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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 145-154 in the reply filed on 10/1/2025 is acknowledged.
Claims 155-171 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/1/2025.
Drawings
The drawings are objected to because:
(1) In Figures 1D and 1E, no label is provided for the vertical bars such that it could be ascertained which IRES performed the best in this assay.
(2) In Figure 4A two bars are identified as the same IRES (Salivirus FHB). Correction and/or clarification is important because associated example 9 concludes that “CVB1 and Salivirus A SZ1 IRES constructs produced the most expression at 24h. Data can be found in FIGs. 4A and 4B.” However, although Figure 4B shows that CVB1 and Salivirus A SZ1 IRES produces the top two most expression in that set of comparison, Figure 4A shows Salivirus FHB and Aichi Virus IRES are the top two. Of note, CVB3 is included in both figures as a standard but this same IRES produces different expression levels in the two sets of comparisons (Fig. 4A and 4B) such it could not concluded by the combination of these data that CVB1 and Salivirus A SZ1 IRES constructs produced the most expression, as stated in the specification. Correction and/or clarification of these experiments is required.
(3) Figures 33-36 use a color scale to show the differences between samples. These figures cannot be evaluated in grayscale.
(3) In Figure 49B no legend is provided to indicate which circle represents which spacer and thus the results in the figure could not be evaluated to ascertain which spacer is about equivalent to the “no spacer” condition.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
Example 1B is directed to the use of spacers to improve circularization efficiency. It states that a series of spacers were designed and concludes that spacers designed to conserve secondary structure result in 87% splicing efficiency. However, not one spacer used in this example is mentioned herein such that it could not evaluated what is the structure of the spacers tested and the structure of the spacers that provide the claimed result.
Such key structural details for constructs in example 2A, 2B, 2C, 5-7 are also missing.
Example 2B is directed to comparing constructs with different components such as differing IRES. The example does not provide the details of these constructs. The example concludes that CVB3 IRES construct produced the most protein. The example does not refer to any of the figures provided. None of the figures support the conclusion that in comparison to other IRES, CVB3 IRES construct produced the most protein (Figures 1-5).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 145-154 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 145 recites sequences that encode for “antigen-like” or “adjuvant-like” polypeptides. Neither the claims nor the specification provides any guidance regarding these terms such that the structure of a sequence that encodes a polypeptide that is like an antigen or like a adjuvant could be determined. There is no guidance regarding what structural or functional features are required for a polypeptide to be considered ‘like’ an antigen or ‘like’ an adjuvant. Although claim 154(1-3) lists proteins and sequences for “adjuvant or adjuvant-like polypeptides”, each of these proteins and sequences are identifies as adjuvants in the specification (Table 10) and not ‘adjuvant-like’ polypeptide. Thus, claim 154(1-3) do not clarify the 112b issue with claim 145.
Claims 146-154 is/are rejected due their dependence on claim 145 because they do not clarify the 112b issue noted with claim 145.
Claims 146 recites circular RNA polynucleotide (hereinafter circRNA) with one “duplex forming region” in options (1) and (2) and, two in options (3). The specification defines “two "duplex forming regions," "homology arms," or "homology regions," complement, or are complementary, to one another when the two regions share a sufficient level of sequence identity to one another's reverse complement to act as substrates for a hybridization reaction” in [0173] (emphasis added). In the context of instant claim that requires only one duplex forming region in option (1) and (2), the structure of this ‘region’ is unclear. It appears that a duplex forming region could comprise any sequence of any length as long it is complementary to another sequence however for options (1) and (2) where there is only one duplex forming region, it is unclear what other structure these regions are complementary to. Thus, it maybe interpreted that any sequence of any length may be considered to fulfill the limitations of options (1) and (2). For option (3), it is unclear if the 5’ and 3’ duplex forming regions form duplex with each other such that it could be ascertained that these regions are structurally complementary. In case, these 5’ and 3’ regions are not required to be complementary to each other, then similar to interpretation of options (1) and (2), any sequence of any length may be considered to fulfill the limitations of options (3).
Claims 147, 148 is/are rejected due their dependence on claim 146 because they do not clarify the 112b issue noted with claim 146.
