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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant’s claims to priority from International Application PCT/JP2020/048154 filed 12/23/2020, and from Foreign Applications JP 2020-087250 filed 05/19/2020 and JP2019-232338 filed 12/24/2019, is hereby acknowledged.
Application Status
This Application is a National Stage entry under 35 U.S.C.§ 371 of PCT/JP2020/048154 filed 12/23/2020.
Amendments to claims filed 03/31/2026 are hereby acknowledged. Claims 1-2, 4-16 are cancelled. Claim 3 is currently amended.
Therefore, claim 3 is under consideration in this office action.
Any objection or rejection not reiterated herein has been overcome by Applicant’s amendments and is therefore withdrawn.
Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follows.
Drawings
The Drawings submitted on 06/23/2022 are acceptable.
Specification
Marked-up copy and Substitute clean copy of the Specification are hereby acknowledged and are acceptable.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claim (claim 3) in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Because these claim limitations are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C.112, sixth paragraph, they are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being
interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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.
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.
Claim 3 is 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.
The claim comprises limitations that invoke 35 U.S.C. 112(f), but the specification
does not link structure to function. Thus, the specification does not disclose adequate structure to perform the claimed functions.
Regarding claim 3, it recites “wherein the gene therapy drug targeting a Regnase-1 gene is a viral vector containing genome editing means targeting the Regnase-1 gene”. The genome editing means are not sufficiently described in the
Specification.
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 3 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.
Regarding claim 3, it recites “wherein the gene therapy drug targeting a Regnase-1 gene is a viral vector containing genome editing means targeting the Regnase-1 gene”.
The terms “genome editing means” invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. Therefore, the claims are indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function.
For more information, see 37 CFR l.75(d) and MPEP §§ 608.0l(o) and 2181.
The following rejections are maintained, but modified from the Office Action dated 12/31/2025, as necessitated by Applicant’s amendments:
Claim Rejections - 35 USC § 112(a)
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.
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.
Claim 3 is 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.A.3.(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 states 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 function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Nature of the Invention:
Claim 3 recites “A method of treating fatty liver disease, comprising: locally administering or delivering a Regnase-1 inhibitor to the liver of a subject in need thereof, wherein the fatty liver disease is nonalcoholic fatty liver disease or nonalcoholic steatohepatitis, wherein the Regnase-1 inhibitor is a nucleic acid capable of inhibiting the expression of Regnase-1 or a gene therapy drug targeting a Regnase-1 gene, wherein the nucleic acid capable of inhibiting the expression of Regnase-1 is a short interfering RNA against a Regnase-1 gene, a short hairpin RNA against the Regnase-1 gene or an antisense oligonucleotide against the Regnase-1 gene, wherein the gene therapy drug targeting a Regnase-1 gene is a viral vector containing genome editing means targeting the Regnase-1 gene.
As the broad and reasonable interpretation of “ a subject in need” encompasses healthy subjects at risk for a specific condition, it includes healthy Humans exposed to Western diets, pharmaceutical drugs adverse events, or genetically predisposed to fatty liver disease.
It is also expected in the disclosure, examples of different subjects, animal models of diseases and humans in case control studies, exposed to the agent that is a Regnase-1 inhibitor or to a placebo.
Claim 3 recites “ a nucleic acid capable of inhibiting the expression of Regnase-1” and “ a gene therapy drug targeting a Regnase-1 gene”.
It is therefore expected a disclosure of types of nucleic acids that can inhibit the expression of Regnase-1 gene, such as DNA oligonucleotides, gapmers, siRNA, shRNA, miRNA and/or mimics, and also nucleic acids involved as carrier, such as constructs comprising these RNAs, or vectors comprising a nucleic acid encoding a truncated or mutated version of Regnase-1 allowing for homologous recombination and deletion of wild-type gene (template). The nucleic acid can be synthetic or naturally occurring. It is expected a reduction into practice of such species in the disclosure, with the naming of compositions acceptable for improving metabolic syndrome, for treating or preventing fatty liver disease, and an enumeration in residues of each nucleic acid in the compositions.
