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 .
Applicant’s cancelation of claims 2, 3, 5-8 and 23 and amendment of claim 1, 4, 14, in the paper of 10/24/2025, is acknowledged. Applicants' arguments filed on 10/24/2025, have been fully considered and are deemed to be persuasive to overcome some of the rejections previously applied. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. Claims 1, 4, 9-16, 18. 19, 21, 23 are still at issue and are present for examination.
Election/Restrictions
Applicant's election without traverse of the invention of Group 1, claims 1-4, 10-15 to a ATP-dependent DNA ligase, in the paper of 7/8/2025, is acknowledged. Applicant's election without traverse of species of SEQ ID NO:1, in the paper of 7/8/2025, is acknowledged.
Claims 9, 16, 18. 19, 21, 23 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claim Objections
Claims 1, 4, 10-15 are objected to because of the following informalities:
Claim 1 recites ”Cronobacter sp.” which shole be ”Cronobacter sp.”.
Appropriate correction is required.
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.
Claim 1, 4 and 10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Claims 1-4 and 10 are directed to an ATP-dependent DNA ligase or an enzymatically active fragment thereof, wherein the DNA ligase comprises an the amino acid sequence of SEQ ID No. 1 or comprises an amino acid sequence having at least 70 % amino acid sequence identity to SEQ ID No. 1 and wherein the DNA ligase is able to ligate a 3'-hydroxyl-deoxyribonucleic acid molecule to a 5'-end of a 5'phosphoryl-ribonucleic acid molecule in the presence of a complementary deoxyribonucleic acid molecule that spans the ligation junction that is not patent-eligible pursuant to the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics, Inc., 106 USPQ2d 1972 (June 13, 2013). Uniprot Accession No. M1EZJ7, Dec 2019 which discloses SEQ ID NO:1 of the present application is an ATP dependent DNA ligase from Cronobacter phage CR9, evidence that a ATP-dependent DNA ligase or an enzymatically active fragment thereof, wherein the DNA ligase comprises the amino acid sequence of SEQ ID No. 1 is a naturally occurring ligase and is thus not patent eligible.
Applicants Response
Applicants submit that they have amended the claims and said DNA ligase being produced recombinantly in a host cell and isolated and purified therefrom. Applicant disagrees with the Examiner's assertion that Uniprot Accession No M1EZJ7 describes is a DNA sequence and an ammo acid sequence and function "Inferred from homology " Uniprot Accession No M1EZJ7 provides no evidence that the putative DNA ligase described there in is in fact a "naturally occurring ligase", or that it was in fact synthesized and active in Cronobacter phage CR9.
Applicants submit that in order to further distance the claims from Uniprot Accession No M1EZJ7, claim 1 has been amended to be limited to claimed DNA ligases which have been produced recombinantly in a host cell and isolated and purified therefrom, excluding naturally occurring ligases.
Applicant submits that although SEQ ID NO 1 was disclosed in Uniprot M1EZJ7, this does not provide sufficient evidence that the protein itself exists in nature or is naturally occurring.
Applicants submit that this is not a protein which has been determined to actually exist in nature, which would be labelled PE2 "Experimental evidence at transcript level" (showing that "the existence of a protein has not been strictly proven but that expression data such as existence of cDNA(s), RT- PCR or Northern blots indicate the existence of a transcnpt) or PE1"Experimental evidence at protein level" (indicating clear experimental evidence for the existence of the protein). Applicants submit additional argument that the protein disclosed by Uniprot M1EZJ7 has not been shown to exist in nature.
Applicants amendment of the claims and applicants complete argument is acknowledged and has been carefully considered, however, is not found persuasive for the reasons previously made of record and for those reasons repeated herein.
