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 .
Claim Status
Amended and new claims 1, 3, 8, 17, 37-39, 41-45, 58, and 97-100 are pending.
Claims 1, 8, 17, 37-39, 41-43, 58, 97-98 and 100 and the species of NASH and SEQ ID NO: 2 are examined in this Action. Claims 3, 44, 45 and 99 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/28/2023.
Priority
All pending claims enjoy the benefit of U.S. provisional application 63/155,327 and 63/159,027, filed on 03/02/2021 and 03/10/2021, respectively.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/07/2026 was filed after the mailing date of the prior non-final action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
35 U.S.C. 112(a): Written Description
Rejection of amended claims 1, 8, 17, 37-39, 41-43, 58, 97-98 is maintained and new claim 100 is rejected as noted below.
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 1, 8, 17, 37-39, 41-43, 58, 97-98, 100 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. Although the specification discloses some ~40,000 sequences of claimed RNF213 inhibitor, the specification does not disclose a single claimed “RNF213 inhibitor” that actually inhibits the expression of RNF213 following hybridization to an RNF213 mRNA in a liver cell of a human subject, as discussed further below.
Claim 1 recites a method of decreasing expression of RNF213 polypeptide in a liver cell in a human following administration of a RNF213 inhibitor to a human subject, wherein the inhibitor comprises one of claimed nucleic acid inhibitor that is fully complementary to an RNF213 mRNA and wherein the subject is RNF213 reference. The specification defines RNF213 reference as “when the human does not have a copy of an RNF213 predicted loss-of-function or missense variant” (par. 25). In light of the specification, the claimed invention encompasses a method of administering any of the claimed RNF213 inhibitor that is fully complementary to a RNF213 mRNA with a subject lacking a copy of an RNF213 predicted loss-of-function or missense variant. Although not recited in claim 1, but in light of the specification, which notes methods of treating a subject having various liver diseases comprising administering an RNF213 inhibitor to the subject (e.g., see pg. 2), the claimed subject matter encompasses treating a disease and the claimed RNF213 inhibitor is therapeutic.
Independent cl. 37 is directed to a method of decreasing expression of RNF213 polypeptide in a liver cell in a human subject comprising 1) determining whether a human subject has a RNF213 predicted loss-of-function or missense variant nucleic acid molecule by genotyping for RNF213 predicted loss-of-function or missense variant nucleic acid molecule and, if the subject is RNF213 reference, then administering a therapeutic agent that treats liver disease and administer to the subject an RNF213 inhibitor, and, if the subject is heterozygous for a RNF213 pLof or missense variant nucleic acid molecule, then administer a lower than standard dose of therapeutic agent and administer an RNF213 inhibitor, wherein the RNF213 pLof or missense variant nucleic acid molecule comprises a nucleic acid molecule encoding claimed variants and the RNF213 inhibitor comprises the claimed nucleic acid inhibitors. Here, there is an explicit aim to treat liver disease in a human subject.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. Although the specification discloses some 40,000 nucleic acid sequences that are fully complementary to the target mRNA, it fails to describe the complete structure of a representative number of species of the large genus that hybridizes to a RNF213 mRNA and that decreases its expression following administration to a human subject.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic is that it is “RNF213 inhibitor.” Such a functional limitation cannot be an identifying characteristic for the claimed diverse genus of molecules since by Applicant’s definition of RNF213 inhibitor or functional equivalent thereof all members of the claimed genus will have that characteristic.
