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 .
Applicant’s amendment and response to restriction requirement of 6/4/26 are entered.
Claims 5 and 14-15 are amended.
Claim 19 is newly presented.
Claims 1-19 remain pending.
Election/Restrictions
Applicant’s election without traverse of Invention group III (present Claims 1-2, 4-7, and 12-19 in the reply filed on 6/4/26 is acknowledged.
It is noted that Claim 5 has been amended in the response of 6/4/26, and thus, it also falls into Invention Groups II and V now.
Claims 3, 5, and 8-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/4/26.
Applicant’s election without traverse of the species of MPS IIIC/HGSNAT and CRISPR/Cas in the reply filed on 6/4/26 is acknowledged.
Claims 1-2, 4, 6-7, and 12-19 are considered with respect to the elected species.
Formalities:
The drawings of 6/27/23 are accepted.
The specification as filed on 6/27/23 is accepted.
The IDS filings of 6/4/26; 3/31/25; 12/31/24; 7/31/23; and 6/27/23, along with the references therein have been considered on the basis of the English portions of the documents submitted. The IDS forms have been signed to confirm the same and are provided herewith.
Applicant’s priority is recognized to be:
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Claim Objections
Claims 1-2, 4, 6-7, and 19 are objected to for belonging in multiple inventions, due to its broad recitations. E.g., Claim 1 encompasses putting lysosomal TM proteins into the cells, vector encoding the lysosomal TM proteins, as well as editing the endogenous lysosomal TM proteins.
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 12-18 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.
As seen by dependent claim 16, which states that the subject is administered an effective amount of the vector, which means that the rejected claims specifically encompass ineffective amounts of the vector. However, the broad claim (Claim 12) specifically requires “treating or ameliorating” the disease/disorder. It is not clear how ineffective amounts could perform such treating or ameliorating. Alternatively, the Artisan would not know what is meant by “an effective amount”. I.e., is it referring to the distinction between ameliorating and treating? The scope of the claims is not clear due to the dependency of the claim limitations.
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.
Claims 1-2, 4, 6-7, and 12-19 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.
The claims are generic for the treating (Claim 1 and depending), and treating or ameliorating (Claim 12 and depending), MPC IIIC (Sanfillipo Type C), in a subject by ex vivo gene editing of endogenous HGSNAT in HSPCs of the subject (Claim 1 and depending) which is then transplanted into the subject (Claim 1 and depending) or in vivo editing of endogenous HGSNAT in a subject (Claim 12 and depending), as the elected species are MPC IIIC (Sanfilippo C) and HGSNAT gene.
The specification provides antecedent basis for the same, teaching the treatment of MPS IIIC (Sanfilippo C) and the use of the HGSNAT gene for the same (e.g., paragraph 8). Further, the protein sequence is given for human HGSNAT (pp. 46-47, identified as SEQ ID NO: 17) as well as the human mRNA sequence (e.g., pp. 47-49, identified as SEQ ID NO: 18). As far as ways to edit by CRISPR/Cas, it is taught to use NHEJ (where DS breaks are repaired by direct ligation of the broken ends, which can result in a deletion), homology-directed repair, where a donor polynucleotide with homology is required to be used as template to repair the cleaved target DNA (allowing for repair including insertions and deletions, gene replacement, tagging, transgene insertion, nucleotide deletion, gene disruption and mutations in general) (paragraph 55). In Example 1, CTNS-/- mice are treated with CTNS-expressing WT HSCs, where positive effects are seen in kidney, eye, thyroid, GI tract, and skin, although the methods of transplant is not given. In Example 2, CTNS-/- mice are exposed to myeloablative drugs and WT CTNS-expressing HSCs, which appears to work, and leads to significant decrease in cystine levels in all tissues. Example 3 address transplanted WT HSCs on CTNS-/- mice, demonstrating positive kidney effects, eye effects, thyroid effects, GI effects, and skin effects. Example 4 addresses the efficacy and toxicity in CTNS-/- mice, of myeloablative conditioning, being relatively benign with the engraftment of HSCs transplanted. Example 5 teaches the mechanism of therapeutic action: macrophages form from the HSCs and cross-correct the tissues. Example 6 is a commentary on the use of autologous cells in such HSC transplantation. Example 7 concerns viral vector selection, reviewing several types of viral vector. Example 8 concerns pre-clinical studies for transplant of transduced HSCs with CTNS transgene expression in the HSCs. Example 9 is to preclinical pharmacology and toxicology, which is relatively positive for the transplanted HSCs and expression of CTNS. Example 10 is to process development, giving protocols for obtain CD34+ HSCs from the subject, transuce and a proposed clinical trial. Example 11 is to treating Danon disease. None of these address the issue of modified HSC correction of MPS IIIC by correction of the endogenous HGSNAT gene.
