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 .
Response to Amendment
Claims 4, 6, 8-17, 21, 28-30, 39-43, 45-50, 52-57, 59-60 are cancelled. Claims 1-2, 5, 7, 18-20, 22, 27, 31-38, and 58 have been amended and Claims 61-63 are newly added as requested in the amendment filed on 19 October 2022. Following the amendment claims 1-3, 5, 7, 18-20, 22-27, 31-38, 44, 51, 58, and 61-63 are pending in the application.
Election/Restrictions
Applicant’s election without traverse of Group I and the species of (xi) dissolution or reduction in size of the one or more RBM20 condensates; an RS-rich region; R634Q; and, a human induced pluripotent stem cell; in the reply filed on 30 January 2026 is acknowledged.
Claims 3, 6, 7, 24, 44, 51, 58 and 61-63 are withdrawn.
Claims 1-2, 5, 18-20, 22-23, 25-27 and 31-38 read upon the elected invention.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/US2020/051329, filed internationally on September 17, 2020, which claims the priority benefit of U.S Provisional Application No. 63/074,985, filed on September 4, 2020, and U.S. Provisional Application No. 62/902,309, filed on September 18, 2019.
Claims 1-2, 5, 18-20, 22-23, 25-27 and 31-38 have an effective US filing date of September 18, 2019.
Claim Objections
Claims 1 and 20 are objected to because of the following informalities: These claims contain abbreviations (i.e. RBM20 and RS-rich) that are not spelled out upon their first appearance within the claims. 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 1-2, 5, 18-20, 22-23, 25-27 and 31-38 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite wherein it recites “determining the characteristic associated with the one or more RBM20 condensates”. It is unclear what process steps are encompassed by “determining” and, thus, the metes and bounds of the process invention are indefinite. It is unclear what method steps would or would not directly infringe the determining step of the claim. This affects the scope of all depending claims.
The terms “dissolution or reduction” in claim 2, and “reduction” in claim 5, are relative terms which render the claims indefinite. These terms are not defined by the claim, nor does the specification provide a standard for ascertaining the requisite degree. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Furthermore, it is unclear what is required for infringement of the method because there are not positively stated method steps whereby dissolution or reduction in the size of one or more RBM20 condensates are measured. Absent such steps, the claim will be anticipated by the active steps recited in the parent claim.
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.
Claims 1-2, 5, 18-20, 22-23, 25-27 and 31-38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Guo et al., Nature Medicine, 18(5): 766-773, May 2012.
Regarding claim 1, the Guo et al. prior art teaches admixing compounds and a cell that comprises one or more RBM20 polypeptides (equivalent of RBM20 condensates). Specifically, Guo et al. teach RBM20 interacts with the following compounds: (1) splice factors Ptbp1 and U2AF65 (Fig.2a), the latter of which contains an RS domain that mediates its recruitment to sites of active splicing; (2) total RNA to which RBM20 binds by crosslinking and immunoprecipitation experiments (Fig.2b); (3) RBM20 interacts with titin RNA, specifically, in a splice reporter assay where exclusion of titin PEVK exons results in reduced reporter activity (Fig.2c) (pg. 3, section titled ‘RBM20 regulates alternative splicing ...”); and, (4) the authors found 31 genes with shared RBM20 genotype dependent splicing in rats and humans (pg. 4, section titled ‘RBM20 regulates select genes….”). The authors teach: “Identification of a novel RBM20 mutation in a human with severe cardiomyopathy and arrhythmia that leads to a change of serine to alanine within the RS domain … the RBM20 deficient individual (S635A) expresses a larger cardiac titin isoform” (pg. 16, Figure 4 legend). In this way, Guo et al teach determining a characteristic associated with the one or more RBM20 polypeptide (namely, regulation of alternative splicing of genes related to cardiomyopathy and, specifically, tinin. Taken together the method of the Guo et al. prior art anticipate the claimed step of admixing a compound with a cell that comprises the one or more RBM20 polypeptides and determining a modulation in a characteristic of RBM20 protein by interaction with the compound.
Regarding claims 2 and 5, there is no explicit definition of “dissolution” in the specification as filed. Therefore, the claimed term is given its plain meaning (see attached Merriam Webster entry), which is decay, disintegration or death. Guo et al. prior art disclose a novel human mutation in RBM20, specifically, S635A, that results in an RBM20 deficiency, which is equivalent to “dissolution” of instant claims 2 and 5.
Regarding claims 18-20, 22 and 23, the Guo et al. prior art teaches: “Compared to control subjects with cardiomyopathy of unrelated cause (CP1 and CP2), the RBM20 deficient individual (S635A) expresses a larger cardiac titin isoform.” Thus, the prior art teach the method comprising wild-type expression of RBM20 (a.k.a. control subjects) as recited by instant claim 18. The method is performed with cells from an individual comprising a mutant RBM20 polypeptide, as recited by instant claim 19. Specifically, Guo et al. disclose the S635A mutation, which is recited in instant claim 23. The Guo prior art reference discloses this change of serine to alanine at position 635, thus teaching the mutation at serine 635 recited by instant Claim 22. Lastly, Figure 4b of the prior art teaches this mutation occurs within an intrinsic RS-rich domain that is conserved across species, therefore teaching a mutation in an RS-rich region, as required by instant claim 20.
