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 .
This action is in response to the amendment filed 04/28/2026, in which claims 1, 2, 10, 18, 29, 32 and 35 were amended, claims 33, 37 and 44 have been canceled and claims 5, 17, 25, 31, 34, 40-42 and 45-49 were previously presented. Claims 1, 2, 5, 10, 17, 18, 25, 29, 31, 32, 34, 35, 40-42 and 45-49 are currently pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Priority
Acknowledgment is made of applicant’s claim for priority based on a provisional application filed as 63/111,118 on 11/09/2020.
All claims are given the priority date of 11/09/2020.
Election/Restriction
A previous restriction of inventions was set forth in the Office Action mailed on 03/09/2026 wherein Applicant’s election without traverse of Group I, drawn to claims 1, 2, 5, 10, 17, 18, 25, 29, 31-34, 41, 42, 44, 45, 48 and 49, in the reply filed on 12/15/2025 was acknowledged. Therefore, claims 35, 37, 40 46 and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/15/2025.
It is noted that the amendment to the claims filed on 04/28/2026 does not comply with the requirements of 37 CFR 1.121(c) because the withdrawn claims are not correctly labeled. However, in the interest of compact prosecution, the amendment to the claims has been entered.
Claims 1, 2, 5, 10, 17, 18, 25, 29, 31, 32, 34, 41, 42, 45, 48 and 49 are currently under examination.
Claim Objections
The previous objection of claim 10 has been withdrawn in view of Applicant’s amendments to the claims filed on 04/28/2026.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 2, 5, 10, 29 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hasick et al (Molecules. 2020 Apr 10;25(7):1755 and Supplemental Material Pages 1/2-2/2; Cited in a prior Office Action). This rejection was made in the Office action mailed 03/09/2026 and has been rewritten to address the amendment to the claims in the reply filed 04/28/2026.
Regarding claims 1 and 2, Hasick teaches a Plexzyme system comprising a cascade of subzymes which are capable of cleaving and releasing their respective DNAzymes to target the bacterial blaKPC (bla carbapenemase) gene (Page 1, Abstract and Page 6, 1st full paragraph). Hasick teaches a feedback system using a pair of cross-catalytic subzymes where, in the presence of a target, the active plexzymes (Bla-KPC sequence), cleave a first subzyme, which separates a first DNAzyme from its MP, allowing the DNAzyme to migrate through the membrane, where it can cleave a second Subzyme (Page 1, Abstract). Hasick teaches this release of a second DNAzyme which can now migrate through the membrane and cleave more of the first Subzyrne, thus initiating a cross-catalytic cascade wherein, finally the activated DNAzyrnes can cleave fluorescent substrates, generating a signal, and thereby, indicating the presence of the target (Page 1, Abstract). Hasick continues to teach that the Subzyrne cascade is universal and can be triggered by any target by modifying the target sensing arms of the PlexZymes (Page 1, Abstract).
Regarding claim 5, Hasick teaches a Plexzyme system comprising a cascade of subzymes which are capable of cleaving and releasing their respective DNAzymes to target the bacterial blaKPC (bla carbapenemase) gene (Page 1, Abstract and Page 6, 1st full paragraph).
Regarding claim 10, Hasick teaches a triethylene glycol linker at the 3’ end of the DNAzyme (Page 12, Supplemental Material A).
Regarding claim 29, Hasick teaches a Plexzyme system comprising a cascade of subzymes which are capable of cleaving and releasing their respective DNAzymes to target the bacterial blaKPC (bla carbapenemase) gene (Page 1, Abstract and Page 6, 1st full paragraph) wherein the blaKPC is targeted from Klebsiella pneumoniae.
Regarding claim 31, Hasick teaches that all reactions contained l x PCR Buffer II, l x of Subzyme 1-MP, 1 PMB containing l x concentration of Subzyme 2-MP, and 15 mM MgCl2 in 125 μL final volume (Page 9, Paragraph 5).
Response to Amendments - Claim Rejections - 35 USC § 102
The previous rejection of claims 1, 10, 17, 29, 31-34 and 44 under 35 U.S.C. 102(a)(1) as being anticipated by Hou et al (Arch Med Sci. 2011 Jun;7(3):414-22) has been withdrawn in view of Applicant’s amendments to the claims filed on 04/28/2026.
The previous rejection of claims 1, 2, 5, 10, 29, 31, 44, 45 and 49 under 35 U.S.C. 102(a)(1) as being anticipated by Hasick et al (Molecules. 2020 Apr 10;25(7):1755 and Supplemental Material Pages 1/2-2/2) has been maintained in view of Applicant’s amendments to the claims filed on 04/28/2026.
