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 .
Claim Status
Applicant’s amendment filed 9/13/2023 has been entered. Claims 2-7, 11, 14, 16-19, 21-25, 27, 29-32, 34, 36-43, and 50 are cancelled. Claims 1, 8-10, 12-13, 15, 20, 26, 28, 33, 35, 44-49, and 51-52 are pending and examined herein.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification in paragraph 243 are not identified by sequence identifiers (i.e., “SEQ ID NO:X”, where “X” is a number) in accordance with 37 CFR 1.831(c). Instead, two sequences appear alongside the phrase “SEQ ID NO: XX” rather than SEQ ID NOs.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The use of the terms MONARCH® - RNA cleanup kit paragraphs 249, 250, and 251; TURBO DNASE™ in paragraph 249; SUPERASE IN™ in Tables 6, 7, and 8; MESSENGERMAX™ in paragraph 252; Q5® Hot Start High-Fidelity 2X Master Mix in Table 4; and CLEANCAP® - in Table 6, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10, 12-13, 28, 33, and 35 are rejected 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.
Claim 10 recites “m2 7,2'-OGppspGRNA” in line 3. It is unclear what this compound is. The specification recites this as a modified 5’-cap at paragraphs 0007 and 0086, but does not provide any further explanation or structure. Accordingly, the limitation is indefinite.
Claim 10 recites the limitation "the modified RNA" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 12 recites the limitation "the modified RNA" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 13 recites the limitation "the modified RNA" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 28 recites the limitation "the modified RNA" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 33 recites the limitation "the modified RNA" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 35 recites the limitation "the modified RNA" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 35, depending from claim 1, recites the limitation “wherein the lipid nanoparticle and the modified RNA have a mass ratio of about 1:2 to about 2:1”. The lipid nanoparticle of claim 1 comprises a lipid and a modified RNA. It is unclear how whether the “mass ratio” is that of the lipid to the modified RNA of the lipid nanoparticle or the lipid nanoparticle (i.e., the sum of the mass ratios of lipid + modified RNA) to the modified RNA. For the purposes of compact prosecution, the Office is interpreting the “mass ratio” as a ratio of the lipid to the modified RNA of a given lipid nanoparticle.
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.
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, 15, 20, 26, 28, 33, 35, 44-49, and 51-52 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).
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 15, 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 for sequence alignment).
Regarding claim 20, Mishra teaches that the subunits are link by a linker and that the linker can be (Gly4Ser)3 or (Gly4Ser)4 (paras 0009-0016 and 0434).
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 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 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).
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.
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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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.
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/KHALEDA B HASAN/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636