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 .
Priority
Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional Application 63/066,539, filed on 08/17/2020. This application claims the benefit of priority to Patent Application PCT/US2021/046280. Acknowledgement is made of Applicants’ claim for benefit to prior filed to Patent Application Number PCT/US2021/046280, filed on 08/17/2021.
Information Disclosure Statement
The Information Disclosure Statements filed 02/10/2023 and 10/07/2024 have been considered by the Examiner.
Status of Claims
Claims 1, and 3-19 are under examination.
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 1, 3-7 and 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over Fabani (Nucleic Acid Research, 2010) and in view of Obad (Nature Genetics, 2011) as evidenced by AnaSpec (2019).
Regarding claim 1, Fabani et al. teach an anti-miR-155 PNA, an antisense inhibitor (a modified anti-miRNA PNA) (page 4466, abstract). Fabani et al. teach the sequence is K-5’-PNA-3'-K3, which is a PNA flanked by 4 lysine residues (page 4467, column 2, paragraph 2). Fabani et al. teach that miRNA targets contain a perfect Watson–Crick matching sequence of 6–8 nt between the 5’-end of a miRNA, the seed region, and the 3’-unstranslated region (3’-UTR) of the mRNAs (page 4471, column 2, paragraph 2).
Fabani does not disclose an anti-seed PNA comprising 5'-Xaa1Xaa2Xaa3 N1N2N3N4N5N6N7N8 N9-Xaa4-3', wherein N8 or N9 may be null.
It would have been obvious to one of ordinary skill in the art to art to have tested various combinations of the PNA of Fabani and arrive at K3-5’-PNA-3’-K. One of ordinary skill in the art would perform normal experimentation to optimize the positioning of the four flanking lysine residues of Fabani. There is a limited number of possible combinations of the four flanking lysine residues and would allow optimization without undue experimentation.
Obad et al. teach the regulation of microRNAs play an important role in physiological processes and development of therapeutic agents (page 371, abstract). Obad et al. teach synthetic oligonucleotides (ONs) of different chemistries have proven successful for blocking miRNA expression (page 371, abstract). Obad et al. teach an 8-base anti-seed oligonucleotide (page 371, abstract). Obad et al. teach PNA high affinity and sequence specificity for complementary RNA, and also bear high chemical and metabolic stability (page 377, left column, paragraph 1).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Fabani et al. for a modified PNA with the teachings of Obad et al. for an 8-base sequence that binds to the seed sequence of a miRNA. Obad et al. provide motivation by teaching high affinity and sequence specificity for complementary RNA and also have high chemical and metabolic stability. One of skill in the art would have had a reasonable expectation of success at combining Fabani et al. and Obad et al. because both teach silencing of microRNA families by seed-targeting tiny LNAs.
Regarding claims 3 and 4, Fabani et al. teach the miRNA is miR-155 (page 4466, introduction).
Regarding claim 5, Obad et al. teach an 8-base sequence, therefore Obad et al. make obvious N9 is null (page 371, abstract).
Regarding claim 6, Obad et al. teach the seed sequence that matches miR-155 is AGCATTAA (page 376, figure 5).
Regarding claim 7, Obad et al. teach an anti-seed PNA comprising a detectable label (Online Methods page, Immunoprecipitation of Ago2 and detection of antimiR-21 in the Ago2 complex).
Regarding claim 11, Fabani et al. teach a composition for in vivo treatment where a synthetic oligonucleotide was dissolved in saline, saline is a pharmaceutically acceptable excipient (page 4468, left column, in vivo experiments).
Regarding claim 12, Fabani et al. teach a method of inhibiting expression of a miRNA in vitro and in vivo. Fabani et al. and Obad et al. make obvious contacting a cell with an inhibitory amount of the modified anti-seed PNA as recited above in regard to claim 1.
Regarding claim 13, Fabani et al. teach emergence of miRNAs as regulators of malignant transformation or autoimmunity. Fabani et al. teach regulation of miRNAs are likely to have an impact on gene therapies designed to block tumor progression or inflammation. Fabani et al. teach the potential for miRNA antagonists as therapeutic agents (page 4466, right column, paragraph 2). Therefore, the regulation of tumors in vivo would constitute a tumor cell.