Therefore, nucleic acid Inhibitors comprise a large genus with multiple species, including naturally occurring or synthetic molecules.
Gene therapy drugs targeting a Regnase-1 gene include, not only antisense RNAs (single and double stranded) RNA, antisense DNA oligonucleotides, gapmers, shRNA, but also guide RNAs for different systems TALEN or CRISPR-Cas; it is expected in the disclosure, examples and naming of such agents, and a reduction into practice using different types of inhibitors, as well as an enumeration in residues of targeted sequences, and inhibitory nucleic acid sequences, for each species.
The State of the Art:
Inhibitors of Regnase-1:
Jeltsch (Jeltsch, K.M. et al. “Cleavage of roquin and regnase-1 by the
paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation”. Nature Immunology, Vol. 15, No. 11 (2014), pp: 1079-1089; previously cited) teaches that Regnase-1 (also known as MCPIP1 or ZC3H12A) is cleaved by MALT1, a paracaspase (see title and abstract). Jeltsch teaches that MALT1 recognizes a consensus sequence within Regnase-1 protein and cleaves it (see Table 1). MALT1 deactivates Regnase-1, and the ectopic expression of the cleavage product is unable to regulate expression or TH17 cells differentiation (see page 1088, “Discussion” section, left column, first paragraph).
Therefore, MALT1 can be reasonably seen as an inhibitor of Regnase-1. A MALT1 recombinant protein or a nucleic acid expressing MALT1 can be used as inhibitor.
Roy (Roy, A. et al. “Antidicer RNAse activity of monocyte chemotactic protein
induced protein-1 is critical for inducing angiogenesis”. American Journal of Physiology and Cell Physiology, Vol. 305 (2013), pp: C1021-C1032; previously cited) teaches that MCPIP inhibits the production of antiangiogenic miRNAs such as miR-20b and miR-34a (see page C1022, left column, third paragraph). Roy also teaches that hypoxia-induced angiogenesis is mediated via MCPIP (see Figure 1). Roy teaches that a siRNA against MCPIP abrogates the ability of MCPIP to induce angiogenesis in hypoxic conditions (see Figure 1). Roy teaches that overexpressing a mutant of MCPIP, MCPIP-D141N also is capable of abrogating MCPIP ability to induce angiogenesis (see Figure 6).
Therefore, overexpressing a mutant MCPIP-D141N in cells counteract the effect of MCPIP, therefore acting as a nucleic acid inhibitor.
Makki (Makki, M.S. et al. “miR-139 modulates MCPIP/IL-6 expression and
induces apoptosis in human OA chondrocytes”. Experimental & Molecular Medicine, Vol. 47 (2015), p:e189; cited previously) teaches that other microRNAs are capable of targeting MCPIP1/Regnase-1 (see title and abstract). Makki teaches that overexpression of miR-139 alters the expression of MCPIP1 in Osteoarthritis (OA) chondrocytes (see page 3, right column, “Results” section, third paragraph). Makki teaches that there is a ‘seed sequence’ in the 3’ UTR of MCPIP1 mRNA (see page 5, left column, second paragraph).
Therefore, Makki teaches the involvement of MCPIP1 in inflammation, and that miR-139 is an inhibitor of MCPIP1 expression.
Yao (Yao, H. et al. “MiR-9 promotes microglial activation by targeting
MCPIP1”, Nature Communications, Vol. 5 (2014), p: 4386; previously cited) teaches that miR-9 downregulates the expression of MCPIP1/Regnase-1 (see title and abstract). Yao teaches that miR-9 regulates MCPIP1 expression in microglia (see page 2, right column, second paragraph). Yao teaches a specific and conserved binding site for miR-9 in MCPIP1 mRNA sequence (see Figure 2A).
