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
Acknowledgement is made of Applicant’s CON of US Application
17/740382 filed on 10th May 2022 and Applicant’s claim to Domestic Benefit of earliest provisional application 63/186838 filed on 11th May 2021.
The priority date of instant is therefore, 05/11/2021.
Election/Restrictions and Amendments
Applicant’s election without traverse of the following invention
Species A = liver disease; Species A1 = NASH; Species B = SEQ ID NO: 26, and Species C = Cas9 in the reply filed on 21st Aug, 2026 is acknowledged.
Claims 3, 41, and 95 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Election was made without traverse in the reply filed on 21st Aug, 2026.
Status of Claims
Claims 1-2, 11-12, 15-18, 20-26, 28-29, 32-33, 42, 44, and 92-94 are currently pending and are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/13/2025 and 07/16/2026 have been considered. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The following is noted: ref in line 6 of the IDS of 5/13/2025; i.e., WO 2020010181, cites the name of patentee as Clarin et al., However, the front page of the document names patentee as Klarin et al.,.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
In the instant case, the abstract of the disclosure is objected to because:
it contains language which can be implied, specifically in the form of the word “provides” (i.e., provides methods) [emphasis added].
it is less than 50 words.
It does not mention “PDE3B variant” which is an essential feature of the invention.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because of the following informalities: Starting on Pg. 62 the applicants disclose an example titled, “Example 1: Loss of Function of the Gene Encoding PDE3B is Associated Lower Liver Fat, and Lower Risk of Liver Injury, Liver Disease and Type 2 Diabetes”. Since only 1 example is disclosed, the recitation of “1” in Example 1 is unnecessary.
Further, the title of the example should recite, “Example: Loss of Function of the Gene Encoding PDE3B is Associated with Lower Liver Fat, and Lower Risk of Liver Injury, Liver Disease and Type 2 Diabetes.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 22-26, 28-29, 32-33, 41-42, 44, and 93-94 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.
Claims 22-24 are rejected because the term “standard dosage amount” render the claim indefinite. As per MPEP 2173.05(b) II, that gives guidance on reference to a standard that is variable, the term “standard dosage amount” in claims 22-24 is a relative term which renders the claim indefinite. In instant case, the amount relies on several unspecified determinants (i.e., condition being treated, drug being administered, etc.) and particularly because it also serves to determine how much of the PDE3B inhibitor compound is administered (if at all).
Although the specification recites that the therapeutic agents can be reduced by about 10-90% in a heterozygous PDE3B pLOF individual compared to a wildtype reference individual (page 41, lines 14-25, and spanning pages 41-42), there is no direction as to what the wildtype reference individual should be given. Additionally, the specification indicates that agents can be given at various time intervals and at the same or different doses (¶ spanning pages 42-43); however, it is still not clear from these teachings what that “standard dosage amount” would be.
The art also does not provide guidance on what a “standard dosage amount” would be. Even the well-known standard hyperglycemia/diabetes drug insulin does not have a “standard dosage amount”. A web article from 2020 indicates that although a starting dosage for long-lasting insulin is about 0.2 units for every 2.2 pounds, the dose may go up 2-4 units every 3 days until the individual reaches their fasting blood sugar target, which is in the range of 80 to 130 mg/dL (Linda Rath, What Are Insulin Dosages for Type 2 Diabetes, WebMD (2025), https://www.webmd.com/diabetes/diabetes-insulin-dosages [retrieved October 8, 2026], 2 pgs.). Likewise, dosages of Metformin are also titrated to determine the desired effects (The dose of this medicine will be different for different patients., pg. 6, 1st line; Metformin (Oral Route), https://www.mayoclinic.org/drugs-supplements/metformin-oral-route/description/drg-20067074, [retrieved October 8, 2026], 11 pgs.).
This indicates that there is no “standard dosage amount” because the dosage amount should be titrated based on an individual’s response, which is variable. Given that in the claimed method, the therapeutic agent must also be given in combination with a PDE3B inhibitor, which is presumed to also cause at least a decrease in blood lipid levels, it would not be clear to the skilled artisan what dose is considered the “standard dosage amount” for any of the agents listed in dependent claims 42 and 93.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
The following claim language for claim 22 is suggested in order to avoid the indefinite phrase:
A method of treating …, wherein the subject is suffering from liver disease, the method comprising the steps of: …. and when the subject is PDE3B reference, then administering a therapeutic agent that treats or inhibits the liver disease and a PDE3B inhibitor… .
