DETAILED ACTION
Notice of Pre-AlA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. The Amendment filed on March 19, 2026, has been entered.
Claim Disposition
3. Claims 2-72 and 101-102 have been cancelled. Claims 113-115 have been added. Claims 1, 73-100 and 103-115 are pending and are under examination.
Claim Objections
4. Claims 1, 73-100 and 103-115 are objected to for the following informalities:
For clarity and precision of claim language it is suggested that claim 1 is amended to read, “A method of producing a bioactive renal cells (BRC)…………, comprising:
delivering to BRC cells:
a Cas 9 endonuclease……..,
and
a guide RNA (gRNA), ……….[[associates]] bonds or fuses, reacts?. For clarity it is suggested that claim 1 is amended to delete (a and b) and recite “….wherein the gRNA reacts with the Cas endonuclease and comprises a nucleotide sequence complimentary to a target…..”.See also claim 107. The dependent claims hereto are also included.
For clarity it is suggested that claim 83 is amended to insert “…..the BRC…..”.
For clarity it is suggested that claim 105 is amended to read, “….wherein the polynucleotide…..the BRC, [[and]] wherein the polynucleotide encoding the……BRC, wherein the polynucleotide encoding the Cas endonuclease is a transfected…. and wherein……. plasmid DNA”.
For clarity it is suggested that claim 107 is amended to read “a, b and c” or delete this notation in lieu of “a, b and b”.
For clarity it is suggested that claim 115 is amended to read, “A method for producing a bioactive renal cell (BRC) comprising a genomic modification in a beta-2 microglobulin (B2M gene, comprising:
delivering to BRC cells………”.
For clarity and precision of claim language it is suggested that claims 1, 107 and 115 are amended to provide a measurable amount of “the reduced B2 M”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
5. Claims 1, 73-100 and 103-115 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention as amended is directed to “a method of producing a bioactive renal cell/a method of producing genomically modified bioactive renal cells, comprising delivering to BRC cells a Cas endonuclease and a guide RNA….(see claims 1, 107 and 115 in its entirety). The claimed invention is not adequately described and encompasses a large variable genus of structures. No correlation is made between structure and function (see claims 1 and 107 for example with recitation of modifications to a gene that no structure is provided in claim 1). The claimed invention encompasses ‘a genomic sequence that is 12 to 25 nucleotides long’ without a reference sequence.
The invention is also directed to a modification that encompasses an insertion of at least one nucleotide in the B2M gene, however, no reference structure is provided. Further, the invention encompasses an insertion of an exogenous DNA element, that comprises a sequence encoding a selectable marker, none of which is described in the claims. The invention encompasses a substitution of at least one nucleotide in the B2M gene which has no upper limit thus could essentially delete active sites and most of the structure with any substitution which does not guarantee activity (see claims 86-87). Moreover the invention encompasses fragments with the recited “portion thereof” language in claim 88 ( and wherein the entire B2M gene can be deleted).The claimed invention is not adequately described and is overly broad. The invention is also directed to a method step that recites that the gRNA associates with the Cas endonuclease but does not define the ‘association’; and the invention sets forth that the Cas 9 endonuclease is a recombinant protein and also a DNA vector (see claims 104 and 106), thus not adequately described. Claims 1, 107 and 115 does not inform the ordinary skilled worker the mechanism in the deliver and modifications, thus not adequately described.
The claimed invention is not adequately described also because it does not inform the ordinary skilled worker about the ‘delivery’ and it is noted that claims such as claim 97 recites that the delivery is across the cell membrane or expression of a Cas9 endonuclease in the BRC. The claimed invention is also not adequately described with respect to the BRC. The invention as claimed is directed to a large genus of Cas endonuclease and guideRNAs. The BRC is recited as being a genomically modified SRC and there are no indicia as to whether this is modified beyond the BRC. The claimed invention is also directed to the SRCs comprises cells expressing cytokeratin CK18 and there is no nexus between that and the claimed method. The method also is directed to modifications in a gene structure that can be a substitution, deletion or deletion of B2M gene or a portion thereof, which is not descriptive.