The inventions of Claims 1 and 37 (dependent claims 8, 17, 38, 39, 41, 42, 43, 58, 97, 98 require the use of the inventions of Claim 1 and 37 and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Claim 100 is directed to a method comprising administering an ASN, siRNA or shRNA molecule that is fully complementary to an RNF213 mRNA to a human subject in need thereof, wherein the subject is RNF213 reference. Although claim 100 does not recite the purpose of administering of claimed nucleic acid molecule, as noted above, when the claim is viewed in light of the specification, which discloses method of treating a subject having liver diseases comprising administering an RNF213 inhibitor to the subject (e.g., see pg. 2), the claimed subject matter encompasses treating a liver disease and the claimed RNF213 inhibitor is therapeutic. Further the specification defines “a human subject in need” encompassing a human subject with liver disease. Thus, although a fully complementary claimed nucleic acid inhibitors are described (see claim 8), the specification does not describe any nucleic acid inhibitor that can be administered to a subject in need that binds to and decreases a RNF213 mRNA in an effective manner. Thus each sequence disclosed amounts to a prophetic example. Thus, claim 100 is also rejected for failing to comply with the written description requirement.
Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163).
In conclusion, Applicant’s disclosure lack any claimed RNF213 inhibitor that accomplishes it intended function of reducing RNF213 mRNA in the liver cell of a human subject, the claimed broad genus is not deemed sufficient to reasonably convey to one skilled in the art that Applicant was in possession of the claimed broad genus at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Response to Arguments
Applicant's arguments filed 07/01/2026 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks argue the following:
The Office failed to uphold its burden since it provided “no evidence of record that any of the thousands of sequences of RNF213 inhibitory nucleic acid molecules that Applicant has disclosed would not inhibit the expression of an RNF213 polypeptide in a liver cell in a human subject” (pg. 13). The Remarks cite a Bofill-De Ros reference that discloses that “RNAi is famous for its ability to target ‘any’ sequence.”
The argument is not persuasive.
The Office has met its burden. The MPEP 2163.04 which describes the burden on the Examiner with regard to the Written Description Requirement indicates that the findings need to identify the claim limitation(s) at issue and then establish a prima facie case, which can be “a simple statement such as ‘Applicant has not pointed out where the new (or amended) claim is supported, nor does there appear to be a written description of the claim limitation . . . in the application as filed” may be sufficient and the applicant has not pointed out where the limitation is supported. Here, the prior and this Action have provided a written description analysis and noted that the specification lacks describing any claimed inhibitor that fulfills its claimed function (i.e. of decreasing expression of target mRNA) in a human subject in need thereof, wherein the subject is RNF213 reference (see pg. 3-5, e.g., see concluding paragraph on pg. 5 of action dated 04/02/2026). Listing prophetic examples of sequences that are complementary to regions of target mRNA is insufficient to fulfill the written description requirement, since it does not indicate that the Applicant is in possession of any claimed nucleic acid inhibitor that fulfills the requirement of claimed invention. Thus, the Office has met its burden.
Regarding the Bofill-De Ros et al. (2016, Methods, 103, 157-166), it is not a relevant art since it does not disclose a nucleic acid inhibitor (a RNAi) that decreases expression of RNF213. Further following the quoted statement, Bofill-De Ros writes the following: “However, many issues still need to be considered to ensure potency and specificity of designed shRNAs” (pg. 162) and earlier in the article note “the shRNA field still faces many challenges. Unsatisfactory knockdown efficacy . . . .continue to hamper its applications, often due to flaws in design” (pg. 158). Thus, a skilled artisan understands that just plugging in any shRNA (in a miRNA platform of Bofill-De Ros) does not equate to achieving satisfactory knockdown efficacy. Generally, a skilled artisan understands that just noting a complementary sequence of a transcript does not mean it will inhibit the target mRNA in a cell or in a subject.
Thus, rejection of examined claims is maintained under 112(a).
112a-enablement
Rejection of claims 1, 8, 17, 37-39, 41-43, 58 and 97-98 is maintained and new claim 100 is also rejected, as noted below.
The statute is noted above.
Claims 1, 8, 17, 37-39, 41-43, 58, 97-98, 100 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
When considering enablement of the invention, the Wands factors need to be reviewed, which poses whether the experimentation needed to practice the invention is undue or unreasonable. Determining undue experimentation requires analysis of, but not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
MPEP 2164.03 provides the following:
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling.
