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
Application status
Claims 1-3 and 5-16 are pending in this application.
Priority
It is acknowledged that the instant application is a CON of PCT/US2021/020933 filed on 03/04/2021, which claims the benefit of US Provisional Application No. 63035638 filed on 06/05/2020 and 62985291 filed on 03/04/2020.
Election
Applicant's election without traverse of Group I, Claims 1-3 and 5-15, and species, CFTR from Table 11E, 5-methylcytidine, Zn finger domain, in the response filed on 11/19/2025, is acknowledged.
Claim 16 is withdrawn from further consideration by the Examiner, 37 CFR 1.142(b) as being drawn to a non-elected invention.
For the reasons provided above, this restriction requirement is deemed proper, and therefore, it is made final.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/19/2023 and 11/19/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objections to the Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, i.e., “https://” six times, on paragraphs [0099]; [0177]; [0652]; [0691] and [0860]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 1, 2 and 10 are objected to because of the following informalities:
Claims 1, 2 and 10 recite abbreviations, i.e., “UTR” and “TAL”. The Examiner suggests writing out the abbreviations in full in the first instance of their use. In the interest of advancing prosecution, the noted terms are interpreted as “untranslated region” and “transcription activator-like”, respectively.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 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.
Claims 1-3, 5-7 and 14 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1-3, 5-7 and 14 recite phrases containing “e.g., …”, “(….)” and/or “(e.g., …)”, which render these claims indefinite. Parenthesis or "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase or inside the parenthesis are part of the claimed invention. See MPEP § 2173.05(d). In the interest of advancing prosecution, the noted phrases are not given any patentable weight with the exception of claim 14 in the recitation of “(circRNAs)” which is an abbreviation.
Claim 1 recites a relative terms, i.e., “increases the expression” under (VI), and “enhanced activity or altered specificity” under (VII), without reciting what the increase, the enhancement, or the alteration is in comparison to, which renders the claim indefinite.
Claim 1 is rejected because claim 1 attempts to incorporate by reference sequences recited in Tables 10A-10D or 11A-11G of the specification. However, as clearly noted in M.P.E.P. 2173.05(s), this kind of reference to a table is only permitted when there is no way to clearly describe the content of the table in words within the claim. It is not, however, permitted merely for Applicant' s convenience.
Claim 2 is rejected because “(a) binds to a smaller number of target DNA sequences” which is indefinite. Since “(a)” cannot bind to a smaller number of target DNA, in the interest of advancing prosecution, the noted phrase is interpreted as “the polypeptide of (a) binds to a smaller number of target DNA sequences”.
The following is a quotation 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.
Claims 1-3 and 5-15 are rejected under 35 U.S.C. § 112(a), written description, as failing to comply with the written description requirement. The claim(s) contains 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 instant claims are directed to a system for modifying DNA comprising:(a) a polypeptide or a nucleic acid encoding a polypeptide, wherein the polypeptide comprises (i) a retrotransposase reverse transcriptase domain and (ii) a retrotransposase endonuclease domain; and (b) a template RNA (or DNA encoding the template RNA) comprising (i) a sequence that binds the polypeptide and (ii) a heterologous object sequence, wherein: (I) the polypeptide comprises a mutation inactivating and/or deleting a nucleolar localization signal; (II) the system is capable of cutting the first strand and the second strand of the target DNA, and wherein the distance between the cuts is the same as the distance between cuts made by the retrotransposase endonuclease domain; (III) (a), (b), or (a) and (b) further comprises a 5' UTR and/or 3' UTR operably linked to the sequence encoding the polypeptide, the heterologous object sequence, or both; (IV) the template RNA, or the DNA encoding the template RNA, further comprises (iii) a ribozyme that is heterologous to (a)(i), (a)(ii), (b)(i), or a combination thereof; (V) the template RNA, or the