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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 2, 2026 has been considered by the examiner.
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 1, 9, 11, 16, 35, 45, and 47 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. This is a written description rejection.
Claim 1 requires “a stagger element” as an alternative to the presence of a second IRES and 35 requires “a stagger element”. Paragraphs [0014, 0016, and 0106] of the instant published disclosure defines a stagger element as a 2A self-cleaving peptide. Paragraph [0403] states:
[0403] As used herein, the term “stagger element” is a moiety, such as a nucleotide sequence, that induces ribosomal pausing during translation. In some embodiments, the stagger element is a non-conserved sequence of amino-acids with a strong alpha-helical propensity followed by the consensus sequence -D(V/I)ExNPG P, where x=any amino acid. In some embodiments, the stagger element may include a chemical moiety, such as glycerol, a non-nucleic acid linking moiety, a chemical modification, a modified nucleic acid, or any combination thereof.
However, other than a 2A self-cleaving peptide, the skilled artisan would not recognize any nucleotide sequence, chemical moiety, non-nucleic acid linking moiety, chemical modification, modified nucleic acid, or any combination thereof, that induces ribosomal pausing, i.e., staggering during translation, as required. Poulis et al. (Biological Chemistry. 2023 Jul 26; 404 (8-9): 755-67) review the state of the art of biological signals and environmental cues resulting in trans-frame editing from the same RNA.
The applicable standard for the written description requirement can be found in MPEP 2163; University of California V. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. V. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. V. Mahurkar, 19 USPQ2d 1111; and University of Rochester V. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the specification is a 2A self-cleaving peptide. A definition by function alone is not sufficient because it is only an indication of what a thing does, rather than what it is. Eli Lily, 119 F.3 at 1568, 43 USPQ2d at 1406.
Vas-Cath Inc. V. Mahurkar, 19USPQ2d 1111, clearly states "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116). Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers V. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
There is no disclosure of sufficient characteristics of the nucleic acids claimed to allow persons of ordinary skill in the art to recognize that applicants were in possession of the exponential quantity of any nucleotide sequence, chemical moiety, non-nucleic acid linking moiety, chemical modification, modified nucleic acid, or any combination thereof, that induces ribosomal pausing, i.e., staggering. The specification does not provide adequate written description of the nucleic acid morbillivirus sequences attributed as porcine. The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. The claims do not meet the written description provision of 35 U.S.C. 112, first paragraph.
Claim Rejections - 35 USC § 103
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.
Claims 1, 9, 13, 16, 35, 45, 47, 51, 59, 60, and 62-69 are rejected under 35 U.S.C. 103 as being unpatentable over Sarnow et al. (WO 97/07825, of record), Yusibov et al. (USPgPub 2007/0275014, of record), and Douin et al. (BMC Biotechnology. 2004 Jul 27; 4 (1):16).
In reply to the rejection of record, applicant argues that Sarnow fails to teach or suggest the claimed circular polyribonucleotide including an IRES element 5' to a polypeptide immunogen sequence followed by a second IRES before a polypeptide adjuvant sequence in the same circular polyribonucleotide. Sarnow fails to provide any motivation to modify the circular polyribonucleotide constructs described to arrive at the claimed invention.
Applicant’s arguments and a review of Sarnow et al. have been fully considered, but are found unpersuasive. On page 15, lines 10-12, Sarnow et al. teach:
In one embodiment, each RNA sequence encoding a polypeptide in an RNA circle is "operatively linked" to a ribosome binding site, preferably an IRES element. The resulting polypeptide chain translated from an RNA circle having this organization comprises copies of polypeptides, each copy separated from the next by amino acid sequence encoded by the ribosome binding site.
Therefore, the circular RNA constructs of Sarnow et al. encode different polypeptides, each copy separated from the next by amino acid sequence encoded by the ribosome binding site.
On page 14, line 3 to page 15, line 4, Sarnow et al. teach the following excerpts (relevant portions underlined for convenience):
…a circular RNA comprises one or more RNA sequences, each of which encode a polypeptide…. Particularly preferred polypeptides include, but are not limited to, at least a portion of a viral envelope protein,… an antigen, … a cytokine…
“According to the present invention, the organization of RNA sequences encoding polypeptides in an RNA circle of the present invention can vary. For example, a circular RNA can contain a single RNA sequence encoding a polypeptide, repeating copies of an RNA sequence encoding the same polypeptide, multiple copies of RNA sequences encoding different polypeptides, or combinations thereof.”
