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.
Election/Restrictions
Applicant’s election of Invention Group I (claims 2-4 and 11-16 drawn to a method of improving, preventing and/or treating a disease that is Metabolic syndrome or Fatty Liver disease) and Species A ( claims 11, 12, 14 and 15 drawn to a Regnase-1 inhibitor that is a gene therapy drug targeting Regnase-1 or a nucleic acid capable of inhibiting the expression of Regnase-1) in the reply filed on 09/16/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 8-10, 13 and 16 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election is considered made without traverse in the reply filed on 09/16/2025.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Application Status
This Application is a National Stage entry under 35 U.S.C.§ 371 of PCT/JP2020/048154 filed 12/23/2020.
Preliminary amendments to claims filed 07/13/2022 are hereby acknowledged. Claims 1, 5-7 are cancelled. Claims 11-16 are newly added. Claims 2-4 and 8-10 are currently amended.
Claims 2-4, 8-16 are pending. Claims 8-10, 13 and 16 are withdrawn from consideration after election requirements. Therefore, claims 2-4, 11-12, 14 and 15 are under consideration in this office action.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 06/23/2022, 07/20/2022, 06/26/2023, 07/05/2023, 12/13/2023, 02/23/2024, 04/15/2024 and 02/07/2025 are hereby acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by
the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, or listed on a submitted IDS, they have not been considered.
Drawings
The Drawings submitted on 06/23/2022 are acceptable.
Specification
The disclosure is objected to because of the following informalities: The disclosure uses the terms “CRISPER/Cas9” instead of “CRISPR/Cas9” (see page 15, [0019]).
Appropriate correction is required.
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 2-4, 11-12 and 14-15 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.
Regarding claims 2 and 3, the claims recite “ administering a therapeutically effective amount of a Regnase-1 inhibitor”. However, the disclosure does not provide with a definition of what would be a “therapeutically effective amount” of the agent.
Claims 4,11-12 and 14-15 are dependent of claims 2 or 3. These claims does not remedy the deficiencies of claims 2 and 3, therefore they are rejected as well.
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.
Claims 2-4, 11-12 and 14-15 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.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 2 recites “A method of improving metabolic syndrome, comprising: administering a therapeutically effective amount of a Regnase-1 inhibitor to a subject in need thereof”.
Inhibitors comprise a large genus with multiple species, including naturally occurring or synthetic molecules, such as protein fragments, e.g. antibodies, small molecules inhibitors, nucleic acid inhibitory molecules, mimics or mutant proteins; it is expected in the disclosure, examples and naming of such agents, and a reduction into practice using different types of inhibitors.
Claim 3 recites “ A method of preventing and/or treating fatty liver disease, comprising: administering a therapeutically effective amount of a Regnase-1 inhibitor to a subject in need thereof”. Claim 4, depending on claim 3, further narrows the disease to nonalcoholic fatty liver disease or nonalcoholic steatohepatitis.
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 or genetically predisposed to a condition.
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.
Claims 11-12 and 14-15 recite “ 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 siRNA, shRNA, miRNA and/or mimics, and also nucleic acids involved in creating mutations in Regnase-1 gene and/or deleting the Regnase-1 gene, such as constructs comprising a CRISPR-Cas system with guide RNAs, or a plasmid comprising a nucleic acid encoding a truncated or mutated version of Regnase-1 allowing for homologous recombination and deletion of wild-type gene. 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.
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) 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) 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) 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) 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). 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) 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) 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) 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) 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 Scientic, 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 in claim 2, 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.
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.
(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.
Claims 2-4 are rejected under 35 U.S.C. § 102(a)(2) as being anticipated by
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) as evidenced by Esposito (Esposito, E. et al. “The metabolic syndrome and inflammation: association or causation?”. Nutrition, Metabolism and Cardiovascular Disease, vol. 14 (2004), pp: 228-232) and Pachos (Pachos, P. et al. “Nonalcoholic fatty liver disease and metabolic syndrome”. Hippokratia, Vol. 12, No. 1 (2009), pp: 9-19).
The applied reference has a common Assignee and Inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. §102(a)(2). This rejection under 35 U.S.C. §102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. §102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. §102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. § 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Regarding claims 2-4, it recites “A method of improving metabolic syndrome, comprising: administering a therapeutically effective amount of a Regnase-1 inhibitor to a subject in need thereof”. 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 describe the disease as “a disease associated with Regnase-1” 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]).