In response to applicants submission that applicants have amended the claims and said DNA ligase being produced recombinantly in a host cell and isolated and purified therefrom, this is not found persuasive as regardless of applicant’s amendment to the claims such that it now comprises a “product by process” type of limitation, it remains that the protein of SEQ ID NO:1 is the protein of SEQ ID NO:1 regardless of how it is produced and/or isolated. As evidenced by Uniprot Accession No M1EZJ7 the protein of SEQ ID NO:1 is a naturally occurring protein. In response to applicants submission that Uniprot Accession No M1EZJ7 provides no evidence that the putative DNA ligase described there in is in fact a "naturally occurring ligase", or that it was in fact synthesized and active in Cronobacter phage CR9, this is not found persuasive on the basis that Uniprot Accession No M1EZJ7 does provide evidence that the protein of SEQ ID NO:1 is a naturally occurring protein. The required conditions wherein said protein would or would not be expressed though unknown does not provide evidence that the protein of SEQ ID NO:1 is not a naturally occurring protein.
In response to applicants submission that applicants that in order to further distance the claims from Uniprot Accession No M1EZJ7, claim 1 has been amended to be limited to claimed DNA ligases which have been produced recombinantly in a host cell and isolated and purified therefrom, excluding naturally occurring ligases, as stated above this is insufficient to overcome the rejection as the protein of SEQ ID NO:1 is a naturally occurring protein as evidenced by Uniprot M1EZJ7 .
In response to applicants submission that applicants that this is not a protein which has been determined to actually exist in nature, which would be labelled PE2 "Experimental evidence at transcript level" (showing that "the existence of a protein has not been strictly proven but that expression data such as existence of cDNA(s), RT- PCR or Northern blots indicate the existence of a transcnpt) or PE1"Experimental evidence at protein level" (indicating clear experimental evidence for the existence of the protein) this is not found persuasive for the reasons stated previously and above that the protein of SEQ ID NO:1 is a naturally occurring protein as evidenced by Uniprot M1EZJ7.
Claim Rejections - 35 USC § 112
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.
The rejection of claim(s) 1-4 and 10-15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, based upon a lack of written description is withdrawn based upon applicants amendment of the claims in the paper of 10/24/2025.
The rejection of claim(s) 1-4 and 10-15 under 35 U.S.C. 112, first paragraph, based upon a scope of enablement is withdrawn based upon applicants amendment of the claims in the paper of 10/24/2025.
Claim(s) 1, 4 and 10-15 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 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 or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Newly amended claim 1 (claims 4 and 10-15 dependent from) drawn to an isolated ATP-dependent DNA ligase, wherein the DNA ligase comprises an amino acid sequence of SEQ ID NO: 1 or comprises an ammo acid sequence having at least 98% ammo acid sequence identity to SEO ID NO: 1 and wherein the DNA ligase is able to ligate a 3'-hydroxyl-deoxyribonucleic acid molecule to a 5'-end of a 5' phosphoryl-ribonucleic acid molecule in the presence of a complementary deoxyribonucleic acid molecule that spans the ligation junction; said DNA ligase being produced recombinantly in a host cell and isolated and purified therefrom, wherein the host cell is not a Cronobacter sp. is not supported by applicants specification at the time of filing and is thus considered new matter. Specifically applicants newly recitation “said DNA ligase being produced recombinantly in a host cell and isolated and purified therefrom, wherein the host cell is not a Cronobacter sp.” is not supported by applicants specification at the time of filing and is considered new matter.
Applicants statement that support for the recitation can be found in the specification on p 25, ll. 34-37 and on p 29, ll. 7-10 is acknowledge had has been checked, however, support for the newly added recitation was not found in the specified sections nor elsewhere in the specification.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
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 and 4 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Uniprot Accession No. M1EZJ7, May 2013.
This rejection was stated in the previous office action as it applied to previous claims 1-4 and 10. In response applicants have amended the claims and traverse the rejection as it applies to the newly amended claims. For applicants convenience the original rejection is repeated herein.
Uniprot Accession No. M1EZJ7, Dec 2019 discloses SEQ ID NO:1 of the present application. It is an ATP dependent DNA ligase from Cronobacter phage CR9. While Uniprot Accession No; M1EZJ7 is silent about the activity of ligating 3’-OH DNA to 5’-phosphate RNA in the presence of a cDNA molecule that spans the ligation junction, this is considered an inherent property of the taught ATP dependent DNA ligase based upon its identical amino acid sequence.
