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 .
DETAILED ACTION
Claims 8-9, 13-23, 29, 35, 37-42, and 49 are pending.
Applicant’s election without traverse for examination of Group I (claims 8-9, 13-23, 29, 35, 37-41) directed to composition comprising: a first gRNA molecule comprising a first targeting domain that binds to a first target sequence of an LDLR gene, and a second gRNA molecule comprising a second targeting domain that binds to a second target sequence of an LDLR gene, wherein the first and second target sequences of the LDLR gene flank the first AU-rich element (ARE1 element) of the 3' untranslated region (UTR) of the LDLR gene on 8/14/26 in their response of office action of 3/12/2026 is acknowledged. Claims 42, and 49 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as non-elected claims. Claims 8-9, 13-23, 29, 35, 37-41 are for examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/2/2026, 6/17/2026 and 7/02/2026 in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the IDS statement.
Claim Objections
Claim 8 is objected in reciting “LDLR” for the following reason.
LDLR is abbreviated term without spelling at least once in the claim.
IT should be spelled out as low-density lipoprotein receptor (LDLR) once. Appropriate correction is required.
Claim Rejections: 35 USC § 112(b)
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 13,14-23 (depends on claim 13), 29, 35, 37, 38-41 ( depends on claim 37) 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 13 is indefinite in reciting” of claim 10 ” make the claim unclear because there is no claim 10 at all. correction required.
Claim 35 is indefinite in reciting” of claim 24 ” make the claim unclear because there is no claim 24 at all. correction required.
Claim 37 is indefinite in reciting” of claim 24 ” make the claim unclear because there is no claim 24 at all. correction required.
Claim Rejections, 35 U.S.C 112 1st Paragraph
The following is a quotation of the first paragraph of 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 8-9, 13-20, 35, 37-41 are rejected under 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
The claims are directed to directed to composition comprising: a first gRNA molecule comprising a first targeting domain that binds to a first target sequence of an LDLR gene, and a second gRNA molecule comprising a second targeting domain that binds to a second target sequence of an LDLR gene, wherein the first and second target sequences of the LDLR gene flank the first AU-rich element (ARE1 element) of the 3' untranslated region (UTR) of the LDLR gene ( claim 8, and dependent claims) and composition of claim 8, wherein the first targeting domain comprises a sequence of SEQ ID NO: 1452 and wherein the second targeting domain comprises a sequence of SEQ ID NO: 1475 .
It is noted that MPEP 2111.01 states that "[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow." In this case, in light of the specification, the examiner has broadly interpreted " a composition comprising: a first gRNA molecule comprising a first targeting domain that binds to a first target sequence of an LDLR gene, and a second gRNA molecule comprising a second targeting domain that binds to a second target sequence of an LDLR gene or first targeting domain comprises a sequence of SEQ ID NO: 1452 and wherein the second targeting domain comprises a sequence of SEQ ID NO: 1475 ( claim 9), a genome editing system comprising: a nucleic acid molecule encoding the first gRNA molecule and the second gRNA molecule of the composition of claim 8; and an RNA-guided nuclease, or a nucleic acid encoding the RNA-guided nuclease of claim 13 ” encompasses a first gRNA molecule comprising a first targeting domain that binds to a first target sequence of an LDLR gene, and a second gRNA molecule comprising a second targeting domain that binds to a second target sequence of an LDLR gene, a genome editing system comprising: a nucleic acid molecule encoding the first gRNA molecule and the second gRNA molecule of the composition of claim 8; or first targeting domain comprises a sequence of SEQ ID NO: 1452 and wherein the second targeting domain comprises a sequence of SEQ ID NO: 1475 ( claim 9) can be any fragment of SEQ ID NO: 1452 and any fragment of SEQ ID NO: 1475 o and an RNA-guided nuclease having any structure and a gene -editing domain having any structure capable of altering any target sequence of LDLR gene or SEQ ID NO: 73 ( claim 29).
The Court of Appeals for the Federal Circuit has recently held that a "written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." University of California v. Eli Lilly and Co., 1997 U.S. App. LEXIS 18221, at *23, quoting Fires v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical).University of Rochester v. G.D. Searle & Co. (69 USPQ2d 1886 (2004)) specifically points to the applicability of both Lilly and Enzo Biochemical to methods of using products, wherein said products lack adequate written description. While in University of Rochester v. G.D. Searle & Co. the methods were held to lack written description because not a single example of the product used in the claimed methods was described, the same analysis applies wherein the product, used in the claimed methods, must have adequate written description (see Enzo paraphrased above).