Here, the art of record and the specification do not provide sufficient disclosure regarding a method of decreasing expression of RNF213 polypeptide in a liver cell in a human subject, the method comprising administering a RNF213 inhibitor, comprising an antisense nucleic acid molecule (ASN), siRNA or shRNA that is fully complementary to RNF213 mRNA, wherein the subject is RNF213 reference. Thus, due to the lack of guidance, the application “need[s] more detail as to how to make and use the invention in order to be enabling.” And here, the application fails to provide details sufficient to make and use the invention and requires an unreasonable need of experimentation. Thus, the claimed invention is not enabling and the rejection is maintained as discussed below.
In the instant case:
The breadth of the claims/nature of the invention: Claim 1 recites a method of decreasing expression of RNF213 polypeptide in a liver cell in a human subject following administration of a RNF213 inhibitor to a human subject, wherein the inhibitor comprises one of claimed nucleic acid inhibitor that is fully complementary to an RNF213 mRNA and wherein the subject is RNF213 reference, and wherein the RNF213 inhibitor comprises an antisense nucleic acid molecule (ASN), siRNA, or a shRNA that hybridizes to an RNF213 mRNA, and wherein the subject is RNF213 reference. The specification defines RNF213 reference as “when the human does not have a copy of an RNF213 predicted loss-of-function or missense variant” (pg. 9, line 2-3). In light of the specification, the claimed invention encompasses a method of administering the claimed RNF213 inhibitor that hybridizes to a RNF213 mRNA with a subject lacking a copy of an RNF213 predicted loss-of-function or missense variant; thus, under BRI, the subject’s RNF213 is considered wild-type. Although not stated, but in light of the specification, which notes treating a subject having various liver diseases comprising administering an RNF213 inhibitor (e.g., see pg. 2, line 12: “methods of treating a subject having liver disease” and cl. 97 and 98), the claimed subject matter encompasses treating a liver disease. Thus, the Wands factor analysis will focus on treatment of claimed liver disease and/or decreasing expression of a RNF213 following administration of claimed RNF213 inhibitor.
Independent cl. 37 is directed to a method of decreasing expression of RNF213 polypeptide in a liver cell in a human subject comprising 1) determining whether a human subject has a claimed RNF213 predicted loss-of-function or missense variant nucleic acid molecule by genotyping of the subject for RNF213 predicted loss-of-function (pLof) or missense variant nucleic acid molecule and, 2) if the subject is RNF213 reference, then administering claimed dose of therapeutic agent that treats liver disease and administer to the subject an RNF213 inhibitor, and, 3) if the subject is heterozygous for an RNF213 pLof or missense variant nucleic acid molecule, then administer claimed dose of therapeutic agent and administer an RNF213 inhibitor, wherein the RNF213 pLof or missense variant nucleic acid molecule comprises a nucleic acid molecule encoding claimed variants and the RNF213 inhibitor is the claimed nucleic acid inhibitors.
As noted above in the written description rejection, claim 100 attempts to strip the purpose of the claim by reciting “method comprising administering” the claimed nucleic acid inhibitor “to a human subject in need thereof, wherein the subject is RNF213 reference.” However, the enablement requirement is for the claims and “the specification describe how to make and use the invention” (MPEP 2164, first paragraph). Here, the claimed invention viewed in light of the specification which indicates that the present disclosure provides methods of treating a subject having a liver disease, the methods comprising administering an RNF213 inhibitor to a subject.
Thus, the Wands factor analysis will focus the elements of the claimed invention: treatment of claimed liver disease and decreasing expression of a RNF213 following administration of claimed RNF213 inhibitor to a human subject in need and is RNF213 reference.
The state of the prior art:
RNF213: Otten et al. (5/2021, Nature, 594, 111-116) note that RNF213 is the largest recognized human E3 ligase, a mass of about 600 kDa, and is a major susceptibility gene for a cerebrovascular disorder called moyamoya disease (MMD), which is caused by a missense mutation in RNF213 (pg. 113). Further, RNF213 physiological and pathophysiological role is not well understood: an involvement in lipotoxicity, lipid droplet formation, cell death and NF-kB signaling have been reported (pg. 113).
