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
Applicant's amendments and remarks filed on April 8, 2026 are acknowledged. Claims 2-8 and 12-15 have been canceled. Claims 1, 9, 10, 11, 16, 17, and 19 were amended. Claims 1, 9, 10, 11, and 16-21 are pending and are examined on the merits herein.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 8, 2026 has been entered.
Withdrawn Objections
In view of Applicant’s amendments and response, the objections to the specification are withdrawn.
In view of Applicant’s amendments and response, the objection to claim 11 is withdrawn.
Priority
This application claims priority to PCT/KR2020/006610 filed on May 20, 2020 which claims priority to KR10-2019-0058805 filed on May 20, 2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 8, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 9-11, and 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over Ligtenberg et al. (Molecular Therapy 2018; reference cited by Applicant) in view of Guccione et al. (US 2020/0377883; reference previously cited by the Examiner), Agrawal et al. (WO 2016/138278), and Lee et al. (WO 2009/078685; reference cited by Applicant).
Regarding claims 1, 9-11, and 16, Ligtenberg et al. teaches a self-delivering small interfering RNA (siRNA) (sdRNA) that knocked down PD-1 expression on healthy donor T cells as well as patient-derived tumor-infiltrating lymphocytes (TIL). Further, antibodies targeting immune checkpoint molecules such as cell death protein 1 pathway (PD-1) are rapidly being approved for multiple cancer types, including as first line therapy for PD-L1-expressing non-small-cell lung cancer [abstract]. Ligtenberg et al. teaches that the self-deliverable RNAi molecule is a chemically synthesized asymmetric siRNA duplex consisting of the 20-nt antisense (guide) strand and 13–15 base sense (passenger) strand conjugated to cholesterol at its 3’ end using tetraethyleneglycol (TEG) linker. Most or all 2’OH positions of ribose residues are substituted with 2’OMe or 2’F modifications, conferring sdRNA molecule resistance to nuclease degradation in both extra- and intracellular environment. Additional nuclease protection is provided by phosphorothioate modifications at 3’ ends of guide and passenger strands [page 1483, right column, first full paragraph]. Figure 1A shows that the 5’ end of the antisense strand and the 3’ end of the sense strand form a blunt end.
Regarding claims 17 and 18, Ligtenberg et al. teaches that the first ACT with chimeric antigen receptor (CAR) T cells engineered to express CD19 for treatment of relapsing B cell acute lymphoblastic leukemia (ALL) was recently
approved [page 1482, right column, first paragraph]. Ligtenberg et al. also teaches that an attractive alternative to the combination of ACT with antibody-mediated checkpoint blockade will be to silence PD-1 expression in the T cells prior to their transfer to the patient [page 1483, left column, second full paragraph]. Thus, the composition of Ligtenberg et al. would be capable of treating cancer such as acute lymphoblastic leukemia and thus meets the limitations of claims 17-18.
Regarding claims 19-21, Ligtenberg et al. teaches a novel self-delivering small interfering RNA (siRNA) (sdRNA) that knocked down PD-1 expression on healthy donor T cells as well as patient-derived tumor infiltrating lymphocytes (TIL). Ligtenberg et al. demonstrated that T cells treated with sdRNA specific for PD-1 had increased interferon Ɣ (IFN-Ɣ) secreting capacity and that this modality of gene expression interference could be utilized in the rapid expansion protocol for production of TIL for therapy [abstract].
However, Ligtenberg et al. does not teach instant SEQ ID NO: 77 (sense strand) or instant SEQ ID NO: 78 (antisense strand). Ligtenberg et al. also does not teach instant SEQ ID NO: 186 (which is instant SEQ ID NO: 77 with chemical modifications) or instant SEQ ID NO: 185 (which is instant SEQ ID NO: 78 with chemical modifications).
Guccione et al. teaches antisense oligonucleotides that modulate the function of the T cell by blocking an immune checkpoint molecule such as PD-1 [0023] and antisense oligonucleotides capable of inducing exon skipping [0001] particularly skipping exon 2 for PD-1 [0014]. Further, the antisense oligonucleotide may comprise a sequence selected from any one of SEQ ID NOs: 1 to 69575 [0030]. Guccione et al. SEQ ID NO: 5625 (designated as Db) has a match to instant SEQ ID NO: 78 (19 nucleotides in length; designated as Qy) as shown in the alignment below.
Query Match 100.0%; Score 19; Length 21;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UGCGGUACCAGUUUAGCAC 19
|||||||||||||||||||
Db 3 UGCGGUACCAGUUUAGCAC 21
Guccione et al. SEQ ID NO: 5625 (designated as Db) is complementary to instant SEQ ID NO: 77 (16 nucleotides in length; designated as Qy) as shown in the alignment below.