Regarding claim 44, a method is a series of steps. Claim 44 recites: determining or having determined the presence … The recitation of “or” means either one of: determining or having determined is optional. Therefore, if considering the option of “having determined the presence …” leaves the claim with no active step. Therefore it is confusing what steps are to be performed in the method.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 44 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature without significantly more. The claim recites “identifying a subject having an increased risk of developing a liver disease... the method comprises: determining … the presence or absence of a Phosphodiesterase 3B (PDE3B) predicted loss-of-function or missense variant nucleic acid molecule”. The claim describes the naturally occurring relationship between the expression of a biomarker (Phosphodiesterase 3B (PDE3B) ) and the presence of liver disease.
The broadest reasonable interpretation of claim 44 as a whole was established and then analyzed as below under 35 U.S.C. 101 for patent-eligible subject matter:
Regarding step 1, Is the Claim to a Process, Machine, Manufacture or Composition of
Matter? YES. The claim is directed to a method as recited below.
Claim 44 recites, “… the method comprises: determining … the presence or absence of a Phosphodiesterase 3B (PDE3B) predicted loss-of-function or missense variant nucleic acid molecule”.
Regarding step 2A prong one, Does the Claim Recite an Abstract Idea, Law of Nature, or Natural
Phenomenon? YES. The claim is directed to a law of nature.
Regarding the law of nature, the claim refers to a method of screening for a biomarker (variant status of PDE3B). Claim 44 further recites “wherein: when the subject is PDE3B reference, then the subject has an increased risk of developing the liver disease or type 2 diabetes; and when the subject is heterozygous or homozygous for a PDE3B predicted loss-of-function or missense variant, then the subject has a decreased risk of developing the liver disease or type 2 diabetes.” which refers to a law of nature because it focusses on the naturally occurring correlation between PDE3B and a disease state. This naturally occurring correlation is a judicial exception.
Regarding step 2A prong two, Does the Claim Recite any Additional Elements that Integrate the Judicial Exception into a Practical Application? NO.
It is noted that claim 44 does not recite any additional elements of the method. Therefore, this lack of additional element(s) does NOT integrate the judicial exception into a practical application. See MPEP 2106.04 II A: If, however, the additional elements do not integrate the exception into a practical application, then the claim is directed to the recited judicial exception (Step 2A: YES), and requires further analysis under Step 2B (where it may still be eligible if it amounts to an ‘‘inventive concept’’). For more information on how to evaluate whether a judicial exception is integrated into a practical application, see MPEP § 2106.04(d)(2).
As directed, we move to analysis under Step 2B “the Inventive Concept”:
Regarding step 2B, Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO.
It is noted that claim 44 does not recite any additional elements. Therefore, this lack of additional element(s) makes the claim ineligible under 35 USC § 101.
Thus, the claimed invention does not recite patent eligible subject.
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.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lord (US 20220054548 A1) as evidenced by American Liver Foundation webpage on the internet <Autoimmune Liver Diseases - American Liver Foundation> 3 pgs. [retrieved on 5th Oct 2026].
Regarding claim 1, Lord teach an antisense inhibitor to PDE3B to treat inflammation ([0005] and [0008]). Lord teach such methods are also appropriate for the treatment of any other disease in which in which PDE3B level or activity is increased or upregulated or a disease associated with or characterized by aberrant or excessive PDE3B ([0011]: Thus, the present invention further provides a method of treating autoimmune disease in a subject, said method comprising the step of administrating an effective amount of an agent which inhibits or reduces PDE3B levels (e.g. protein or mRNA levels) or activity, to said subject.). As evidenced by the liver foundation at <Autoimmune Liver Diseases - American Liver Foundation>, pg. 1, a liver disease called, Autoimmune hepatitis, is a type of autoimmune disease affecting the liver.
Thus, Lord’s method of treating a disease with an inhibitor of PDE3B anticipates instant claim 1.
Claims 1 and 2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Guo (Guo et al., Int J Med Sci. 2018 Jul 30;15(11):1194–1202., IDS of 5/13/2025) as evidenced by niddk.nih.gov website at <Nonalcoholic Fatty Liver Disease (NAFLD) & NASH - NIDDK> 2 pgs. [retrieved on 5th Oct 2026].