One case study of two patients with MMD, indicates an association with liver disease and a variant RNF213 genotype. Strong et al.’s (5/2021, American Medical J. of Medical Genetics, 185A, 2168-2174) analysis of a couple of children patients with MMD identified RNF213 variants potentially associated with MMD (L4139W, C4856R) and other symptoms, such as “liver disease with elevated aminotransferase [AST],” along with other physiological abnormalities, but indicate that it “is unknown at this time why these patients demonstrate such severe cerebral and extra-cerebral manifestations” and noting that the RNF213 variants identified could be a culprit (pg. 2172). Further, the authors note that it “will be interesting to determine if RNF213 variants can produce exclusively extra-cerebral disease with isolated kidney, liver and skin findings. Such patients would be critical in truly elucidating the biology of RNF213 and the mechanism of disease” (pg. 2173).
Morito and Nagata (JP2020105134, pub date 07/09/2020, of record) disclose that RNF213 (also known as mysterin) is associated with the accumulation of lipid droplets, Morito and Nagata teach that inhibiting or suppressing the expression of RNF213/mysterin by use of siRNA targeting RNF213 leads to decomposition/metabolism of lipid droplets consequently leading to reduction in lipid droplets in cells, and leading the authors to conclude the potential role of these mutations in MMD (par. 6 (pg. 4) and par. 8 (pg. 6) of Espacenet provided machine translation, accessed 07/09/2023, of record). Further, based on its in vitro studies, the authors extrapolate that mysterin inhibitors can be used to treat lifestyle diseases caused by the accumulation of lipid droplets, one such disease is non-alcoholic hepatis, cirrhosis (par. 17).
Nucleic Acid inhibitors: The claims encompass treatment with RNF213 inhibitor comprising antisense nucleic acid molecule (ASN), siRNA, or shRNA that hybridizes to an RNF213 mRNA. It is known that various nucleic acid inhibitors, including siRNAs and antisense oligonucleotide (ASOs), have been approved for human treatment. Usually, prior to human administration, there are series of steps/studies that need to be taken before a siRNA/shRNA/ASN drug can be administered to a human subject. Focusing on one type of nucleic acid inhibitor, an siRNA, Paton (2017, Drugs of the Future, 42, 335-343) discloses steps taken to identify a therapeutic siRNA: 1) identify siRNA(s) that specifically hybridizes with the target gene, ideally in multiple species, including human; 2) conduct bioinformatic analysis to design ~100 siRNAs for cross-species hybridization/activity (pg. 337); 3) conduct in vitro studies to identify a handful of siRNAs with ideal inhibition (i.e. ED50) values (pg. 337); 4) conduct in vivo studies in model organisms (usually includes mice and monkeys) to demonstrate inhibition of target gene using modified siRNA that is sufficiently stable and is protected from in vivo degradation enzymes and effects (pg. 337); 5) identify a delivery vehicle to improve delivery of siRNAs and maximize potency, which either includes further modification of the siRNA or identify a vector to deliver the siRNA to target organ/tissue (pg. 337-338); 6) undergo clinical studies to identify modified siRNAs in delivery vehicle that has least side-effects with optimal outcome (pg. 338-339).
The level of predictability in the art: The level of predictability in the art is low. As noted above under MPEP 2164.03, due to the lack of guidance in the prior art, the application needs more detail as to how to make and use the invention in order to be enabling. However, the specification fails to provide sufficient guidance.
First, as Otten notes that there is a lack of understanding of RNF213: there is uncertainty regarding its cellular and physiological function, and its role in liver disease, and, further, uncertainty whether the inhibition of RNF213 mRNA in a human subject of RNF213 reference will treat any liver disease or NASH. Further, prior art of record does not indicate that therapeutic agents that treat a liver disease would treat a human subject with a liver disease harboring a RNF213 reference, i.e. without a pLoF or missense variant.