Query Match 100.0%; Score 16; Length 21;
Best Local Similarity 81.2%;
Matches 13; Conservative 3; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CUAAACUGGUACCGCA 16
|:||||:||:||||||
Db 18 CTAAACTGGTACCGCA 3
Guccione et al. teaches that ASOs need to be chemically modified to improve their resistance to nucleases and provide favorable pharmacokinetic and pharmacodynamic properties for in vivo use [0009]. For example, the modified polynucleotide backbone may comprise at least one modified internucleotide linkage such as a phosphorothioate [0040] or the antisense oligonucleotide comprises a backbone such as 2′-O-methyl-oligoribonucleotide and 2′-O-methyl-oligodeoxyribonucleotide or 2′-F-phosphorothioate [0041]. Guccione et al. also teaches that the oligonucleotide may be chemically linked to one or more conjugates that enhance the activity, cellular distribution, or cellular uptake of the antisense oligonucleotide [0043].
Agrawal et al. teaches compounds and compositions for inhibiting PD1. In certain embodiments, the compounds are gene silencing compounds [0073] wherein the gene silencing compounds are targeted to the human PD1 nucleic acid sequence set forth in GENBANK Accession No. NM_005018 [0076]. Agrawal et al. also teaches that a target region is a structurally defined region of the target nucleic acid and may encompass an exon [00111].
Lee et al. teaches a double-stranded small interfering RNA molecule (siRNA molecule) capable of silencing the expression of a target gene comprising a 19-21 nucleotide (nt) antisense strand and a 15-19 nt sense strand having a sequence complementary to the antisense sequence, wherein the 5 ' end of the antisense strand has a blunt end and the 3 ' end of the antisense strand has an overhang [abstract]. Lee et al. also teaches that the term "16+3 A siRNA structure" refers to a double-stranded siRNA molecule comprising a 19 nt antisense strand and a 16 nt sense strand having a sequence complementary thereto, wherein the 5 ' end of the antisense strand is a blunt end and the 3' end of the antisense strand has a 3 nt overhang [page 7, second paragraph]. Further, the 16+3 A siRNA structure shows high gene silencing efficiency and minimizes off-target effects resulting from the sense strand of siRNA [page 8, first full paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the siRNA of Ligtenberg et al. with the specific sequence taught by Guccione et al. and to have modified the sequence of Guccione et al. using the design principles taught by Lee et al. because Ligtenberg et al. teaches a self-delivering small interfering RNA (siRNA) (sdRNA) that knocked down PD-1 expression, Guccione et al. teaches antisense oligonucleotides that modulate the function of the T cell by blocking an immune checkpoint molecule such as PD-1, Agrawal et al. teaches gene silencing compounds targeted to the human PD1 nucleic acid sequence and compositions for inhibiting PD1, and Agrawal et al. teaches that a target region is a structurally defined region of the target nucleic acid and may encompass an exon. Therefore, it would have amounted to applying known design principles for preparing antisense compounds by known means to yield predictable results. One of skill in the art would have been motivated to use the specific sequence taught by Guccione et al. to modulate the function of the T cell by blocking PD-1 and would have had a reasonable expectation of success in preparing the modified oligonucleotides because as evidenced by Agrawal et al. it was well within the purview of the skilled artisan to target the human PD1 nucleic acid sequence for gene silencing where the target region may encompass an exon and as evidenced by Lee et al. it was well within the purview of the skilled artisan to design a double stranded siRNA molecule comprising a 19 nt antisense strand and a 16 nt sense strand with a 3 nt overhang on the 3’ end of the antisense strand for high gene silencing efficiency and to minimize off-target effects.
Further, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the antisense oligonucleotide of Guccione et al. with a reasonable expectation of success. Based on the teachings of Ligtenberg et al. and Guccione et al., it was well-within the purview of the skilled artisan to design modified oligonucleotides comprising the recited modifications. One of ordinary skill in the art would have arrived at the specific patterns of modifications recited in the instant claims because it would have amounted to applying a known chemical modification design strategy to an obvious siRNA by known means to yield predictable results.
Response to Arguments
Applicant's arguments filed April 8, 2026 have been fully considered but they are not persuasive.
Applicant asserts that neither Ligtenberg et al. alone, nor the combination of Ligtenberg et al., Guccione et al., and Lee et al. teaches or suggests amended claim 1.
