DETAILED ACTION
Claims 38-42, 121-129 and 131-132 are currently pending.
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 .
Election/Restrictions
Applicant’s election without traverse of Group II (claims 38-42, 121-129 and 131-132) in the reply filed on 7/22/2026 is acknowledged.
Claims 1-37, 43-120 and 130 are cancelled.
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/US2022/074491, filed August 3, 2022, which claims the benefit of provisional application No. 63/228,892, filed August 3, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/18/2024 and 7/22/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: typographical.
It is noted the specification at paragraphs [0017], [0044], and [0123] recites the term “N1-methylpsuedo”. It appears the term should be spelled “N1-methylpseudo”.
Appropriate correction is required.
Claim Objections
Claims 42 and 121 are objected to because of the following informalities: typographical.
Claims 42 and 121 recite the term “N1-methylpsuedo”. It appears the term should be spelled “N1-methylpseudo”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 129 and 132 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claims 129 and 132 recite the limitation “…a fragment there of, a variant thereof…” in reference to the recited biologically active polypeptide(s).
To satisfy the written description aspect of 35 U.S.C. 112, first paragraph, for a claimed genus of molecules, it must be clear that: (1) the identifying characteristics of the claimed molecules have been disclosed, e.g., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed cor-relation between function and structure, or by a com-bination of such identifying characteristics; and (2) a representative number of species within the genus must be disclosed. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
In giving the terms ‘a fragment there of’, and ‘a variant thereof' their broadest reasonable interpretation, the number and types of compounds which can be considered derivatives of the recited biologically active polypeptides is extraordinarily great, and can be interpreted to even include elemental carbon, nitrogen and hydrogen as ‘a fragment thereof’ or ‘a variant thereof’. Applicants’ disclosure of such compounds is limited to IL-la, IL-1p, IL-IRA, IL-18, IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-3, IL-5, GM-CSF, IL-6, IL-l1, G-CSF, IL-12, LIF, OSM, IL-10, IL-20, IL-14, IL-16, IL-17, IFN-a, IFN-p, IFN-y, CD154, LT-p, TNF-a, TNF-p, 4-1BBL, APRIL, CD70, CD153, CD178, GITRL, LIGHT, OX40L, TALL-1, TRAIL, TWEAK, TRANCE, TGF-p, TGF-pl, TGF-p2, TGF-p3, Epo, Tpo, Flt-3L, SCF, M-CSF, MSP, per se, there is no disclosure of acceptable fragments or variants of the recited polypeptides, or fragments or variants of the mRNA that would encode fragments or variants of the recited polypeptides. Applicant’s specification only sets forth 8 (eight) polynucleotide sequences: SEQ ID NOs: 1-8 and does not set forth any further fragments or variants of polynucleotides that would encode variants or fragments of the recited polypeptides.
A review of the specification fails to provide a definition of what structural characteristics for each of IL-la, IL-1p, IL-IRA, IL-18, IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-3, IL-5, GM-CSF, IL-6, IL-l1, G-CSF, IL-12, LIF, OSM, IL-10, IL-20, IL-14, IL-16, IL-17, IFN-a, IFN-p, IFN-y, CD154, LT-p, TNF-a, TNF-p, 4-1BBL, APRIL, CD70, CD153, CD178, GITRL, LIGHT, OX40L, TALL-1, TRAIL, TWEAK, TRANCE, TGF-p, TGF-pl, TGF-p2, TGF-p3, Epo, Tpo, Flt-3L, SCF, M-CSF, and MSP that the derivatives (i.e., fragments or variants) encompassed by the current claims must have; Applicants have not identified any particular core chemical structure or function (along with a correlation between function and a specific conserved structure) of these polypeptides which must be shared by all the fragments or variants thereof; and thus one of ordinary skill in the art would not immediately envisage all fragments or variants of IL-la, IL-1p, IL-IRA, IL-18, IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-3, IL-5, GM-CSF, IL-6, IL-l1, G-CSF, IL-12, LIF, OSM, IL-10, IL-20, IL-14, IL-16, IL-17, IFN-a, IFN-p, IFN-y, CD154, LT-p, TNF-a, TNF-p, 4-1BBL, APRIL, CD70, CD153, CD178, GITRL, LIGHT, OX40L, TALL-1, TRAIL, TWEAK, TRANCE, TGF-p, TGF-pl, TGF-p2, TGF-p3, Epo, Tpo, Flt-3L, SCF, M-CSF, and MSP, as currently claimed. Therefore, Applicants have not disclosed the identifying characteristics of the claimed molecules.