Regarding claims 1 and 2, Guo teach effects of a Chinese medicinal formula, BNG-1, on phosphodiesterase 3B expression, hepatic steatosis, and insulin resistance in high fat diet-induced NAFLD mice (title). Guo teach BNG-1-mediated reduction of hepatic PDE3B expression and increased PDE3B expression in adipose tissues may be associated with imbalanced oxidative/antioxidative status and metabolic profiles in those HFD-fed mice (pg. 1200, R col., last sentence). BNG‑1 significantly reduced hepatic steatosis (reduced liver fat content compared to HFD only mice, in a dose dependent manner, Table 3) and improved insulin resistance (Insulin sensitivity improved significantly in BNG 1–treated mice, as measured by standard metabolic assays, figure 3) in high‑fat diet–induced NAFLD mice, alongside changes in phosphodiesterase 3B (PDE3B) expression (down regulated hepatic PDE3B protein levels, figure 2). Significantly, Guo teach BNG-1-mediated reduction in abnormal ALT levels (a liver enzyme often elevated in inflamed hepatocytes) compared to high‑fat diet (HFD) + saline controls, suggesting less hepatic injury and inflammation (figure 3).
As evidenced by niddk.nih.gov website at <Nonalcoholic Fatty Liver Disease (NAFLD) & NASH - NIDDK>, NAFLD is an umbrella term that includes NASH (pg. 1). As evidenced by Fielding (Fielding and Angulo, Curr Hepatology Rep (2014) 13:151–158), further distinction and characterization of NASH includes signs of inflammation in the latter (pg. 1, R col., 2nd para, 2nd sentence).
Thus, it can be inferred from Guo’s method of treating NAFLD resulting in a decrease in inflammatory markers (liver enzymes) that Guo’s method is a method of treating NASH, and thus anticipates instant claims 1 and 2.
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 nonobviousness.
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(s) 11-12, 17, 20-21, 44 and 92 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo (Guo et al., Int J Med Sci. 2018 Jul 30;15(11):1194–1202., IDS of 5/13/2025) as evidenced by niddk.nih.gov website at <Nonalcoholic Fatty Liver Disease (NAFLD) & NASH - NIDDK> 2 pgs. [retrieved on 5th Oct 2026] as applied to claims 1 and 2 above in view of Klarin (WO 2020010181, IDS of 5/13/2025).
The teachings of Guo are described above and apply.
Guo had not taught the method further comprising detecting the presence or absence of a PDE3B predicted loss-of-function or missense variant nucleic acid molecule encoding a human PDE3B polypeptide in a biological sample from the subject.
However, before the effective filing date of instant invention, Klarin had taught an association between various genetic variants as a result of loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site, i.e., predicted loss-of-function (pLOF) variants, with, inter alia, lipid disorders (Abst., brief summary). Klarin discover that the loss-of-function variant of phosphodiesterase 3B (PDE3B) which results in a truncated, non-functional protein (Arg783Ter, wherein the arginine at position 783 has been mutated to a stop codon; coded for by transcript rs150090666) is associated with protection from coronary artery disease (association between pLoF in PDE3B with HDL and TG, [0131]; Fig. 4A-C). Klarin demonstrates an individual homozygous for the PDE3B Arg783Ter allele (i.e., “human knockout”) were associated with reduced risk for coronary artery disease as a result of HDL (Desirable) cholesterol of 73 mg/dL and Triglycerides 56 mg/dL ([0228]-[0229]), thus demonstrating that homozygous loss-of-function is not lethal and suggesting a positive association of pLOF variants of PDE3B with good (healthy) liver metabolism.
Regarding claims 11 and 12, Klarin teach a method of altering expression of at least one gene product, wherein the at least one gene product is a gene product from a PDE3B loss of function variant, wherein the method comprises administering a) a guide RNA that hybridizes with a target sequence, wherein the target sequence comprises the PDE3B loss of function variant, and b) a Cas protein or gene encoding a Cas protein, whereby the guide RNA targets the target sequence and the Cas9 protein cleaves the nucleic acid molecule which comprises the PDE3B loss of function variant, whereby expression of the at least one gene product is altered (claim 39).
Regarding claim 17, 44, and 92, Klarin teach methods of detecting and screening for one or more PDE3B variants. Klarin’s methods comprise: obtaining a sample from a subject; detecting whether one or more PDE3B loss of function or damaging variants is present in the sample; diagnosing the subject as having a greater likelihood of responding to PDE3B inhibitors when there is an absence of the one or more PDE3B loss of function or damaging variant; and administering an effective amount of a PDE3B inhibitor to the subject (Abstract, claims 9-12, 20).