Regarding claim 25, the Guo et al. teach the methods in cells from rats that heterozygously express the S635A mutation (see Figure 4 legend). Therefore, the prior art teaches the method wherein the RBM20 polypeptide is heterologously expressed in the cell.
Regarding claim 26, the Guo prior art reference further teaches rats that homozygously express the S635A mutation express the larger N2BA tinin isoforms. Therefore, the prior art teaches the method wherein the RBM20 polypeptide is homologously expressed in the cell.
Regarding claim 27, the Guo et al. prior art discloses: “Heterozygous and homozygous Rbm20 null alleles resulted in left ventricular dilatation as determined by echocardiography in adult animals” (pg. 3 second to last paragraph). The authors go on to state: “The sub-endocardial fibrosis increases with age and is accompanied by electrical abnormalities such as widening of the QRS complex, atrioventricular conduction delay, and a predisposition to arrhythmia (Fig.3c–f, Supplement Fig.4-6). Both Rbm20 deficient rats and humans with RBM20 mutations17,18 can experience sudden death that occurs well after adolescence. Thus, Rbm20 deficient rats mirror the pathological features of the previously reported corresponding human disease17,18 (Supplement Table S1)” (paragraph bridging pgs. 3-4). Therefore, the prior art discloses methods comprising cells that are models of cardiac cell types.
Regarding claim 31, the Guo et al. prior art further teaches the methods were performed in “HEK 293 cells (human fibroblasts) for expression-, localization-, and RNA/protein-binding studies” (pg. 8, section titled ‘Tissue culture’). This discloses the human embryonic kidney (“HEK”) cells of the instant claim.
Regarding claims 32 and 33, the Guo et al. prior art discloses heterologous expression wherein it teaches, “HL-1 cells (mouse atrial myocytes), C2C12 (mouse myoblasts), and HEK 293 cells (human fibroblasts) for expression-, localization-, and RNA/protein-binding studies “ (pg. 8, section titled ‘Tissue culture’). Additionally, the prior art teaches heterologous expression wherein it teaches, human studies comprising evaluating “a cohort of 120 unrelated subjects with idiopathic dilated cardiomyopathy (DCM) for mutations in RBM20 using PCR and Sanger sequencing. In the individual with the novel heterozygous RBM20 missense mutation (Ser635Ala), myocardial biopsies were obtained after diagnostic coronary angiography and immediately” (pg. 8, section titled ‘Human studies’).
Regarding claim 34, the Guo et al. prior art teaches methods to validate RBM20 dependent titin splicing and its relevance for human disease, by testing 3,000 alleles from ethnically matched individuals without cardiomyopathy as controls and were unable to detect this variant (pg. 4, first full paragraph). Thus, the prior art method anticipates methods comprising the cell admixed with a control agent, namely, wild-type tinin and wild-type RBM20.
Regarding claim 35, the Guo et al. prior art teaches the method further comprising imaging at least a portion of the “composition” wherein it demonstrates Western blots for the different tinin splice variants (Figure 1d, bottom panel). The Guo et al. prior art teaches the method further comprising imaging at least a portion of the cell in Figure 2a, depicting Rbm20 partially colocalizes with the splice factor U2AF65 and Ptbp1, but not with additional splice factors tested (Cugbp1 and SC-35) or coilin, a marker for Cajal bodies.
Regarding claim 36, the Guo et al. prior art teaches the method further comprises determining one or more cellular features of the cell wherein it teaches C2C12 cells were stained for α-actinin (red) as a marker of sarcomere maturation and staged for low, medium, and high differentiation based on the fluorescence pattern. Rbm20 expression (green) was restricted to the nuclei (DAPI, blue) (see Figure 2h).
Regarding claim 37, the Guo et al. prior art teach the method further comprising contacting at least a portion of the cell with a fixative, wherein it teaches, “To detect fibrosis, we fixed hearts from 2 to 20 months old rats in 4% paraformaldehyde, paraffin-embedded, and stained with Masson’s trichrome or Sirius red” (pg. 8, section titled ‘Histopathology’).
Regarding claim 38, the Guo et al. prior art reference discloses, further comprising contacting at least a portion of the cell with a stain, wherein it teaches. “ C2C12 cells were stained for α-actinin (red) as a marker of sarcomere maturation and staged for low, medium, and high differentiation based on the fluorescence pattern. Rbm20 expression (green) was restricted to the nuclei (DAPI, blue)” (Figure 2h).
Therefore, the method of the invention fails to distinguish over the methods disclosed in the art prior to the effective filing date of the application. Claims 1-2, 5, 18-20, 22-23, 25-27 and 31-38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Guo et al., Nature Medicine, 18(5): 766-773, May 2012.
Conclusion
No claim is allowed.
Correspondence
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/STACEY N MACFARLANE/Examiner, Art Unit 1675