Second, although Strong et al. show an association between RNF213 and a liver disease, the authors indicate that it “is unknown at this time why these patients demonstrate such severe cerebral and extra-cerebral manifestations” and indicate that further studies need to be conducted (pg. 2172, 2173). Strong et al. is silent whether RNF213 inhibition would treat the patient with noted liver ailment. Thus, the art of record does not provide studies/suggestion that demonstrate that inhibition of non-variant RNF213 in a human subject or decreasing the levels of RNF213 mRNA treats any liver disease (claims 1, 37) or NASH (claims 97,98). Based on the little information known about the large 600 kDa protein, it is unpredictable whether administration of any one of ASN, siRNA or shRNA that is fully complementary to an RNF213 mRNA of a human subject, who is RNF213 reference, will treat a human subject having any liver disease or decrease the expression of RNF213.
Third, even following extensive in vitro/in vivo studies and optimal outcome in clinical studies, it is still uncertain that the drug may achieve its desired results. Paton article, noted above, discusses the steps of bringing the siRNA drug inclisiran to market, and Zhang (1/2021, Biochemical Pharmacology, 189, 1-12) indicates, despite noting some promising possibilities with siRNA drugs, that “[d]espite inclisiran’s projected success, however, some experts caution that it may not live up to expectations,” that although it decreased the target gene’s expression level, it did not achieve desired outcome, i.e. an improved cardiovascular outcome (pg. 8). Thus, it is unpredictable that inhibiting a transcript’s expression at its optimal level will result in desired physiological outcome, here it is unpredictable whether inhibiting expression of RNF213 in a human subject with RNF reference will treat any liver disease or NASH.
Also, here, the claimed subject matter recites some 40,000 ASNs and siRNAs that are fully complementary, and under BRI and, also, one of skill in the art would expect that all these Markush group species when administered along with a recited dosage of therapeutic agent to a human subject having NASH or any liver disease, will treat the aforementioned disease or decrease expression of a RNF213 by hybridization in a human subject. However, here, the specification does not disclose a specific single a fully complementary siRNA or ASN or shRNA hybridizing to the target mRNA in a human subject, nor disclose an in vitro study to show inhibition of target molecule, nor disclose a study of a human subject treated with recited RNF213 inhibitor(s) that hybridizes to and inhibits expression of target mRNA in vivo and bring about the outcome of treating any liver disease/NASH. Including the results of aforementioned studies would aid a skilled artisan in overcoming the uncertainty regarding the subject matter of the invention.
One of skill in the art is aware of many software platforms that identify exemplary siRNAs, however, Gavrilov (2012, Yale J. Biol. Med., 85, pg. 187-200) points out that “[o]ff-target silencing cannot be ignored in developing siRNA-based therapeutics, and all potential therapeutic siRNA candidate sequences must be heavily tested for perturbation of normal protein expression profiles” (pg. 191).
Exome sequencing studies — Although genome/exome sequence studies are gaining in prominence due to reduced costs, there are still issues concerning the causal link that is suggested between the genetic variation and a disease phenotype. Burgess et al. (2018, Ann. Rev. of Genomics and Human Genetics, 19, 303-327) disclose that an observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of risk factor will have a causal impact on the outcome (correlation is not causation) (Abstract). It could be an issue of confounders, common determinants of the risk factor and the outcome, that give rise to the association (pg. 305).
Another observation noted in the specification is a “strongest variant for AST” is Glu3915Gly, while strongest variant for ALT was an intronic variant that results in Val3838Leu protein mutation. ALT, alanine transaminase, is produced only in hepatocytes and is a “very specific marker of hepatocellular injury,” while AST, aspartate transaminase, is a cytosolic enzyme present in various tissues, such as skeletal muscle, heart muscle, and kidney tissue, not just only liver tissues (Hall and Cash, Ulster Medical Journal, 2012, Table 1). Thus, Hall and Cash caution in using AST levels to evaluate hepatocellular damage and note that AST usually rises in conjunction with ALT to indicate hepatocellular injury (Hall and Cash, 2012, Ulster Medical Journal, 81, pg. 30-36, Table 1). Thus, leading one to question if the putative protective genetic mutations are correlative with AST or ALT levels and not associated with reducing the risk of NASH/liver damage since AST levels are not conclusively tied with status of liver function.
