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
Applicant’s claim to priority from Provisional Applications 63/844,433 filed 07/15/2025, 63/825,195 filed 06/17/2025, 63/802,341 filed 05/08/2025, 63/793,971 filed 04/24/2025, 63/744,463 filed 01/13/2025 and 63/714,186 filed 10/31/2024, is hereby acknowledged.
Application status
Amendments to claims filed 06/09/2026 are hereby acknowledged.
Claim 5 is cancelled. Claims 1, 3, and 10 are currently amended.
Claims 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Therefore, claims 1-4, 6-20 are pending and claims 1-4 and 6-18 are under consideration in this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/09/2026 was filed after the mailing date of the Office Action on 03/11/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
Replacement sheets for Figures 26A-N filed 10/24/2025 are acceptable.
The following rejections are maintained from Office Action dated 03/11/2026, but modified as necessitated by Applicant’s amendments:
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 1-3, 7-11 and 13-14 are rejected under 35 U.S.C. § 103 as being unpatentable over Horhota (Horhota, A.T. et al. US Patent No. 11,679,120 B2 dated 06/20/2023) in view of Allan (Allan, B. US Patent No. 11,623,956 B2 dated 04/11/1023).
Regarding claims 1 and 2, Horhota teaches a circular RNA that comprises:
(a) a translation initiation element comprising an internal ribosome entry site (IRES) sequence (see abstract). This IRES sequence is 100% identical to SEQ ID NO: 217 (see alignment below; Qy = Query (SEQ ID NO: 217); Db = Database (Horhota- US Patent no. 11,679,120- SEQ ID NO: 678).
RESULT 1
US-17-202-223A-678
(NOTE: this sequence has 3 duplicates in the database searched.
See complete list at the end of this report)
Sequence 678, US/17202223A
Patent No. 11679120
GENERAL INFORMATION
APPLICANT: ORNA THERAPEUTICS, INC.
TITLE OF INVENTION: CIRCULAR RNA COMPOSITIONS AND METHODS
FILE REFERENCE: OBS-011WOC1
CURRENT APPLICATION NUMBER: US/17/202,223A
CURRENT FILING DATE: 2021-03-15
PRIOR APPLICATION NUMBER: PCT/US2020/063494
PRIOR FILING DATE: 2020-12-04
PRIOR APPLICATION NUMBER: 63/087,582
PRIOR FILING DATE: 2020-10-05
PRIOR APPLICATION NUMBER: 63/022,248
PRIOR FILING DATE: 2020-05-08
PRIOR APPLICATION NUMBER: 62/972,194
PRIOR FILING DATE: 2020-02-10
PRIOR APPLICATION NUMBER: 62/943,797
PRIOR FILING DATE: 2019-12-04
PRIOR APPLICATION NUMBER: 62/943,779
PRIOR FILING DATE: 2019-12-04
NUMBER OF SEQ ID NOS: 717
SEQ ID NO 678
LENGTH: 675
TYPE: DNA
ORGANISM: Unknown
FEATURE:
OTHER INFORMATION: Description of Unknown:
Picornavirales sp. isolate RtMruf-PicoV sequence
Query Match 100.0%; Score 675; Length 675;
Best Local Similarity 100.0%;
Matches 675; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TTTGCTCAGCGTAACTTCTCCGGGTTACGTGGAGACCAAAAGGCTACGGAGACTCGGGCT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 TTTGCTCAGCGTAACTTCTCCGGGTTACGTGGAGACCAAAAGGCTACGGAGACTCGGGCT 60
Qy 61 ACGGCCCTGGAGCACCTAGGTGCTCCTAAAGACGTTAGAAGTTGTACAAACTCGCCCAAT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ACGGCCCTGGAGCACCTAGGTGCTCCTAAAGACGTTAGAAGTTGTACAAACTCGCCCAAT 120