In the instant case, there is no structure associated with function with regard to the members of a genus of gRNA molecule and genome editing system comprising nucleic acid encoding a genus of RNA-guided nuclease comprising any structure or any fragment of SEQ ID NO: 1452 and any fragment of SEQ ID NO: 1475 capable of editing an LDLR gene in a target cell. Therefore, the claims encompass genus of gRNA molecule and genome editing system comprising nucleic acid encoding a genus of RNA-guided nuclease comprising any structure capable of editing an LDLR gene in a target cell comprises a Cas protein having any structure and a base-editing domain having any structure . The genus of guide RNA (gRNA) having any structure and a base-editing domain having any structure capable of editing an LDLR gene in a target cell DNA required in the claimed invention is an extremely large structurally and functionally variable genus. Specification disclose only gRNA having the first targeting domain comprises a sequence selected from the group consisting of any one of SEQ ID NO: 1452 and wherein the second targeting domain comprises a sequence e of SEQ ID NO: 1475, and RNA-guided nuclease comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1338-1347 as described below, the art clearly teaches the "Practical Limits of Function Prediction":
A. Davos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that "Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, and page 105).B. Wristlock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340,) also highlight the difficulties associated with "Prediction of protein function from protein sequence and structure": "To reason from sequence and structure to function is to step onto much shakier ground", closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein's role fundamentally (page 323, paragraph 1).C. This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polypeptides do not necessarily share the same function and many functionally similar proteins will have little or no structural homology to disclosed proteins. For example, proteins having similar structure have different activities (structure does not always correlate to function); Kwiatkowski et al., (Biochemistry 38:11643-11650, 1999) teaches that one conservative amino acid substitution transforms a beta -ketoacyl synthase into a malonyl decarboxylase and completely eliminates beta-ketoacyl synthase activity. The art also teaches that functionally similar molecules have different structures; Kisselev L., (Structure, 2002, Vol. 10: 8-9) teach that polypeptide release factors in prokaryotes and eukaryotes have same function but different structures.
As stated above, no information beyond the characterization of gRNA having the first targeting domain comprises a sequence selected from the group consisting of any one of SEQ ID NO: 1452 and wherein the second targeting domain comprises a sequence e of SEQ ID NO: 1475, and RNA-guided nuclease comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1338-1347 disclosure of the structure of has been provided by the applicants’, which would indicate that they had the possession of the claimed genus of polypeptides and the encoding polynucleotides. The claimed genera of polypeptides and the encoding polynucleotides have widely variable structures and associated functions. As it is discussed above, a minor changes in structure may result in changes affecting function, since, the specification provided no additional information (species/variant/mutant) correlating structure with function, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Furthermore, "Possession may not be shown by merely describing how to obtain possession of members of the claimed ,genus or how to identify their common structural features" (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895). A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the .gene does (function), rather what it is (structure), see University of California v. Eli Lilly & Co., 43 USPQ2d 1938, thus above claims lack adequate written description.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov
Claim Rejection 35 U.S.C 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 8-9 , 13-20, 23, 29, 37 are rejected as anticipated Emmanuel et al. (WO2022/204087 A1, 09-29-2022, also published as US20240175035. IDS) .
D1 Emmanuel et al. (Abstract; paragraph [0007]; paragraph [0013]- paragraph [0017]; paragraph [0023]; paragraph [0024]; paragraph [0046]; paragraph [0066]- paragraph [0068]; paragraph [0076]; paragraph paragraph [0149]; paragraph [0152]- paragraph [0153]; paragraph [0189]; claims 1-39; table 1) discloses compositions and methods for treating hypercholesterolaemia, increasing the expression of low-density lipoprotein receptor (LDLR) in a cell. The method of D1 comprises introducing to the cell of a subject a composition comprising a CRISPR-nuclease and an RNA molecule comprising a guide sequence or molecule defined by the sequence identity,
D1 Emmanuel et al. teach a guide RNA (gRNA) molecule comprising a targeting domain that targets a target sequence of LDLR gene, wherein the target sequence comprises a nucleotide sequence of SEQ ID NO: 732 and/or first targeting domain targeting domain of the corresponding SEQ ID NO: 732 which is 100% identical to applicants SEQ ID NO: 1452 and second targeting domain of SEQ ID NO: 1718 which is 100% identical to applicants SEQ ID NO: 1475; a composition comprising a first gRNA molecule comprising a first targeting domain that binds to a first target sequence of an LDLR gene, and a second gRNA comprising a second targeting domain that binds to a second target sequence of an LDLR gene, wherein the first and second target sequences of the LDLR gene flank the first AU-rich element (ARE1 element) of the 3’ untranslated region (UTR) of the LDLR gene, as characterized by SEQ ID NO: 732 which is 100% identical applicants SEQ ID NO: 73; a genome editing system comprising at least one gRNA molecule a delivery system for delivering a genome editing system according to preceding claims as characterized by said SEQ ID NOs: 73 and/or targeting domain of the corresponding SEQ ID NO: 1452; a genome editing system, a RNP complex.