A doctoral thesis by Lin (The Role of Ring Finger Protein 213 in Fatty Acid-induced lipotoxicity, 6/1/2023) evaluating the role of RNF213 in RNF213 knock out (KO) mice in a dietary NASH model indicated that KO mouse livers “show a mild protection phenotype against liver damage and does not alter hepatic steatosis” and the results led the author to conclude that “the data did not favorably support the role of RNF213 in NASH in the context of saturated fatty acid toxicity in vivo, which may be due to the diet not raising levels conducive for severe NASH development” (Abstract).
The amount of direction provided by the inventor/existence of working examples: Here, the applicant claims to have a probable “rare variant” or a list of probable rare variants with a reduced risk of liver disease (pg. 7, line 28-29). The specification describes a “discovery analysis in UKB and GHS was performed to identify new genetic variants and genes associated with liver injury as measured by aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are widely used measures of liver damage” (pg. 96, lines 22-25). The goal of the genome association studies was to “discover protective genes” (pg. 96, line 24-25, line 29; Ex. 1). Second, association of rare predicted loss-of-function (pLof) in RNF213 gene with ALT and AST was estimated using exome sequence data (pg. 97, lines 2-4). The result demonstrated that 1,773 carriers of a pLoF variants in RNF213 had significantly reduced circulating AST and ALT levels (pg. 98, line 10).
Paton provides needed steps to identify a therapeutic siRNA and these studies are usually expected by a person skill in the art (including a medical professional) before attempting to administer the siRNA drug to a human subject: the siRNA hybridization to target mRNA and consequent decrease in the expression of target mRNA/protein, treatment of the recited ailment following, and, ideally, also understanding of potential unexpected side-effects. Instant specification also does not provide any studies demonstrating administration of recited RNF213 inhibitor in an in vivo animal model with a reference RNF213 mRNA that treats liver disease, alone or co-administration with a therapeutic agent. Nor does the specification provide “protective” studies with the pLoF/missense variants recited in claim 37. All these studies, i.e. in vitro and in vivo studies, are missing in instant specification for one of skill in the art to practice the invention as claimed.
The quantity of experimentation: undue experimentation: MPEP 2161.01 (III) provides that for enablement:
The specification need not teach what is well known in the art. However, applicant cannot rely on the knowledge of one skilled in the art to supply information that is required to enable the novel aspect of the claimed invention when the enabling knowledge is in fact not known in the art. ALZA Corp. v. Andrx Pharms., LLC, 603 F.3d 935, 941, 94 USPQ2d 1823, 1827 (Fed. Cir. 2010) ("ALZA was required to provide an adequate enabling disclosure in the specification; it cannot simply rely on the knowledge of a person of ordinary skill to serve as a substitute for the missing information in the specification.") . . .The Federal Circuit has stated that "‘[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement.’" Auto. Technologies, 501 F.3d at 1283, 84 USPQ2d at 1115 (quoting Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366, 42 USPQ2d 1001, 1005 (Fed. Cir. 1997)). . . Therefore, the specification must contain the information necessary to enable the novel aspects of the claimed invention. Id. at 941, 94 USPQ2d at 1827; Auto. Technologies, 501 F.3d at 1283-84, 84 USPQ2d at 1115 ("[T]he ‘omission of minor details does not cause a specification to fail to meet the enablement requirement. However, when there is no disclosure of any specific starting material or of any of the conditions under which a process can be carried out, undue experimentation is required.’") (emphasis added).
As provided by MPEP2161.01(III), here the specification does not provide adequate enabling disclosure of its claimed novel aspects of the invention. The specification does not provide 1) if a) the “predicted loss-of-function” is actually a loss-of-function mutant and not a benign mutation; b) any studies demonstrating a causal link between genetic mutations and their protective nature, either in vivo or in vitro, and/or 2) how the noted mutations are able to lower the risk of NASH or liver disease and 3) studies demonstrating the use of any ASN, siRNA or shRNA RNF213 inhibitor that hybridizes to the target RNF213 mRNA in human subject and that treats any liver disease, including NASH, in a human subject. Thus, the quantity of experimentation needed to make or use the invention is undue or unreasonable.