Therefore, Yao teaches that there are specific binding sites for miRNA regulation of MCPIP1. Thus, specific sequences of synthetic or naturally occurring inhibitory nucleic acids are necessary to be able to target the gene.
Design of an inhibitory nucleic acid:
Lam (Lam, J.K.W. et al. “ siRNA versus miRNA as therapeutics for gene
silencing”. Molecular Therapy-Nucleic acids, Vol. 4 (2015), p:e252; cited previously). Lam teaches miRNAs are produced in a cell following post-transcriptional processing (Table 1). First the primary miRNA transcript (pri-miRNA) produces a 70-100 nucleotide precursor (pre-miRNA). The pre-miRNA precursors are then processed by Dicer into a 18-25-mer miRNA duplex which associates with RISC and binds to the target mRNA through partial complementary base pairing with the consequence that the target gene silencing occurs via translational repression, degradation, and/or cleavage.
Lam further teaches (see Section “Design of therapeutic siRNA-Strand selection”):
“Since this phenomenon can occur with both siRNA and miRNA,48,49,50 the RNA duplex needs to be carefully designed to warrant correct guide strand selection by the RISC. Two major sequence parameters are known to determine the guide strand selection: (i) the asymmetry rule and (ii) 5′ nucleotide preference; both of which can be applied to … miRNA design.”
Lam also teaches (same paragraph) the asymmetry rule means the guide strand should have a more thermodynamically unstable 5’ end vs. the passenger strand and the 5’ nucleotide preference rule instructs that the guide strand should have a U or A at the 5’ end whereas the passenger strand should always contain C and G at the 5′ end to minimize the risk of being incorrectly selected as a guide strand.
An incorrect loading orientation into RISC results in the intended guide strand being discarded and off-target effects produced since the remaining (intended passenger strand) strand base-pairs to non-intended mRNA (see section “Design of therapeutic siRNA-Strand selection”).
With respect the use of claimed miRNA for in vivo use in a subject, Lam teaches RNA therapies face barriers of stability, delivery challenges, and off-target effects (Main text, third paragraph). Lam teaches synthetic miRNA precursors with longer sequences (from a few extra nucleotides to a full-length pri-miRNA) have been proposed as therapeutic agents and these pri-miRNAs require processing in the nucleus, whereas pre-miRNAs and miRNAs do not, so different strategies are required for delivery of different types of miRNA to their cellular targets (section “Design of therapeutic miRNA”, second paragraph). Lam teaches in section “Design of therapeutic miRNA” (second paragraph) that miRNA has an intracellular site of action, but is poorly permeable across biological membranes ( section “Design of therapeutic miRNA”, second paragraph). Lam teaches viral vectors can be effective for delivery but are associated with serious safety concerns (section “Viral vectors”). Regarding stability, Lam teaches RNA exhibits poor stability and chemical modifications can address that (Section “Chemical modification”).
Ying (Ying, S-Y. et al.” The MicroRNA (miRNA): Overview of the RNA genes
that modulate gene function”. Molecular Biotechnology, Vol.38 (2008), pp:257–268; cited previously) teaches (section,“MicroRNA”) miRNAs are small single-stranded RNA genes possessing the reverse complement of another protein-coding gene’s mRNA transcript. Like Lam, Ying similarly teaches, (same section, second paragraph) miRNA are made from primary transcripts that are processed in the nucleus to precursors, which are then cut by Dicer into shorter miRNAs that are 18-25 nucleotide long (section “Introduction”, first paragraph).
Ying teaches miRNAs suppress gene expression via complementarity to an mRNA target (Section “MicroRNA”, third paragraph):
“miRNAs suppress gene expression based on their complementarity to a part of one or more messenger RNAs (mRNAs), usually at a site in the 3’ UTR. The annealing of the miRNA to the target mRNA inhibits protein translation… [or] triggers the degradation of the mRNA transcript through a process similar to RNAi...” [emphasis added.]