According to Sarnow et al., the first sequence could encode a viral envelope protein and the second could encode a cytokine protein, i.e., an adjuvant. Alternatively, the first sequence could encode a cytokine protein adjuvant the second sequence could encode a viral envelope protein. Each expression product is preceded by an IRES according to specific circular RNA organization discussed on page 15, lines 10-12. Regarding the requirement of 5’ to 3’ expression. Selection of any order of mixing ingredients, i.e. IRES-antigen or IRES-adjuvant, is prima facie obvious, see In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930), especially in view of the circular loop RNA from which the elements are expressed.
Therefore, the teachings of Sarnow et al. teach or at least explicitly suggest a circular RNA comprising, from 5’ to 3’: an IRES, a sequence encoding a polypeptide viral envelope protein antigen, an IRES, and a cytokine protein adjuvant, as required by instant claims 1, 9, 13, 16, and 62. Claim 9 and page 33, line 1 to page 34, line 13 of Sarnow et al. are drawn to a method of inducing an effective immune response in a subject against the infectious virus by administering an effective amount, i.e., plurality, of circular RNAs encoding therapeutic polypeptides, as required by instant claim 60. Claim 5 and page 4, lines 7-14 and page 29, lines 8-13, anticipate a pharmaceutical composition comprising the circular RNA, as required by instant claim 59.
Applicant argues that Sarnow teaches the use of proteases to release individual polypeptides (see, e.g., Sarnow page 15, lines 5-9). Absent hindsight, the skilled person would not have considered combining multiple IRESs and encoding a polypeptide immunogen and polypeptide adjuvant or an immunogenic composition encoding the same. Sarnow does not provide one of skill with a reasonable expectation that an adjuvant protein encoded by a circular polyribonucleotide can be expressed in a cell to subsequently increase the immune response elicited by a polypeptide immunogen encoded also by a circular polyribonucleotide.
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 the instant case, Sarnow et al. teach or at least explicitly suggest a circular RNA comprising, from 5’ to 3’: an IRES, a sequence encoding a polypeptide viral envelope protein antigen, an IRES, and a cytokine protein adjuvant in at least page 14, line 3 to page 15, line 12.
Claim 9 and page 33, line 1 to page 34, line 13 of Sarnow et al. are drawn to a method of inducing an effective immune response in a subject against the infectious virus by administering an effective amount, i.e., plurality, of circular RNAs encoding therapeutic polypeptides. Claims 4 and 8 of Sarnow et al. are drawn to cells expressing a polypeptide in a cell transformed with circular RNA expressing the polypeptide from an IRES.
However, Sarnow et al. do not demonstrate a reasonable expectation that an adjuvant protein encoded by a circular polyribonucleotide can be expressed in a cell to subsequently increase the immune response elicited by a polypeptide immunogen encoded also by a circular polyribonucleotide. Sarnow et al. also do not mention expressing two polypeptide immunogens of the same target having at least 90% amino acid sequence identity, as recited in instant claim 35, 45, 47, 51, and 63-69.
Yusibov et al. claim a vaccine comprising at least two antigens comprising at least one domain selected from HA, NA, and M2, see claim 32. Also see paragraph [0173]. In paragraph [0032], Yusibov et al. teach the influenza antigens have at least 95%, 96%, 97%, or 98% identity to a domain of HA and/or NA and/or M2, which would share at least one or more epitopes of the target, as required by instant claim 54. Claim 51 of Yusibov et al. is drawn to inducing a protective immune response against influenza in a subject by administering a composition comprising at least one HA, NA, and M2, as required by instant claim 60.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have expressed at least two polypeptide immunogens having at least 95%, 96%, 97%, or 98% amino acid sequence identity to the same target, as taught by Yusibov et al., in the circular RNAs of Sarnow et al., to induce a therapeutic and/or prophylactic immune response against one or more influenza subtypes or strains, see paragraphs [0032, 0145, 0147, 0148, and 0173] and claim 51 of Yusibov et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have expressed at least two polypeptide immunogens having at least 95% amino acid sequence identity, as taught by Yusibov et al., in the circular RNAs of Sarnow et al. since Yusibov et al. teach the relevant immunogenic domains of each antigen comprises approximately 570 residues or less (derived from SEQ ID NOs recited in claim 33 of Yusibov et al.) and Sarnow et al. teach expressing a long protein larger than 106 kD in size in Figure 4, described on page 43, lines 11-28. An estimated number of amino acid residues in a 106 kD protein is approximately 964 residues (106,000 Da divided by the average molecular weight of an amino acid residue, 110 Da).
One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success for increasing an immune response elicited by polypeptide immunogens of Yusibov et al. and the polypeptide adjuvant of Sarnow et al., where both polypeptide immunogens and the polypeptide adjuvant are preceded by IRES because Douin et al. express three polyproteins, each from an IRES in a tricistronic vector, see the abstract, the paragraph bridging the columns on page 2, and Figure 2, generated high translation of all three translation gene products, see “Human cells”, bridging pages 6-7.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have expressed three IRES, each encoding different polypeptides as taught by Douin et al., including those of Yusibov et al., in the circular RNA of Sarnow et al. because Sarnow et al. teach circular RNA continuously translates polypeptides, is not as susceptible to exonuclease activity, and is more stable during storage and use than linear RNA on page 3, lines 10-18 and page 7, lines 5-19. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have expressed at least two polypeptide immunogens, each from different IRES, as taught by Douin et al. in the circular RNAs of Sarnow et al. because Sarnow et al. teach expressing a long protein larger than 106 kD in size in Figure 4, described on page 43, lines 11-28.
Claims 11 and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Sarnow et al., Yusibov et al., and Douin et al. as applied to claims 1, 9, 13, 16, 35, 45, 47, 51, 59, 60, and 62-69 above, and further in view of Wesselhoeft et al. (Nature communications. 2018 Jul 6; 9 (1): 2629) and Coit et al. (USPgPub 2010/0291129). Both references of record.
See the teachings of Sarnow et al., Yusibov et al., and Douin et al. above. Sarnow et al. teach the maximized production of a desired protein is within the preview of the ordinary artisan on page 22, line 22 to page 23, line 3 and page 25, lines 6-12. However, none of the references suggest the sequence encoding the polypeptide immunogen is at least two-fold greater than the sequence encoding the adjuvant, as required.
In “Exogenous circRNA is efficiently translated”, Wesselhoeft et al. describe various IRES, polyA, and/or spacer elements that enhance or suppress protein expression from circular RNA constructs.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have incorporated the various IRES, polyA, and/or spacer elements of Wesselhoeft et al. in the circular RNA of Sarnow et al. to enhance expression of the immunogenic polypeptide by any number of fold higher than expression of the adjuvant polypeptide to present a larger quantity of antigen to antigen-presenting cells. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success for enhancing expression of the immunogenic polypeptide by any number of fold higher than expression of the adjuvant polypeptide using the various IRES, polyA, and/or spacer elements of Wesselhoeft et al. because Coit et al. formulate an immunogenic composition comprising a recombinant polynucleotide encoding at least two antigens from Norovirus or Sapovirus with a single sequence encoding an adjuvant, see claim 1, demonstrating conventionality of at least two-fold polypeptide immunogen expression compared to adjuvant expression.
Applicant points to Examples 52-55 of the instant published disclosure, demonstrating circular translation of IL12 in mammalian cells and increased IFN-γ and cellular responses when the claimed construct is administered. Applicant asserts that the instant subject matter is surprising and could not have been predicted.
Applicant’s arguments, working examples, and corresponding Figures 39-42 have been fully reviewed, but are found unpersuasive to demonstrate an unexpected result. It would have been within the purview of the ordinary artisan to have enhanced expression of the immunogenic polypeptide and an adjuvant polypeptide from cells comprising a recombinant circular RNA expressing each of the polypeptides from separate IRES elements because claim 9 and page 33, line 1 to page 34, line 13 of Sarnow et al. are drawn to a method of inducing an effective immune response in a subject against the infectious virus by administering an effective amount, i.e., plurality, of circular RNAs encoding therapeutic polypeptides. Examples 3 and 4 and claims 4 and 8 of Sarnow et al. are drawn to cells expressing a polypeptide in a cell transformed with circular RNA expressing the polypeptide from an IRES. Sarnow et al. teach circular RNA continuously translates polypeptides, i.e., resulting in repeated translation every time a eukaryotic ribosome travels around the RNA circumference, producing any quantity of desired amounts of polypeptide, see the paragraph under “Summary of Invention”. Douin et al. express three polyproteins, each from an IRES in a tricistronic vector, see the abstract, the paragraph bridging the columns on page 2, and Figure 2, generated high translation of all three translation gene products, see “Human cells”, bridging pages 6-7. In “Exogenous circRNA is efficiently translated”, Wesselhoeft et al. describe various IRES, polyA, and/or spacer elements that enhance or suppress protein expression from circular RNA constructs. Coit et al. formulate an immunogenic composition comprising a recombinant polynucleotide encoding at least two antigens from Norovirus or Sapovirus with a single sequence encoding an adjuvant, see claim 1, demonstrating conventionality of at least two-fold polypeptide immunogen expression compared to adjuvant expression. Therefore, repeated translation from circular RNA comprising IRES prior to each of three polypeptides, were appreciated in the art prior to the instant effective filing date. A reasonable expectation of success would have been achieved by the ordinary artisan to vary or amplify polypeptide expression levels with the combined materials.
Conclusion
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 SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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/Shanon A. Foley/ Primary Examiner, Art Unit 1671