Regarding disclosure of a representative number of species within the genus a review of the specification shows that Applicants have disclosed the target mRNA encodes a p35 subunit of IL-12 and a p40 subunit of IL-12 ([0010], [0048]) or the target mRNA encodes IL-la, IL-1p, IL-IRA, IL-18, IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-3, IL-5, GM-CSF, IL-6, IL-l1, G-CSF, IL-12, LIF, OSM, IL-10, IL-20, IL-14, IL-16, IL-17, IFN-a, IFN-p, IFN-y, CD154, LT-p, TNF-a, TNF-p, 4-1BBL, APRIL, CD70, CD153, CD178, GITRL, LIGHT, OX40L, TALL-1, TRAIL, TWEAK, TRANCE, TGF-p, TGF-pl, TGF-p2, TGF-p3, Epo, Tpo, Flt-3L, SCF, M-CSF, and MSP ( [0010], [0046], [0127]), per se, but no specific species of, fragments thereof or variants thereof. Disclosure of single species does not constitute a representative number for such a broad genus as is encompassed by the breadth of ‘a fragment thereof’ or ‘a variant thereof’ regarding IL-la, IL-1p, IL-IRA, IL-18, IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-3, IL-5, GM-CSF, IL-6, IL-l1, G-CSF, IL-12, LIF, OSM, IL-10, IL-20, IL-14, IL-16, IL-17, IFN-a, IFN-p, IFN-y, CD154, LT-p, TNF-a, TNF-p, 4-1BBL, APRIL, CD70, CD153, CD178, GITRL, LIGHT, OX40L, TALL-1, TRAIL, TWEAK, TRANCE, TGF-p, TGF-pl, TGF-p2, TGF-p3, Epo, Tpo, Flt-3L, SCF, M-CSF, and MSP. Therefore, Applicants have not disclosed a representative number of species, as would be required to support description and to show possession of the entire genus.
Thus, one of ordinary skill in the art, in looking to the instant specification, would not be able to determine that Applicants were in possession of the invention, as claimed, at the time the invention was filed. Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
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 124-125 and 131 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.
In claims 124-125 and 131, given that parent claim 38 is directed to a polynucleotide composition, it is unclear if applicant is claiming a method step of using/administering the polynucleotide by indicating increased expression. It appears said limitations are directed to the intended use of the claimed polynucleotide. Please note that it is well settled that “intended use” of a composition or product will not further limit claims drawn to a composition or product, so long as the prior art discloses the same composition as that instantly claimed. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In re Hack 114, USPQ 161.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 38-42, 122, 124-125, 127-129 and 131 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Bancel et al., (US 2013/0259924, Published Oct. 3, 2013; see PTO-892) (“Bancel”), as evidenced by Reyes et al., (British Journal of Cancer 80, 229-235 (1999); see PTO-892) (“Reyes”).
Bancel, at [1523]-[1524], teaches an embodiment disclosing a polynucleotide comprising G-CSF mRNA (SEQ ID NO:21438, claims 127-129) that has been modified to comprise 5-methylcytosine (5mC) (instant claims 42 and 122) and pseudouridine (pseudoU) (i.e. a modified rNTP, instant claim 41). Bancel teaches several variations of the G-CSF mRNA as follows:
completely modified with 5mC and pseudoU (100% modification), (2) not modified with 5mC and pseudoU (0% modification) or (3) was partially modified with 5mC and pseudoU so the mRNA would contain 50% modification, 25% modification (instant claims 38-40), 10% modification (instant claims 38-39), 5% modification (instant claims 38-39), 1% modification (instant claims 38-39) or 0.1% modification (instant claims 38-39).
Reyes evidences that G-CSF (Granulocyte colony-stimulating factor) is a cytokine that promotes growth and maturation of neutrophils, i.e., a cytokine, a growth factor (Abstract).
Hence, Bancel’s teaching anticipates claims 38-42, 122 and 127-129.
Regarding claims 124-125 and 131, as set forth above at the rejection under 35 USC 112(b), given that parent claim 38 is directed to a polynucleotide composition, it appears said limitations are directed to the intended use of the claimed polynucleotide and do not further limit the polynucleotide, and thus are included in the rejection of claim 38.
It is noted however, Bancel’s disclosed mmRNA comprising substitution with 5-methyl cytidine and N1-methyl-pseudouridine showed the highest level of G-CSF production (Table 77), relative to mRNA not comprising modified nucleic acids.
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.
Claim(s) 121, 123 and 132 are rejected under 35 U.S.C. 103 as being unpatentable over Bancel, as evidenced by Reyes, as applied to claims 38-42, 122, 124-125, 127-129 and 131 above.
