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 .
Application Status
This action is written in response to applicant’s correspondence received 6/4/2026. Claims 2-7, 11, 14-25, 27, 29-32, 34, 36-43, and 50 are cancelled. Claims 1, 8-10, 12-13, 26, 28, 33, 35, 44-49, and 51-54 are currently pending. Claims 53 and 54 are new. Claims 1, 8-10, 12-13, 26, 28, 33, 35, 44-49, and 51-54 are examined herein.
Objections to the specification are withdrawn in view of Applicant’s amendments to the specification (filed 6/4/2026) to include proper symbols for trademarks and trade names and to include the sequence listing file size in bytes.
Rejection of claims 10, 12-13, 28, 33, and 35 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of Applicant’s amendment to claims filed 6/4/2026 to correct antecedent basis in claims 10, 12, 13, 28, 33, and 35 and to delete “m2 7,2'-OGppspGRNA” from claim 10 and 35.
Applicant cancelled claims 15 and 20 and added claims 53 and 54. Accordingly, a new rejection of record under 35 U.S.C. 103 is necessitated by amendment.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103 – new necessitated by amendment
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.
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, 8-10, 12-13, 26, 28, 33, 35, 44-49, and 51-54 are rejected under 35 U.S.C. 103 as being unpatentable over Mishra et al. (US20200102363A1; published 4/2/2020 and EFD 5/18/17), in view of Li et al. (Nano Letters 15 (12): 8099-8107; published 11/3/2015; cited in IDS filed 9/26/2025). This is a new rejection necessitated by amendment to cancel claims 15 and 20 and to add claims 53 and 54.
Mishra’s disclosure is directed to mRNA encoding tethered interleukin-12 (IL-12) comprising an IL-12 polypeptide and a membrane domain and compositions comprising the polynucleotides, vectors, host cells, or polypeptides and a delivery agent; and uses thereof, including treatment of cancer (entire document).
Regarding claims 1 and 8, Mishra teaches a lipid nanoparticle comprising a lipid and a modified mRNA comprising a sequence that encodes an IL-12 molecule (abstract; and Examples 1-5). Mishra teaches several delivery agents comprising lipid compounds (paras 0810-1027). Mishra further teaches that the modified mRNA is not self-replicating (paras 0673-0708, 1160, and 1180).
However, Mishra does not specifically teach that the lipid comprises a compound of Formula I of claim 1 or claim 8.
Li’s disclosure is directed to optimization of lipid-like nanoparticles for mRNA delivery in vivo (entire document). Li teaches that PEGylation of TT3 LLNs showed dramatic effects on particle stability, particle size, and mRNA delivery efficiency (p. 8099, right column, para 1).
Regarding claims 1 and 8, Li teaches lipids TT2-TT8, which includes the claimed N1,N3,N5-tris(3-(didodecylamino)propyl)benzene-1,3,5-tricarboxamide (TT3) (Figure 1). Li further teaches that the optimized lead material TT3 LLNs improved delivery efficiency over 350-fold with significantly reduced experimental workload (p. 8099, right column, para 1; Figure 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Mishra’s lipid nanoparticles comprising modified mRNA encoding IL-12 with the optimized TT3 lipid-like nanoparticles of Li. Li teaches optimized TT3 LLNs having improved delivery efficiency over 350-fold with significantly reduced experimental workload (p. 8099, right column, para 1; Figure 2). One of ordinary skill in the art would have been motivated to use Li’s optimized TT3 LLNs for Mishra’s IL-12 mRNA delivery to treat cancer because of the greatly improved efficiency of the TT3 LLNs. One would have had a reasonable expectation of success in doing so because Mishra and Li are directed to improved methods and compositions of mRNA therapeutics using nanoparticles. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 9, Mishra teaches lipid nanoparticles further comprising DOPE (paras 0834, 0933, and 1017).
Regarding claim 10, Mishra teaches modified mRNA comprising a modified 5’-cap and wherein the modified 5'-cap is selected from the group consisting of m7GpppG, m7Gppppm7G, m2 (7,3'-0)GpppG, m2 (7,2'-O)GppspG (D1), m2 (7,2'-O)GppspG (D2), m2 (7,3'-O)Gppp(m12'-O)ApG, (m7G-3'mppp-G; which may equivalently be designated 3' O-Me-m7G(5')ppp(5')G), N7,2'-O-dimethyl- guanosine-5'-triphosphate-5'-guanosine, m7Gm-ppp-G, N7-(4-chlorophenoxyethyl)-G(5')ppp(5')G, N7-(4-chlorophenoxyethyl)-m3'-OG(5')ppp(5')G, 7mG(5')ppp(5')N,pN2p, 7mG(5')ppp(5')N1mpNp, 7mG(5')-ppp(5')N1mpN2 mp, m(7)Gpppm(3)(6,6,2')Apm(2')Apm(2')Cpm(2)(3,2')Up (Cap4), inosine, N1-methyl-guanosine, 2' fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA- guanosine, 2-azido-guanosine, N1-methylpseudouridine, m7G(5')ppp(5')(2'OMeA)pG, and combinations thereof (paras 0020, 0027, 0138-0140, 0691-0703, 1104, and 1167).
Regarding claim 12, Mishra teaches that the modified mRNA can be circular RNA (paras 0029, 0794, and 1244).
Regarding claim 13, Mishra teaches the modified mRNA further comprises a half-life extending moiety comprising an Fc region of an antibody, an albumin, a PAS sequence, transferrin, and combinations thereof (paras 0586-0592, 0688-0694, 0701-0714, and 1100).
Regarding claim 26, Mishra teaches nucleotide sequence SEQ ID NO: 221 encoding mRNA coding IL-12 having 100% sequence identity to Applicant’s claimed SEQ ID NO: 6 (see OA.Appendix from Non-Final OA mailed 9/26/2025 for sequence alignment).
Regarding claim 28, Mishra teaches that the modified RNA can comprise regulatory elements selected from the group consisting of at least one TEE, a translation initiation sequence, at least one microRNA binding site or seed thereof, a 3' tailing region of linked nucleosides, an AU rich element (ARE), a post transcription control modulator, and combinations thereof, and wherein the 3' tailing region of linked nucleosides comprises a poly-A tail, a polyA-G quartet, or a stem loop sequence, and/or (ii) at least one modified nucleoside, wherein the at least one modified nucleoside is selected from the group consisting of 6-aza-cytidine, 2-thio-cytidine, α -thio-cytidine, pseudo-iso-cytidine, 5-aminoallyl-uridine, 5-iodo-uridine, N1-methyl-pseudouridine, 5,6- dihydrouridine, α -thio-uridine, 4-thio-uridine, 6-aza-uridine, 5-hydroxy-uridine, deoxy- thymidine, pseudo-uridine, inosine, α -thio-guanosine, 8-oxo-guanosine, 06-methyl- guanosine, 7-deaza-guanosine, N1-methyl adenosine, 2-amino-6-chloro-purine, N6-methyl- 2-amino-purine, 6-chloro-purine, N6-methyl-adenosine, α-thio-adenosine, 8-azido- adenosine, 7-deaza-adenosine, pyrrolo-cytidine, 5-methyl-cytidine, N4-acetyl-cytidine, 5-methyl-uridine, 5-iodo-cytidine, and combinations thereof (0020, 0136, 0543-0572, 0642, 0665-0681, 0687-0690, and 1230).
Regarding claim 33, Mishra teaches SEQ ID NO: 337 having 100% sequence identity to the modified RNA comprising Applicant’s claimed SEQ ID NO: 8 (see OA.Appendix from Non-Final OA mailed 9/26/2025 for sequence alignment).
Regarding claim 35, Mishra teaches lipid nanoparticles having a diameter of about 30-500nm (paras 0909-0911) and wherein the lipid nanoparticle and modified mRNA have a mass ratio of about 2:1, which teaches a mass ratio within the range of about 1:2 to about 2:1 (paras 0892-0895 and 0917-0920)
Regarding claim 44, Mishra teaches pharmaceutical compositions comprising lipid nanoparticles and a pharmaceutically acceptable carrier (paras 0141, 0153-0161, 0793, 0797, 1055-1057, and 1174-1177).
Regarding claim 45, Mishra teaches pharmaceutical compositions formulated for intratumoral, intrathecal, intramuscular, intravenous, subcutaneous, inhalation, intradermal, intralymphatic, intraocular, intraperitoneal, intrapleural, intraspinal, intravascular, nasal, percutaneous, sublingual, submucosal, transdermal, and transmucosal administration (paras 0034, 0259, and 1053; and Examples 4 and 5).
Regarding claim 46, Mishra teaches a method of treating cancer comprising administering to a subject an effective amount of the lipid nanoparticle comprising a lipid and a modified mRNA comprising a sequence that encodes an IL-12 molecule (paras 0267-0273).
Regarding claim 47, Mishra teaches that the subject is a human patient having or suspected of having a cancer (paras 0267-0273).
Regarding claim 48, Mishra teaches that the human patient has a cancer that is melanoma, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, peritoneal cancer, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, gastric cancer, and head and neck cancer (paras 0267-0273).
Regarding claim 49, Mishra teaches administering the lipid nanoparticle in a single dose (paras 0214-0215; and Examples 4 and 5).
Regarding claim 51, Mishra teaches the pharmaceutical composition comprising C14-PEG2000 (paras 0856-0863).
Regarding claim 52, Mishra teaches the lipid nanoparticle comprising cholesterol (paras 0033; 0849-0855, 0870-0873, and 0901-0905).
Regarding claim 53, Mishra teaches that the IL-12 molecule comprises IL-12, IL-12α, IL-12β, or a mutant IL-12 molecule that retains the immunomodulatory function (paras 0300-0307). Mishra further teaches SEQ ID NO: 241 having 100% sequence identity to Applicant’s SEQ ID NO: 4 encoding mutant IL-12 molecule (see OA.Appendix from Non-Final OA mailed 9/26/2025 for sequence alignment).
Regarding claim 54, Mishra teaches that the subunits are linked by a linker and that the linker can be (Gly4Ser)3 or (Gly4Ser)4 (paras 0009-0016 and 0434).
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 6/4/2026 have been fully considered but they are not persuasive. Applicant argues that the Office has failed to show a prima facie case of obviousness because a person of ordinary skill in the art would not have been motivated to combine Mishra and Li to arrive at the lipid nanoparticle of claim 1 with a reasonable expectation of success. Applicant argues that Mishra does not specifically teach that the lipid comprises a compound of Formula I of claim 1 or claim 8 and alleges that the secondary reference Li merely demonstrates use of the alleged TT3 LLNs for transfection of firefly luciferase and hFIX, reporting improved "reduced experimental workload" (Li, Abstract) and thus provides no teaching or suggestion of the alleged TT3 LLNs for delivery of a modified mRNA encoding IL-12. Applicant argues that a person of ordinary skill in the art would recognize that optimizing delivery and biodistribution for different molecules - particularly those that are intended to achieve distinct biological effects - is a nontrivial endeavor and that taken together, a person of ordinary skill in the art would not have any legitimate reason or motivation to modify Mishra in view of Li to arrive at the claimed invention.
The Office disagrees.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Applicant is reminded of Li’s teachings discussed above that not only teaches lipids TT2-TT8, but specifically teaches that optimized lead material TT3 LLNs improved delivery efficiency over 350-fold with significantly reduced experimental workload and further that PEGylation of TT3 LLNs showed dramatic effects on particle stability, particle size, and mRNA delivery efficiency (p. 8099, right column, para 1; Figure 2). Applicant admits that TT3 LLNs were used to efficiently transfect firefly luciferase and also hFIX. Importantly, and in the same paragraph of p. 8099, Li teaches that the transfection produced hFIX at a therapeutically relevant level in both wild-type and FIX-knockout mice. Accordingly, one of ordinary skill in the art would have been motivated to use Li’s optimized TT3 LLNs for Mishra’s IL-12 mRNA delivery to treat cancer because of the greatly improved efficiency of the TT3 LLNs. Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Mishra teaches delivery of IL-12 for cancer treatment (see 103 discussion above) and Li teaches improved particle stability, particle size, and mRNA delivery efficiency with optimized TT3 LLNs. Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Applicant further argues that the skilled artisan would not have arrived at the claimed invention with a reasonable expectation of success in the desired results outlined below. Applicant argues the present application provides that the TT3-LNP can induce immunogenic cell death (ICD) in cancer cells, allowing the "modified RNA [to] work synergistically with the TT3-LNP to induce higher level of ICD in tumor cells compared to TT3-LNP alone" (paragraph [0060] of the published application). Applicant cites Example 3 of the present specification arguing that it demonstrates a significant tumor reduction in animals treated with an exemplary lipid nanoparticle according to the claim 1 (the combination of the TT3-LNP and modified RNA encoding IL-12), compared to control animals in B16-F10, a highly difficult to treat mouse model of melanoma (paragraphs [0254] and [0255] of the published application). A skilled artisan considering the cited references, alone or in combination, would not have achieved or predicted such induction of ICD in cancer cells, nor the synergistic effect arising from the combination of modified RNA encoding IL-12 and LNPs comprising the lipid specified in Formula I in treating tumor. Applicant further argues that even if there were motivation to combine Mishra and Li, which the Applicant does not concede, a person of ordinary skill in the art would not have achieved or predicted the above-noted unexpectedly beneficial results of the claimed lipid nanoparticle as recited in claim 1.
The Office disagrees. As discussed above, Mishra teaches LNP delivery of IL-12 to treat cancer and Li teaches significant improvement with PEGylated TT3 LLNs on particle stability, particle size, and mRNA delivery efficiency (p. 8099, right column, para 1; Figure 2). Li further teaches transfection produced hFIX at a therapeutically relevant level in both wild-type and FIX-knockout mice, thus teaching successful delivery of mRNA with the TT3 LLNs. Accordingly, one of ordinary skill in the art would have been motivated to improve IL-12 mRNA delivery with improved lipid nanoparticles and further would have had a reasonable expectation of success in making the lipid nanoparticle of claim 1 and further would have had a reasonable expectation of success in achieving beneficial results using the products to treat cancer in a subject in need thereof. Applicant’s arguments citing Example 3 to demonstrate a significant tumor reduction in animals treated with an exemplary lipid nanoparticle according to the claim 1 (the combination of the TT3-LNP and modified RNA encoding IL-12), compared to control animals in B16-F10, a highly difficult to treat mouse model of melanoma, is unpersuasive because the “subject” in the claims is not limited to a specific model or strain of mouse. Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 7:30am-5pm.
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/KHALEDA B HASAN/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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