Regarding claim 20, Klarin disclose various pLoF PDE3B. See Figure 2 showing pLoF mutations i.e. frameshift, splice donor/acceptor, stop gain.
Regarding claim 21, Klarin identify 15 pLoF mutations associated with lipids at a genome-wide level of significance, including a protein-truncating variant of PDE3B i.e. Arg783Ter or rsl50090666 (Fig. 24 and 25).
It would have been obvious to a person of ordinary skill in the art, before the time of the effective filing date, to determine whether an individual has one or more PDE3B loss of function variants and administer a PDE3B inhibitor to the individual to treat or prevent a liver disease if the individual DOES NOT have a PDE3B loss of function variant with a reasonable expectation of success because Klarin teaches that PDE3B LOF variants, specifically Arg783Ter, is associated with a better lipid profile and that a PDE3B inhibitor, such as cilostazol, can mimic the phenotype of normal lipid profile in individuals WITHOUT the PDE3B LOF variant and because a PDE3B inhibitor would not be effective, or at least less effective, in individuals with a truncated, non-functional variant of PDE3B. Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to introduce the teachings of Klarin into the method of treating NAFLD (and thus NASH) where a correlation between expression of PDE3B (variants) and the disorder are seen, as this would simply be the use of a known technique in the art, namely the use of a method of detecting and screening for one or more PDE3B variants, wherein said technique is used in the same way with predictable results. See MPEP 2143 I (D).
Thus, Guo in view of Klarin make obvious instant claims 11-12, 17, 20-21, 44, and 92.
Claim(s) 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo (Guo et al., Int J Med Sci. 2018 Jul 30;15(11):1194–1202., IDS of 5/13/2025) in view of Klarin (WO 2020010181) as evidenced by niddk.nih.gov website at (<Nonalcoholic Fatty Liver Disease (NAFLD) & NASH - NIDDK> 2 pgs. [retrieved on 5th Oct 2026]) as applied to claims 11-12, 17, 20-21, 44 and 92 above and further in view of Mali (Prashant Mali et al., RNA-Guided Human Genome Engineering via Cas9.Science339,823-826(2013), GenBank (GenBank, Homo sapiens PDE3B mRNA, NM_ NM_000922.4, revision Apr 15 2021, retrieved Oct 5 2026, 7pgs).
The teachings of Guo and Klarin are discussed above and apply.
Specifically in the rejection of claim 11, it was discussed that Klarin taught a method of altering expression of at least one gene product, wherein the at least one gene product is a gene product from a PDE3B loss of function variant, wherein the method comprises administering a) a guide RNA that hybridizes with a target sequence, wherein the target sequence comprises the PDE3B loss of function variant, and b) a Cas protein or gene encoding a Cas protein, whereby the guide RNA targets the target sequence and the Cas9 protein cleaves the nucleic acid molecule which comprises the PDE3B loss of function variant, whereby expression of the at least one gene product is altered (claim 39).
Neither Guo nor Klarin had taught the length of the gRNA or sequence of the gRNA.
However, before the effective filing date, i. the various recited accession numbers for the PDE3B gene were known in the prior art in Genbank, and ii. CRISPR-Cas for genome editing is a mature field and one of skill in the art knows the teachings of Mali with respect to Cas9 mediated genome editing with gRNAs. As per the well-known rules of gRNA design taught by Mali:
Rational design of gRNAs is robust and allows for targeting of any DNA sequence of interest with few constraints beyond the presence, in the target DNA, of a GG dinucleotide (PAM) adjacent to the targeted sequence (pg. 823 middle column, last para).
Thus, the genomic sequence must be of the form GN20 GG (Fig. 1 legend).
The requirement for the PAM (protospacer-adjacent motif) sequence is Cas-dependent (pg. 826 left column, first para).
A -NGG following the 20–base pair (bp) spacer region is for SpCas9 (pg. 3 supplementary info).
Some mismatches but not in the 3’ end of the spacer are tolerated (pg. 4 supplementary info).