Applicants Response:
Applicants submit that Uniprot M1EZJ7 discloses a strand of DNA in a virus which has no ability to synthesize protein on its own Uniprot M1EZJ7 does not disclose the existence or properties of a protein. Applicants submit that the inherent features of prior art proteins are not relevant here because, as described above, no prior art proteins have been isolated or analyzed. Only the present inventors have reduced the claimed DNA ligases to practice.
Applicants amendment of the claims and applicants complete argument is acknowledged and has been carefully considered, however, is not found persuasive for the reasons previously made of record and for those reasons repeated herein.
In response to applicants submission that Uniprot M1EZJ7 discloses a strand of DNA in a virus which has no ability to synthesize protein on its own and that Uniprot M1EZJ7 does not disclose the existence or properties of a protein, this is not found persuasive on the basis that as stated previously and repeated above, Uniprot Accession No. M1EZJ7, Dec 2019 discloses the protein of SEQ ID NO:1 of the present application. It is an ATP dependent DNA ligase from Cronobacter phage CR9 as identified by Uniprot M1EZJ7. In response to applicants submission that only the present inventors have reduced the claimed DNA ligases to practice, this is not found persuasive as previously stated, Uniprot Accession No. M1EZJ7, Dec 2019 discloses the protein of SEQ ID NO:1 of the present application. It is an ATP dependent DNA ligase from Cronobacter phage CR9 as identified by Uniprot M1EZJ7.
Thus claim(s) 1 and 4 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Uniprot Accession No. M1EZJ7, Dec 2019.
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.
Claim(s) 1, 4 and 10-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Uniprot Accession No. M1EZJ7, Dec 201 and Sekiguchi et al. (Biochemistry, Vol 36, pgs 9073-9079, July 1997).
This rejection was stated in the previous office action as it applied to previous claims 10-15. In response applicants have amended the claims and traverse the rejection as it applies to the newly amended claims. For applicants convenience the original rejection is repeated herein.
Sekiguchi et al. (Biochemistry, Vol 36, pgs 9073-9079, July 1997) disclose that they are studying the structure and function of the eukaryotic ligases using the vaccinia virus enzyme as a model. Sekiguchi et al. teach studies and assays for characterizing ligation of RNA-containing duplexes by Vaccinia DNA ligase. In their studies, Sekiguchi et al. disclose that they analyzed the ability of vaccinia DNA ligase to seal nicked substrates containing one or more RNA strands, including 3’-OH-terminated RNA to 5’-phosphate-terminated DNA. Sekiguchi et al.disclose that vaccinia DNA ligase is much less effective at joining 3’-Oh-terminated DNA to 5’-phosphate-terminated RNA and is extremely weak at phosphodiester formation between two RNA strands (pg 9074). In order to perform the above assays, Sekiguchi et al. teach compositions comprising the various components necessary to perform the assays, including the vaccinia DNA ligase, a ligation buffer comprising ATP, Mn2+ and Mg2+, RNA 5’-end adapters, a 3’-OH DNA molecule, a 5-phosphate RNA molecule and a complementary cDNA.
Uniprot Accession No. M1EZJ7, Dec 2019 discloses SEQ ID NO:1 of the present application. It is an ATP dependent DNA ligase from Cronobacter phage CR9. While Uniprot Accession No; M1EZJ7 is silent about the activity of ligating 3’-OH DNA to 5’-phosphate RNA in the presence of a cDNA molecule that spans the ligation junction, this is considered an inherent property of the taught ATP dependent DNA ligase based upon its identical amino acid sequence.
One of skill in the art before the time of invention would have been motivated to create the compositions taught by Sekiguchi et al. to perform the assays taught by Sekiguchi et al. using the DNA ligase from Cronobacter phage CR9, as taught by Uniprot Accession No. M1EZJ7, instead of the vaccinia DNA ligase as a means of characterizing the DNA ligase from Cronobacter phage CR9. These compositions include the DNA ligase from Cronobacter phage CR9 comprising the amin acid sequence of SEQ ID NO:1 and a ligation buffer comprising ATP, Mn2+, Mg2+, RNA 5’-end adapters, a 3’-OH DNA molecule, a 5-phosphate RNA molecule and a complementary cDNA. One would have been further motivated to include all the other reagents necessary to perform the assays taught by Sekiguchi et al. together with the obvious composition thus comprising a kit. The expectation of success is high based upon the high level of expertise in the art of recombinant DNA technology as exemplified by the teaching of Sekiguchi et al.