D1 Emmanuel et al. discloses in paragraphs [0050] and [0140], for example, the use of Cas9, specifically spCas9, and in paragraph [0161] the use of targeted liposomes. Therefore D1 Emmanuel et al. anticipates applicants invention of claims 8-9 , 13-20, 23, 29, 37.
Claim Rejections: 35 USC § 103
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) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
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 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.
According to MPEP 2143:"Exemplary rationales that may support a conclusion of obviousness include:(A) Combining prior art elements according to known methods to yield predictable results;(B) Simple substitution of one known element for another to obtain predictableresults;(C) Use of known technique to improve similar devices (methods, or products) in the same way;(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel."
Claims 38--41 are rejected under 35 U.S.C. 103(a) as being unpatentable over D1 Emmanuel et al. (WO2022/204087 A1, 09-29-2022, also published as US20240175035. IDS), in view of D4: KASIEWICZ LISA N. ET AL: "GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy", NATURE COMMUNICATIONS,2023, vol. 14, no. 1, 15 May 2023 (2023-05-15), IDS).
D1 Emmanuel et al. teach a guide RNA (gRNA) molecule comprising a targeting domain that targets a target sequence of LDLR gene, wherein the target sequence comprises a nucleotide sequence of SEQ ID NO: 732 and/or first targeting domain targeting domain of the corresponding SEQ ID NO: 732 which is 100% identical to applicants SEQ ID NO: 1452 and second targeting domain of SEQ ID NO: 1718 which is 100% identical to applicants SEQ ID NO: 1475; a composition comprising a first gRNA molecule comprising a first targeting domain that binds to a first target sequence of an LDLR gene, and a second gRNA comprising a second targeting domain that binds to a second target sequence of an LDLR gene, wherein the first and second target sequences of the LDLR gene flank the first AU-rich element (ARE1 element) of the 3’ untranslated region (UTR) of the LDLR gene, as characterized by SEQ ID NO: 732 which is 100% identical applicants SEQ ID NO: 73; a genome editing system comprising at least one gRNA molecule a delivery system for delivering a genome editing system according to preceding claims as characterized by said SEQ ID NOs: 73 and/or targeting domain of the corresponding SEQ ID NO: 1452; a genome editing system, a RNP complex.
D1 Emmanuel et al. discloses in paragraphs [0050] and [0140], for example, the use of Cas9, specifically spCas9, and in paragraph [0161] the use of targeted liposomes.
D1 Emmanuel et al. did not disclose the delivery system comprises a lipid nanoparticle (LNP) nor targeting moiety is one or more N- acetylgalactosamine (GalNAc) nor ionizable lipid. ( subject matters of instant claims 38-41)
D4: KASIEWICZ ET AL disclose lipid nanoparticles have demonstrated utility in hepatic delivery of range of therapeutic modalities and typically deliver their cargo via low-density lipo protein receptor-mediated endocytosis. For patients lacking sufficient low density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3gene, the introduction of an optimized GalNAc based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61%with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homo zygous familial hypercholesterolemia ( abstract).
Therefore it would have been obvious to a person of ordinary skill in the art, at the time of the instant invention is filled to combine the teaching of D1; Emmanuel et al. and D4: KASIEWICZ LISA N. ET AL to have delivery system comprising a lipid nanoparticle (LNP) such as GalNAc-Lipid nanoparticle for delivering the genome comprises the first and second gRNA molecules and the RNA molecule encoding the RNA-guided nuclease.
Conclusion
Claims 8-9, 13-23, 29, 35, 37-41 are rejected. No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MOHAMMAD Y MEAH whose telephone number is (571)272-1261. The examiner can normally be reached on monday-friday (8-7).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on 4089187584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MOHAMMAD Y MEAH/ Examiner, Art Unit 1652
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