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See the FASTA format of NM_000922.4 with instant SEQ Id NO: 26 highlighted (OA Appendix I), attached. Thus, one skilled in the art would know to look for GG dinucleotide, as this is the required PAM for Cas9 and further nucleotides in the 5’-region, such as the GG dinucleotide, are not in the seed region and therefore, inconsequential for CRISPR-Cas9 recruitment.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to try to make a guide RNA using the gRNA design system of Mali along with the GenBank mRNA sequence in order to target PDE3B. Before the effective filing date of Applicant’s invention, Mali taught a design need for gRNAs which direct Cas9 to the target of choice. GRNA targeting systems rely on a finite number of identified parameters such as target length, limited RNA nucleotides, combinations of nucleotides, and nucleotide length less than 20nt but ideally ~ 13nt, with a finite number of identified, predictable sequences. The length of human PDE3B mRNA is ~ 5995 nucleotides long and gRNAs are ~13 nucleotides. In the case of PDE3B there are 262 GG-dinucleotides (OA Appendix II). Of these ~50% do not have the required 13-bp stretch free of GG that would serve as potential gRNAs. Thus, further eliminating the available choices of sequences for gRNA. Thus, there are ~3000/13 = 230 possible 13-mers that can target known RNA with 100% identity. As such, there are finite number of identified solutions evidenced by the GenBank sequences. The large, but finite number of possible solutions becomes much smaller and their function even more predictable once the skilled artisan makes use of the known screening tools such as BLAST to eliminate off-target bindings. It would have been obvious to try guide sequences from NM_000922.4 to target a PDE3B because Mali demonstrates that given a known target, gRNA can be generated within their design system to influence gene expression with a measured and predictable outcome and because Klarin taught it is possible to target PDE3B with gRNA/Cas9, further establishing a motivation to “try” the sequences to find optimal candidates. The skilled artisan would have had a reasonable expectation of success using Mali’s gRNA design system to make gRNA targets for NM_000922.4 of the PDE3B gene because Mali teaches the known parameters of successful gene targeting such as ~13 nucleotide length upstream of the GG-dinucleotide. Thus, Mali’s gRNA design system to generate sufficiently a gRNA to PDE3B from a known target would yield gRNA which predictably suppresses the PDE3B gene. See MPEP 2143 I (E).
Thus, Guo and Klarin in view of Mali and GenBank make obvious instant claims 15-16.
Claim(s) 18, 42, and 93-94 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo (Guo et al., Int J Med Sci. 2018 Jul 30;15(11):1194–1202., IDS of 5/13/2025) in view of Klarin (WO 2020010181, IDS of 5/13/2025) as evidenced by niddk.nih.gov website at (<Nonalcoholic Fatty Liver Disease (NAFLD) & NASH - NIDDK> 2 pgs. [retrieved on 5th Oct 2026]) as applied to claims 11-12, 17, 20-21, 44 and 92 above and further in view of Lotta (US 20220184114 claiming priority to provisional 63233258 filed 8/14/2021).
The teachings of Guo and Klarin are discussed above and apply.
Regarding claim 18, Klarin had further taught, a method comprising: a. obtaining a biological sample from a subject; b. detecting whether one or more PDE3B loss of function variants are present in the sample; c. diagnosing the subject as having a greater likelihood of responding to PDE3B inhibitors when there is an absence of the one or more PDE3B loss of function variants; and administering an effective amount of a PDE3B inhibitor/antagonist to the subject (claim 10). Klarin further taught wherein the compound is cilostazol (claim 14). As evidenced by Oh, (Oh (Oh, Y. J., et al., (2018). Cilostazol Improves HFD-Induced Hepatic Steatosis by Upregulating Hepatic STAMP2 Expression through AMPK. Molecular pharmacology, 94(6), 1401–1411), cited in the 102 rejection of claim 1), Cilostazol is used in the treatment of liver disorders (title).Thus, Klarin contemplate treating subjects that do not have a loF variant of PDE3B as “reference” ; i.e., as subjects that must be treated with PDE3B inhibitors, in order to gain the protective effect against lipid disorders seen in the individuals who have the PDE3B Arg783Ter allele or the subjects may be treated with a liver-disease treating agent such as cilostazol, thus treat liver disease with a PDE3B inhibitor.
Neither Guo nor Klarin teach methods where the subject is also administered a therapeutic agent that treats or inhibits a liver disease.