Thus, for all the reasons noted above, claims 1, 8, 17, 37-39, 41-43, 58, 97-98 do not provide adequate disclosure to enable a person of ordinary skill in the art to use the claimed invention without resorting to undue experimentation and are rejected under 35 U.S.C. 112(a).
Response to Arguments
Applicant's arguments filed 07/01/2026 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks appear to repeat arguments of prior Remarks of 07/11/2025 and have been addressed in the Action of 10/24/2025. The response to the Remarks of 10/24/2025 have been edited and copied below for convenience.
The Remarks make the following arguments:
The state of the art favors Applicant’s position (pg. 14-16). The Remarks argue that the cited references are not relevant: Otten is not relevant since claims “do not recite any purported mechanism underlying RNF213 inhibitors’ ability to affect a subject’s physiology or pathophysiology (pg. 14). Strong’s not relevant since it does not disclose patients having a variant of RNF213 gene and liver disease but rather had an elevated levels of aminotransferase (pg. 15). Morito is not relevant either since the heterogeneity of RNF213 “calls into question the value, if any, of Morito’s reports” (pg. 15). Paton is not relevant since “Applicant’s claims do not recite the safe or efficacious administration of a RNF213 inhibitor” (pg. 16).
The level of predictability in the art favors Applicant's position (pg. 16-21): with the basis from MPEP 2164.02 that the "mere fact that something has not previously been done clearly is not, in itself, a sufficient basis for rejecting all applications purporting to disclose how to do it" (pg. 17), the Remarks insist that a skilled artisan "would not have had to know the function of RNF213 protein to administer an inhibitory nucleic acid molecule that hybridizes RNF213 mRNA" (pg. 17); then cite a Mak reference and a reference of an Arrowhead Pharmaceutical clinical trial targeting a protein in patients with NASH or suspected NASH, "despite the fact that 'the physiological function and the disease-relevant substrate of HSDl 7B13 remain unknown" (pg. 18); and insist that requiring working examples is improper (pg. 19).
The amount of direction provided favors Applicant’s position (pg. 21-23): the Remarks insist that the specification is "replete with enabling disclosure" and provides a 9 bullet point guidance provided in the specification (pg. 24).
The limited quantity of experimentation required to practice the claim favors Applicant’s position (pg. 23-24): the Remarks note that "the literal scope of claim 37 does not require the recited RNF213 predicted loss-of-function variant nucleic acid molecule to be an actual RNF213 loss-of function nucleic acid molecule" (pg. 23) and then points to sequencing/hybridization methodology for a skilled artisan to determine ploF based on instant specification and again notes that the Office is improper in requiring working examples (pg. 23).
The argument is not persuasive.
The cited art (Otten, Strong, Morita and Nagata, Paton) is relevant for the reasons noted in the action. Addressing Strong, the issue is not of the exact diagnosis but although there may be a connection between RNF213 variant and liver symptoms/pathology/disease, the suggestion is that there is uncertainty regarding the function RNF213 and its variants and the need for further studies to connect its mutation with liver disease. The conclusion of Wands factor analysis is not that "a perfected, commercially viable embodiment" is needed, but if it exists then it removes the noted uncertainty. Further, since there is uncertainty surrounding the physiological role of RNF213 protein, all the cited references (Otten, Strong, Morita and Nagata) indicate that further studies are required in understanding its role.
Regarding the nucleic acid inhibitor, a skilled artisan understands that once it hybridizes to its complementary target transcript, it will reasonably inhibit the target's expression. However, Paton points out that various steps need to be taken to optimize an inhibitory nucleic acid molecule sequence to overcome the in vivo physiological obstacles so it can hybridize to its target mRNA in vivo (noted in action pg. 7). Here, the specification fails to provide any of those of studies/steps. A correlation GWAS study is not sufficient to overcome the noted uncertainty. Thus, there is uncertainty whether the claimed subject matter can be practiced with reasonable success by a skilled artisan.