Specifically, Applicant asserts that Ligtenberg et al. uses a 20 nt antisense / 13-15 nt sense format which is structurally distinct from the instantly claimed 19 nt antisense / 16 nt sense architecture. Further, Applicant asserts that there is no teaching, suggestion, or motivation for one of ordinary skill in the art to modify Ligtenberg et al.’s format to the instantly claimed architecture. Applicant also asserts the following:
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Applicant asserts that according to the sequence listing of Guccione et al., SEQ ID NO: 5625 is a synthetic oligonucleotide designed to target the PD-1 exon 2 region and does not establish that the sequence is a functional antisense oligonucleotide capable of inhibiting PD-1 expression. Applicant further asserts that the distinction between a sequence that merely “targets” a genomic region and one that has been demonstrated to functionally inhibit expression of the corresponding gene product is important. Applicant asserts that nowhere in the specification of Guccione et al. is there experimental data or teaching demonstrating that SEQ ID NO: 5625 exhibits PD-1 inhibitory activity. Applicant further provides the following assertions:
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These arguments are not found persuasive. Ligtenberg et al. was used in combination with Guccione et al., Agrawal et al., and Lee et al. to render obvious the instant claims. As discussed in the 35 U.S.C. 103 rejection above, Ligtenberg et al. taught a self-delivering small interfering RNA (siRNA) (sdRNA) that knocked down PD-1 expression, Guccione et al. taught antisense oligonucleotides that modulate the function of the T cell by blocking an immune checkpoint molecule such as PD-1 [0023] and antisense oligonucleotides capable of inducing exon skipping [0001] particularly skipping exon 2 for PD-1 [0014], Agrawal et al. taught gene silencing compounds targeted to the human PD1 nucleic acid sequence and compositions for inhibiting PD1, Agrawal et al. taught that a target region is a structurally defined region of the target nucleic acid and may encompass an exon, and Lee et al. taught a double-stranded small interfering RNA molecule (siRNA molecule) capable of silencing the expression of a target gene comprising a 19-21 nucleotide (nt) antisense strand and a 15-19 nt sense strand having a sequence complementary to the antisense sequence, wherein the 5 ' end of the antisense strand has a blunt end and the 3 ' end of the antisense strand has an overhang [abstract]. Lee et al. also taught that the term "16+3 A siRNA structure" refers to a double-stranded siRNA molecule comprising a 19 nt antisense strand and a 16 nt sense strand having a sequence complementary thereto, wherein the 5 ' end of the antisense strand is a blunt end and the 3' end of the antisense strand has a 3 nt overhang [page 7, second paragraph]. Further, the 16+3 A siRNA structure shows high gene silencing efficiency and minimizes off-target effects resulting from the sense strand of siRNA [page 8, first full paragraph]. Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the siRNA of Ligtenberg et al. with the specific sequence taught by Guccione et al. and to have modified the sequence of Guccione et al. using the design principles taught by Lee et al. based on the teachings of the cited references. One of ordinary skill in the art would have been motivated to do so because it would have amounted to applying known design principles for preparing antisense compounds by known means to yield predictable results and as evidenced by Agrawal et al. it was well within the purview of the skilled artisan to target the human PD1 nucleic acid sequence for gene silencing where the target region may encompass an exon and as evidenced by Lee et al. it was well within the purview of the skilled artisan to design a double stranded siRNA molecule comprising a 19 nt antisense strand and a 16 nt sense strand with a 3 nt overhang on the 3’ end of the antisense strand for high gene silencing efficiency and to minimize off-target effects. Furthermore, even if Guccione et al. discloses tens of thousands of candidate ASO sequences targeting PD-1 as Applicant asserts, this is a finite number of sequences to test.
Applicant points to Figure 2 and Example 1 asserting that a large number of the screened sequences exhibited insufficient PD-1 mRNA inhibition despite all targeting PD-1 and sharing the same general structural architecture. Therefore, Applicant asserts that this directly refutes any suggestion that the identification of an effective PD-1 siRNA sequence is predictable or routine even when the general structural format is already known. Applicant further asserts that a second round of targeted screening (Examples 6-8) was necessary because of the unpredictability that was observed in Example 1 and thus demonstrates that success was not predictable from general design principles alone. Applicant further asserts that the combination of Ligtenberg et al., Guccione et al., and Lee et al. is an example of impermissible hindsight reconstruction. Applicant asserts that a person of ordinary skill in the art at the time of the invention, without knowledge of the claimed sequences, would have faced the following obstacles:
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Therefore, Applicant asserts that the proposed combination of a large number of candidate sequences, the mechanistic gap between ASOs and siRNAs, and the sensitivity of siRNA efficacy to seed region sequence is speculative rather than obvious. Lastly, as further evidence of non-obviousness, Applicant asserts that the approximately 80% inhibition of PD-1 expression demonstrated by asiPD-8-039 as shown in Figure 10 represents an unexpected and superior result. Specifically, the identification of a sequence achieving approximately 80% inhibition given that a substantial number of the screened sequences achieved less than 50% or even less than 20% inhibition reflects a result that would not have been expected or predicted.
These arguments are not found persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). With respect to Applicant’s arguments, the Examiner’s response to the arguments above also apply here. With respect to Applicant's arguments regarding Figure 2, Figure 2 demonstrates that not all asiRNAs comprising a sense strand that is 16 nucleotides in length and an antisense strand that is 21 nucleotides in length is capable of inhibiting PD-1 mRNA because the level of PD-1 mRNA inhibition varies significantly. Although the level of PD-1 mRNA inhibition varies significantly, this does not refute any suggestion that the identification of an effective PD-1 siRNA sequence is predictable or routine even when the general structural format is already known. Contrary to Applicant’s assertion that asiPD-8-039 represents an unexpected and superior result, FIG. 10 (reproduced below) shows that all of the asymmetric siRNAs evaluated (8-039, 8-046, 8-048, 8-050, 8-053, 8-054, 8-068, and 8-070) exhibited a similar inhibitory effect on PD-1 expression. Furthermore, in an assertion of unexpected results, one must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). See MPEP 716.02(e). Specifically, Applicant did not compare the instantly claimed double-stranded siRNA to the double-stranded siRNA of the closest prior art.
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Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights