role of ATL2 in ER morphology and co-localization disclosed by Liang et al., and Ferro et. al. Liang teaches Atlastins are key positive effectors and targets of ER-phagy where Atlastins are ER-resident GTPases are needed in ER membrane morphology, and where Atlastin-depleted cells have decreased ER-phagy (abstract). Liang further teaches Atlastin’s role in ER-phagy requires a functional GTPase domain and proper ER localization, both of which are also involved in ER architecture (abstract). Liang teaches the three Atlastin family members functionally compensate for one another during ER-phagy and that Atlastins interact with the key FAM134B ER-phagy receptor, such that depletion of Atlastins represses ER-autophagy (abstract). Ferro teaches that FAM134B is involved in degradation at ER-mitochondrial contact sites of co-localization (pg 637 para 4) and supports Liang by also disclosing that the ATL proteins, ATL1, ATL2, and ATL3, substitute for each other during ER-phagy and remodel the ER to facilitate fragmentation during autophagosomal engulfment (pg 632 para 2). Regarding claim 7, the disruption of the co-localization of endoplasmic reticulum (ER) binding with mitochondria, just described by Lian and Ferro, would be expected, absent evidence to the contrary, to also substantially disrupt mitochondrial function thus inhibit the known marker of cellular health, mitochondrial superoxide.
Conclusion
No Claims are allowed.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637