DNA encoding the template RNA, further comprises (iii) a 5' UTR capable of being cleaved into a fragment and a cleaved template RNA, wherein the 5' UTR is optionally the sequence that binds the polypeptide, wherein the 5' UTR comprises one or more mutations which increase the affinity of the fragment for the cleaved template RNA; (VI) (a), (b), or (a) and (b) comprise an intron that increases the expression of the polypeptide, the heterologous object sequence, or both; (VII) the heterologous object sequence comprises a sequence; (VIII) the polypeptide is modified for enhanced activity or altered specificity; or (IX) the template RNA comprises one or more chemical modification selected from dihydrouridine, inosine, 7-methylguanosine, 5-methylcytidine (5mC), 5' Phosphate ribothymidine, 2'-O-methyl ribothymidine, 2'-0-ethyl ribothymidine, 2'-fluoro ribothymidine, C-5 propynyl-deoxycytidine (pdC), C-5 propynyl-deoxyuridine (pdU), C-5 propynyl-cytidine (pC), C-5 propynyl-uridine (pU), 5-methyl cytidine, 5-methyl uridine, 5-methyl deoxycytidine, 5-methyl deoxyuridine methoxy, 2,6- diaminopurine, 5'-Dimethoxytrityl-N4-ethyl-2'-deoxycytidine, C-S propynyl-f-cytidine (pfC), C-S propynyl-f-uridine (pfU), 5-methyl f-cytidine, 5-methyl f-uridine, C-S propynyl-m-cytidine (pmC), C-S propynyl-f-uridine (pmU), 5-methyl m-cytidine, 5-methyl m-uridine, LNA (locked nucleic acid), MGB (minor groove binder) pseudouridine ('P), 1-N-methylpseudouridine (1-Me-'P), or 5- methoxyuridine (5-MO-U).
To satisfy the written description aspect of 35 U.S.C. § 112(a) for a claimed genus of [compositions or methods], it must be clear that: (1) the identifying characteristics of the claimed [compositions or methods] have been disclosed, 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; and (2) a representative number of species within the genus must be disclosed.
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 be 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 Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (bracketed material in original). 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 Inc. v. Gen-Probe Inc. (CAFC (2002) 63 USPQ2d 1609).
The specification discloses only a diagram of the single representative species of claimed system comprising a genus of polypeptides, i.e., a polypeptide comprising a DBD, RBD, RT and EN (see Fig. 30A). The Examiner notes that there is not a single SEQ ID NO in the specification that describes the structure of the genus of polypeptides comprised in the claimed systems, and that SEQ ID NOs 1-43 are “skipped sequences” according to the sequence listing filed on 04/19/2023 which do not provide any meaningful information regarding the description of said genus of polypeptides. As such, this single disclosed diagram fails to provide adequate written description for a genus of any polypeptides comprising any retrotransposase reverse transcriptase domain having any sequence and a retrotransposase endonuclease domain having any sequence as encompassed by the claims.
In support of this notion, the specification fails to describe any identification of structural characteristics or properties of any and all retrotransposase reverse transcriptase/endonunclease domains having any sequence, which possess the functional characteristics recited under any one of (I)-(IX) (the Examiner notes that the list (I)-(IX) is written in the alternative of, with the use of “or”).
Claims 2-3 and 5-15 are included in this rejection because these claims all have similar issues as noted above regarding written description requirement, if not identical, as with claim 1, and none of the dependent claims remedy the deficiencies of claim 1 in this regard.
While M.P.E.P. section 2163 acknowledges that a single species can describe a genus, it also acknowledges that for a genus that encompasses widely variant species, disclosure of a single species within the genus fails to adequately describe all members of the genus. Please refer to the M.P.E.P. section 2163.05 [R-7.2022] under I, B for more details with respect to sufficient number of representative species that should be disclosed to describe a widely variant genus.
Given the lack of additional representative species of a broad genus of systems comprising any polypeptides comprising any retrotransposase reverse transcriptase domain having any sequence and a retrotransposase endonuclease domain having any sequence as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112(a) published in the Official Gazette and also available at www.uspto.gov.