Qy 121 AGGGCCCCCCAACCAGGGGGGTAGCGGGCAAGCACTTCTGTTTCCCCGGTATGATCTCAT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AGGGCCCCCCAACCAGGGGGGTAGCGGGCAAGCACTTCTGTTTCCCCGGTATGATCTCAT 180
Qy 181 AGGCTGTACCCACGGCTGAAAGAGAGATTATCGTTACCCGCCTCACTACTTCGAGAAGCC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 AGGCTGTACCCACGGCTGAAAGAGAGATTATCGTTACCCGCCTCACTACTTCGAGAAGCC 240
Qy 241 CAGTAATGGTTCATGAAGTTGATCTCGTTGACCCGGTGTTTCCCCCACACCAGAAACCTG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 CAGTAATGGTTCATGAAGTTGATCTCGTTGACCCGGTGTTTCCCCCACACCAGAAACCTG 300
Qy 301 TGATGGGGGTGGTCATCCCGGTCATGGCGACATGACGGACCTCCCCGCGCCGGCACAGGG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 TGATGGGGGTGGTCATCCCGGTCATGGCGACATGACGGACCTCCCCGCGCCGGCACAGGG 360
Qy 361 CCTCTTCGGAGGACGAGTGACATGGATTCAACCGTGAAGAGCCTATTGAGCTAGTGTTGA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 CCTCTTCGGAGGACGAGTGACATGGATTCAACCGTGAAGAGCCTATTGAGCTAGTGTTGA 420
Qy 421 TTCCTCCGCCCCCGTGAATGCGGCTAATCCCAACTCCGGAGCAGGCGGGCCCAAACCAGG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 TTCCTCCGCCCCCGTGAATGCGGCTAATCCCAACTCCGGAGCAGGCGGGCCCAAACCAGG 480
Qy 481 GTCTGGCCTGTCGTAACGCGAAAGTCTGGAGCGGAACCGACTACTTTCGGGAAGGCGTGT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GTCTGGCCTGTCGTAACGCGAAAGTCTGGAGCGGAACCGACTACTTTCGGGAAGGCGTGT 540
Qy 541 TTCCTTTTGTTCCTTTTATCAAGTTTTATGGTGACAACTCCTGGTAGACGTTTTATTGCG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 TTCCTTTTGTTCCTTTTATCAAGTTTTATGGTGACAACTCCTGGTAGACGTTTTATTGCG 600
Qy 601 TTTATTGAGAGATTTCCAACAATTGAACAGACTAGAACCACTTGTTTTATCAAACCCTCA 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 TTTATTGAGAGATTTCCAACAATTGAACAGACTAGAACCACTTGTTTTATCAAACCCTCA 660
Qy 661 CAGAATAAGATAACA 675
|||||||||||||||
Db 661 CAGAATAAGATAACA 675
Horhota teaches that an IRES sequence isolated picornavirales species performed better compared an IRES sequence isolated from Salivirus, and well with no large significant differences when compared to IRES sequences isolated from caprine Kobuvirus or Parabovirus (see Figure 39).
And (b) Horhota also teaches a circular RNA that expresses a CD19 binding molecule, a chimeric antigen receptor CAR (see Figures 39, 41A-C, 42A-B, and 44; and column 30, lines 1-26; column 57).
In column 957, Horhota teaches a specific example of constructs including an intro/exon regions, an anti-CD19 CAR expression sequence, i.e. encoding for a CD19 binder domain (see column 957, lines 16-36 and lines 51-67; Examples 20-22).
In column 26, Horhota teaches that the targeting moiety is an scfv, nanobody,
peptide, minibody, heavy chain variable region, light chain variable region, an extracellular domain of a TCR or a fragment thereof (column 26, lines 12-16).
Horhota also teaches that “the CAR comprises an antigen binding domain specific for an antigen selected from the group CD19, CD123, CD22, CD30, (…)” (see column 74, lines 55-67). Therefore, the CD19 binding region comprised within the CAR can be a CD19 binding domain. And of note, Horhota teaches CD19 as a first alternative/choice for the CAR antigen binding domain.
However, Horhota does not teach SEQ ID NOs: 424-429, SEQ ID NO: 381 nor SEQ ID NO: 382.