Ying further teaches miRNAs should have complementarity to 8-10 nucleotide of the target mRNA and that experimentally validating miRNAs is necessary (section “Identification”, third paragraph):
“There are numerous new computational methods that provide ways to estimate the total number of miRNA genes in different animals [55–58]. Fundamentally, each program identifies highly conserved genomic non-coding regions that possess stem-loop structures with specific “seed” sequences, and complementarity of the first 8–10 nucleotides… computational techniques may suffer from a high false alarm rate. Therefore, validation of the identified miRNAs by Northern blot analysis and functional study is critical”. [emphases added.]
Altogether the teachings of Ying indicate that a miRNA should comprise complementarity to 8-10 consecutive nucleotides of its target mRNA (i.e., complementarity of the first 8–10 nucleotides) and that experimentally validating miRNA function is necessary to determine whether a given miRNA actually binds its target and functions as intended.
Gorski (Gorski, S. et al. “RNA-based recognition and targeting: sowing the
seeds of specificity”. Nature Reviews/ Molecular Cell Biology, Vol.18 (2017), pp: 215-228; cited previously) teaches that essential to a regulatory RNA’s function is the presentation of short 'seed sequences' in a target (abstract). While regulatory RNAs may vary in length, 1) secondary and tertiary structures are important in target recognition and 2) target binding usually involves partial complementarity with only a short stretch of nucleotides (Fig. 1). For example, duplexes containing 8 nucleotides are unstable, whereas a 20-nucleotide RNA–RNA duplex is nearly irreversible under physiological condition (2nd paragraph). While mismatches are allowed within the seed region, the location of these mismatches can have different effects on guide–target binding: mismatches at nucleotides 2–5 of the guide reduce the association rate more than mismatches at positions 6–8. In the absence of a matched seed sequence, the RNP finds targets more slowly and binds to them less stably (page 219, 1st paragraph, right-side column). For 21-nucleotide miRNA and siRNAs, nucleotides 2–8 make the largest contribution to the energy of target binding, with mismatches at the center of the seed decreasing binding the most (page 224,1st paragraph, left-side column).
Tang (Tang, Q. et al. “RNAi-based drug design: considerations and future
directions”. Nature Reviews in Drug Discovery, Vol. 23, No. 5 (2024), pp: 341-364; cited previously) reviews RNAi designs, including siRNAs that target the liver (see title). Tang also emphasizes that bringing this innovative class of medicines to patients has been riddled with substantial challenge, with delivery issues at the forefront (see abstract). Tang reminds that oligonucleotide-based drugs include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), aptamers and siRNAs (see pages 2 and 3, “Medicinal chemistry of siRNA design” section).
Tang teaches challenges in designing siRNAs, because of masking effects of secondary and/or tertiary structures or RNA-binding proteins at the target sites. Therefore, in silico prediction models for target sites need more advances methods (see page 38, box 2, first and second paragraphs). Tang also teaches that one or more siRNAs can be designed to target same gene, e.g. multivalent scaffolds, that increase the likelihood of specific targeting (see page 39, box 3), or to target more than one gene (see page 40, box 4). Tang teaches that the advantage of multi-targeting siRNA drugs over combination therapies is the predictable biodistribution of drug molecules (box, second paragraph). Tang also teaches specific modifications for siRNAs to alter stability, specificity of target and delivery sites and pharmacodynamics-pharmacokinetics of the molecules (page 3, “Necessity for chemical modifications” section; page 4 “Basic scaffold stabilization” section; page 7, “Fine-tuning siRNA chemistries” section; page 18, “On-tissue target selectivity” section).
Therefore, according to the teachings of Lam, Ying and Tang, specific guidance is needed according to the species of inhibitor used, the target gene and the target organ, especially when designing an inhibitory nucleic acid; an enumeration in residues and a specific pattern of modification are necessary for each type of nucleic acid used to make a composition effective for improving metabolic syndrome, and/or preventing and/or treating fatty liver disease.