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 1-3 an 5-15 are rejected under 35 U.S.C. 103 as being unpatentable over Anzalone et al. ("Search-and replace genome editing without double-strand breaks or donor DNA”, Nature (2019) Vol. 576, No. 7785, pp. 149-157, see IDS) in view of Feng et al. (“Human L1 Retrotransposon Encodes a Conserved Endonuclease Required for Retrotransposition”, Cell, Vol. 87, 905–916, November 29, 1996), and Goodier et al. (A potential role for the nucleolus in L1 retrotransposition, Human Molecular Genetics, 2004, Vol. 13, No. 10 1041–1048), Friedland et al. (US Patent No. 11001844, first published on 09/06/2018), Yin et al. (US Patent No. 10047355, first published on 06/01/2017), and KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007).
The instant claims are directed to a system for modifying DNA comprising:(a) a polypeptide or a nucleic acid encoding a polypeptide, wherein the polypeptide comprises (i) a retrotransposase reverse transcriptase domain and (ii) a retrotransposase endonuclease domain; and (b) a template RNA (or DNA encoding the template RNA) comprising (i) a sequence that binds the polypeptide and (ii) a heterologous object sequence, wherein: (I) the polypeptide comprises a mutation inactivating and/or deleting a nucleolar localization signal; (II) the system is capable of cutting the first strand and the second strand of the target DNA, and wherein the distance between the cuts is the same as the distance between cuts made by the retrotransposase endonuclease domain; (III) (a), (b), or (a) and (b) further comprises a 5' UTR and/or 3' UTR operably linked to the sequence encoding the polypeptide, the heterologous object sequence, or both; (IV) the template RNA, or the DNA encoding the template RNA, further comprises (iii) a ribozyme that is heterologous to (a)(i), (a)(ii), (b)(i), or a combination thereof; (V) the template RNA, or the DNA encoding the template RNA, further comprises (iii) a 5' UTR capable of being cleaved into a fragment and a cleaved template RNA, wherein the 5' UTR is optionally the sequence that binds the polypeptide, wherein the 5' UTR comprises one or more mutations which increase the affinity of the fragment for the cleaved template RNA; (VI) (a), (b), or (a) and (b) comprise an intron that increases the expression of the polypeptide, the heterologous object sequence, or both; (VII) the heterologous object sequence comprises a sequence; (VIII) the polypeptide is modified for enhanced activity or altered specificity; or (IX) the template RNA comprises one or more chemical modification selected from dihydrouridine, inosine, 7-methylguanosine, 5-methylcytidine (5mC), 5' Phosphate ribothymidine, 2'-O-methyl ribothymidine, 2'-0-ethyl ribothymidine, 2'-fluoro ribothymidine, C-5 propynyl-deoxycytidine (pdC), C-5 propynyl-deoxyuridine (pdU), C-5 propynyl-cytidine (pC), C-5 propynyl-uridine (pU), 5-methyl cytidine, 5-methyl uridine, 5-methyl deoxycytidine, 5-methyl deoxyuridine methoxy, 2,6- diaminopurine, 5'-Dimethoxytrityl-N4-ethyl-2'-deoxycytidine, C-S propynyl-f-cytidine (pfC), C-S propynyl-f-uridine (pfU), 5-methyl f-cytidine, 5-methyl f-uridine, C-S propynyl-m-cytidine (pmC), C-S propynyl-f-uridine (pmU), 5-methyl m-cytidine, 5-methyl m-uridine, LNA (locked nucleic acid), MGB (minor groove binder) pseudouridine ('P), 1-N-methylpseudouridine (1-Me-'P), or 5- methoxyuridine (5-MO-U).
Anzalone et al. teach a programmable DNA modification system comprising a fusion polypeptide comprising a reverse transcriptase (RT) domain, i.e., a first DNA binding domain M-MLV RT, to an endonuclease (EN) domain, i.e., a second DNA binding domain Cas9 nickase with H840A, and a template RNA, i.e., a priming editing guide RNA (pegRNA), that binds the polypeptide and comprises a heterologous object sequence, i.e., an edit sequence CFTR for the purposes of correcting a genetic defect of cystic fibrosis (see abstract; pg. 149, right column, 1st para; and Figure 1b-f on pg. 150). Anzalone et al. further teach the Cas9 nickase (the second DNA binding domain) binding to five different genomic sites and making edits in Figures 2 and 3 (see pg. 151 and 152).
