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 .
Application Status
This office action is in response to the paper filed on 2/27/2026. Claims 1, 6, 8, 10, 12, 15, 18-20, 22, 26-28, 30-31, 33-34, 37, 39, 41, 44-46, 49-50, 52-54, 58, 60-61, 85, 87, 89-90, and 92 were previously presented. Claims 26-27, 30, 33-34, 54, 58, 60-61, 85, 87, 89-90, and 92 have been cancelled. Claims 98-104 are newly added. Claims 1, 6, 8, 10, 12, 15, 18-20, 22, 28, 31, 37-39, 41, 44-45, and 98-104 are currently under examination on the merits.
Election/Restriction
Applicant’s election of the of the inventions of Group I (Claims 1, 6, 8, 10, 12, 15, 18-20, 22, 26-28, 30-31, 33-34, 37, 38, 39, 41, and 44-45), without traverse, is acknowledged. Applicant failed to elect a single “duplex number” corresponding to the SEQ ID NOs: (e.g. D-1682 for SEQ ID NO: 1773 and 2621 or D-1858 for SEQ ID NO: 2842 and 3096). However, in the interest of compact prosecution, examiner will examine duplex number “D-1682” comprising SEQ ID NOs: 1773 and 2621.
Applicant further elects the following species:
RNAi construct related to SEQ ID NO: 671.
RNAi construct comprising a sense strand comprising SEQ ID NO: 127 and an antisense strand comprising SEQ ID NO: 671, corresponding to trigger family “2144” in the specification.
A long chain fatty acid as the ligand, the fatty acid having 22 carbons in particular.
Claims 46, 49-50, and 52-53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Priority
The application claims priority to provisional application 63/391,860 filed on 7/25/2022.
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, 6, 8, 10, 12, 15, 18, 19, 20, 22, 28, 37, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Eisenhut et al. (FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival, OncoImmunology, Volume 6, Issue 1, all pages, 2017) in view of Haeberli et al. (WO 2005/044981 A2, published 2005) and Sohail et al. (Selecting optimal antisense reagents, Advanced Drug Delivery Reviews, Volume 44, Issue 1, pg. 23-24, 2000).
Regarding claims 1, 6, 8, 10, 12, 15, 18-20, 22, 28, 37, and 45, Eisenhut teaches that through genome-wide association studies (GWAS) associated with Family with sequence similarity 13, member A (FAM13A) revealed that increased numbers of FAM13A protein expressing cells were found in the tumoral region of lung tissues from a cohort of patients with NSCLC (see introduction). Eisenhut discloses targeting inhibition of FAM13A via siRNA in lung tumor cells in order to understand the role of FAM13A in controlling tumor cell proliferation and survival. Eisenhut teaches siRNA silencing of FAM13A in A549, a human lung cell line, resulted in downregulation of both the FAM13A isoform 1 and 2 (See Fig. 6A). RNA-Seq analysis found that many genes involved in tumor cell proliferation including FAM13A were downregulated, whereas tumor suppressor genes and genes linked to cell migration were upregulated (see Fig. 6B and 6C). The specific knockdown of FAM13A and its RhoGAP domain also reduced the proportion of total cells (Fig. 6D) as well as their proliferation as shown by decreased Ki67+ A549 cells, which further confirms the important role of FAM13A in tumor cell proliferation (see Fig. 6E).
Eisenhut does not teach SEQ ID NO: 671 or the RNAi construct used for gene inhibition as described in the instant application.
Regarding claim 1, Haeberli teaches a short interfering nucleic acid molecule (siNA) comprising an antisense strand further comprising a nucleotide sequence that is complementary to a target polynucleotide sequence or a portion thereof (see page 12, line 3). Haeberli teaches where a siNA molecule of the invention comprises an antisense region having about 15 to about 30 nucleotides, wherein the antisense region if complementary to a target DNA sequence, and wherein said siRNA further comprises a sense region having about 15 to about 30 nucleotides, wherein said sense region and said antisense region are comprised in a linear molecule where the sense region comprises at least about 15 nucleotides that are complementary to the antisense region (see pg. 12 line 27). Haeberli further teaches where, in some embodiments, the invention consist of duplex nucleic acid molecules containing about 15 to about 30 base pairs between oligonucleotides comprising about 15 to about 30 nucleotides (see page 13, line 20).