According to the instant Specification (see [0462]), SEQ ID NOs: 424-426 are comprised in VH chain, as follow:
“ In some embodiments, the CD19 binding molecule comprises a heavy chain
variable (VH) domain and a light chain variable (VL) domain, wherein the heavy chain variable domain comprises a VH CDR1 comprising KASGHTISSYAYS (SEQ ID NO: 424), a VH CDR2 comprising DIIPAYGSPN (SEQ ID NO: 425), a VH CDR3 comprising
AREDFGKNYAMDV (SEQ ID NO: 426)”. (see [0462]).
In Table 10, page 507 of the instant Specification, these sequences are part of SEQ ID NO: 381.
And also SEQ ID NOs: 427-429 are comprised in VL chain as described in [0462]:
“and wherein the light chain variable domain comprises a VL CDR1 comprising RASQHVSSHYLA (SEQ ID NO: 427), a VL CDR2 comprising YGASSRAT (SEQ ID NO: 428), and a VL CDR3 comprising QHYGQSQFT (SEQ ID NO: 429)”. In Table 10, page 507 of the instant Specification, these sequences are part of SEQ ID NO: 382.
Allan teaches molecules that bind to CD19, and more specifically anti-human CD 19 antibodies (see abstract). Allan teaches a sequence that is 100% identical to instant SEQ ID NO: 381, as shown in the alignment below (Qy = SEQ ID NO: 381; Db = SEQ ID NO: 37 of Allan):
RESULT 1
US-17-181-184-37
Sequence 37, US/17181184
Patent No. 11623956
GENERAL INFORMATION
APPLICANT: Eli Lilly and Company
TITLE OF INVENTION: ANTI-HUMAN CD19 ANTIBODIES
FILE REFERENCE: X22706
CURRENT APPLICATION NUMBER: US/17/181,184
CURRENT FILING DATE: 2021-02-22
PRIOR APPLICATION NUMBER: 62/983,093
PRIOR FILING DATE: 2020-02-28
NUMBER OF SEQ ID NOS: 57
SEQ ID NO 37
LENGTH: 120
TYPE: PRT
ORGANISM: ARTIFICIAL SEQUENCE
FEATURE:
OTHER INFORMATION: Synthetic Construct
Query Match 100.0%; Score 626; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGSSVKVSCKASGHTISSYAYSWVRQAPGQGLEWMGDIIPAYGSPNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGSSVKVSCKASGHTISSYAYSWVRQAPGQGLEWMGDIIPAYGSPNY 60
Qy 61 AQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREDFGKNYAMDVWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREDFGKNYAMDVWGQGTLVTVSS 120
Allan also teaches a sequence that is 100% identical to instant SEQ ID NO: 382, according to the alignment shown below (Qy = SEQ ID NO: 382; Db = SEQ ID NO: 41 of Allan):
RESULT 1
US-17-181-184-41
Sequence 41, US/17181184
Patent No. 11623956
GENERAL INFORMATION
APPLICANT: Eli Lilly and Company
TITLE OF INVENTION: ANTI-HUMAN CD19 ANTIBODIES
FILE REFERENCE: X22706
CURRENT APPLICATION NUMBER: US/17/181,184
CURRENT FILING DATE: 2021-02-22
PRIOR APPLICATION NUMBER: 62/983,093
PRIOR FILING DATE: 2020-02-28
NUMBER OF SEQ ID NOS: 57
SEQ ID NO 41
LENGTH: 108
TYPE: PRT
ORGANISM: ARTIFICIAL SEQUENCE
FEATURE:
OTHER INFORMATION: Synthetic Construct
Query Match 100.0%; Score 567; Length 108;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPGTLSLSPGERATLSCRASQHVSSHYLAWYQQKPGQAPRLLIYGASSRATGIP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPGTLSLSPGERATLSCRASQHVSSHYLAWYQQKPGQAPRLLIYGASSRATGIP 60
Qy 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGQSQFTFGQGTKVEIK 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGQSQFTFGQGTKVEIK 108
Allan teaches that in some embodiments, the antibody fragments comprise a VH comprising SEQ ID NO: 37 and a VL comprising SEQ ID NO: 41 (see column 3, lines 21-23 and see claim 2 of Allan, column 77, lines 60-61).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Horhota with the teachings of Allan, using a circular RNA comprising an IRES as taught by Horhota for expressing the anti-CD19 antibodies fragments taught by Allan. One with ordinary skills in the art, motivated in an IRES sequence that performs well in initiating
translation in a synthetic expression system, could have made this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 3, Horhota teaches that in some embodiments, the targeting moiety is a single chain Fv (scFv) fragment (see column 22, lines, 62-63).
Allan teaches that the CD19 binding molecule can be a Fab or scFv molecule (see column 3, lines 12-13).
The obviousness of combining the references Horhota and Allan is described above.
Regarding claim 7, Horhota teaches that in some embodiments, the circular RNA polynucleotide comprises one or more microRNA binding sites (see column 16, lines 25-26).
Regarding claim 8, Horhota teaches a circular RNA further comprising a 3’ self-spliced exon segment upstream of the IRES and a 5’ self-spliced exon segment downstream of the expression sequence, since “In some embodiments, the circular RNA polynucleotide comprises, in the following order a) a post-splicing intron fragment of a 3’ group I intron fragment, b) an IRES, c) an expression sequence, and d) a post-splicing intron fragment of a 5’ group I intron fragment” ( see column 16, lines 37-53).
Regarding claim 9, Horhota teaches that the circular RNA comprises modified RNA nucleotides (5-methylcytidine, 5-methyluridine, N6-methyladenosine, 2-thiouridine…) (see column 54, lines 41-67; and columns 55-56).
Regarding claim 10, Horhota teaches a pharmaceutical composition comprising:
A circular RNA, comprising a translation initiation element comprising (i) an IRES sequence (see abstract), 100% identical to SEQ ID NO: 217 (as shown above),
An expression sequence encoding a CD19 binding molecule (see Figure 39; column 30, lines 1-26).
Specifically, Horhota also teaches a circular RNA that expresses a CD19 binding molecule, a chimeric antigen receptor CAR (see Figures 39, 41A-C, 42A-B, and 44; and column 30, lines 1-26; column 57).
In column 957, Horhota teaches a specific example of constructs including an intro/exon regions, an anti-CD19 CAR expression sequence, i.e. encoding for a CD19 binder domain (see column 957, lines 16-36 and lines 51-67; Examples 20-22).
In column 26, Horhota teaches that the targeting moiety is an scfv, nanobody, peptide, minibody, heavy chain variable region, light chain variable region, an extracellular domain of a TCR or a fragment thereof (column 26, lines 12-16).
Horhota also teaches that “the CAR comprises an antigen binding domain specific for an antigen selected from the group CD19, CD123, CD22, CD30, (…)” (see column 74, lines 55-67). Therefore, the CD19 binding region comprised within the CAR can be a CD19 binding domain. And of note, Horhota teaches CD19 as a first alternative/choice for the CAR antigen binding domain.
Allan teaches specifically a VH and a VL as shown in SEQ ID NOs: 381 and 382 as
shown above and as disclosed by Allan’s SEQ ID NOs: 37 and 41 (see Allan’s claim 2, column 77).
Horhota teaches a pharmaceutical composition comprising a lipid nanoparticle
comprising the circular RNA polynucleotide (see column 25, lines 47-54). In some embodiments, the nanoparticles comprises ionizable lipids and PEG-modified lipids (column 26, lines 16-26), phospholipids (see column 699, lines 45-67; column 703, lines 1-30), structural lipids (column 704, lines 13-48).
Horhota teaches phospholipids at 20 mol % compared to other components in
the nanoparticle (see column 960, Table 31b)
The obviousness of combining the references Horhota and Allan is described above regarding claims 1 and 2. The elements of claims 1 and 2 are claimed in claim 10, therefore these elements are taught by Horhota modified by Allan. The elements claimed in claim 10(b) are taught by Horhota, therefore, they are also rendered obvious by the combination of references.
Regarding claim 11, (a), Horhota teaches 50 mol% of ionizable lipid (see column 21, line 35-39; column 958, lines 34-37). Horhota also teaches 16 mol% of ionizable lipid and therefore teaching a range from 16 mol% to 62 mol% of ionizable lipid (see column 29, lines 25, 37, 47, 52 and 57).
