Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Priority
This application is a National Stage Entry of International Application Number PCT/EP2022/078869, which was filed on October 17, 2022 and claimed priority to International Application Number PCT/EP2021/078828, which was filed on October 18, 2021 that is hereby acknowledged by the Examiner.
Status of the Claims
The amendment dated 06/25/2025 is acknowledged. Claims 1-2, 5, 8-10, 13, 20, 22-23, 27, 29-30, 35-36, 38, 54, 58, 60, 62, 65, 68 and 70 are pending and under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/17/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the Examiner.
Drawings
The drawing filed on 04/17/2024 are acknowledged and accepted by the Examiner.
Specification
The disclosure is objected to because of the following informalities: The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pages 23, 30-31, 67). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Appropriate correction is required.
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.
Claims 1, 13, 20, 23, 35, 38, 54, 58 and 70 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Regarding claims 1 and 35 recite “partially”. The term “partially” is not clear in that it is a relative term. Further, the specification does not define the term “partially” and does not provide a standard for ascertaining the requisite degree, thus a skilled artisan would not be apprised to the metes and bounds of the recitations. Thus, the claims are rendered indefinite.
Regarding claims 13, 20, 23, 54, 58 and 70, the term "preferably" is a relative term which renders the claim indefinite. The term "preferably" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, the claim is rendered indefinite.
Regarding claim 38, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
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.
Claims 1-2, 5, 8-10, 20, 23, 27, 30 and 35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Irvine et al. “Irvine” (US PGPUB 2020/224174, IDS of record dated 04/17/2024).
The claims are directed to a method for identifying a sequence change in a replicable RNA (rRNA) comprising a modified nucleotide (modified rRNA) that at least partially restores or increases a function of the modified rRNA, the method comprising: (a) transfecting cells expressing an RNA-dependent RNA polymerase (replicase) with a modified rRNA encoding a gene of interest; [[and]] (b) isolating rRNA molecules encoding the gene of interest from the transfected cells expressing the gene of interest to provide isolated rRNA molecules; (c) transfecting cells expressing the replicase with a subsequent generation of rRNA molecules encoding the gene of interest and comprising the modified nucleotide, which subsequent generation is provided by replicating the isolated rRNA molecules; and (d) identifying a sequence change within the rRNA molecules encoding the gene of interest present in the transfected cells expressing the gene of interest.
Regarding claims 1-2, 5, 20, 27, 30 and 35, Irvine discloses a method for in vitro evolution of the self-replicating RNA of the alpha virus comprising engineering and synthesizing a synthetic replicon construct, transfecting the synthesized replicon RNA into cells, culturing the transfected cells for a first predetermined length of time, sorting portions of the cultured transfected cells at selected time intervals based on the presence of the replicon RNA or the expression of a gene product encoded by the replicon RNA, separately culturing the sorted portions of the transfected cells for a second predetermined period of time, and optionally repeating the steps of sorting and culturing the transfected cells for subsequent predetermined length(s) of time and identification of the causative mutations (Irvine, claims 1, 2, 19; Fig. 1; page 2, last par.; page 3, par. 4; page 4, penultimate par.; Example 1).
Regarding claims 8-10 and 23, Irvine discloses the disclosure provides methods of comparing the persistence of mutations occurring in mutated synthetic RNA replicons to wild-type replicons. The methods include isolating replicon RNA from the injected animal model after a predetermined length of time, reverse-transcribing the extracted RNA to complementary deoxyribonucleic acid (cDNA), amplifying one or more regions, sequencing the cDNA library to determine the persistence of the mutated synthetic RNA replicons, and comparing the persistence of the mutated synthetic RNA replicons to the persistence of wild-type replicons assayed using the same animal model. In some embodiments, the one or more regions are regions E1-E7. In some embodiments, sequencing the cDNA library is done with at least 6-fold coverage (para. [0028]); and identifying mutations that increase transfected RNA replicon persistence and/or transfected RNA replicon expression strength in host cells comprising: extracting the total RNA from the sorted cultured transfected cells of claim 1 expressing the top 1-30%, optionally the top 20% of fluorescence; reverse-transcribing the extracted total RNA to complementary deoxyribonucleic acid (cDNA); amplifying one or more regions of the alphavirus cDNA, optionally regions E1-E7;
cloning the amplified regions into a vector to produce a cDNA library; and sequencing the cDNA library to identify the mutation(s), optionally with 6-fold coverage (claim 18 of Irvine); and testing a synthetic ribonucleic acid (RNA) replicon comprising: transfecting an RNA replicon comprising the identified mutation(s) of claim 18 into cells; tracking the expression of a gene product encoded by the mutated replicon RNA; and optionally repeating the steps of transfecting and tracking for each identified sequenced mutation in the replicon RNA, or any combination thereof (claim 19 of Irvine).
Therefore, the cited prior art anticipates the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 13, 22, 36, 54, 58, 60, 62, 65 and 68 are rejected under 35 U.S.C. 103(a) as being unpatentable over Irvine et al. “Irvine” (US PGPUB 2020/224174, IDS of record dated 04/17/2024) as applied to claim 1 above, in view of Geall et al. “Geall” (WO2011/005799, IDS of record dated 04/17/2024). The teachings of Irvine et al. are outlined above and incorporated herein.
Regarding claims 13, 62, Irvine does not disclose the modified nucleotide is a modified uridine.
Geall, however, discloses self-replicating RNA molecules that contain modified nucleotides, compositions that contain the self-replicating RNA molecules, and methods for using the self-replicating RNA molecules, for example, to raise an immune response (Abstract). Geall discloses “In one aspect the invention is a self-replicating RNA molecule comprising at least two nucleosides that each, independently, comprise at least one chemical modification. The modified nucleosides can be the same or different. For example the self-replicating RNA molecule can contain two or more pseudouracil nucleosides, or a first pseudouracil nucleoside and a second -methylcytosine nucleoside. The modified nucleosides in the self-replicating RNA molecules are components of modified nucleotides. In some embodiments, about 0.01% to about 25% of the nucleotides in the self-replicating RNA molecule are modified nucleotides. For example, about 0.01% to about 25% of the nucleotides that contain uracil, cytosine, adenine, or guanine in the self-replicating RNA molecule can be modified nucleotides” and “provides self-replicating RNA molecule that contains a pseudouridine at two or more positions” (para. [0008], [0009], [0012], [0020] and [0021], Examples 1 and 9; claims 1, 5, 10, 14-18 of Geall).
It would have been obvious to generate a method for identifying a sequence change in a replicable RNA (rRNA) comprising a modified nucleotide as discloses by Irvine, whereby the modified nucleotide is a pseudouridine as disclosed by Geall. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success given the knowledge that Geall demonstrates increased expression of proteins relative to non-modified uridine proteins (Tables 10 and 11, Results para. [00214] and [00215]) as well as vaccine immunogenicity (para. [00220]).
Regarding claim 22, Irvine does not explicitly state the rRNA comprises a 5’ regulatory region that has no start codons.
Geall, however, discloses an embodiment whereby “the self-replicating RNA molecules of the invention will cause a host cell to produce more gene product (e.g., antigen encoded by heterologous sequence), relative to the amount of gene product produced by the same cell type that contains the corresponding self- replicating RNA molecule that does not contain modified nucleotides. Methods of determining translation efficiency are well known in the art, and include, e.g. measuring the activity or amount of an encoded protein (e.g. luciferase and/or GFP), the method described in Phillips AM et al, Effective translation of the second cistron in two Drosophila dicistronic transcripts is determined by the absence of in- frame AUG codons in the first cistron” (para. [0082]).
It would have been obvious to one of ordinary skill in the art to generate a method for identifying a sequence change in a replicable RNA (rRNA) comprising a modified nucleotide as discloses by Irvine, whereby the rRNA comprises a 5’ regulatory region that has no start codons as taught by Geall. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success given the knowledge Geall teaches that the absence of in-frame AUG codons for the benefit of causing a host cell to produce more gene product.
Regarding claims 36, 54, 58, 60, 62, 65 and 68, the claims recite a process for producing the composition of claim 1.
According to the MPEP (2113), PRODUCT-BY-PROCESS CLAIMS ARE NOT LIMITED TO THE MANIPULATIONS OF THE RECITED STEPS, ONLY THE STRUCTURE IMPLIED BY THE STEPS
"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). Furthermore, "[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes." Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1370 n 14, 92 USPQ2d 1289, 1312, n 14 (Fed. Cir. 2009).
Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Barry Chestnut whose telephone number is (571)270-3546. The examiner can normally be reached on M-Th 8:00 to 4:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BARRY A CHESTNUT/Primary Examiner, Art Unit 1672
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