However, before the effective filing date of instant invention, Lotta taught a comprehensive association study of pLOF genetic variants in INHBE in human subjects especially with respect to lipid profiles (Table 11). Lotta had taught a method of treating a subject having NASH by administering a nucleic acid inhibitor to Inhibin Subunit Beta E (INHBE) to the subject (title, claim 1). Lotta taught the method further comprising detecting the presence or absence of an INHBE variant nucleic acid molecule encoding an INHBE predicted loss-of-function polypeptide in a biological sample from the subject (claim 22). Lotta taught the method wherein when the subject is INHBE reference, the subject is also administered a therapeutic agent that treats or inhibits metabolic disorder (NASH) in a standard dosage amount, and when the subject is heterozygous or homozygous for an INHBE variant nucleic acid molecule encoding an INHBE predicted loss-of-function polypeptide, the subject is also administered a therapeutic agent that treats or inhibits metabolic disorders or cardiovascular diseases in a dosage amount that is the same as or lower than a standard dosage amount (claim 23).
The method comprises administering an inhibitory agent and further administering additional therapeutic agents (claim 19). Such a method has several advantages. See recitation from pg. 100 of the provisional document:
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer a therapeutic agent that treats or inhibits a liver disease to the PDE3B reference subject along with a PDE3B inhibitor, if the individual DOES NOT have a PDE3B loss of function variant with a reasonable expectation of success because Klarin teaches that, a PDE3B pLOF variant is positively correlated with a better lipid profile (positive liver function) and Lotta had taught a strategy of treating liver disease in a similar scenario where another genetic variant (INHBE) was found to have lower susceptibility to liver disease and in the absence of that pLOF genetic variant, the subject was also administered an additional agent specific for liver disease. Thus, one of ordinary skill in the art would be motivated to administer a PDE3B inhibitor to a subject that does NOT express PDE3B pLOF mutation in order to inhibit its expression and bring the subject population to the same level as a population with a pLOF of PDE3B, and then treat both subject population with a therapeutic agent that is known to treat liver disease; i.e., utilize the strategy of Lotta in the method of Guo and Klarin. See MPEP 2143 I (C).
Regarding claim 42 Lotta teach the therapeutic agent is chlorothiazide (pg. 122 of the provisional document).
Regarding claims 93 and 94 Lotta teach the therapeutic agent for NASH is obeticholic acid (pg. 123 of the provisional document).
Thus, Guo and Klarin in view of Lotta make obvious instant claims 18, 42, and 93-94.
Claim(s) 22-26 and 28-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo (Guo et al., Int J Med Sci. 2018 Jul 30;15(11):1194–1202., IDS of 5/13/2025) in view of Klarin (WO 2020010181, IDS of 5/13/2025) as evidenced by niddk.nih.gov website at (<Nonalcoholic Fatty Liver Disease (NAFLD) & NASH - NIDDK> 2 pgs. [retrieved on 5th Oct 2026]) and further in view of Lotta (US 20220184114 claiming priority to provisional 63233258 filed 8/14/2021).
Regarding claims 22-26 and 28-29, the teachings of Guo, Klarin and Lotta discussed above as applied to claims 11-12, 17-18, 20-21, 44 and 92 are similarly applied to claim 22-26.
Thus, Guo and Klarin in view of Lotta make obvious instant claims 22-26 and 28-29.
Claim(s) 32-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo (Guo et al., Int J Med Sci. 2018 Jul 30;15(11):1194–1202., IDS of 5/13/2025) in view of Klarin (WO 2020010181, IDS of 5/13/2025) as evidenced by niddk.nih.gov website at (<Nonalcoholic Fatty Liver Disease (NAFLD) & NASH - NIDDK> 2 pgs. [retrieved on 5th Oct 2026]) as applied to claims 22-26 above and further in view of Mali (Prashant Mali et al. ,RNA-Guided Human Genome Engineering via Cas9.Science339,823-826(2013), GenBank (GenBank, Homo sapiens PDE3B mRNA, NM_ NM_000922.4, revision Apr 15 2021, retrieved Oct 5 2026, 7 pgs).
Regarding claims 32-33, the teachings of Guo, Klarin and Lotta discussed above as applied to claims 22-26 and 28-29 are similarly applied to claims 32-33.
Neither Guo nor Klarin nor Lotta had taught the length of the gRNA or sequence of the gRNA.
However, as discussed for claims 15-16 above, Mali in view of GenBank make obvious the sequence of gRNA for PDE3B.
With the same motivation and reasonable expectation of success, as discussed for claims 15-16 above, Guo, Klarin, and Lotta in view of Mali and GenBank make obvious instant claims 28-29 and 32-33.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Conclusion
No claims are allowed.
Correspondence
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/ Examiner, Art Unit 1635
/CATHERINE KONOPKA/ Primary Examiner, Art Unit 1635
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