Applicants Response:
Applicants submit that for an obviousness rejection to be proper, the Examiner must meet the burden of establishing that all elements of the invention are disclosed in the prior art, that the prior art relied upon, or knowledge generally available in the art at the tine of the invention, must provide some suggestion or incentive that would have motivated the skilled artisan to modify a reference or combined references.
Applicants submit that, Uniprot M1EZJ7 discloses a genome fragment from a virus, but does not disclose an ATP-dependent DNA ligase enzyme of the present claims. Applicants submit that Sekiguchi et al , which discloses methods for characterizing ligases, does not cure this deficiency.
Applicants submit that at best, this combination of references is an invitation to experiment with no expectation of success. Applicants submit that The requirement for a determination of obviousness is that "both the suggestion and the expectation of success must be founded m the prior art, not in applicant's disclosure.
Applicants submit that at best Uniprot MlEZJ7 discloses a 'Protein inferred by homology' indicating that the existence of a protein is probable because clear orthologs exist in closely related species. Applicants submit that Uniprot M1EZJ7 provides no evidence that the inferred DNA ligase would in fact have any ligase activity. Applicants submit that thus, the combination of Uniprot M1EZJ7 and Sekiguchi et al is an invitation to experiment, with no expectation of success .
Applicants amendment of the claims and applicants complete argument is acknowledged and has been carefully considered, however, is not found persuasive for the reasons previously made of record and for those reasons repeated herein.
In response to applicants submission that the Examiner must meet the burden of establishing that all elements of the invention are disclosed in the prior art, that the prior art relied upon, or knowledge generally available in the art at the time of the invention, must provide some suggestion or incentive that would have motivated the skilled artisan to modify a reference or combined references, the requirements of the rejection based upon obviousness are acknowledged and appreciated. As stated previously and repeated above, one of skill in the art before the time of invention would have been motivated to create the compositions taught by Sekiguchi et al. to perform the assays taught by Sekiguchi et al. using the DNA ligase from Cronobacter phage CR9, as taught by Uniprot Accession No. M1EZJ7, instead of the vaccinia DNA ligase as a means of characterizing the DNA ligase from Cronobacter phage CR9. These compositions include the DNA ligase from Cronobacter phage CR9 comprising the amino acid sequence of SEQ ID NO:1 and a ligation buffer comprising ATP, Mn2+, Mg2+, RNA 5’-end adapters, a 3’-OH DNA molecule, a 5-phosphate RNA molecule and a complementary cDNA. One would have been further motivated to include all the other reagents necessary to perform the assays taught by Sekiguchi et al. together with the obvious composition thus comprising a kit. The expectation of success is high based upon the high level of expertise in the art of recombinant DNA technology as exemplified by the teaching of Sekiguchi et al. Further as stated previously the protein disclosed by Uniprot M1EZJ7 is identified as being a DNA ligase. Thus there was motivation as stated previously and above and there was an expectation of success.
While it is recognized that Uniprot M1EZJ7 discloses a genome fragment from a virus, it also discloses the encoded protein and identifies it as a ATP-dependent DNA ligase enzyme. This clearly evidences the function of the disclosed protein which is inherent to the protein itself. Thus contrary to applicants submission, "both the suggestion and the expectation of success are found in the prior art.
Applicants submit that at best Uniprot MlEZJ7 discloses a 'Protein inferred by homology' indicating that the existence of a protein is probable because clear orthologs exist in closely related species. Applicants submit that Uniprot M1EZJ7 provides no evidence that the inferred DNA ligase would in fact have any ligase activity. Applicants submit that thus, the combination of Uniprot M1EZJ7 and Sekiguchi et al is an invitation to experiment, with no expectation of success .
Thus, claim(s) 1, 4 and 10-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Uniprot Accession No. M1EZJ7, Dec 201 and Sekiguchi et al. (Biochemistry, Vol 36, pgs 9073-9079, July 1997).
Remarks
No claim is allowed.
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 RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached on 6-3 EST Mon-Fri.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (571) 272-0956. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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rgh
12/5/2025
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652