The specification provides general guidance (9 bullet points of pg. 22 of Remarks) on how to practice the claimed invention and do not overcome the obstacles noted by Paton. E.g. there is uncertainty which one of the claimed thousands of siRNA will hybridize in vivo to a RNF213 transcript in a human subject with RNF213 reference and treat a liver disease. The fact a gene mutation that results in decreased gene expression is associated with positive phenotype in a subject does not necessarily mean that decreasing that gene's expression could be effectively used as a therapeutic treatment for a disease (see Zhang above and Burgess, correlation is not causation and could be due to other factors). Thus the general guidance provided in the disclosure does not overcome the required undue experimentation.
MPEP has an enablement requirement and requires a consideration of the "Wands factor" analysis and thus "how to do it" is a critical requirement under the MPEP. Both Mak and Thamm are post-filing references. Even if Thamm were a pre-filing reference based on when the clinical trial began, as the Remarks indicate, i.e. before filing of instant application, Thamm specifically provides a the target protein's (HSD17B13) inhibitor "BI-3231" and provides sufficient characterization of its properties. Here, again, the specification fails to fully enable the claimed subject matter; the claims are directed to both the recited RNF213 inhibitors and a therapeutic agent; thus even if the therapeutic agent is known to treat a liver disease, there is no guidance in the specification whether the therapeutic agent will treat a human subject of claimed subject matter (i.e. heterozygous/homozygous for RNF213 reference).
Again, the disclosure of thousand ASN and siRNA (and shRNA) sequences amounts to prophetic examples and is insufficient since it still fails to overcome the obstacles noted in prior art and fails to disclose those that specifically "decreasing expression of a RNF213 polypeptide" in a human subject as required by the claims or required by the disclosed intention of the specification.
Regardless of whether the recited ploF variant is an actual ploF variant, the uncertainty
remains, since the subject matter of the invention is that, allegedly, the particular genetic variant is protective and the GWAS/statistical analysis provides a correlation, but the specification fails to provide a functional study confirming a causal link between the recited variant(s) and protective nature of the variant or even inhibition of the non-RNF-213 variant (i.e. reference) and its treatment of liver disease. Here, the recited variant mutation(s) has a function in the context of liver disease and is required by the claim to achieve any effect. A correlation is not sufficient to demonstrate that the claimed subject matter can be successfully practiced with a reasonable expectation of success. The action noted some
biological studies that would aid in overcoming the uncertainty, including actual LoF study, cellular study demonstrating positive phenotype, in-vivo expression of variant genotype; to name a few. Simply providing a sequencing/hybridization protocol only provides a method to identify existence of a variation, but not the function, i.e. whether it has loss-of-function or is a missense mutant nor whether it has protective phenotype.
Regarding the argument there is no evidence that the disclosed siRNAs would not hybridize to an RNF213 mRNA (pg. 26). Here, the Examiner has met the burden of providing reasons explaining the uncertainty of enablement of claimed subject matter by noting various references, see Paton (pg. of 7 of 4/11/25 Action) (MPEP 2164.04). Further, the claimed siRNAs/ASNs (cl. 8) are “designed” by stating a complementary sequence of region by "oligowalking" across the genome/transcript by shifting a single-nucleotide. If that is the basis of the current siRNA design, then Khvorova (provided as exhibit in earlier Remarks) indicates in Fig. 2 that not all siRNAs result in inhibition of the target transcript, which suggests either that the siRNA did not bind to the target transcript (most likely argument) or that even if it hybridizes there is no inhibition. Thus it would require undue experimentation to practice the claimed subject matter with likelihood of reasonable success.
Thus, examined claims are rejected under 112(a).
Allowable Subject Matter
No claims are allowed.
Closing Paragraph
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST).
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