Regarding claims 6 and 8, Haeberli teaches where the duplex nucleic acid molecules contain about 15 to about 30 base pairs between the oligonucleotides comprising about 15 to about 30 nucleotides (see pg. 13, line 20). Haeberli further teaches where, in another embodiment, the siNA molecules of the invention comprise duplex nucleic acid molecules with overhanging ends, for example, about 21-nucleotide duplexes with about 19 base pairs and an overhang (see pg. 13, line 25).
Regarding claim 10, Haeberli teaches wherein the siNA molecule of the invention comprises an antisense region having about 15 to about 30 nucleotides, wherein the antisense region is complementary to a target DNA sequence, and wherein said siRNA further comprises a sense region having about 15 to about 30 nucleotides (see pg. 12, line 26).
Regarding claim 12, Haeberli teaches siNA molecules of the invention comprise duplex nucleic acid molecules with overhanging ends of about 1 to about 3 nucleotides (see pg.13, line 23).
Regarding claim 15, Haeberli teaches where the invention features one or more chemically-modified siNA constructs having specificity for a target polynucleotide (see pg.13, line 30).
Regarding claim 18, Haeberli teaches where a siNA molecule of the invention can comprise modified nucleotides as a percentage of the total number of nucleotides present in the siNA molecule. As such, a siNA molecule of the invention can generally comprise about 5% to about 100% modified nucleotides (see pg. 14, line 20).
Regarding claims 19, 20, and 22 Haeberli teaches where non-limiting examples of chemical modifications include, without limitation, 2’-O-methyl ribonucleotides, 2’-deoxy-2’-flouro ribonucleotides, inverted deoxy abasic residue incorporation, and/or phosphorothioate antinucleotide linkages (see pg.14, line 5).
Regarding claim 37, Haeberli teaches where the invention features a method for generating siNA molecules of the invention with improved bioavailability comprising introducing a conjugate into the structure of a siNA molecule. Such conjugates can include ligands for cellular receptors and other co-factors such as N-acetyl galactosamine (see pg. 73, line 21).
Regarding claim 45, Haeberli teaches where in one embodiment, the invention features a composition comprising a siNA molecule of the invention, which can be chemically-modified, in a pharmaceutically acceptable carrier or diluent (see pg. 64, line 27).
Regarding the claims listed above, Haeberli does not teach where the antisense strand is at least 15 contiguous nucleotides from SEQ ID NO: 671 (claim 1), or where the sense and antisense strand, respectively, comprise SEQ ID NO: 127 and 671 (claim 28).
Regarding claims 1 and 28, Sohail discloses methods for the selection of optimal antisense reagents (see introduction). Sohail teaches methods for the identification of accessible sites on target mRNAs in relation to antisense design such as the random ‘shot-gun’ approach, computer folding of mRNAs, oligonucleotide scanning arrays, hybridization to a scanning array, and oligomer library/ribonuclease H digestion-based screens (see section 2). Sohail concludes that the selection of sites in the target RNA which are accessible to antisense reagents is a prerequisite for all antisense oligonucleotide methods (see conclusion). The presented two empirical methods – Rnase H cleavage in the presence of oligonucleotide libraries, and analysis of targets on oligonucleotide arrays – can be used to map the position of accessible sites in RNA molecules. Both methods are simple to apply and are suitable for experimental targets as well as those intended for the development of therapeutic reagents (see conclusion).
As shown below, the alignment of SEQ ID NO: 671 with the FAM13A sequence (SEQ ID NO:1) reveals a 100% match for the 21’mer sequence, indicating that SEQ ID NO: 671 is an antisense sequence that targets the naturally occurring FAM13A gene.
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It would have been obvious to one of ordinary skill in the art, at the time of the invention, to prepare an RNAi construct comprising of a sense strand and antisense strand, where the sense strand comprises a sequence that is sufficiently complementary to the sequence of the antisense strand to form a duplex region, wherein the antisense strand comprises at least 15 contiguous nucleotides from SEQ ID NO: 671, or comprises of SEQ ID NO: 671.