The teaching of Bancel, as evidenced by Reyes, is set forth above and anticipates claims 38-42, 122, 124-125, 127-129 and 131.
Regarding claim 121 and the limitation the modified nucleotide comprises N1-methylpseudo uracil, it is noted that, although Bancel’s modified mRNA disclosed at [1523]-[1524] comprises pseudouridine (i.e., pseudouracil) and does not further teach N1-methylpseudo uracil, Bancel ([1521]) further teaches substitution with N1-methylpseudo uracil, in lieu of pseudouridine, provided a modified mRNA having reduced inflammatory cytokine response (Table 78).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute N1-methylpseudo uracil for pseudouracil since both are known mRNA modifications. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of modified uracil for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Additionally, given that Bancel has shown that mRNA comprising N1-methylpseudo uracil has a better anti-inflammatory characteristic as compared to mRNA comprising pseudouracil, one would be motivated to substitute N1-methylpseudo uracil for pseudouracil for the predictable result of providing therapeutic mRNA having a reduced anti-inflammatory property.
Regarding claim 123, Bancel’s modified mRNA disclosed at [1523]-[1524] comprises pseudouridine (i.e., pseudouracil) and 5-methyl cytidine. Bancel at [1523]-[1524] does not further teach the modified mRNA comprises N6-methyladenosine, as recited at claim 123. However, Bancel at [0512], further teaches the mRNA can be prepared to comprise a variety of modified nucleobases, including modified adenosine, specifically N6-methyladenosine. Thus, Bancel does render obvious a target mRNA comprising modified nucleic acid molecules, including modified adenosines, specifically N6-methyladenosine, that is, Bancel teaches the limitation required by the current claim and as said limitation is found in one reference it is held that a target mRNA comprising N6-methyladenosine is within the scope of the teachings of Bancel, and thus renders the invention of claim 123 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to modify the mRNA to include N6-methyladenosine. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Bancel.
Regarding claim 132, it is noted that Bancel’s modified mRNA disclosed at [1523]-[1524] encodes the cytokine G-CSF. Bancel’s teaching at [1523]-[1524] does not further teach the mRNA encodes IL-12. However, Bancel further teaches the modified mRNA (mmRNA) is self-replicating RNA that encodes antigens which raise the immune response ([0932]-[0933]), specifically the mmRNA encodes antigens that rapidly stimulate an immune response to a newly identified virus ([0988]), and said antigens include, for example, G-CSF and IL-12 ([1067]). Thus, Bancel does render obvious a target mRNA encoding IL-12, that is, Bancel teaches the limitation required by the current claim and as said limitation is found in one reference it is held that a target mRNA encoding IL-12 is within the scope of the teachings of Bancel, and thus renders the invention of claim 127 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to prepare modified mRNA that encodes IL-12. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Bancel.
Claim 126 is rejected under 35 U.S.C. 103 as being unpatentable over Bancel, as evidenced by Reyes, as applied to claims 38-42, 122, 124-125, 127-129 and 131 above, and further in view of Liu et al., (RNA Biol. 2017 Sep 21;14(12):1715-1721; see PTO-892) (“Liu”) and Wesselhoeft et al., (Nature Communications 9, Article No: 2629 (2018), 10 pages; see PTO-892) (“Wesselhoeft”).
The teaching of Bancel, as evidenced by Reyes, is set forth above.
Regarding claim 126, Bancel does not further teach the modified RNA is circular RNA. However, Liu teaches circular RNA is abundant in eukaryotic cells, and circular RNA is more resistant to RNA exonucleases as compared to linear RNA molecules. Furthermore, Liu teaches that circular RNA escapes normal RNA turnover and thus has improved stability (Abstract).
Wesselhoeft teaches a fundamental limitation regarding the use of mRNA in biological systems is its relatively short half-life, thus Wesselhoeft developed exogenous circular RNA (circRNA) in order to extend the duration of protein expression in eukaryotic cells and shows that circRNA is a promising alternative to linear mRNA (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ circular RNA.
The person of ordinary skill in the art would have been motivated to modify the mRNA composition of Bancel to include circular RNA, as taught by Liu and Wesselhoeft, for the predictable result of successfully improving RNA stability against in vivo exonucleases and extending the half-life of the RNA thus permitting improved duration of protein expression, thus meeting the limitation of claim 126.
The skilled artisan would have had a reasonable expectation of success in combining the teaching of Bancel with Liu and Wesselhoeft because each of these teachings are directed at RNA molecules.
Conclusion
No claim is allowed. No claim is free of prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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