Regarding claims 14 and 15, Fabani et al teach miR-155 regulation could be beneficial in treating lymphoma (page 4474, paragraph 3).
Regarding claim 16, Fabani et al. teach emergence of miRNAs as regulators of malignant transformation or autoimmunity. Fabani et al. teach regulators of miRNAs for gene therapies designed to block inflammation. Fabani et al. teach the potential for miRNA antagonists as therapeutic agents in vivo (page 4466, right column, paragraph 2).
New Rejections:
Regarding claim 17, Obad et al. teach an anti-seed PNA comprising a detectable label (Online Methods page, Immunoprecipitation of Ago2 and detection of antimiR-21 in the Ago2 complex). The detectable label would be chosen from commercially available detectable labels. PEG linkers are commonly used to connect molecules. One of ordinary skill in the art would have been motivated to use 5’ Tamra because it is preferred for some complicated biological applications where reproducibility is critical might. The dye is specially formulated to easily dissolve in DMF and to convert to the NHS ester as evidenced by (AnaSpec).
Regarding claim 18, Fabani et al. teach therapies aimed at increasing Inpp5d levels by reducing miR-155 expression could be beneficial in the treatment of specific types of lymphoma Fabani et al. teach treatment of Diffuse large B-cell lymphoma (DLBCL) (page 4474, left column).
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Fabani (Nucleic Acid Research, 2010) and in view of Obad (Nature Genetics, 2011) as applied to claim 1 above, and further in view of Moccia et al. (DNA: PNA & XNA, 2014).
Fabani et al. and Obad et al. make obvious an anti-seed PNA, an antisense inhibitor (a modified anti-miRNA PNA). Fabani et al. and Obad et al. make obvious the sequence is K-5’-PNA-3'-K3, which is a PNA flanked by 4 lysine residues. Fabani et al. and Obad et al. make obvious an anti-seed PNA comprising 5'-Xaa1Xaa2Xaa3-N1N2N3N4N5N6N7N8 N9-Xaa4-3', where N9 null.
Regarding claim 8, Fabani et al. and Obad et al. make obvious an anti-seed PNA. Fabani et al. and Obad et al. do not teach the PNA is a gamma modified PNA.
Moccia et al. teach PNAs as useful synthetic devices targeting natural miRNAs. Moccia et al. teach PNAs with γ backbone modification (page 1, abstract). Moccia et al. teach γ modification of the backbone which are indispensable to obtain polymers that recognize DNA complementary strands with high affinity. Moccia et al. teach the γ modification provided compounds with the diverse ability to bind (page 1, introduction). Moccia et al. teach improved thermal stability of γ-Lys PNAs. Moccia et al. teach the γ-modification was effective at improving the DNA binding ability (page 11, paragraph 5).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Fabani et al. and Obad et al. for peptide nucleic acids to efficiently block a miRNA with the teachings of Moccia et al. for a γ modification of the PNA. Moccia et al. provide motivation by teaching that the γ modification provides further binding ability and improved thermal stability. One of skill in the art would have had a reasonable expectation of success at combining Fabani et al., Obad et al. and Moccia et al. because both teach inhibition of miR-155 by antisense PNAs.
Regarding claim 9, Fabani et al. and Obad et al. make obvious an anti-seed PNA. Fabani et al. and Obad et al. do not teach encapsulation of the modified anti-seed PNA in a nanoparticle.
Moccia et al. teach the delivery of antisense peptide nucleic acids encapsulated in nanoparticles inhibited miRNA-155 and slowed the growth of pre-B-cell tumors in vivo. Moccia et al. further teach these constructs as promising therapeutics for lymphoma/and leukemia (page 6, left column, paragraph 5).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Fabani et al. and Obad et al. for a modified anti-seed PNA with the teachings of Moccia et al. for a nanoparticle encapsulation of PNAs for delivery and treatment. Moccia et al. provide motivation by teaching that delivery in nanoparticles slowed the growth of pre-B-cell tumors in vivo. One of skill in the art would have had a reasonable expectation of success at combining Fabani et al., Obad et al. and Moccia et al. because they teach treatment with antisense PNAs.
Regarding claim 10, Moccia et al. teach the nanoparticle is polylactic-co-glycolic acid (PLGA) (page 6, left column, paragraph 3).
New rejection:
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Fabani (Nucleic Acid Research, 2010) in view of Obad (Nature Genetics, 2011) as applied to claims 1 and 16 above, and further in view of Mendlein (WO2020/023390 A1).
Regarding claim 19, Fabani and Obad make obvious a method of treating, comprising administering to a subject in need thereof a modified anti- seed PNA. Fabani and Obad do not teach the method for treating Gaucher disease.
Mendlein teaches treatments of lysosomal storage disorders including Gaucher disease with mRNA (cover page, abstract).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of Fabani et al. and Obad et al. for obvious a method of treating, comprising administering to a subject in need thereof a modified anti- seed PNA with the teachings of Mendlein et al. for a treatment Gaucher disease. Mendlein et al. provide motivation by teaching that mRNA therapeutics of the invention are particularly well-suited for the treatment of LSDs as the technology provides for the intracellular delivery of mRNA within target cells (page 2, summary). One of skill in the art would have had a reasonable expectation of success at combining Fabani et al. and Obad et al. and Mendlein et al. because both teach treatments of disease related to mRNA related therapeutics.
Response to Arguments
Applicant's arguments filed 02/13/2020 have been fully considered but they are not persuasive.
Applicant’s argument: Applicant argues the prior art must provide some suggestion or incentive that would have motivated the skilled artisan to modify a reference or combine references.
Examiner’s response: There is a limited number of possible combinations of the four flanking lysine residues and would allow optimization without undue experimentation. Fabani et al. provide motivation teaching that the that miRNA targets contain a perfect Watson–Crick matching sequence of 6–8 nt between the 5’-end of miRNA (referred to as the “seed” region) and the 3’-unstranslated region (3’-UTR) of the mRNAs. Fabani et al. teach the enrichment in 3’-UTR sequences complementary to the miR-155 seed region reflects direct targeting by the miRNA (page 4471, right column).
Applicant Argues: "Obad et a. teach PNA ONs show high affinity and sequence specificity..., and also bear high chemical and metabolic stability (page 4467, left column, paragraph 1)", Office Action at 4, these citations (and every other Obad citation in the Office Action) cites to pages not present in Obad, which is published on pages 371-378 of Volume 43, Issue 4, of Nature Genetics.
Examiner’s response: Obad et al. teach LNA high affinity and sequence specificity for complementary RNA, and also bear high chemical and metabolic stability (page 377, left column paragraph 1). The Obad reference was improperly cited and the section cited is located on page 377, left column, paragraph 1.
Applicant’s Arguments: Obad relates to tiny locked nucleic acid (LNA) or tiny LNAs, not peptide nucleic acids (PNAs). Thus, like Fabani, Obad also does not teach anti-seed peptide nucleic acids (PNAs). Thus, none of the cited references, in this inherently unpredictable art, teach or even suggest anti-seed peptide nucleic acids (PNAs), as is recited in the claimed invention.
Examiner’s response: Fabani et al. teach peptide nucleic acids (PNAs) efficiently block a key inducible miRNA (page 4466, abstract). Fabani et al. teach targeting the “seed” region (page 4471, right column). The combination of Fabani and Obad make obvious anti-seed peptide nucleic acids (PNAs) of the present invention.
Applicant Argues: There would not be a reasonable expectation of success in combining Fabani with Obad without data, as locked nucleic acid (LNA) oligonucleotides and peptide nucleic acids (PNAs) are distinct technologies having significantly different backbone structures and properties.
Examiner’s response: Both teach silencing of microRNA families by seed-targeting. Fabani et al. further teach synthetic oligonucleotides including LNA/DNA mixmers, MOEs and antagomirs have also proven successful for blocking miRNA expression in vivo, as exemplified by targeting of miR-122 and miR-155 (page 4473, discussion, left column). Fabani et al. teach PNA for miRNA targeting in primary cell culture (page 4473, discussion, left column). Therefor combining known techniques would provide a predictable result.
Applicant’s arguments: Neither Fabani, nor Obad, teach or suggest a modified anti-seed peptide nucleic acid comprising arginine.
Examiner’s response: The inclusion of arginine is not a limitation of the claims at present.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/C.L.M./Examiner, Art Unit 1638
/Anna Skibinsky/
Primary Examiner, AU 1635
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