It would have been obvious to combine prior art elements according to known methods to yield predictable results. SEQ ID NO: 671 is a 21’mer sequence targeting the human FAM13A mRNA transcript (SEQ ID NO: 1). Sohail discloses methods of screening for RNA accessible sites within a target mRNA that is feasible and not as expensive or time-consuming as the traditional shot-gun random approach (see conclusion). RNaseH cleavage and analysis of targets on oligonucleotide arrays can be used to map the position of accessible sites in RNA molecules in a way that they are open to antisense attack in vivo. Both methods are easy to apply, suitable for experimental targets as well as those intended for the development of therapeutic reagents, and have the advantage that the target can be explored exhaustively, so that particularly effect sites will not be missed (see conclusion). Though the exact 21’mer antisense strand of SEQ ID NO: 671 and the corresponding complimentary sense strand of SEQ ID NO: 127 was not known in the art, through the methods presented in Sohail, one could effectively screen the FAM13A mRNA sequence and arrive at the claimed SEQ ID NOs.
One would be motivated to combine the prior arts discussed above in order to produce an RNAi construct which targets human FAM13A as FAM13A as Eisenhut discloses FAM13A gene plays a key role in tumor cell proliferation and the inhibition of FAM13A with siRNAs exhibited a decreased proportion of total cells and proliferation in in vitro experiments.
In view of the foregoing, claims 1, 6, 8, 10, 12, 15, 18-20, 22, 28, 37, and 45 are rejected under 35 U.S.C. 103 as being prima facie obvious before the effective filing date.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Eisenhut et al. (FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival, OncoImmunology, Volume 6, Issue 1, all pages, 2017), in view of Haeberli et al. (WO 2005/044981 A2, published 2005) and Sohail et al. (Selecting optimal antisense reagents, Advanced Drug Delivery Reviews, Volume 44, Issue 1, pg. 23-24, 2000).
Regarding claim 31, the combined arts of Eisenhut and Sohail teach siRNA regulation of FAM13A expression, and a method to screen for mRNA entry sites when selecting antisense sequences as described above.
Regarding claim 31, Haeberli teaches the RNAi construct of claim 31 and where a siNA molecule of the invention can comprise modified nucleotides as a percentage of the total number of nucleotides present in the siNA molecule. As such, a siNA molecule of the invention can generally comprise about 5% to about 100% modified nucleotides, as described above.
Haeberli also teaches where modified siNA constructs have “improved toxicologic profile”, meaning that these modified constructs exhibits decreased toxicity in a cell, subject, or organism compared to an unmodified siNA or siNA molecule having few modifications (see pg. 70, line 1 of Haeberli).
Haeberli does not teach where the sense and antisense strands, respectively, comprise the modified nucleotide sequences of SEQ ID NOs: 1773 and 2621 or SEQ ID NOs: 2842 and 3096.
It would have been obvious to one of ordinary skill in the art, at the time of the invention, to prepare an RNAi construct comprising of a sense strand and antisense strand, respectively, comprising of the modified nucleotide sequences of SEQ ID NO. 1773 and 2621 or 2842 and 3096.
One would have been motivated to target the FAM13A gene with RNAi constructs and determine antisense sequences through routine optimization, and expect a reasonable expectation of success, as described above. One would further be motivated to modify the antisense and sense sequences as Haeberli discloses that modified sequences have an “improved toxicologic profile”, exhibiting decreased toxicity in a cell or subject (see pg. 8, line 13).
In view of the foregoing, claim 31 is rejected under 35 U.S.C. 103 as being prima facie obvious before the effective filing date.
Claims 38, 39, 41, 44 are rejected under 35 U.S.C. 103 as being unpatentable over Eisenhut et al. (FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival, OncoImmunology, Volume 6, Issue 1, all pages, 2017), in view of Haeberli et al. (WO 2005/044981 A2, published 2005), Sohail et al. (Selecting optimal antisense reagents, Advanced Drug Delivery Reviews, Volume 44, Issue 1, pg. 23-24, 2000), Ganesh et al. (WO 2022/187622 A1, published 9/9/2922, filed 3/4/2022), and Biscans et al. (Docosanoic acid conjugation to siRNA enables functional and safe delivery to skeletal and cardiac muscles, Molecular Therapy, Volume 29, Issue 4, pg. 1382-1394, 2021).
Regarding the claims listed, the combined arts of Eisenhut, Haeberli, and Sohail disclose an RNAi construct comprising of a sense strand sufficiently complementary to an antisense strand comprising of SEQ ID NO: 671 and a multivalent N-acetyl-galactosamine moiety.
Regarding the claims listed, the combined arts of Eisenhut, Haeberli, and Sohail does not teach where in the RNAi construct, the multivalent N-acetyl-galactosamine moiety is trivalent or tetravalent, or where the targeting ligand further comprises of a long-chain fatty acid that is 22 carbons in length.
Regarding claim 38, Ganesh teaches RNAi conjugates, where in some embodiments, the targeting ligand comprises a N-acetyl galactosamine moiety. The N-acetyl galactosamine moiety comprises of a single, a bivalent, a trivalent, or a tetravalent moiety (see paragraph 0051).
Regarding claim 39 and 41, Ganesh teaches, where in some embodiments, the targeting ligand is a saturated fatty acid moiety, and where the saturated fatty acid moiety has a length of C22 (see paragraph 0050).
Regarding claims 39 and 41, Biscans teaches N-acetyl galactosamine siRNA conjugated to docosanoic acid (22 carbons in length) (see introduction). Biscans discloses lipid conjugation, such as cholesterol and fatty acids, significantly improves the systematic delivery of oligonucleotide to tissues beyond the liver and supports productive silencing in these extrahepatic tissues (see introduction).
Regarding claim 41, Biscans further discloses lipid conjugates, which are examples of a targeting ligand based off Haeberli and Ganesh, are directly attached to siRNAs using a phosphodiester carbon linker (PO-C7 linker) as phosphodiester linker has enough in vivo stability sufficient to support initial tissue distribution, but gets quickly degraded upon cellular uptake to allow siRNA release from the conjugate (See Fig. S1 and Results section).
It would have been obvious to one of ordinary skill in the art, at the time of the invention, to prepare an RNAi construct with a ligand that comprises a multivalent N-acetyl-galactosamine moiety that is trivalent or tetravalent and further comprises of a long-chain fatty acid that is 22 carbons long, or docosanoic acid, to arrive at claims 38, 39, 41, and 44 of the instant application.
One would expect a reasonable expectation of success as Ganesh teaches the delivery of RNAi conjugates with a targeting ligand comprising of a trivalent or tetravalent N-acetyl galactosamine moiety with a 22 carbon long-chain fatty acid (see paragraph 50 and 51), further supported by Biscans, which used a similar construct with the ligand linked to the siRNA via a phosphodiester linkage, to modulate gene expression (see introduction).
One would be motivated to do so as combining the RNAi construct, as taught by the prior art, with the art of Ganesh and Biscans would allow for the RNAi construct to exhibit extrahepatic delivery and stability (taught by results of Biscans) with tissue specific targeting derived from the N-acetyl galactosamine moiety (see introduction of Biscans). In the case of the instant application, this target would be the human FAM13A sequence which is associated with certain lung diseases or conditions.
In view of the foregoing, claims 38, 39, 41, and 44 are rejected under 35 U.S.C. 103 as being prima facie obvious before the effective filing date.
Claims 98, 99, 100, 101, 102, 103, and 104 are rejected under 35 U.S.C. 103 as being unpatentable over Eisenhut et al. (FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival, OncoImmunology, Volume 6, Issue 1, all pages, 2017), in view of Haeberli et al. (WO 2005/044981 A2, published 2005), and Biscans et al. (Docosanoic acid conjugation to siRNA enables functional and safe delivery to skeletal and cardiac muscles, Molecular Therapy, Volume 29, Issue 4, pg. 1382-1394, 2021).
Regarding claims 98 and 101, Haeberli teaches a short interfering nucleic acid molecule (siNA) comprising an antisense strand further comprising a nucleotide sequence that is complementary to a target polynucleotide sequence or a portion thereof (see page 12, line 3). Haeberli teaches where a siNA molecule of the invention comprises an antisense region having about 15 to about 30 nucleotides, wherein the antisense region if complementary to a target DNA sequence, and wherein said siRNA further comprises a sense region having about 15 to about 30 nucleotides, wherein said sense region and said antisense region are comprised in a linear molecule where the sense region comprises at least about 15 nucleotides that are complementary to the antisense region (see pg. 12 line 27). Haeberli further teaches where, in some embodiments, the invention consist of duplex nucleic acid molecules containing about 15 to about 30 base pairs between oligonucleotides comprising about 15 to about 30 nucleotides (see page 13, line 20).
Regarding claim 98 and 102, Haeberli teaches where non-limiting examples of chemical modifications include, without limitation, 2’-O-methyl ribonucleotides and 2’-deoxy-2’-flouro (see pg. 14, line 5).
Haeberli does not teach where the sense and antisense strand, respectively, comprise of SEQ ID NO: 127 and 671, nor where the RNAi construct further comprises a long-chain fatty acid with 22 carbon linked to the RNAi construct with a phosphodiester or phosphonothioate linkage.
