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 .
Election/Restrictions
Applicant’s election of Group I (claims 1-10) and ABE8.8-m of Species Group A in the reply filed on 07/22/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). However, the species election requirement has been withdrawn.
Claims 11-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (claims 11-30), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/22/2026.
Claims Status
Claims 1-30 is/are currently pending with claims 11-30 withdrawn. Claims 1-10 is/are under examination.
Information Disclosure Statement
The information disclosure statement filed 08/07/2023 fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. The information disclosure statement has been placed in the application file, but the information referred to therein has not been considered. Two references were provided but were not listed in the IDS: “Dynamics of Stem Cells in Liver Homeostasis, Injury and Carcinogenesis” by W. Cao, published Feb. 2018; and “Accurate and rapid analysis of genome editing data from nucleases and base editors with CRISPResso2”, by Clement et al., published Mar. 2019.
The information disclosure statement filed 08/07/2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein which has been struck through in the annotated IDS provided has not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. A hyperlinks was found on page 36 line 1. Applicant is advised to review the specification in order to ensure that all hyperlinks are identified and appropriately removed.
Claim Objections
Claim 6 is objected to because of the following informalities: “a PAM sequence AGG” is not grammatically correct as currently presented within the claim. As it is the guide strand that comprises the PAM sequence, the phrase “a PAM sequence AGG” should be immediately preceded by the word “and” to indicate that the guide strand comprises SEQ ID NO:54 (or a sequence 95% identical thereto) and a PAM sequence AGG, and should be followed by a comma to separate it from the limitation regarding the restoration of Idua activity. Claim 6 should thus read: “The ABE complex of claim 5, wherein said ABE complex is ABE7.10 or ABE8.8-m, said guide strand comprises SEQ ID NO:54 or a sequence at least 95% identical thereto and comprises a PAM sequence AGG, and said restoration of Idua activity ameliorates symptoms of Hurler’s disease.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1, 3, 5, 7-10 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 recites “a lysosomal storage disease comprising, a modified TadA enzyme, a catalytically impaired Cas 9 protein and a single guide RNA (sgRNA)” (lines 3-4). The plain reading of the text would indicate that it is the disease which comprises these proteins; however, only the ABE complex of claim 1 could reasonably comprise these components. This creates uncertainty as to what structures are described and required by claim 1. The following amendment of lines 3-4 would be remedial if it is the ABE complex which is referenced and not the lysosomal storage disease: “…associated with a lysosomal storage disease, said ABE complex comprising a modified TadA enzyme, a catalytically impaired Cas9 protein, and a single guide RNA (sgRNA) which directs said ABE complex to said…” Claim 1 is thus rendered indefinite. Claims 2-3 and 5-10 depend on claim 1 but do not clarify this indefiniteness, and so are also rendered indefinite.
Claim 1 recites the term “which” in line 5, referencing a structure. The structure immediately preceding this term, which by a plain reading would be the structure referenced by “which”, is “said mutated target DNA molecule”. However, as “which” structure “upon contact converts adenine in said mutation to inosine”, it is unclear whether “which” refers to this “mutated target DNA molecule” and thus mutates itself, or “which” refers to a different structure in the claim. As such, claim 1 is rendered indefinite. Claims 2-3 and 5-10 depend on claim 1 but do not clarify this indefiniteness, and so are also rendered indefinite. If “which” refers to the ABE complex, amending “which” to “which ABE complex” would be remedial.
Claim 3 recites the limitation "The ABE complex of claim 1 for the treatment of Hurler syndrome" in line 1. Claim 1 does not recite an ABE complex for the treatment of Hurler syndrome. There is insufficient antecedent basis for this limitation in the claim.
Claim 5 recites that the ABE complex is capable of G[Wingdings font/0xE0]A conversion; however, adenosine deaminases catalyze A[Wingdings font/0xE0]G conversion (see page 3 lines 3-6). It is unclear what structure or function is required by the claims to enable G[Wingdings font/0xE0]A conversion using a base editor capable of A[Wingdings font/0xE0]G conversion.
MPEP 2173.05(p) states the following:
A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1318, 97 USPQ2d 1737, 1748-49 (Fed. Cir. 2011). In Katz, a claim directed to "[a] system with an interface means for providing automated voice messages…to certain of said individual callers, wherein said certain of said individual callers digitally enter data" was determined to be indefinite because the italicized claim limitation is not directed to the system, but rather to actions of the individual callers, which creates confusion as to when direct infringement occurs. Katz, 639 F.3d at 1318, 97 USPQ2d at 1749 (citing IPXL Holdings v. Amazon.com, Inc., 430 F.3d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005), in which a system claim that recited "an input means" and required a user to use the input means was found to be indefinite because it was unclear "whether infringement … occurs when one creates a system that allows the user [to use the input means], or whether infringement occurs when the user actually uses the input means."); Ex parte Lyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990) (claim directed to an automatic transmission workstand and the method of using it held ambiguous and properly rejected under 35 U.S.C. 112, second paragraph).
Claims 7, 9, and 10 are drawn to a composition (“The ABE complex”) and comprise method steps (“said complex is delivered to said patient” in claim 7, “wherein a first and second AAV9 vector are administered” in claim 9, “which is delivered to said patient” in claim 10). Claim 8 requires all of the limitations of claim 7, and thus encompasses both a product and a process. This renders claims 7-10 indefinite.
112(d):
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 5 depends on claim 1. Claim 1 recites that the ABE complex performs an A[Wingdings font/0xE0]G conversion; however, claim 5 requires that the ABE complex performs a G[Wingdings font/0xE0]A conversion. These are not the same process, and thus, claim 5 does not require all of the limitations of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
(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.
Claim(s) 1-3, 5-8, 10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bryson (WO2019217943A1, of record).
Regarding claim 1, Bryson teaches an ABE complex comprising a modified TadA enzyme, a catalytically impaired Cas9 protein, and an sgRNA which directs the ABE complex to a mutated IDUA gene DNA molecule, wherein the ABE complex catalyzes the conversion of an A-T base pair to a G-C base pair, wherein the ABE complex is for base editing in a patient in need thereof (claims 161-166, 168, 171; paragraph [0083]).
Regarding claim 2, Bryson teaches that the ABE complex is ABE7.10 (claim 165).
Regarding claim 3, Bryson teaches that the Cas9 protein is SpCas9 (claim 162).
Regarding claim 5, Bryson teaches that the human target sequence comprises an A at nucleotide 1246 (corresponding with stop codon TAG), while the human sequence comprises a G at nucleotide 1246 (corresponding to codon TGG, encoding Trp or W) (paragraphs [0583]-[0584]). Thus, Bryson teaches that the targeted human IDUA sequence encodes W402X (see also Table 7, page 204). Bryson teaches that the subject has Hurler’s syndrome (claims 161, 168-171; paragraph [0029] teaches MPS1 is Hurler’s syndrome). The base editor taught by Bryson (ABE7.10, claim 165) is a nickase and thus cannot catalyze a double stranded break (paragraph [0363]). Bryson teaches that A[Wingdings font/0xE0]G conversion by the ABE7.10 restores IDUA activity (claim 171).
Regarding claim 6, Bryson teaches that the ABE complex is ABE7.10 (claim 165). Bryson teaches that the guide strand comprises SEQ ID NO:54 and PAM sequence AGG (the guide sequence of claim 167 is 100% identical to instant SEQ ID NO:54 and comprises the AGG PAM sequence, see alignment below). As the structures are identical between what is taught in Bryson and what is recited in the instant claims, the functionalities are considered identical.
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Regarding claims 7-8, Bryson teaches that the ABE complex is packaged in an AAV vector (paragraphs [0503]-[0506]).
Regarding claim 10, Bryson teaches that the ABE complex may be packaged in a lipid nanoparticle (paragraph [0497]) or may be present as a ribonucleoprotein complex (paragraph [0498]).
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-8 and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bryson (WO2019217943A1, of record), in view of Koblan (2018, of record).
Regarding claim 1, Bryson teaches an ABE complex comprising a modified TadA enzyme, a catalytically impaired Cas9 protein, and an sgRNA which directs the ABE complex to a mutated IDUA gene DNA molecule, wherein the ABE complex catalyzes the conversion of an A-T base pair to a G-C base pair, wherein the ABE complex is for base editing in a patient in need thereof (claims 161-166, 168, 171; paragraph [0083]).
Regarding claim 2, Bryson teaches that the ABE complex is ABE7.10 (claim 165).
Regarding claim 3, Bryson teaches that the Cas9 protein is SpCas9 (claim 162).
Regarding claim 4, Bryson teaches that the guide strand comprises SEQ ID NO:1 (the guide sequence of claim 167 is 100% identical to instant SEQ ID NO:1, see alignment below).
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Regarding claim 5, Bryson teaches that the human target sequence comprises an A at nucleotide 1246 (corresponding with stop codon TAG), while the human sequence comprises a G at nucleotide 1246 (corresponding to codon TGG, encoding Trp or W) (paragraphs [0583]-[0584]). Thus, Bryson teaches that the targeted human IDUA sequence encodes W402X (see also Table 7, page 204). Bryson teaches that the subject has Hurler’s syndrome (claims 161, 168-171; paragraph [0029] teaches MPS1 is Hurler’s syndrome). The base editor taught by Bryson (ABE7.10, claim 165) is a nickase and thus cannot catalyze a double stranded break (paragraph [0363]). Bryson teaches that A[Wingdings font/0xE0]G conversion by the ABE7.10 restores IDUA activity (claim 171).