Gene therapy and vectors:
Zittersteijn (Zittersteijn, H.A. et al. “A primer to gene therapy: Progress,
prospects, and problems”. Journal of Inherited Metabolic Disease, Vol. 44 (2021), pp: 54-71; cited previously) teaches that there are a variety of therapeutic products that are currently used for genetic diseases (see title and abstract). Zittersteijn teaches that there are several options using viral vectors, retroviral vectors, adenoviral and adeno-associated viral vectors (see abstract, sections 1, 2 and 3). Zittersteijn also teaches that viral and retroviral vectors can lead with serious adverse events in clinical trials (see page 57, right column, second paragraph). Zittersteijn teaches that Adeno-Associated viral (AAV) vectors are attracting much attention because they are not associated with known pathologies (see page 61, section 3, left column). Zittersteijn also states: “However, generating the amounts of functional AAV vector particles needed for in vivo administration to large animal models and patients remains a substantial hurdle in the AAV-based gene therapy field.” (see page 61, right column, second paragraph).
Zittersteijn also teaches that “a gene therapy drug” for targeting expression of a gene encompasses compositions using sequence-specific programmable nucleases for DNA editing (see page 62, section 4). Zittersteijn teaches targeted genome modifications using zinc-finger nucleases (ZFNs) (page 63, section 5), or transcription activator-like effector nucleases (TALENs) (section 6), or CRISPR-Cas9 systems (page 64, section 7). Zitternsteijn also teaches that these systems are the most recent and are in their infancy for use in clinical trials (see page 62, section 4). Therefore, it is important to obtain clear guidance for one of ordinary skills in the art, to be able to reproduce any of the nucleic acid constructs to be used as a composition for treating, or preventing, a disorder.
What the Specification does and does not teach:
The Specification introduces the fact that the invention relates to an agent capable of reducing body fat ( [0001]). The specification is drawn to Metabolic syndrome, which is a cluster including obesity and diabetes mellitus, and manifested in the liver as nonalcoholic fatty liver disease (NAFLD) ([0002]).
The Specification teaches that the inhibitor is “a body fat reducing agent” that is useful for improving metabolic syndrome, and for preventing and/or treating fatty liver disease ([0008]).
The Specification teaches transgenic mice with a floxed Regnase-1 exons 4 to 6 fragment, (after injection of Addgene plasmid # 107787 expressing a Cre recombinase; i.e. AAV.TBG(Thyroxine-binding globulin promoter).Cre) (Figure 1). Figure 2 shows measurement of liver enzymes and lipids in the serum of Regnase-1 deficient mice. Figure 3 shows liver-specific deficient Regnase-1 KO mice and their body weight, adipose tissue weight and liver-to-body weight, compared to control mice. Figures 4 and 5 shows body weight and liver-to-body weight of liver-specific deficient Regnase-1 mice, fed a normal or a NASH diet. Figure 6 shows the comparison after NASH diet, between liver enzymes in serum of normal versus liver-specific deficient KO mice. Figures 7-8 show pathology and histological analysis of liver harvested from mice, control and transgenic. Figure 9 shows serum levels of enzymes and lipids comparing the wild-type mice to KO mice, with or without feeding with a NASH diet.
Figure 10 shows results of Example 4, wherein a siRNA that is commercially available and targeting the mouse Regnase-1 gene (ThermoFisher Scientific, siRNA ID : 170484, catalog # AM16708) is used. A mouse fed NASH diet or control diet, received the AAV expressing the siRNA against Regnase-1 gene or control virus. The accumulation of fat is shown in absence of siRNA against Regnase-1 (Figure 10) .Liver weight is decreased in mice fed a NASH diet and injected with siRNA, pathological/histological observation and staining (figures 12-14) corroborating the data in figure 10.