Anzalone et al. do not teach the use of retrotransposase RT domain and retrotransposase EN domain; the use of inactivating mutation in nucleolar localization signal as recited under (I) in addition to (II)-(VI) and (IX) of claim 1; and the use of lipid nanoparticles.
Feng et al. teach human LINE-1 (L1) retrotransposon comprising both RT and EN domains (see abstract), which is capable of cutting 1st and 2nd strand of the target DNA (see pg. 908, right column, 1st para). Feng et al. further teach that the endonuclease activity of L1, along with its RT activity is essential for target-primed reverse transcription (see Figure 6 on pg. 911).
Goodier et al. teach eight substitutions of basic residues between 53-71 of human LINE-1 inactivate nucleolar localization signal (see pg. 1043, left column, last para).
Friedland et al. teach that gRNAs can comprise “a promoter region, an enhancer region, an intron, the 3′ UTR, the 5′ UTR, or a polyadenylation signal region of said HSV viral gene” (see claim 4) in addition to “locked nucleic acids (LNA) in which the 2′ hydroxyl can be connected, e.g., by a C.sub.1-6 alkylene or C.sub.1-6 heteroalkylene bridge, to the 4′ carbon of the same ribose sugar, where exemplary bridges can include methylene, propylene, ether, or amino bridges; O-amino (wherein amino can be, e.g., NH.sub.2; alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, or diheteroarylamino, ethylenediamine, or polyamino) and aminoalkoxy, O(CH.sub.2).sub.n-amino, (wherein amino can be, e.g., NH.sub.2; alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, or diheteroarylamino, ethylenediamine, or polyamino). In certain embodiments, the “oxy”-2′ hydroxyl group modification can include the methoxyethyl group (MOE), (OCH.sub.2CH.sub.2OCH.sub.3, e.g., a PEG derivative” (boldfaced for added emphasis, see column 144, lines 39-52).
Yin et al. teach a lipid nanoparticle for the use with a system for modifying DNA, i.e., CRISPR-Cas gene editing system (see claim 22).
It would have been obvious to a person of ordinary skill in the art (POSITA) prior to the effective filing date of the instant application to make and use the system for modifying DNA comprising the fusion polypeptide comprising a first DNA binding domain, M-MLV reverse transcriptase, and a second DNA binding endonuclease domain, Cas9 nickase, and a template RNA as taught by Anzalone et al. and replace the polypeptide with human LINE-1 (L1) retrotransposon comprising both RT and EN domains as taught by Feng et al. while mutating nucleolar localization signal in LINE-1 as taught by Goodier et al. A POSITA would have been motivated to make and use such system because [1] it would be easier to use LINE-1 retrotransposon which already possesses both RT and EN domains required for target-primed reverse transcription rather than making a fusion protein as taught by Feng et al.; and [2] apply a known optimization to disrupt the nucleolar localization signal in order to control the localization of LINE-1 as taught by Goodier et al.
As discussed in KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007), it is considered obvious to combine prior art elements known to be used in equivalent fields of endeavor together into a single combination. The references of Friedland et al. and Yin et al. clearly demonstrate that the claimed system comprising the use of various template RNA, i.e., guide RNA, with various features, i.e., the use of 5’ or 3’-UTRs, introns, or LNA modifications, in addition to the use of lipid nanoparticles, were known to be used in equivalent fields of endeavor; thus, it is considered obvious to combine them together.
Since the Office does not have the facilities for examining and comparing applicants’ [1] polypeptide having either Zn finger or TAL domain in the DNA binding domain which are common secondary structures found in DNA binding domains (as recited in Applicants’ claim 2); [2] system which is capable of cutting at least twice (as recited in Applicants’ claim 3); and [3] genomic safe harbor site with the genomic site of the prior art (as recited in Applicants’ claim 11), the burden is on the applicant to show a novel or unobvious difference between the claimed polypeptide, system and genomic safe harbor site from those of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
A POSITA would have had a reasonable expectation of success to make and use such system because all of the required biochemical reagents and techniques were readily available and rampantly used as evidenced by Anzalone et al., Feng et al., Goodier et al., Friedland et al., and Yin et al. prior to the filing of the instant application.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 1-3 an 5-15 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant Office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656