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 .
Claim Status Summary
Claims 1- 20 are pending.
Claims 1- 20 are considered on the merits.
Claims 1- 16 are objected.
Claims 1- 20 are rejected.
No Claims are allowed.
Claim Objections
Claims 1 and 9 are objected to because of the following informalities: Claims 1 and 9 each recite “wherein said first RNA and said second RNA are not attached or tethered.” It is unclear whether the first and second RNA are not attached to each other (as the specification indicates) or not attached to anything. This examiner interprets this limitation as “wherein said first RNA and said second RNA are not attached or tethered to each other.”
Claim 8 is objected to because of the following informalities: Claim 8 recites “The system of claim 1, wherein the combination of said first and said second RNA is less then 4.5 kB.” This is improper grammar. This examiner interprets this to claim to read ““The system of claim 1, wherein the combination of said first and said second RNA is less than 4.5 kB.”
Claim 18 recites the limitation “wherein said first RNA and said second RNA are encased within said AAV.” The claim from which this instant claim depends (claim 17) recites an AAV delivery system but fails to recite an AAV. Therefore, it is unclear whether the first and second RNA of the instant claim are incased in the delivery system (which may encompass multiple AAVs) or encased in the (single) AAV. This examiner interprets this claim to read “wherein said first RNA and said second RNA are encased within said AAV delivery system.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 18 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.
The instant limitation does not further limit the claim upon which it depends. Instead, it simply states a scientific truism as evidenced by Zwi-Dantsis “From a structural proteins perspective, the icosahedral capsid is composed of 60 subunits with a mixture of three capsid (Cap) proteins—VP1, VP2, and VP3—at a molar ratio of 1:1:10 which are involved in structural stability, receptor binding, cellular entry, and DNA [or RNA] encapsidation.” (page 239, 4th paragraph). Furthermore, the instant specification describes AAV systems enclose their nucleic acid content “The [AAV] genome comprises ITRs at both ends of the DNA strand, and two open reading frames (ORFs) encoding the rep and cap proteins. The rep ORF is composed of four overlapping genes encoding Rep proteins required for 5 the AAV life cycle. The cap ORF is composed of overlapping nucleotide sequences of capsid proteins (e.g., VPl, VP2 and VP3) which interact to form a capsid with icosahedral symmetry.” [page 31, 1st paragraph).
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.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 6, 8, 14, and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Breadth Of The Claims And Nature Of Invention
Claims 6 and 8 depend from claim 1 and claims 14 and 16 depend from claim 9. Claims 6 and 14 further recite the limitation, “wherein said first RNA is less than 4.5 kB” and Claims 8 and 16 further recite the limitation, “wherein the combination of said first and said second RNA is less than 4.5 kB.” The claims are directed toward a modular prime editing system. The claimed invention comprises two separate RNAs: a first RNA encoding a Cas9 nickase and a reverse transcriptase and a second RNA encoding a sgRNA, a primer binding site, and a template. Prime editing systems are gene editing systems.
State Of The Prior Art And Level Of One Of Ordinary Skill And Level Of Predictability In The Art
Prime editors (PE) composed of a Cas9 nickase fused to an engineered reverse transcriptase have enabled precise nucleotide changes, sequence insertions and deletions that does not induce double-stranded DNA breaks and does not require homology directed repair [instant specification, page 1, line 8]. Prime (RT) editor consists of a Cas9 nickase (H840A)-reverse transcriptase fusion protein paired with a pegRNA with desired edits. However, the potential of clinical use of PE is hampered by the large size for delivery (total length>6.3kb ) [instant specification, page 1, line 30]. AAV vectors commonly used for packaging and delivering RNA cargos are limited to approximately 4.5kb. Cas9 (approximately 4.1 kb) and reverse transcriptase (approximately 2.1 kb) together are too large to fit into a single vector [instant specification, page 16, line 19].
Amount Of Direction Provided By The Inventor And Existence Of Working Examples
The instant specification provides no direction nor working examples showing they have enabled the limitations “wherein said first RNA is less than 4.5 kB” and “wherein the combination of said first and said second RNA is less than 4.5 kB.” As stated above, the applicant admits the current dilemma is the combined size of Cas9 and reverse transcriptase exceeds the common method of AAV delivery. Instead, the applicant describes an RNA vector combination in their Figure 13A and 13B, where the first RNA vector encodes the nCas9. This alone (absent transcript data) is not sufficient to enable the claim, since the total RNA packaging is likely to exceed 4.5 kb. Furthermore, this first RNA does not encode the reverse transcriptase, as required by claim 1. Furthermore, Figure 14B similarly discloses nCas9 and the reverse transcriptase encoded by separate RNA.
Quantity Of Experimentation Needed To Make Or Use The Invention
Based on the enclosed disclosure and current state of the art, it would require undue experimentation by a person having ordinary skill in the art (PHOSITA) to make and use the invention as claimed.
