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 .
Application Status
This action is written in response to applicant’s correspondence received 17 March 2026. Claims 1, 7, 9-14, 18-22, 24, 28-30, and 32-34 are currently pending. Claims 20-22, 24, and 28-30 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1, 7, 9-14, 18, and 32-34 are examined herein. The restriction requirement mailed 13 January 2025 is still deemed proper. Applicant's elected Group I, claims 1-3, 7, 9-14, 18-19, and 28-29 without traverse in the reply filed 14 July 2025.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
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 1, 7, 9-14, 18-22, 24, 28-30, and 32-34 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.
Regarding claim 1, the claim recites “a PCSK9 or TTR meganuclease”. It is unclear if the claimed meganucleases are intended to claim meganucleases that target PCSK9 and TTR target sequences (i.e., a “PCSK9 meganuclease” is an engineered meganuclease that can target and cleave a PCSK9 target sequence) or if the claims are intended to limit the meganucleases to meganucleases that are derived from the PCSK9 and TTR genes. It is noted that the instant specification teaches that “a meganuclease may be selected from those described in WO 2018/195449 A1” (pg. 15) or “see, WO 2018/195449, describing certain PCSK9 meganucleases, which is incorporated herein in its entirety” (pg. 33). However, as discussed in Bartsevich (PG Pub No. WO 2018/195499, filed 20 April 2018) the meganucleases present in WO 2018/195449 A1 are engineered meganucleases that target PCSK9 genes, not meganucleases derived from PCSK9 (see Abstract and Claim 1). Therefore, it is unclear what the term “PCSK9 or TTR meganuclease” is intended to claim.
Regarding claim 32, the claim recites “a first nuclease modulating sequence”. However, claim 1 (i.e., the claim from which claim 32 depends) already claims the presence of at least one nuclease modulating sequence (i.e., see part (b) of claim 1). Accordingly, it is unclear if this nuclease modulating sequence of claim 32 is the same or a different nuclease modulating sequence when compared to the nuclease modulating sequence present in claim 1.
Regarding claims 33-34, the claim recites “a nuclease modulating sequence”. However, claim 1 (i.e., the claim from which claims 33-34 depend) already claims the presence of at least one nuclease modulating sequence (i.e., see part (b) of claim 1). Accordingly, it is unclear if the nuclease modulating sequences present in claims 33-34 are the same or different nuclease modulating sequences when compared to the nuclease modulating sequence already present in claim 1.
Regarding claims 7, 9-14, 18-22, 24, and 28-30, as the claims are ultimately dependent on claim 1 and do not rectify the currently outstanding 35 USC 112(b) rejections of record, the claims are also rejected under 35 USC 103.
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.
Claims 11-12 are 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.
Regarding claim 11, the claim recites that the nuclease is a meganuclease and further limits the modulating sequence to about 22 nucleotides in length. However, claim 1 (i.e., the claim from which claim 11 depends) already claims that the nuclease is a PCSK9 or TTR meganuclease and that the modulating sequence is selected from SEQ ID NOs: 5-7 (i.e., modulating sequences that are each 22 nucleotides in length). Therefore, claim 11 does not further limit the subject matter of claim 1.
Regarding claim 12, the claim recites that the protein degradation signal is 10-50 amino acids in length. However, claim 1 recites that the peptide degradation signal is the claimed SEQ ID NO: 4 which is 42 amino acids in length. Accordingly, claim 12 does not include all of the limitations of the claim from which it depends because it suggests that the peptide degradation signal could be shorter than 42 amino acids in length.
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 § 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, 7, 9-14, 19, and 32-34 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dombrowski (PG Pub No. US 2017/0260547 A1, cited on the IDS filed 29 September 2023) in view of Bartsevich (Pg Pub No. US 2020/0131489 A1, filed 20 April 2018), Bartsevich sequence alignment (accessed 10 June 2026), Weiss (PG Pub No. US 2020/0040338 A1, claiming priority to Provisional Application No. 62/713,186, filed 1 August 2018), and Weiss sequence alignment (accessed 10 June 2026).
For the purposes of examination, the claimed PCSK9 meganuclease is interpreted as claiming a meganuclease that targets a PCSK9 gene.
Regarding claims 1 and 11, Dombrowski is drawn to an invention concerned with compositions and methods for enhancing the efficiency of gene editing by timing the expression and activity of a nuclease to correspond with availability of a repair template (Abstract). Dombrowski teaches the use of a self-regulating vector (i.e., a self-modulating gene editing nuclease expression cassette) comprising a CRISPR/Cas9 nuclease system that cleaves a target sequence on a target nucleic acid molecule, the CRISPR/Cas9 system comprising a Cas9 protein and a guide RNA, wherein the vector comprises (a) a nucleotide sequence encoding the Cas9 protein (i.e., a nuclease coding sequence) operably linked to a first promoter (i.e., a first regulatory sequence which direct expression of the nuclease following delivery to a host cell), a nucleotide sequence encoding the guide RNA operably linked to a second promoter, and (b) the target sequence which reduces the expression of the Cas9 protein or the guide RNA (i.e., at least one nuclease modulating sequence selected from the target sequence for the nuclease); and a template sequence flanked at each end by the target sequence ([0011]). Dombrowski teaches that (c) the Cas9 nuclease may be in frame and fused to a protein domain selected from a PEST degradation signal ([0048], [0050], [0136]). Dombrowski teaches that the nuclease system of the invention may be chosen from a nuclease other than a Cas protein, including a meganuclease that targets and cleaves DNA sequences of about 12-40 base pairs (i.e., Dombrowski teaches that the nuclease may be a meganuclease and the modulating sequence a meganuclease target sequence) ([0043]).
Dombrowski teaches that the target sequence for vector self-destruction can be the same sequence as a desired genomic target site (i.e., the host cell has a sequence to which the nuclease is targeted) ([0101]). Dombrowski teaches that the vector encoding the nuclease system can comprise at least one target sequence within the vector in order to create a self-destroying vector system to control the amount of the nuclease system to be expressed in the target cell ([0088]).
Dombrowski does not teach or suggest that the meganuclease is a PCSK9 meganuclease (Claims 1 and 11) the nuclease modulating sequence is selected from SEQ ID NO: 5 (Claims 1 and 11), or that the PEST sequence comprises the claimed SEQ ID NO: 4 (Claim 1).
Bartsevich is drawn towards an invention concerned with an engineered meganuclease that can target and cleave a recognition sequence within a human PCSK9 gene (Abstract). Bartsevich teaches that the recognition sequence may comprise a sequence that has 100% identity to the claimed SEQ ID NO: 5 and is 22 nucleotides in length ([0016]-[0017]; see SEQ ID NO: 4 in attached sequence alignment).
Weiss is drawn towards a study concerned with genetic circuits for detecting the microDNA profile of a cell (Abstract). Weiss teaches the use of a PEST degradation signal that has 100% identity to the claimed SEQ ID NO: 4 and can be fused to another protein or polypeptide ([0043]-[0044]; see SEQ ID NO: 10 in attached sequence alignment).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the meganuclease and PEST degradation signal of Dombrowski with a meganuclease that targets the claimed SEQ ID NO: 5 and a PEST degradation signal that comprises the claimed SEQ ID NO: 4 because it would have merely amounted to a simple substitution of one known meganuclease and one known PEST signal for another to obtain predictable results. A person of ordinary skill in the art could have substituted the PSCK9 meganuclease and PEST signals of Dombrowski and would have expected to maintain the self-modulating vector’s ability to self-regulate and target a gene of interest within a cell because Bartsevich and Weiss teach using the claimed SEQ ID NOs: 5 and 4 for a similar purpose as Dombrowski: to target a PCSK9 target sequence with an engineered meganuclease and subsequently degrade a protein or polypeptide fused to the PEST signal, respectively.
Regarding claim 7, Bartsevich teaches that the recognition sequence targeted by the engineered meganuclease comprises two recognition half-sites (i.e., two nuclease modulating sequences) that are separated by a 4 base pair central sequence ([0051]; see Figure 1).
Regarding claim 9, Bartsevich teaches that the recognition sequence targeted by the engineered meganuclease comprises two recognition half-sites that are different (i.e., different mutated target sequences relative to on another) ([0051]; see Figure 1).
Regarding claim 10, Bartsevich teaches that the recognition sequence may be 22 nucleotides in length ([0016]-[0017]; see SEQ ID NO: 4 in attached sequence alignment).
Regarding claim 12, Weiss teaches that the degradation signal is 42 amino acids in length ([0043]-[0044]; see SEQ ID NO: 10 in attached sequence alignment).
Regarding claim 13, Dombrowski teaches that the nuclease may be fused to two or more heterologous protein domains ([0048]). Dombrowski teaches that the protein domain may be a signal peptide for protein degradation (i.e., a protein degradation signal) ([0050]).
Regarding claim 14, Dombrowski teaches that HEK293 cells were transfected with the vectors alongside Lipofectamine LTX (i.e., a carrier) ([0130]).
Regarding claim 19, Dombrowski teaches that the vector may be an AAV (i.e., a viral vector) ([0076]). Dombrowski teaches that HEK293 cells were transfected with the vectors alongside Lipofectamine LTX (i.e., a carrier) ([0130]).