Therefore, the Specification, with the examples and Drawings shows data for inhibitors that are either a composition for knocking-out Regnase-1 in the liver specifically, or a siRNA against Regnase-1 with activity resulting in same outcome. The Specification presents commercially available vectors and one siRNA without any specifics about it.
However the Specification does not include inhibitors that are small molecule inhibitors, antibodies or other proteins known to inhibit Regnase-1 activity. The Specification does not give details on the siRNA used, no enumeration in residues nor specific chemical modification pattern. The Specification does not presents data on shRNA, miRNA and mimics either. The disclosure does not present a dose-response evaluation to establish the “therapeutically effective amounts” in human and other animal models.
The disclosure does not present any data or method with a gene therapy composition to be used in healthy and/or genetically predisposed humans to prevent fatty liver disease. Also, the claims do not limit this inhibitor agent to a body fat reducing agent.
Therefore, A skilled artisan would not be able to use any other compositions encompassed by claim 3, for targeting mRNA of MCPIP1/Regnase-1 and degrading/inactivating MCPIP1/Regnase-1 mRNA, since they are not disclosed, based on guidance provided in the specification and art at the time of the filing of the application.
Conclusion:
Taking into consideration the factors outlined above, including the nature of the
invention, the state of the art, the guidance provided by the applicant and the specific example, it is the conclusion that Applicant does not possess the whole scope of the claimed invention. There is no specific written example within the Specification that would lead one with ordinary skills in the art to a different conclusion.
Response to Arguments
Applicant's arguments filed 03/31/2026 have been fully considered but they are not persuasive.
In response, Examiner would like to remind that even though the Specification discloses one method and one structure, i.e., a commercially available siRNA from ThermoFisher Scientific, siRNA ID: 170484, catalog# AM16708 (see [0056]), this is the only concrete structure disclosed by Applicant. However, the issue is the broadness of the claim encompassing many different alternatives as inhibitors, while there is no reduction into practice for at least one species of each alternative/group, each one may correspond to a different patentable invention, once each structure is presented in an application.
The following rejection is new, as necessitated by Applicant’s amendment:
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 (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 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 non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 3 is rejected under 35 U.S.C. § 103 as being unpatentable over Akira (Akira, S. et al. US 2022/0125891 A1, published April 28, 2022, benefitting priority from US Application 15/734,885 filing date June 6, 2019; cited previously), in view of Bae (Bae, E.J. et al. “Liver-specific p70S6 Kinase depletion protects against hepatic steatosis and systemic insulin resistance”. The Journal of Biological Chemistry, Vol. 287. No. 22 (2012), pp: 18769-18780), Kolattukudy (Kolattukudy, P. et al. US 2007/0142288 A1, published June 21, 2007; previously cited), Pachos (Pachos, P. et al. “Nonalcoholic fatty liver disease and metabolic syndrome”. Hippokratia, Vol. 12, No. 1 (2009), pp: 9-19; previously cited), Pydyn (Pydyn, N. et al. “Analysis of MCPIP1 level in NAFLD patients”. FEBS Open Bio, Vol. 9 (Suppl. 1) (October, 2019), pp: 65-431 (Poster P-01-007; page 69); cited on IDS submitted on 06/23/2022), Habacher (Habacher, C. et al. “Ribonuclease-mediated control of body fat”. Developmental Cell, Vol. 39 (2016), pp: 359-369; cited on IDS submitted on 06/23/2022; previously cited), and Younce (Younce, C.W. et al. “MCP-1 (Monocyte Chemotactic Protein-1)-induced protein, a recently identified Zinc Finger Protein, induces adipogenesis in 3T3-L1 pre-adipocytes without Peroxisome Proliferator-activated Receptor ɣ”. The Journal of Biological Chemistry, Vol. 284, No. 40 (2009), pp: 27620-27628; previously cited).