(b) Horhota teaches phospholipid varying from 5 mol% to 20 mol% ( see columns 959-961, Table 31b), however, Horhota also teaches combination of PEG-modified phospholipid (see column 700, lines 1-6).
(c) Horhota teaches structural lipids such as cholesterol, a sterol such as phytosterol with concentrations ranging from 18.5 mol% to 53.5 mol%(see column 704, lines 16-43; column 959-961,Table 31b).
(d) Horhota teaches PEG-modified phospholipid in a molar ratio from about 0% to about 20%, about 0.5% to about 20%, about 1% to about 15%, about 4% to about 10%, or about 2% of the total lipid present in a liposomal lipid nanoparticle (see column 700, lines 1-6; see columns 959- 960, Table 31b).
In KSR Int 'l v. Teleflex, the Supreme Court, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability”. KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date, to have tried multiple combinations of lipids in different concentrations as taught by Horhota modified with Allan. Horhota teaches concentration ranges that include, or overlap with, the claimed ranges for the lipids in the nanoparticle. The level of skills in the art is high. One with ordinary skills in the art motivated in formulating a nanoparticle with optimum efficiency in delivering a therapeutic nucleic acid composition to a target cell, could have tried and optimized the composition, through routine experimentation, with a reasonable expectation of success and arrived at the claimed invention.
Regarding claims 13 and 14, Horhota teaches a pharmaceutical composition comprising DSPC, cholesterol and PEG2K (see Tables 32b and 34; column 965). Horhota also teaches beta-sitosterol, DOPE, DMG-PEG, DSPE-PEG(2000) (see column 20, lines 17-26; column 21, lines 1-39). Horhota teaches structural lipids that can be fecosterol, ergosterol, alpha-tocopherol, bassicasterol, tomatidine and tomatine (see column 704, lines 11-32).
Horhota also specifically teaches DMG-PEG2k (see Table 31a, column 959), DSPE-PEG2k (columns 979, line 54; column 980, line 67).
The obviousness of combining the references Horhota and Allan is described above.
Claims 12 and 15-16 are rejected under 35 U.S.C. § 103 as being unpatentable over Horhota (Horhota, A.T. et al. US Patent No. 11,679,120 B2 dated 06/20/2023) in view of Allan (Allan, B. US Patent No. 11,623,956 B2 dated 04/11/1023), as applied to claim 10 above, and in further view of Zhang (Zhang, Y. et al. “Lipids and lipid derivatives for RNA delivery”. Chemical Reviews, vol. 121 (2021), pp: 12181-12277), Liu (Liu, J. et al. “The many faces of the adamantyl group in drug design”. European Journal of Medicinal Chemistry, Vol. 46 (2011), pp: 1949-1963) and Štimac (Štimac, A. et al. “Adamantane in drug delivery systems and surface recognition”. Molecules, Vol. 22 (2017), p: 297).
The rejection of claim 10 is described above. The combination of references Horhota and Allan does render obvious the elements of claim 10.
Regarding claim 12, Horhota teaches formulas for synthesizing cationic lipids and specifically ionizable lipids; among those formulas, formula IV stands out (see column 167, lines 25-35):
PNG
media_image1.png
164
205
media_image1.png
Greyscale
Horhota teaches that in some embodiments, Z-L combination in formula IV, has one of the following structures among other alternatives (see column 184, lines 40-50):
PNG
media_image2.png
200
219
media_image2.png
Greyscale
Horhota teaches that in this formula, X can be CRa which can be H, C1-C2 alkyl, C1-C12 hydroxylalkyl, C1-C12 aminoalkyl among other alternatives (see column 167, lines 58-62); in other embodiments, X is CH (see column 168, line 57; column 176, line 20).
Horhota also teaches bridged cyclic structures in the design of ionizable lipids (see Table 11, columns 383-394). See example below (columns 391-392, Table 11):
PNG
media_image3.png
368
508
media_image3.png
Greyscale
Horhota also teaches adamantane moieties attached to hydrophobic groups as shown in columns 721-724, Table 16, see compounds 39, 165, and 172; see example compound No. 172 below:
PNG
media_image4.png
160
356
media_image4.png
Greyscale
However, Horhota does not teach a compound with the “AX” formula as claimed in claim 12. the combination of Horhota and Allan does not render obvious the formula AX, as described in claim 12.
However, Zhang teaches a general formula for lipids, with DOTMA as an example, in Figure 2, page 12187, shown below:
PNG
media_image5.png
538
719
media_image5.png
Greyscale
Zhang teaches three essential parts to a lipid: A head group, a linker and a hydrophobic tail. Among alternatives, an “ N” can be the head group, i.e., a “tertiary amine”; An “ester group” can be a linker. These two parts combined are shown in Horhota’s Z-L group as shown in column 184, lines 40-50 :
PNG
media_image2.png
200
219
media_image2.png
Greyscale
Zhang also teaches that an Adamantane derivative can be substituted to obtain an hydrophobic tail (see Figure 2, above).
Liu teaches the use of adamantyl group in drug design (see title) and specifically shows that attaching a linker and a head group, as shown above, can be performed as shown in Figure 1, species 4, 6 and 7 (see Figure 1, page 1952):
PNG
media_image6.png
201
796
media_image6.png
Greyscale
Štimac teaches specifically the use of adamantane in drug delivery systems (see title). Štimac teaches that the adamantane moiety is widely applied in design and synthesis of new drug delivery systems to form liposomes, because of self-assembling properties (see Abstract, and section 2 on page 2 of 14).
Štimac teaches an example of dendrimer that can be synthesized using adamantane moieties attached to a triazole-type head group and an amide-type linker, with additional hydrophobic tails (see figure 10, page 10 of 14):
PNG
media_image7.png
329
527
media_image7.png
Greyscale
Thus, Štimac shows the use of adamantane-derived structures that can mimic lipids in liposomes . Štimac also teaches that two or three additional hydrophobic tails can be attached to one adamantane moiety using amide-type linkers similar to the ones present in a naturally occurring lipid, as shown in Figure 2 of Zhang.
Therefore, it would have been obvious to one with ordinary skills before the effective filing date of the claimed invention to have substituted the CH or CRa group called “X” in the formula IV of Horhota or substituted a bridged cyclic moiety as taught by Horhota in columns 391-391, with an adamantane moiety with linkers, as taught by Zhang and Liu. One with ordinary skills in the art, motivated in synthesizing a dendrimer-type liposomes for gene delivery, benefitting from the self-assembling properties of adamantane-derived structures, could have performed this substitution with a reasonable expectation of success, as taught by Liu and Štimac, and would arrived at the claimed invention, i.e., an “AX” structure type of ionizable lipid.
Regarding claim 15, Horhota teaches sphingomyelin as a lipophilic tail derived from a lipid, that can be selected as a phospholipid moiety (see column 96, lines 40-41; see column 703, section “Helper Lipids”, lines 13-30). Horhota teaches structural lipid that can be cholesterol (see column 704, section “Structural Lipids”, lines 16-51).
Horhota also teaches a PEG lipid that is a DMG-PEG2k (see column 699, section “PEG Lipids”, lines 45-67 and column 700, line 43, and column 959, Table 31a).
Regarding claim 16, (a) Horhota teaches PEG-DMG compound at a concentration of 1.5 mol% (see columns 959-960, Table 31b). (b) Horhota teaches the use of cholesterol in a mixture with DODAP, DOPE and DMG-PEG2k at 20 mol % (see column 959, Table 31a, formulations number 2 and 3). (c) Horhota teaches that the helper lipid can comprise a molar ration of 5% to about 90%, or about 10% to about 70% of the total lipid present in the nanoparticle (see column 704, lines 5-10). (d) Horhota teaches that the ionizable lipid can be at a molar concentration of 50% (see Examples 24 and 25, column 958). Horhota also teaches a range of 16 mol% to 62 mol% for the ionizable lipid (see columns 979, lines 53-56 and 980, lines 45-49).