Regarding claim 32, Dombrowski teaches that the nuclease modulating sequence may be located upstream of the nuclease coding sequence ([0012]; see Fig. 1).
Regarding claim 33, Dombrowski does not specifically teach that the nuclease modulating sequence is located downstream of the nuclease coding sequence (Claim 33).
However, Dombrowski teaches that one or more target sequences may be located at any place on the vector such that, upon expression of the nuclease, the nuclease recognizes and cleaves the target sequence in the vector that contains the nuclease-encoding sequence ([0088]). Dombrowski teaches that a target sequence may be located within a non-coding region on the vector encoding the nuclease ([0088]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have included a nuclease modulating sequence downstream of the nuclease coding sequence because it would have been obvious to try to position an additional nuclease modulating sequence downstream of the nuclease coding sequence. Because Dombrowski already teaches that there was a need to include target sequences in non-coding regions of the vector, and relative to the nuclease coding sequence there is either an upstream or a downstream, one of ordinary skill in the art would have identified that there are two possible locations that the target sequence present within a non-coding region can be: upstream or downstream relative to the nuclease coding sequence. Further, one or ordinary skill in the art would have been able to pursue the potential solution since the art already teaches the inclusion of a target sequence upstream of the nuclease coding sequence within a non-coding region of the vector.
Regarding claim 34, Dombrowski teaches that the target sequence may be located within the nucleotide sequence encoding the nuclease ([0088]).
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dombrowski (PG Pub No. US 2017/0260547 A1, cited on the IDS filed 29 September 2023) in view of Bartsevich (Pg Pub No. US 2020/0131489 A1, filed 20 April 2018), Bartsevich sequence alignment (accessed 10 June 2026), Weiss (PG Pub No. US 2020/0040338 A1, claiming priority to Provisional Application No. 62/713,186, filed 1 August 2018), and Weiss sequence alignment (accessed 10 June 2026) as applied to claims 1, 7, 9-14, 19, and 32-34 above, and further in view of Yan (Journal of virology 79.1 (2005): 364-379).
Regarding claim 18, Dombrowski in view of Bartsevich and Weiss renders obvious claims 1, 7, 9-14, 19, and 32-34 as discussed above.
Dombrowski does not teach or suggest that the AAV vector comprises a vector genome packed in the AAV capsid and comprises AAV inverted terminal repeats required for packaging the expression cassette into the capsid (Claim 18).
Yan is drawn towards a study concerned with how inverted terminal repeat sequences are important for intermolecular recombination and circularization of adeno-associated virus genomes (Abstract). Yan teaches the use of a novel AAV hybrid-ITR vector characterized by an AAV-2 and an AAV-5 ITR at opposite ends of a viral genome (Abstract). Yan teaches that the hybrid genome was efficiently packaged into either AAV-2 or AAV-5 capsids to generate infectious virions (Abstract). Yan teaches that utilizing the AAV hybrid-ITR vector resulted in a significantly lower capacity to form circular intermediates in infected cells than homologous AV2:2 and AV5:5 ITR vectors despite their similar capacity to express an encoded enhanced green fluorescent protein (EGFP) transgene (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the AAV vector of Dombrowski for the AAV hybrid-ITR vector of Yan because it would have merely amounted to a simple substitution of known elements for others to obtain predictable results. Because both Yan and Dombrowski utilize AAVs for the expression of transgenes, one of ordinary skill in the art would have expected that utilizing the hybrid AAV of Yan for the expression of the expression cassette of Dombrowski in view of Bartsevich and Weiss would have predictably resulted in the successful expression of the self-modulating nuclease system. Further, since Yan teaches that the hybrid AAV advantageously resulted in lower circular intermediates compared to traditional AAVs, one of ordinary skill in the art would have been motivated to have used the hybrid AAV over the traditional AAV of Dombrowski.
Response to Arguments
Applicant's arguments filed 17 March 2026 have been fully considered but they are not persuasive.
Applicant alleges that neither Dombrowski nor the previously cited art teaches or suggests a meganuclease sequence selected from the claimed SEQ ID NOs: 5, 6, or 7 (Remarks; pg. 1). Applicant alleges that neither Dombrowski nor the previously cited teaches or suggests the use of a PEST degradation signal selected from the claimed SEQ ID NO: 4 (Remarks; pg. 1).
These arguments are not found pervasive because the newly amended claims necessitated the newly filed rejections above. It is the combination of Dombrowski, Bartsevich, and Weiss that renders the newly claimed invention obvious. Because Applicant’s arguments are not drawn towards the newly rejections of record, Applicant’s arguments are not found persuasive.
Conclusion
Applicant's amendment necessitated the new 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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