As far as Sanfilippo C, a study of one populationof dutch MPS IIIC patients showed 14 distinct mutations associated with MPS IIIC (e.g., Ruijter, et al. (2008) Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands”, Molecualr Genetics and Metabolism, 93: 104-11, e.g., ABSTARCT). However, the locations of these mutations include frameshift, insertions, nonsense, and missense mutations. These distinct mutations, just in this one population require distinct mechanisms of correction, being that of NHEJ or HDR, as taught by Applicant’s specification, but the locations and the locations of the nearest PAM site on the opposite strand for these are not given, and thus, it is not known yet whether any of them could be treated without further consulting, whether it be by HDR or NHEJ. For example, assuming a PAM is present in the gene, it is not known whether it is close enough for a gRNA to target the site for cleavage to obtain an NHEJ that results in a correcting indel and which indels would solve the issue, and also, it is not known if a co-supplied template would be close enough to correct the mutation(s).
The Art recognizes that one of the major problems with CRISPR/Cas treatment of cells, is that of a properly localized PAM site. Hille, et al. (2016) “CRISPR-Cas: biology, mechanisms and relevance”, Philosophical Transactions, Royal Society B, 371: 20150496, 12 pages long, discusses the import and the problems of an improperly placed PAM to exert a gene correction: “The selection of a target sequence that is integrated into the CRISPR locus is not random. It has been demonstrated that in type I, II and V CRISPR-Cas systems, a short sequence, called the protospacer adjacent motif (PAM), is located directly next to the protospacer and is crucial for acquisition and interference [24–29]. In type II-A CRISPR-Cas systems, the PAM-recognizing domain of Cas9 is responsible for protospacer selection [21,22].” (p. 3, col. 1, paragraph 2) and “In all of the aforementioned genome manipulation strategies, the existence of a PAM adjacent to the target site is a strict requirement[9]” (p. 7, col. 1 last paragraph). Thus, it is recognized that a PAM must be properly present at a correct distance. Additionally, it is noted that NHEJ correction is error prone and will often lead to point mutations/deletions/frameshifts that would be negative to correcting the endogenous gene (e.g., p. 6, paragraph bridging columns). Moreover, delivery in vivo is a problem, in that the cells targeted by any particular system may target other cells before reaching the target cells. For example, in vivo, the cells of the system for MPS IIIC are protected by the blood-brain barrier, and thus, a vector would not be expected to reach the cells need correction, and simple infusion of HSPCs would not be expected to reach the brain in high enough amounts to effect therapy, by the bystander effect of the protein, particularly given that it is a transmembrane protein, and does not enter other cells, unlike other lysosomal disease gene problems.
Applicant has not addressed any of this, but has addressed a distinct gene and its problems in the examples. It is not clear to the Examiner how these results demonstrate a possession of the invention as claimed, as it is to a distinct disease, distinct tissues, and distinct modifications, which do not use CRISPR/Cas to correct the endogenous gene(s). At best, the disclosure seems to be a wish for it in other genes, as distinct diseases are shown to be resolved and the disease is related through the large genera of lysosomal disorders.
Given the complete lack of disclosure of the mutations involved in MPS IIIC, the lack of knowledge of properly localized PAM sites, the lack of description of which mutations will happen to cure any mutant HGSNAT rather than cause an exacerbating mutation, the lack of description of which template nucleic acids should be used for HDR repair, and whether they will reach the mutation, given the location of any particular PAM on the opposite strand, the lack of disclosure of how the CRISPR system will traverse the BBB or how HSCs will cross-correct the tissues in the brain, through traveling there after transplant, the Artisan would not have understood Applicant to have been in possession of the invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT M KELLY whose telephone number is (571)272-0729. The examiner can normally be reached M-F: 8a-5p.
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ROBERT M. KELLY
Examiner
Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638
Prosecution Insights