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date, to have tried multiple combinations of lipids in different concentrations as taught by Horhota/Allan and substituted the ionizable lipid taught by Horhota with an AX type ionizable lipid, as taught by Horhota modified with Zhang/Liu and Štimac, within the mixture. Horhota teaches concentration ranges that include the claimed ranges for the lipids in the nanoparticle. The level of skills in the art is high. One with ordinary skills in the art motivated in formulating a nanoparticle with optimum efficiency in delivering a therapeutic nucleic acid composition to a target cell, could have tried and optimized the composition, through routine experimentation, with a reasonable expectation of success and arrived at the claimed invention.
Response to Arguments
Applicant's arguments filed 06/09/2026 have been fully considered but they are not 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).
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, Horhota introduces a CD19 binding domain comprised within a CAR as the first alternative of many, but finite number of possibilities (see column 74, lines 55-67). Horhota also teaches many figures and examples comprising specifically a CAR with a CD19 targeting domain (see column 30; Figures 38-44; column 957, examples 20-22).
Horhota is not the first prior art presenting with an IRES sequence identical to instant SEQ ID NO: 217. On the IDS filed 01/30/2026, Applicant cites Wesselhoeft (WO2021/189059 A2; published 09/23/2021) which also presents the sequence as part of the IRES sequences that can be used in a circular RNA (see SEQ ID NO: 678 (page 471, Table 7; [0679]).
One of ordinary skills in the art has access to high-throughput assays for optimization of sequences. One of ordinary skills in the art motivated in assaying possibilities and finding an optimized IRES for their construct, could have included all the sequences in one high-throughput assay, including a construct comprising SEQ ID NO: 678, before the effective filing date.
One with ordinary skills in the art motivated in improving on a CD19 antibody fragment to design specific CAR would be interested in the teachings of Allan, presenting specific antibodies for CD19 that are specific for binding to B cells and inhibit them, without the inconvenience of depleting them, for treating B cell associated disorders (column 1, lines 64-67). Therefore, one with ordinary skills in the art motivated in having a construct that does not have the inconvenience of DNA constructs, e.g., deleterious or oncogenic effects, could have performed a substitution of sequences for constructing new CAR constructs within a circular RNA as taught by Wesselhoeft and Horhota, well before the effective filing date of the instant application.
Regarding Applicant’s arguments on page 11, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “evaluate the single chain binding molecule format”, “evaluate the expression of anti-CD19 CARs in T cells”, and “evaluate T cell cytotoxic function”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
These “evaluations” read as method steps. The current rejections are for a composition/compound, that can be rendered obvious by a combination of references in the prior art.
In response to Applicant’s argument on page 12, stating “Applicant submits the Examiner has failed to provide any reason why the ionizable lipids/compounds recited in the present claims would have been obvious in light of these alleged teachings of Zhang, Liu, and Stimac and why a person of skill in the art would have been motivated to combine these teachings to arrive at those compounds. While the Office points to Zhang, Liu, and Stimac as teaching compounds comprising adamantanes, the Office has not shown why a person of skill in the art would have prepared the particular compounds recited in the claims for use as lipid carriers in concert with the recited circular RNA polynucleotide” , Examiner would like to remind that the proposed lipids and chemical structures claimed, are within the possibilities claimed by the prior art references. With the search for “adaptable” lipids, all lipids claimed are functioning towards the same goal and are substitutable as well. Mostly, these are generic structures for compounds, unlike the AX-6 which Examiner identified as a unique compound and therefore patentable, the other generic formulas for lipid compounds can be subjected to rejection under KSR:
In KSR Int 'l v. Teleflex, the Supreme Court, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability”. KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
In response to Applicant stating “the LNP formulation must be optimized and tested for delivery of the specific nucleic acid payload to the desired cell type for the desired applications”. Examiner would like to remind that the claims are drawn to a compound/product/composition, and not to a method of use.
In response to applicant's argument, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Allowable Subject Matter
SEQ ID NOs: 292, 293, 395 and 396 seem to be free from prior art.
An ionizable lipid with the AX-6 structure seems to be free from prior art.
Claim Objections
Claims 4, 6, 17 and 18 are 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
Claims 4, 6, 17 and 18 are objected to. Claims 1-3, 7-11 and 13-14 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA G DACE DENITO whose telephone number is (703)756-4752. The examiner can normally be reached Monday-Friday, 8:30-5:00EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights