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 .
Application Status
The action is written in response to applicant’s correspondence received on 7/1/2026. Claims 1-21 are currently pending in the instant application.
Priority
The instant application claims priority to US Provisional Application 63/194,431, filed on 5/28/2021.
Election/Restriction
Applicant’s election without traverse of the inventions of Group I, drawn to a polynucleotide and compositions that comprise said polynucleotide, in the reply filed on 7/1/2026 is acknowledged.
Claims 17-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim.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 7/1/2026.
Applicant elects the following species:
The sequence of the intron is derived from an HBB sequence, as recited in claim 7
The intron comprises a sequence having at least 85% identity to SEQ ID NO: 227, as recited in claim 8
The altered catalytic residue of the deaminase domain is Glu59 (E59), as recited in claim 11
And the polynucleotide sequence is SEQ ID NO: 192, as recited in claim 13.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Claims 1-16 are currently under examination on the merits.
Claim Objections
Claim 5 objected to because of the following informalities: Claim 5 is objected to as being in an unacceptable dependent claim form because the claim does not refer to a preceding claim. See MPEP § 608.01(n).
Appropriate correction is required.
Claim Rejection – Improper Markush Groups
Claims 7, 8, and 13 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 7, 8, and 13 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: they do not share a single structural similarity.
The introns of claim 7 and the sequence of the intron in claim 8 are targeted towards different introns of various genes, each with unique sequences.
Regarding claim 13, the sequence encoding the base editor system would comprise of introns from different genes, as well as unique nucleotide sequences, that do not share a single structural similarity.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 15 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Regarding claim 15, the instant claims recite a cell comprising a vector comprising a polynucleotide encoding a self-inactivating base editor or a fragment thereof. Looking towards the specification for guidance, applicant states “in any of the above aspects, or embodiments thereof, the cell is in vitro or in vivo (see page 16 of the instant specification). Applicant further discloses that the nucleobase editing proteins provided herein can be used for gene editing-based human therapeutics in vitro or in vivo (see page 216 of the instant specification). As the compositions disclosed can be administered to cells of various types within an organism, specifically a human organism, and the claim does not recite an “isolated”, “cultured”, “ex-vivo”, or “non-human” cell, under broadest reasonable interpretation, a cell comprising a vector reads on a cell inseparable from the body of a living human patient who has been administered the therapeutic agent (see page 236 of the instant specification), and thus, is unpatentable under 35 U.S.C. 101.
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 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.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Bryson et al. (WO 2019/217943 A1, published 11/14/2019) in view of Kotin et al. (WO 2019/113310 A1, published 6/13/2019) and Luke et al. (US 2007/0059710 A1, published 3/15/2007).
Regarding claim 1, Bryson teaches a polynucleotide encoding a deaminase domain or a nucleic acid programmable DNA binding protein (NapDNAbp) domain (see paragraphs 0007, 0008, and 0131) or a fragment thereof and where the polynucleotide comprises an intron (see paragraph 0252).
Regarding claim 3, Bryson teaches where the nucleic acid encoding a base editor comprising a deaminase domain and a programmable DNA binding protein (see paragraphs 0007, 0008, and 0131).
Regarding claim 4, Bryson teaches a polynucleotide encoding a deaminase domain or a nucleic acid programmable DNA binding protein (NapDNAbp) domain (see paragraphs 0007, 0008, and 0131) or a fragment thereof and where the polynucleotide comprises an intron (see paragraph 0252).
Regarding claim 6, Bryson teaches the deaminase domain is a cytidine deaminase domain or an adenosine deaminase domain (see paragraph 0037).
Regarding claim 16, Bryson teaches where various aspects of this disclosure provide kits comprising a base editor system (see paragraph 0541).
Regarding claims 1 and 4, Bryson does not teach where the intron is inserted in an open reading frame encoding the deaminase or a napDNAbp or fragment thereof.
Regarding claim 2, Bryson does not teach where the intron comprises an alteration at a splice acceptor or splice donor site, wherein the alteration reduces or eliminates splicing of base editor mRNA, thereby reducing or eliminating expression of a base editor polypeptide.
Regarding claim 5, Bryson does not teach wherein the intron comprises an alteration at a splice acceptor or donor site that reduces splicing of the base editor mRNA.
Regarding claim 7, Bryson does not teach where the intron is derived from a sequence selected from the group consisting of HBB.
Regarding claim 8, Bryson does not teach where the intron comprises a sequence that has at least 85% nucleic acid sequence identity with SEQ ID NO: 227.
Regarding claims 1 and 4, Kotin teaches vectors comprising polynucleotides encoding base editor moieties encoding a deaminase (see paragraphs 0065, 0351) and introns (see paragraphs 0043) wherein the intron is inserted in an open reading frame encoding the deaminase (“ORF for insertion of a transgenic editor”, see paragraph 0096, 0098, and Fig. 1C).
Regarding claims 2 and 5, Kotin teaches where the base editor (gRNA) targets a splice acceptor or donor (see paragraph 0043) positioned at the end of an intron sequence (see paragraph 0043) where a template sequence can be inserted that is substantially identical to a portion of an endogenous target gene sequence and where repair of the cleaved target nucleic acid molecule can result in gene knockdown or knockout. In other embodiments, the template sequence can comprise an exogenous sequence which can result in gene knock-in where the integration can result in a gene knockout (see paragraph 0364). The exogenous sequence can therefore target the base editor polypeptide, reducing its expression.
Regarding claim 7, Kotin discloses exemplary genes for targeting in table 10 to include HBB. Kotin further teaches where the guide RNAs will target known ZFN sequence targeted regions successful for knock-ins, or knock-out deletions, or for the correction of defective genes. This includes, for example, gRNA sequences for the human beta-globin (see paragraph 0388).
Regarding claim 8, Luke teaches SEQ ID NO: 39744 which has 99.7% identity with SEQ ID NO: 227 of the instant application.
It would have been obvious to one with ordinary skill and creativity in the art, before the effective filing date of the claimed invention, to combine the teachings of Bryson, Kotin and Luke to arrive at a polynucleotide encoding a base editor polypeptide where an intron is inserted into an open reading frame encoding the base editor polypeptide and comprises an alteration at a splice acceptor or donor site, wherein the intron is encoded by SEQ ID NO: 227.
One would expect a reasonable chance of success as Kotin discloses vectors comprising polynucleotides encoding base editor moieties encoding a deaminase and introns where an intron is inserted in an open reading frame encoding the deaminase and where base editor gRNA targets a splice acceptor or donor site positioned at the end of an intron sequence (see paragraph 0043 of Kotin).
One would be motivated to do so as Kotin teaches compositions that target a gene of interest, that gene of interesting utilizing an HBB intron as disclosed by Luke, using a base editor polynucleotide to alter expression level of the target gene, induce gene knockdown or knockout, or restore gene function. By inserting the intron into the open reading frame of Bryson, a skilled artisan could utilize the splice acceptor and targeting sites present in the intron to target the gene encoding the base editor polypeptide, therefore reducing base editor expression and off target effects.
In view of the foregoing, claims 1-7, and 16 are rejected under 35 U.S.C. 103 as being prima facie obvious before the effective filing date.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Beam (WO 2020/051561 A1, published 3/12/2020) in view of Bryson et al. (WO 2019/217943 A1, published 11/14/2019) and Kotin et al. (WO 2019/113310 A1, published 6/13/2019).
Regarding claim 9, Beam teaches compositions for delivering a nucleobase editing system, where two polypeptides, each encoding a fragment of a deaminase and cCas9, are split. The first polynucleotide is fused encodes an N-terminal fragment of nCas9 fused to an intein-N of a split intein pair and the second polynucleotide encodes a C-terminal fragment of NCas9 fused to intein-C of a split intein pair (see abstract).
Regarding claim 9, Beam does not teach an intron is inserted into the open reading frame of the polynucleotides.
Regarding claim 9, the combined teachings of Bryson and Kotin teaches a polynucleotide encoding a base editing polypeptide with an intron in the open reading frame of the polynucleotide, as described above.
It would have been obvious to one with ordinary skill in the art and creativity, to combine the teachings of Beam, Bryson, and Kotin, to arrive at a composition or pharmaceutical composition comprising a first and second polynucleotide fused to a split intein-N and intein-C.
One would have expected a reasonable chance of success as Beam discloses fragments of a polynucleotide encoding a deaminase that recombine together (see summary of invention). As Bryson discloses polynucleotides encoding a deaminase, one could envision splitting the same polynucleotide into fragments.
One would be motivated to do so because Beam teaches that fusion proteins improve base editing efficiency by improving delivery. Beam discloses that small packaging capacity of AAV vectors make the delivery of a number of genes that exceed this size and/or the use of large physiological regulatory elements challenging. By dividing the proteins to be delivered into two fragments, these fragments are then packaged into two or more AAV vectors (see page 133, line 22 of Beam). As disclosed above, the insertion of the intron into the open reading frame allows base editor or deaminase domains to target specific genes for knock down. Therefore, by combing these inventions, one skilled in the art would envision a system or composition, wherein a large polynucleotide encoding a base editor can be readily delivered to cells, and wherein the inserted intron would allow base editors to target the gene encoding the base editor to limit base editing expression.
In view of the foregoing, claim 9 is rejected under 35 U.S.C. 103 as being prima facie obvious before the effective filing date.
Claims 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Bryson et al. (WO 2019/217943 A1, published 11/14/2019) in view of Kotin et al. (WO 2019/113310 A1, published 6/13/2019) in further view of Liu et al. (Analysis and minimization of cellular RNA editing by DNA adenine base editors, Science Advances, Volume 5, No. 5, all pages, published 5/8/2019).
Regarding claims 10 and 11, the teachings of Bryson and Kotin describe a base editor system, wherein the polynucleotide encoding the base editor is an adenosine deaminase (see paragraph 0037 of Bryson), and one or more directs the base editor to edit the site of the genome in a cell wherein the edit results in decreased activity or expression of the encoded base editor (see paragraphs 0043, 0065, 0351, and 0388 of Kotin, as Kotin describes introns having a splice acceptor or donor site inserted into a target gene of interest in order to recruit a base editor with a deaminase domain to reduce gene expression).
Regarding claims 11, Bryson and Kotin does not teach where the base editor has an altered catalytic residue in the deaminase domain and the altered catalytic residue is E59.
Regarding claims 10 and 11, Liu teaches an analysis and minimization of cellular RNA editing by DNA adenine base editors where the effects of off-target editing of cellular RNA by ABEs have not been examined in depth (see introduction). Liu teaches that to identify which TadA monomers mediate RNA editing in adenosine base editors, E59A inactivating mutations were introduced into either the TadA or TadA* monomer and cellular RNA was then measured (see Fig. 1C and 1D, and results section). Liu specifically targets the wild type TadA monomer (see results section) which is an adenosine deaminase and targets the same corresponding position (E59) as recited in the instant claims. The results showed that despite the modest reduction in RNA editing activity associated with the ABEmax adenosine base editor with the TadA E59A mutation, the base editor maintains high DNA base editing activity similar to the unmodified base editor (see results section).
It would have been obvious to one with ordinary skill and creativity in the art, before the effective filing date of the claimed invention, to combine the teachings of Bryson, Kotin, and Liu, to arrive at a base editing system capable of targeting itself with an altered catalytic residue at E59.
One would expect a reasonable chance of success as Liu teaches modifying an adenosine base editor, ABEmax, with an E59A mutation.
One would be motivated to do so as the combined teachings of Bryson and Kotin describes a base editor system that comprises an intron at the open reading frame of the polynucleotide encoding the base editor. This intron with a splice acceptor and donor site can be a target for cleave with a Cas9/gRNA system that results in gene knockdown, described in Kotin. One would further be motivated to modify this system with an E59 mutation taught by Liu as an E59 mutation reduces off target cellular RNA activity while still maintaining high DNA base editing activity.
In view of the foregoing, claims 10 and 11 are rejected under 35 U.S.C. 103 as being prima facie obvious before the effective filing date.
Claim 14 and 15 rejected under 35 U.S.C. 103 as being unpatentable over Bryson et al. (WO 2019/217943 A1, published 11/14/2019) in view of Kotin et al. (WO 2019/113310 A1, published 6/13/2019).
Regarding claim 14, Bryson teaches a polynucleotide encoding a deaminase domain or a nucleic acid programmable DNA binding protein (NapDNAbp) domain (see paragraphs 0007, 0008, and 0131) or a fragment thereof and where the polynucleotide comprises an intron (see paragraph 0252).
Regarding claim 15, Bryson teaches a cell produced by introducing into the cell, a base editor, a polynucleotide encoding the base editor, to the cell, wherein the base editor comprises a polynucleotide programmable DNA binding domain and an adenosine deaminase domain (see claim 22 of Bryson).
Regarding claim 14, Kotin teaches vectors comprising polynucleotides encoding base editor moieties encoding a deaminase (see paragraphs 0065, 0351) and introns (see paragraphs 0043) wherein the intron is inserted in an open reading frame encoding the deaminase (“ORF for insertion of a transgenic editor”, see paragraph 0096, 0098, and Fig. 1C). Kotin further teaches where the base editor (gRNA) targets a splice acceptor or donor (see paragraph 0043) positioned at the end of an intron sequence (see paragraph 0043) where a template sequence can be inserted that is substantially identical to a portion of an endogenous target gene sequence and where repair of the cleaved target nucleic acid molecule can result in gene knockdown or knockout. In other embodiments, the template sequence can comprise an exogenous sequence which can result in gene knock-in where the integration can result in a gene knockout (see paragraph 0364). The exogenous sequence can therefore target the base editor polypeptide, reducing its expression.
It would have been obvious to one with ordinary skill and creativity in the art, before the effective filing date of the claimed invention, to combine the teachings of Bryson and Kotin to arrive at a vector comprising a polynucleotide encoding a base editor polypeptide where an intron is inserted into an open reading frame encoding the base editor polypeptide and comprises an alteration at a splice acceptor or donor site.
One would expect a reasonable chance of success as Kotin discloses vectors comprising polynucleotides encoding base editor moieties encoding a deaminase and introns where an intron is inserted in an open reading frame encoding the deaminase and where base editor gRNA targets a splice acceptor or donor site positioned at the end of an intron sequence (see paragraph 0043 of Kotin).
One would be motivated to do so as Kotin teaches compositions that target a gene of interest using a base editor polynucleotide to alter expression level of the target gene, induce gene knockdown or knockout, or restore gene function. By inserting the intron into the open reading frame of Bryson, a skilled artisan could utilize the splice acceptor and targeting sites present in the intron to target the gene encoding the base editor polypeptide, therefore to reduce its expression and off target effects.
In view of the foregoing, claims 14 and 15 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID YU whose telephone number is (571)272-1118. The examiner can normally be reached Monday-Friday 7:30 am -5 pm.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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