Regarding claim 3, Akira teaches that using inhibitors interfering with Regnase-1 activity, whether it is by preventing its phosphorylation or its binding to partners such as TK1, IKKi, Act-I, IKK and IRAK, is an effective way of treating and/or preventing diseases (see title and abstract). Akira also teaches a method of abolishing Regnase-1 expression and activity via targeting exons 5 and 6 using a targeting vector and loxP/Cre system (see Figure 1-2, A). Akira teaches a list of compounds, including antibodies, that are capable of inhibiting Regnase-1 activity (see [0424]-[0429], [0438]-[0439]).
Akira further teaches that the diseases that can be prevented or treated using Regnase-1 inhibitors include “inflammatory diseases” and “autoimmune diseases” (see [0008]). Akira also describes the disease as “a disease associated with Regnase-1” that may be a disease in the following tissues or organs: kidney, lung, skin, liver, heart, pancreas, bone marrow…” (see [0308]).
Akira also teaches that the disease can be a fibrotic disease that is a complication of metabolic disorder (see [0217]).
Akira also teaches that the therapeutic agent can be administered locally, i.e., intralesional, “if desired for local treatment” (see [0329]).
Akira also teaches a viral vector for delivery of the nucleic acid therapeutic agent ([0380]).
Akira does not teach nucleic acid capable of inhibiting the expression of Regnase-1.
However, Bae teaches a method of protecting against obesity-associated hepatic steatosis and systemic insulin resistance using a short hairpin RNA against p70 S6 kinase mRNA delivered using an Adeno0associated virus (AAV) (see title, abstract; page 18770, left column, second paragraph).
And Kolattukudy teaches that their invention “also related to methods for treating disease associated with elevated monocyte chemoattractant protein inducible protein (MCPIP), comprising inhibiting MCPIP expression, activation, nuclear localization or DNA binding ([0012]).
Kolattukudy teaches methods for therapies of a variety of diseases associated with MCPIP using overexpression, gene transfer, protein delivery, inhibition of activation, gene-knockout, inhibition by siRNA (see [0062]).
Kolattukudy teaches that their invention relates to cellular transcription factors that affect inflammation and for methods for their therapeutic use ([0003]-[0004]).
Kolattukudy teaches the use of a pharmaceutical composition comprising an MCPIP inhibitor and this inhibitor can be a siRNA (see Kolattukudy’s claims 18-19).
Kolattukudy also teaches a siRNA against MCPIP1, i.e. “a Regnase-1 inhibitor that is a nucleic acid capable of inhibiting the expression of Regnase-1” (see Kolattukudy’s claims 18-19). Kolattukudy teaches a method of using an anti-MCPIP1 siRNA as a gene therapy drug (see [0062] and claims 18-19).
Kolattukudy also teaches the administering of one or more MCPIP inhibitors compositions locally (see [0066]-[0067]).
Kolattukudy also teaches viral vectors as expression vectors ( [0042]-[0043]).
Pachos teaches clinicopathologic features of Nonalcoholic fatty liver (NAFLD) includes simple steatosis and steatohepatitis (NASH), steatosis being determined by estimation of proportion of hepatocytes containing fat droplets, and NASH features including hepatocellular injury, inflammation and fibrosis (page 10, right column, first paragraph).
Pachos teaches that obesity is present in majority of individuals with NAFLD, it is an independent risk factor and strongly associates with the progression of the disease (see page 11, left column, first paragraph).
Pachos teaches that 30-50% of individuals with steatohepatitis will develop fibrosis, and that insulin resistance (i.e., a metabolic disorder) plays a fundamental role in the pathogenesis of fatty liver (see page 11, left column, second paragraph and “Pathophysiology” section and third paragraph).
Pachos teaches NAFLD is strongly associated with obesity (i.e., a metabolic disorder) and especially intra-abdominal fat, which also correlate to insulin resistance (see page 13, left column, third paragraph).