The claimed invention encompassed a large genus of modifications that are not adequately described. There are no indicia in the claims about how the genomic modification comprising a substitution or addition of at least one nucleotide in the B2M gene or a portion thereof, informs the ordinary skilled worker about a specific structure for the gene to be able to practice the claimed method. The method objective is to produce a bioactive renal cell with a genomic modification in a B2M gene, however it is not described what the at least one nucleotide is, that is recited as substituted or added in the B2M gene. It is described what portion of the B2M gene is deleted. The specification discloses at paragraph [0007], that “In an aspect, provided herein is a method of producing a genetically modified bioactive renal cell (BRC). In certain embodiments, the genetically modified BRC is a genomically modified BRC (i.e., a BRC with a genetic modification in the genome thereof). In certain embodiments, the genetically modified BRC comprises an exogenous polynucleotide (such as a plasmid or a viral vector) that expresses an RNA interference (RNAi) molecule that reduces expression of a genomic immunogenicity gene in a BRC. In certain embodiments, the RNAi molecule is a short interfering or a short hairpin RNA molecule. In certain embodiments, the method includes genetically modifying a genomic immunogenicity gene in a BRC”, which is broad and does not specifically define the modification. Thus the claimed invention is not adequately described with respect to the genomic modification which is critical to the claimed method.
Claim 1 as amended comprises a Cas endonuclease that is not adequately described and said endonuclease genomically modifies the B2M gene and said modifications are not adequately described. It is well established in the art that a single change in the DNA structure can be detrimental to the protein structure-function. The claimed invention encompasses a large variable genus of structures for the gene and ways to modify the gene, therefore, the claimed method is not descriptive with respect to the methodology to achieve the method objective. The dependent claims to claim 1 and 107 does not rectify the missing information in these independent claims, which needs to stand on their own. The claims recite that the transfected mRNA is coupled with at least one cell-penetrating peptide, however, none is specifically described (see claims 103-105, for example). Further, the claimed invention encompasses any modified nucleic acid bases or polyadenylation sequences and any cell penetrating peptide, that is not adequately described. The claimed invention also encompasses any gene editing protein or delivering any gene editing protein across the cell membrane, any Cas protein and any RNA guide, for example. Thus, the claimed invention is not adequately described.
The specification fails to provide any additional representative species of the claimed genus to show that applicant was in possession of the claimed genus. A representative number of species means that the species which are adequately described are representative of the entire genus. 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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. Therefore, for all these reasons the specification lacks adequate written
description, and one of skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
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.
6. Claims 1, 73-100 and 103-115 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 1 and 107 lacks clarity with respect to “associates” because it could be construed as “a fusion, a reaction, a bond or something more distant”.
Claim 92 lacks clarity with respect to the production of VEGF and KIM-1 for markers and does not provide clear antecedent basis for “the presence of viable and functionally progeny”.
Claim 104 lacks clear antecedent basis for the recitation of “the gRNA ex vivo to form a complex”.
Claim 106 is indefinite for the recitation of the “Cas endonuclease is a DNA vector” when the lead claim 1 recites a DNA encodes the Cas endonuclease which is also recited as a recombinant protein in claim 104, thus the claim has ambiguity.
Claim 82 is lacks clarity for the recitation of the SRCs comprises cells that express cytokeratin 18 because there is no nexus made between that and the method permeable. Thus the metes and bounds of the claim is unclear. See also claim 81 with a similar scope.
Response to Arguments
7. Applicant’s comments have been considered in full. Withdrawn objections/rejections will not be discussed herein as applicant’s comments are moot.
Note that new rejections have been instituted based on amendments made to the claims. Note that the rejections have been maintained under 112, first and second paragraphs for the reasons stated above and herein, however some issues remain that were not persuasively argued or modified. The applicant traverses the 112 first paragraph rejection with statements of amended claims and points to the specification, such as below, that “in the Examples (e.g., Example 5 at pages 124-126), electroporation was used to transfect gene editing systems (Cas9 endonuclease and gRNA) into cells. However, it is stated that other methods including lipofection, transfection, micro-injection, etc. may be used. See, e.g., specification at page 125, lines 2-3”. However, note that none of the independent claims recite this information but instead recites “delivering’, when the method could recite, “transfect BRC cells with a polynucleotide encoding a Cas endonuclease”, for example. The claimed invention is not adequately described as outlined above as applicant has not demonstrated possession of the entire genus encompassed in the claims. The 112, 2nd paragraph rejection is primarily due to lack of antecedent basis based on amendments made to the claims. Thus the rejection is made final.
Conclusion
8. No claims are presently allowable.
9. Applicant’s amendment necessitated the new/modified 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOPE A ROBINSON whose telephone number is (571)272-0957. The examiner can normally be reached 9-5pm, Monday- Friday.
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/HOPE A ROBINSON/Primary Examiner, Art Unit 1652
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