Regarding claims 98 and 101, Eisenhut teaches the delivery of RNAi, specifically siRNA, for inhibiting FAM13A expression in A549 cells (see Fig. 6A-C). Eisenhut teaches that FAM13A gene is associated with tumor proliferation in lung cells. Sohail discloses methods for the selection of optimal antisense reagents (see introduction). Sohail teaches methods for the identification of accessible sites on target mRNAs in relation to antisense design such as the random ‘shot-gun’ approach, computer folding of mRNAs, oligonucleotide scanning arrays, hybridization to a scanning array, and oligomer library/ribonuclease H digestion-based screens (see section 2). Sohail concludes that the selection of sites in the target RNA which are accessible to antisense reagents is a prerequisite for all antisense oligonucleotide methods (see conclusion). The presented two empirical methods – Rnase H cleavage in the presence of oligonucleotide libraries, and analysis of targets on oligonucleotide arrays – can be used to map the position of accessible sites in RNA molecules. Both methods are simple to apply and are suitable for experimental targets as well as those intended for the development of therapeutic reagents (see conclusion).
Regarding claims 99, 100, 103, and 104, , Biscans teaches N-acetyl galactosamine siRNA conjugated to docosanoic acid (22 carbons in length) (see introduction). Biscans discloses lipid conjugation, such as cholesterol and fatty acids, significantly improves the systematic delivery of oligonucleotide to tissues beyond the liver and supports productive silencing in these extrahepatic tissues (see introduction). Biscans further discloses lipid conjugates, which are examples of a targeting ligand based off Haeberli, are directly attached to siRNAs using a phosphodiester carbon linker (PO-C7 linker) as phosphodiester linker has enough in vivo stability sufficient to support initial tissue distribution, but gets quickly degraded upon cellular uptake to allow siRNA release from the conjugate (See Fig. S1 and Results section).
It would have been obvious to one of ordinary skill in the art, at the time of the invention, to prepare an RNAi construct as described in Haeberli, to include a sense strand and antisense strand, respectively, comprising of SEQ ID NO: 127 and 671. Though the exact sequence of SEQ ID NO: 127 and 671 are free from the art, Eisenhut teaches that FAM13A is a target of interest for siRNA inhibition, and SEQ ID NO: 671 is an unmodified sequence that targets a fragment of the human FAM13A mRNA sequence. Routine screening for antisense sequences, as taught by Sohail, would lead to the eventual discovery and use of the antisense SEQ ID NO: 671 and the complimentary SEQ ID NO: 127.
Furthermore, Biscans discloses a targeting ligand moiety which comprises of N-acetyl galactosamine and docosanoic acid linked to siRNA through a phosphodiester linkage (see introduction, results, and Fig. S1).
One would be motivated to do so as Eisenhut teaches siRNA silencing of FAM13A in A549, a human lung cell line, resulted in downregulation of both the FAM13A isoform 1 and 2 (See Fig. 6A). RNA-Seq analysis found that many genes involved in tumor cell proliferation including FAM13A were downregulated, whereas tumor suppressor genes and genes linked to cell migration were upregulated (see Fig. 6B and 6C). The specific knockdown of FAM13A and its RhoGAP domain also reduced the proportion of total cells (Fig. 6D) as well as their proliferation as shown by decreased Ki67+ A549 cells, which further confirms the important role of FAM13A in tumor cell proliferation (see Fig. 6E).
One would be further motivated to use the targeting ligand moiety N-acetyl galactosamine as Biscans discloses N-acetyl galactosamine siRNA has demonstrated functional tissue delivery (which includes the lungs). Biscans also teaches docosanoic acid lipid conjugation significantly improves the systematic delivery of oligonucleotide to tissues beyond the liver and supports productive silencing in these extrahepatic tissues, and phosphodiester linker has enough in vivo stability sufficient to support initial tissue distribution, but gets quickly degraded upon cellular uptake to allow siRNA release from the conjugate, making this combined system an efficient construct to target FAM13A expression in specific cells.
In view of the foregoing, claims 98, 99, 100, 101, 102, 103, and 104 are rejected under 35 U.S.C. 103 as being prima facie obvious before the effective filing date.
Conclusion
No claim are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID YU whose telephone number is (571)272-1118. The examiner can normally be reached Monday-Friday 7:30 am -5 pm.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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