Regarding claim 6, Bryson teaches that the ABE complex is ABE7.10 (claim 165). Bryson teaches that the guide strand comprises SEQ ID NO:54 and PAM sequence AGG (the guide sequence of claim 167 is 100% identical to instant SEQ ID NO:54 and comprises the AGG PAM sequence, see alignment below). As the structures are identical between what is taught in Bryson and what is recited in the instant claims, the functionalities are considered identical.
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Regarding claims 7-8, Bryson teaches that the ABE complex is packaged in an AAV vector (paragraphs [0503]-[0506]).
Regarding claim 10, Bryson teaches that the ABE complex may be packaged in a lipid nanoparticle (paragraph [0497]) or may be present as a ribonucleoprotein complex (paragraph [0498]).
However, Bryson does not teach that the ABE complex comprises ABEmax.
Koblan teaches that ABEmax is a modified version of ABE7.10 which exhibits higher editing efficiency.
Regarding claim 4, Koblan teaches that ABEmax is a modified version of ABE7.10 which exhibits higher editing efficiency than unmodified ABE7.10 (page 845). It would have been obvious to an artisan at the time of filing that the ABE7.10 of Bryson should be replaced with the ABEmax, as the ABEmax exhibits superior gene editing properties and would not require redesign of guide RNAs, as the Cas9 protein domain is unchanged (Koblan teaches that the ABEmax differs from ABE7.10 by the addition of an NLS and by codon optimization, page 845).
Claim(s) 1-3 and 5-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bryson (WO2019217943A1, of record), in view of Grimm (2008).
Regarding claim 1, Bryson teaches an ABE complex comprising a modified TadA enzyme, a catalytically impaired Cas9 protein, and an sgRNA which directs the ABE complex to a mutated IDUA gene DNA molecule, wherein the ABE complex catalyzes the conversion of an A-T base pair to a G-C base pair, wherein the ABE complex is for base editing in a patient in need thereof (claims 161-166, 168, 171; paragraph [0083]).
Regarding claim 2, Bryson teaches that the ABE complex is ABE7.10 (claim 165).
Regarding claim 3, Bryson teaches that the Cas9 protein is SpCas9 (claim 162).
Regarding claim 5, Bryson teaches that the human target sequence comprises an A at nucleotide 1246 (corresponding with stop codon TAG), while the human sequence comprises a G at nucleotide 1246 (corresponding to codon TGG, encoding Trp or W) (paragraphs [0583]-[0584]). Thus, Bryson teaches that the targeted human IDUA sequence encodes W402X (see also Table 7, page 204). Bryson teaches that the subject has Hurler’s syndrome (claims 161, 168-171; paragraph [0029] teaches MPS1 is Hurler’s syndrome). The base editor taught by Bryson (ABE7.10, claim 165) is a nickase and thus cannot catalyze a double stranded break (paragraph [0363]). Bryson teaches that A[Wingdings font/0xE0]G conversion by the ABE7.10 restores IDUA activity (claim 171).
Regarding claim 6, Bryson teaches that the ABE complex is ABE7.10 (claim 165). Bryson teaches that the guide strand comprises SEQ ID NO:54 and PAM sequence AGG (the guide sequence of claim 167 is 100% identical to instant SEQ ID NO:54 and comprises the AGG PAM sequence, see alignment below). As the structures are identical between what is taught in Bryson and what is recited in the instant claims, the functionalities are considered identical.
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Regarding claims 7-8, Bryson teaches that the ABE complex is packaged in an AAV vector (paragraphs [0503]-[0506]).
Regarding claim 9, Bryson teaches that the AAV vector is delivered to the liver to enable gene editing in the liver (Table 7, page 204), and that different AAV serotypes should be used for delivery to neuronal tissues, cardiac tissues, liver (paragraph [0506]). Bryson teaches that each component of a base editing complex may be encoded on separate vectors (paragraph [0262]).
Regarding claim 10, Bryson teaches that the ABE complex may be packaged in a lipid nanoparticle (paragraph [0497]) or may be present as a ribonucleoprotein complex (paragraph [0498]).
However, Bryson does not teach that the AAV serotype used is AAV9.
Grimm teaches the AAV9 serotype.
Regarding claim 9, Grimm teaches that the AAV9 serotype is capable of transducing any tissue (page 5887). It would have been obvious to an artisan at the time of filing that the AAV vectors of Bryson should be replaced with AAV9 vectors, as an AAV9 vector would enable targeting of multiple tissues simultaneously, simplifying and streamlining the design of delivery vectors targeting different tissues and comprising the same sequences encoding base editing complex components.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM EST.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636
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