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)(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- 5 and 9- 13, and 17, 18 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by D. Liu (Liu WO 2021/226558 A1, effectively filed May 8, 2020); claim 18, is further evidenced by Zwi-Dantsis (Zwi-Dantsis et al. Viruses. 2025 Feb 9;17(2):239.); claims 7 and 15 are further evidenced by NovoPro (2014. https://www.novoprolabs.com/support/articles/7sk-u6-and-h1-promoters-202408021593.html), Gao (Gao et al. Mol Ther Nucleic Acids. 2018 Mar 2;10:36-44), Sutcliffe (Sutcliffe et al. Proc Natl Acad Sci U S A. 1978 Aug;75(8):3737-41.), De Saeger (De Saeger 2025. SynBio. MDPI 2025, 3(4), 19).
Regarding claims 1, D. Liu teaches a prime editing (PE) system with all of the components (composition) of the claimed prime editing system, “prime editor complexes comprises (I) a prime editor comprising (i) a nucleic acid programmable DNA binding protein (napDNAbp), and (ii) a polypeptide having an RNA-dependent DNA polymerase activity; and (2) a pegRNA comprising a spacer sequence, gRNA core, a DNA synthesis template, and a primer binding site,” [Abstract]; and “the napDNAbp has a nickase activity… a Cas9 nickase (nCas9)” [0021]; and D. Liu further teaches the component nickase, reverse transcriptase, sgRNA, primer binding site, and template are encoded by vector RNA, “The use of RNA … viral based systems for the delivery of nucleic acids… Integration in the host genome is possible with the retrovirus, lentivirus, and adeno-associated virus gene transfer methods” [0813]; and D. Liu further teaches the components are each are encoded by a first and second RNA that are not attached “the vectors may comprise one or more [RNA] polynucleotides that encode napDNAbps, reverse transcriptase, and extended guide RNAs [pegRNA] on the same or separate vectors”[0062]; furthermore, “In certain embodiments involving two or more vectors (e.g., a vector system in which the components described herein are encoded on two or more separate vectors) … a vector encoding the nuclease system may deliver the PE [prime editor nuclease-transcriptase fusion] prior to the vector encoding the [pegRNA] template. In other embodiments, the vector encoding the PEgRNA may deliver the guide prior to the vector encoding the PE system. In some embodiments, the vectors encoding the PE system and PEgRNA are delivered simultaneously” [0670].
Regarding claim 9, D. Liu teaches all of the elements of claim 1.
Furthermore, D. Liu teaches a composition comprising a vector ribonucleic acid (RNA) delivery system as described above.
Regarding claims 2 and 10, D. Liu teaches the second [separate from nuclease] RNA comprises the pegRNA of the prime editing system as described above in regards to claim 1.
Regarding claims 3, and 11, D. Liu teaches the second [separate from nuclease] RNA comprises the petRNA [a DNA synthesis template] of the prime editing system as described above in regards to claim 1.
Regarding claims 4, 5, 12, and 13, D. Liu further teaches the vector RNA components described in claim 1 above (including the petRNA) may be circularized or linear “The term "phage," as used herein interchangeably with the term "bacteriophage," refers to a virus that infects bacterial cells. Typically, phages consist of an outer protein capsid enclosing genetic material. The genetic material can be ssRNA, dsRNA, ssDNA, or dsDNA, in either linear or circular form.” [0313].
Regarding claims 7 and 15, D. Liu further teaches the second RNA encoding a component selected from a sgRNA, a primer binding site, and a template is less than 4.5 kb in their Figure 54. While no specific lengths are noted, the lengths of the elements comprising the RNA vector are known. For example, the U6 promoter is less than 0.3 kb (NovoPro 2014), the spacer sequence is 0.02 kb (De Saeger 2025. SynBio. MDPI.), the sgRNA scaffold is less than 0.1 kb (De Saeger 2025. SynBio. MDPI), the template (as described in D. Liu’s Figure 27, shown beneath Fig. 54) is less than 0.02 kb, the U6 poly T sequence is less than 0.01 kb (Gao et al. Mol Ther Nucleic Acids. 2018 Mar 2;10:36-44.), and the AmpR gene is less than 1.0 kb (Sutcliffe et al. Proc Natl Acad Sci U S A. 1978 Aug;75(8):3737-41.); totaling approximately 1.5 kb.
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Regarding claims 17 and 18, D. Liu further teaches “The use of RNA or DNA viral based systems for the delivery of nucleic acids… is possible with … adeno-associated virus gene transfer methods.” [0813].
Regarding claim 18, the instant limitation simply states a scientific truism as evidenced by Zwi-Dantsis as described above. Therefore, Liu anticipates claim 18.
Regarding claims 19, D. Liu further teaches “prime editors may be delivered by non-viral delivery strategies involving delivery of … (i.e., a PE ribonucleoprotein complex” [0867].
Regarding claims 20, D. Liu further teaches the alternative embodiment, RNA delivery is a liposome system, “Methods of nonviral delivery of nucleic acids include … liposomes” [0867].
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AARON DUREL WARD whose telephone number is (571)272-8495. The examiner can normally be reached Monday to Thursday 8:00AM 6:00PM.
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/AARON DUREL WARD/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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