Pydyn also teaches that MCPIP1 levels in patients with obesity and NAFLD are elevated in peripheral blood mononuclear cells and liver biopsies. Pydyn teaches a positive correlation between MCPIP1 levels and Body Mass Index (i.e. obesity) of patients. Pydyn teaches that MCPIP1 can be considered as a new important player involved in the progression of NAFLD (see abstract).
Habacher teaches that in Caenorhabditis elegans, REGE-1, also known as Regnase-1, MCPIP1 or ZC3H12A, controls body fat and is a regulator of innate immunity as well (see abstract). Habacher teaches that REGE-1 promotes fat accumulation under normal growth conditions (see Figure 2).
Habacher teaches RNAi inhibition of REGE-1 and observes a reduction in body fat (see Figure 2A). Habacher also teaches a connection between REGE-1, inflammation and lipid metabolism (see page 365 left column, first paragraph and Figure 7).
Younce teaches that in mammal cells, MCPIP1 also regulates adipogenesis (see title, abstract, and Figure 1).
Younce teaches the use of siRNA against MCPIP, with a clear negative effect on adipogenesis and lipid droplets accumulation in preadipocyte cells (see Figure 3).
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date, to have combined the teachings of Akira about a method of inhibiting Regnase-1 to treat or prevent diseases, and substituted the antibodies or nucleic acid sequences encoding these antibodies with the nucleic acid inhibitor as taught by Bae. It would have been obvious to one with ordinary skills in the art to have used the anti-MCPIP1 siRNA taught by Kolattukudy, since Pachos, Pydyn, Habacher and Younce teach a correlation between obesity, insulin resistance and NAFLD, and also a correlation between body fat, adipogenesis and MCPIP1 expression. Obesity and insulin resistance being associated with chronic inflammation due to release of proinflammatory cytokines in excess from adipose tissue, the method of treating inflammation taught by Kolattukudy is applicable to treating NAFLD. It would have been obvious to use an anti-MCPIP1 siRNA in a method to treat fatty liver since NAFLD is linked to Obesity and insulin resistance as taught by Bae and Pachos, and there is a correlation between obesity, NAFLD and MCPIP1 expression as taught by Pydyn, Habacher and Younce. One with ordinary skills in the art, motivated in treating obesity complications, insulin resistance and fatty liver, could have applied the method of preventing fatty liver using an inhibitory nucleic acid taught by Bae, to the method of treating inflammation inhibiting MCPIP gene, with a reasonable expectation of success and arrived at the claimed invention.
Response to Arguments
Applicant’s arguments with respect to claim 3 have been considered but are moot because the new ground of rejection does not rely on the same combination of references applied in the prior rejection of record.
And in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In this case, Akira presents a method of treating disease inhibiting Regnase-1, but not with a nucleic acid inhibiting Regnase-1 expression directly. However Akira teaches the fact that a fibrotic disease, that can be a liver disease, could be treated with an agent that interferes with Regnase-1 activity. Bae teaches a method of preventing fatty liver and insulin resistance using a nucleic acid inhibitor specific to the liver, delivered using a viral vector AAV. Kolattukudy teaches an inhibitory nucleic acid for Regnase-1 used to treat an inflammatory disease. Pachos teaches that NAFLD is obesity-derived/associated, and a result of lipid metabolism disorder, inflammation and insulin resistance. Pydyn teaches a positive correlation between MCPIP1 levels and Body Mass Index (i.e. obesity) of patients. Pydyn teaches that MCPIP1 can be considered as a new important player involved in the progression of NAFLD. Habacher teaches RNAi inhibition of REGE-1 and observes a reduction in body fat. Younce teaches the use of siRNA against MCPIP, with a clear negative effect on adipogenesis and lipid droplets accumulation in preadipocyte cells.
Therefore, the abundance of evidence from the combination of references, Akira, Bae, Kolattukudy, Pachos, Pydyn, Habacher and Younce renders the elements of claim 3 obvious.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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