Applicant arguments have been fully considered but have not been found persuasive. Applicant argues the plexzymes of Hasick targeting the Bla-KPC genes are composed of two inactive components, known as PartZymes (Partzyme A and Partzyme B), termed PzA-Bla-KPC and PzB-Bla-KPC. Applicant continues to argue the sequences of the two halves are provided in the supplemental materials A and the “underlined bases represent DNAzymes” but a review of the table showed no underlined sequence in the PzA-Bla-KPC and PzB-Bla-KPC showing they are not DNAzymes. Applicant argues, therefore, that the Plexzyme is not a DNAzyme and each component half is not a DNAzyme.
However, Hasick teaches a feedback system using a pair of cross-catalytic subzymes where, in the presence of a target, the active plexzymes (Bla-KPC sequence), cleave a first subzyme, which separates a first DNAzyme from its MP, allowing the DNAzyme to migrate through the membrane, where it can cleave a second Subzyme (Page 1, Abstract). Hasick teaches this release of a second DNAzyme which can now migrate through the membrane and cleave more of the first Subzyrne, thus initiating a cross-catalytic cascade wherein, finally the activated DNAzyrnes can cleave fluorescent substrates, generating a signal, and thereby, indicating the presence of the target (Page 1, Abstract). Hasick continues to teach that the Subzyrne cascade is universal and can be triggered by any target by modifying the target sensing arms of the PlexZymes (Page 1, Abstract). Such as, using the sequence of the Bla-KPC target to specify the DNAzyme system to specifically targeting KPC. The sequence that Applicant refers to as PzA-Bla-KPC and PzB-Bla-KPC in the supplemental material are the sequence specifically for targeting the bacterial KPC gene and the used in combination with the DNAzyme system to target the gene within the bacteria.
Therefore, Hasick anticipates the currently claimed invention of, at least, claim 1.
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.
Claims 17, 25, 45, 48 and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Hasick et al (Molecules. 2020 Apr 10;25(7):1755 and Supplemental Material Pages 1/2-2/2; Cited in a prior Office Action) in view of Bhindi et al (The American Journal of Pathology, Vol. 171, No. 4, October 2007; Cited in a prior Office Action). This rejection was made in the Office action mailed 03/09/2026 and has been rewritten to address the amendment to the claims in the reply filed 04/28/2026.
The teachings of Hasick are as described and applied above.
Regarding claim 17, Hasick does not specifically teach wherein when said modification comprises a base modification, a sugar modification, or an internucleotide linkage modification, or a combination thereof, said modification is selected from the group consisting of locked nucleic acids (LNA), phosphorothioate, 2-0-fluor, 2-0-methyl, 2-0-methoxyethyl, methylcytosine, 2-fluoro, and a 2-Fluoroarabinooligonucleotides.
Bhindi teaches LNA bases comprise a 2'-0 4-C methylene bridge that locks in a C3'-endo conformation, which places constraint on the ribose ring, increasing affinity for complementary sequences (Page 1801, Column 1). Bhindi teaches locked nucleic acids (LNAs) have been attractive monomers for modifying oligonucleotides and DNAzymes, in an attempt to increase binding affinity (Page 1801, Column 1). Bhindi teaches a commonly used modification is the incorporation of a 3'-3' inverted nucleotide at the 3' end of the DNAzyme to prevent exonuclease degradation, which can dramatically increase stability of the molecule, extending the half-life from -70 minutes to >21 hours in human serum (Page 1080, Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Hasick to include the locked nucleic acid and/or 3’-3’ inverted nucleotide modifications of DNAzymes as taught by Bhindi because Hasick teaches it is within the ordinary skill in the art to use a Plexzyme system comprising a cascade of subzymes which are capable of cleaving and releasing their respective DNAzymes to target the bacterial blaKPC (bla carbapenemase) gene and Bhindi teaches the locked nucleic acid modification increases the affinity for complementary sequence as well as the 3’-3’ inverted nucleotide at the 3’ end of the DNAzyme prevents exonuclease degradation and increases stability of the molecule extending its half-life.
One would have been motivated to make such a modification in order to receive the expected benefit of increased binding affinity as well as prevention of exonuclease degradation and increased stability as taught by Bhindi.
Regarding claim 25, Hasick teaches the Plezxyme system is tethered to microparticles for delivery (Page 1, Abstract).
Hasick does not specifically teach the oligonucleotide further comprising a permeability enhancing moiety attached to a nucleotide of the at least one DNAzyme, wherein the permeability enhancing moiety is a cholesterol moiety, a cell penetrating peptide, a lipid nanoparticle, or a viral capsid.
Bhindi teaches the use of delivery agents such as polymer, cationic lipids, PEGylated liposomes and/or complexes are known in the art for delivery of DNAzymes and siRNA molecules (Page 1080, Column 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Hasick to include the delivery agents such as polymer, cationic lipids, PEGylated liposomes and/or complexes as taught by Bhindi because Hasick teaches it is within the ordinary skill in the art to use a Plexzyme system comprising a cascade of subzymes which are capable of cleaving and releasing their respective DNAzymes to target the bacterial blaKPC (bla carbapenemase) gene and Bhindi teaches delivery agents such as polymer, cationic lipids, PEGylated liposomes and/or complexes are known in the art for delivery of DNAzymes and siRNA molecules.
One would have been motivated to make such a modification in order to receive the expected benefit of successful delivery of DNAzymes as taught by Bhindi.
Regarding claim 45, Hasick teaches a triethylene glycol linker at the 3’ end of the DNAzyme (Page 12, Supplemental Material A).
Regarding claim 48, Hasick teaches the Plezxyme system is tethered to microparticles for delivery (Page 1, Abstract).
Hasick does not specifically teach the oligonucleotide further comprising a permeability enhancing moiety attached to a nucleotide of the at least one DNAzyme, wherein the permeability enhancing moiety is a cholesterol moiety, a cell penetrating peptide, a lipid nanoparticle, or a viral capsid.
Bhindi teaches the use of delivery agents such as polymer, cationic lipids, PEGylated liposomes and/or complexes are known in the art for delivery of DNAzymes and siRNA molecules (Page 1080, Column 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Hasick to include the delivery agents such as polymer, cationic lipids, PEGylated liposomes and/or complexes as taught by Bhindi because Hasick teaches it is within the ordinary skill in the art to use a Plexzyme system comprising a cascade of subzymes which are capable of cleaving and releasing their respective DNAzymes to target the bacterial blaKPC (bla carbapenemase) gene and Bhindi teaches delivery agents such as polymer, cationic lipids, PEGylated liposomes and/or complexes are known in the art for delivery of DNAzymes and siRNA molecules.
One would have been motivated to make such a modification in order to receive the expected benefit of successful delivery of DNAzymes as taught by Bhindi.
Regarding claim 49, Hasick teaches a triethylene glycol linker at the 3’ end of the DNAzyme (Page 12, Supplemental Material A).
Claims 32, 34, 41 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Hasick et al (Molecules. 2020 Apr 10;25(7):1755 and Supplemental Material Pages 1/2-2/2; Cited in a prior Office Action) in view of Hou et al (Arch Med Sci. 2011 Jun;7(3):414-22; Cited in a prior Office Action). This is a NEW rejection to address the amendment to the claims in the reply filed 04/28/2026.
The teachings of Hasick are as described and applied above.
Regarding claims 32 and 34, Hasick does not teach the composition further comprises an antibiotic wherein said antibiotic is a B-lactam or said antibiotic is selected from the group consisting of penicillin, methicillin, oxacillin, cephalosporin, aztreonam, cefoxitin, carbapenem, imipenem, and meropenem and wherein said oligonucleotide and said antibiotic are in a co-formulation or are in separate formulations.
Hou teaches the reaction buffer includes the DNAzymes that are then electroporated into MRSA strain cells (Page 415, Column 2 bridging Page 516, Column 1). Hou teaches after electroporation, the cells were recovered in preheated broth medium containing 6 mg/l of oxacillin (Page 416, Column 2). Hou teaches in liquid medium containing oxacillin (6 mg/I), the growth of PS-DRz1366-treated MRSA080302 and PS-DRz1694-treated MRSA080305 cells was inhibited, respectively (Page 419, Column 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the teachings of Hasick to include a surface coated with the oligonucleotide and oxacillin as taught by Hou because Hasick teaches it is within the ordinary skill in the art to a Plexzyme system comprising a cascade of subzymes which are capable of cleaving and releasing their respective DNAzymes to target the bacterial blaKPC (bla carbapenemase) gene and Hou teaches the use of a two DNAzyme system (DRz1694 and DRz1366) that are anti-mecRl and anti-blaRl phosphorothioated deoxyribozymes capable of successful knockdown of mecRl and blaRl resulting in increased susceptibility of MRSA strains and the Mueller-Hinton agar and/or broth medium containing 6 mg/l of oxacillin.
One would have been further motivated to make such a modification in order to receive the expected benefit of fully restored sensitivity to oxacillin for bacterial strains as taught by Hou.
Regarding claims 41 and 42, The current specification states the term "surface" is defined herein as any surface which may be covered, at least in part, by bacteria (e.g. by biofilm) (Page 58, Lines 4-5).
Hasick does not teach the composition further comprises an antibiotic wherein said antibiotic is a B-lactam or said antibiotic is selected from the group consisting of penicillin, methicillin, oxacillin, cephalosporin, aztreonam, cefoxitin, carbapenem, imipenem, and meropenem and wherein said oligonucleotide and said antibiotic are in a co-formulation or are in separate formulations.
Hou teaches the diluted cells (comprising the DNAzymes; DRz1694 and DRz1366) were spread onto plates of Mueller-Hinton agar containing 6 mg/l of oxacillin, and the plates were incubated for 48h at 35°C (Page 416, Column 2). Huo teaches the combination treatment of PS-DRz1694 and PS-DRz1366 on MRSA080309 resulted in synergic effects on susceptibility restoration to oxacillin (Page 421, Column 1 bridging Column 2). Hou teaches it is particularly encouraging that MICs of oxacillin to MRSA080302, MRSA080305 and MRSA080309 were fully restored to values within the sensitivity defining range by PS-DRz1366, PS-DRz1694 and combined administration of these two DNAzymes, respectively (Page 421, Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the teachings of Hasick to include a surface coated with the oligonucleotide and oxacillin as taught by Hou because Hasick teaches it is within the ordinary skill in the art to a Plexzyme system comprising a cascade of subzymes which are capable of cleaving and releasing their respective DNAzymes to target the bacterial blaKPC (bla carbapenemase) gene and Hou teaches the use of a two DNAzyme system (DRz1694 and DRz1366) that are anti-mecRl and anti-blaRl phosphorothioated deoxyribozymes capable of successful knockdown of mecRl and blaRl resulting in increased susceptibility of MRSA strains and the Mueller-Hinton agar and/or broth medium containing 6 mg/l of oxacillin.
One would have been further motivated to make such a modification in order to receive the expected benefit of fully restored sensitivity to oxacillin for bacterial strains as taught by Hou.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claim 18 under 35 U.S.C. 103 as being unpatentable over Hou et al (Arch Med Sci. 2011 Jun;7(3):414-22) in view of Blatt et al (WO 02/068637 A2) has been withdrawn in view of Applicant’s amendments to the claims filed on 04/28/2026.
The previous rejection of claims 41 and 42 as being unpatentable over Hou et al (Arch Med Sci. 2011 Jun;7(3):414-22) has been rewritten as claims 32, 34, 41 and 42 under 35 U.S.C. 103 as being unpatentable over Hasick et al (Molecules. 2020 Apr 10;25(7):1755 and Supplemental Material Pages 1/2-2/2) in view of Hou et al (Arch Med Sci. 2011 Jun;7(3):414-22).
The previous rejection of claims 17, 25 and 48 under 35 U.S.C. 103 as being unpatentable over Hasick et al (Molecules. 2020 Apr 10;25(7):1755 and Supplemental Material Pages 1/2-2/2) in view of Bhindi et al (The American Journal of Pathology, Vol. 171, No. 4, October 2007) has been maintained and re-written to include the rejection of claim 45 as well.
Applicant’s arguments have been fully considered but have not been found to be persuasive. Applicant argues, as discussed above, Hasick does not teach the independent claim 1, and therefore is applicable and extends to the claims rejected under 103 as well as unpatentable over Hasick in view of Bhindi. Applicant continues to argue that Bhindi is a review article describing small-molecule gene siliencing strategies and is silent in DNAzyme targeting a Carbenpenemase RNA transcript. Applicant continues to argue that Bhindi does not cure the deficiencies of Hasick and therefore, is not obvious to teach alone or in combination every feature of the dependent claims 17, 25 and 48.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Applicant argues that Bhindi does not teach DNAzymes for targeting a Carbapenemase RNA transcript and therefore, does not render obvious the current limitations of the rejected claims. However, Bhindi is relied on for its teachings regarding the use of delivery agents such as polymer, cationic lipids, PEGylated liposomes and/or complexes are known in the art for delivery of DNAzymes and siRNA molecules (Page 1080, Column 1). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Hasick to include the delivery agents such as polymer, cationic lipids, PEGylated liposomes and/or complexes as taught by Bhindi because Hasick teaches it is within the ordinary skill in the art to use a Plexzyme system comprising a cascade of subzymes which are capable of cleaving and releasing their respective DNAzymes to target the bacterial blaKPC (bla carbapenemase) gene and Bhindi teaches delivery agents such as polymer, cationic lipids, PEGylated liposomes and/or complexes are known in the art for delivery of DNAzymes and siRNA molecules. One would have been motivated to make such a modification in order to receive the expected benefit of successful delivery of DNAzymes as taught by Bhindi.
Allowable Subject Matter
Claim 18 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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 ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637
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