As evidenced by Esposito, Akira’s teachings include metabolic syndrome, since it is an inflammatory disease. Esposito states “ All the parameters included in the diagnosis of the metabolic syndrome are associated with a low-grade inflammation state. Elevated levels of C-reactive (CRP), an easily measured inflammatory biomarker, has been proven to be a strong, independent predictor of both incident diabetes and incident cardiovascular disease. Obesity, insulin resistance, and diabetes are associated with a proinflammatory state” (see page 229, right column, second section). Esposito also states “A growing body of evidence implicates adipose tissue in general, and visceral adiposity in particular, as key regulators of inflammation” (see page 231, left column, second paragraph). Esposito concludes that “There has been a recent explosion of interest in the notion that chronic low-grade inflammation and activation of the innate immune system are closely associated with the metabolic syndrome” (see page 231, “Conclusions” section, first paragraph).
As evidenced by Pachos, Akira teachings’ include a method for preventing NAFLD, since Nonalcoholic fatty liver (NAFLD) is a component in the cluster of metabolic syndrome (see abstract). Pachos teaches Metabolic syndrome’s diagnosis as the presence of three or more following components: abdominal obesity, elevated triglycerides, reduced HDL-C level, hypertension, and impaired fasting glucose (see page 9, right column, first paragraph). Pachos teaches that “Chronic inflammation is frequently associated with the MS and the main inflammatory mediators are adipocytokines and FFAs” (see page 10, “Pathophysiology” section, third paragraph).
Pachos teaches NAFLD is strongly associated with obesity and especially intra-abdominal fat, which also correlate to insulin resistance (see page 13, left column, third paragraph).
Therefore, Akira anticipates claims 2-4.
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.
Claims 2-4, 11-12 and 14-15 are rejected under 35 U.S.C. § 103 as being unpatentable over Kolattukudy (Kolattukudy, P. et al. US 2007/0142288 A1, published June 21, 2007), Pachos (Pachos, P. et al. “Nonalcoholic fatty liver disease and metabolic syndrome”. Hippokratia, Vol. 12, No. 1 (2009), pp: 9-19), 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), 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).
Regarding claims 2 and 3-4, 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.
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 does not teach metabolic syndrome or improvement of metabolic syndrome. Kolattukudy does not teach treating or preventing fatty liver disease.
However, Pachos teaches that “Chronic inflammation is frequently associated with the MS and the main inflammatory mediators are adipocytokines and FFAs” (see page 10, “Pathophysiology” section, third paragraph). FFAs are Free Fatty Acids; they are released , as adipocytokines, from adipocytes/adipose tissue (see page 10, “Pathophysiology” section, third paragraph and Figure 1).
Pachos teaches that Nonalcoholic fatty liver (NAFLD) is a component in the cluster of metabolic syndrome (see abstract). Pachos teaches that “Primary NAFLD is associated with insulin resistance and metabolic syndrome” (see page 10, “Nonalcoholic Fatty Liver Disease definition” section, second paragraph). Pachos teaches metabolic syndrome’s diagnosis as the presence of three or more following components: abdominal obesity, elevated triglycerides, reduced HDL-C level, hypertension, and impaired fasting glucose (see page 9, right column, first paragraph).
Pachos teaches NAFLD is strongly associated with obesity 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).
Younce teaches that in mammal cells, MCPIP1 also regulates adipogenesis (see title, abstract, and Figure 1).
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date, to have used the anti-MCPIP1 siRNA taught by Kolattukudy to treat inflammation, in a method to improve metabolic syndrome, since Pachos, Pydyn, Habacher and Younce teach a correlation between obesity and metabolic syndrome, and also a correlation between body fat, adipogenesis and MCPIP1 expression. Metabolic syndrome being associated with chronic inflammation due to release of proinflammatory cytokines in excess from adipose tissue, the method of treating inflammation is applicable to improving metabolic syndrome. It would have been obvious to use an anti-MCPIP1 siRNA in a method to prevent or treat fatty liver since NAFLD is a component of metabolic syndrome as taught by Pachos, and there is a correlation between obesity, NAFLD and MCPIP1 expression as taught by Pydyn. One with ordinary skills in the art, motivated in reducing intraabdominal fat in a subject with metabolic syndrome, to prevent development of fatty liver, could have applied the method of treating inflammation to improving metabolic syndrome, with a reasonable expectation of success and arrived at the claimed invention.
Regarding claims 11-12 and 14-15, the combination of references rendered the elements of claims 2-4 obvious.
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).
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 the use of siRNA against MCPIP, with a clear negative effect on adipogenesis and lipid droplets accumulation in preadipocyte cells (see Figure 3).
The obviousness of combining the references Kolattukudy, Pachos, Pydyn, Habacher and Younce is described above.
Conclusion
No claim is allowed.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636