Claim Rejections - 35 USC § 112(a)
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 149 and 154 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.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claim 149 recites IRES with “a sequence of an IRES” from the listed viruses. The broadest reasonable interpretation of the phrase “a sequence of” embraces fragments of the IRESs from the listed viruses. The specification defines “an "internal ribosome entry site" or "IRES" refers to an RNA sequence or structural element ranging in size from 10 nt to 1000 nt or more, capable of initiating translation of a polypeptide in the absence of a typical RNA cap structure” (emphasis added; [0185]). Thus, the claims require the recited IRES to be functionally capable of initiating translation. The specification discloses IRES sequences from the listed viruses in Table 1 (SEQ ID NOs: 1-72). The specification does not disclose any fragment of these IRES sequences or a sequence that is less than 100% identical to these IRESs which could functions as a IRES. Considering the only length limitation to an IRES is 10nt, fragments of 10nt of SEQ ID NO: 1-72 vary substantially. There is no teaching in the specification in which a fragments of SEQ ID No. 1-72 retain the ability of the sequence to function as a IRES. Consequently, there is no information about which nucleotides can vary in any one of the SEQ ID NOs: 1-72 or could be removed such that the resultant fragment still retain the required activity.
Similar issues are present for claim 154, option (3) that recites “an amino acid sequence […] of SEQ ID NOs:337-348”. The broadest reasonable interpretation of the phrase “an amino acid sequence of” embraces fragments of the recited SEQ IDs. The specification teaches sequences that are 100% identical to SEQ ID NOs:337-348 in Table 10 as the sequences for adjuvant polypeptides. The specification does not disclose any fragment of SEQ ID NOs:337-348 or a sequence that is less than 100% identical to SEQ ID NOs:337-348 and still function as an adjuvant. Considering there is no length limitation to fragments recited in this claim, fragments of SEQ ID NOs:337-348 vary substantially. There is no teaching in the specification in which a fragments of SEQ ID NOs:337-348 retain the ability of the sequence to function as a adjuvant. Consequently, there is no information about which nucleotides can vary in any one of the SEQ ID NOs:337-348 or could be removed such that the resultant fragment still retain the required activity.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by “whatever characteristics sufficiently distinguish it).
Further, the breadth of the genus of fragments of IRESs from the listed viruses (SEQ ID NO: 1-72) and SEQ ID NOs:337-348 lack a written description.
According to the MPEP § 2163, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
In the instant case, the only factor present in the claims is a reference to structure. There is no identification of any particular portion of the structure that must be conserved. It is not clear what region of the sequence has the activity clearly associated with SEQ ID NOs: 1-72, 337-348 The specification does not provide a complete structure of those fragments of SEQ ID NOs: 1-72, 337-348 and fails to provide a representative number of species for the encompassed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the recited genus.
Therefore, the claimed invention, as a whole, is not adequately described. The claims require essential or critical elements which are not adequately described in the specification, and are not conventional in the art before the effective filing date.
Claim Interpretation
Claim 145 recites a circular RNA polynucleotide (hereinafter circRNA) comprising “a post-splicing 3’ group I intron fragment” and “a post-splicing 5’ group I intron fragment” (components a, d). The structure(s) embraced by these components are interpreted according to the analysis from the art and the specification.
The specification does not provide an explicit definition for the structure of “post-splicing” group I intron fragment. The claim is directed to a circRNA product and the components of a, d appear to recite a product-by-process limitation i.e. fragments of 3’ or 5’ group I introns produced after a “splicing” step. According to MPEP 2113, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps”. Herein, the specification provides guidance regarding the structure of the 3’ and 5’ group I intron fragments post-splicing in [0224]. Referencing Umekage et al (Ch. 4, Innovations in Biotech., IDS 8/30/2024), the specification states that “As described by Umekage et al. (2012), external portions of the 3' group I intron fragment and 5' group I intron fragment are removed in circularization, causing the circular RNA provided herein to comprise only the portion of the 3' group I intron fragment formed by the optional exon sequence of at least 1 nt in length and 5' group l intron fragment formed by the optional exon sequence of at least 1 nt in length, if such sequences were present on the non-circularized precursor RNA. The part of the 3' group I intron fragment that is retained by a circular RNA is referred to herein as the "post splicing 3' group I intron fragment". The part of the 5' group I intron fragment that is retained by a circular RNA is referred to herein as the "post splicing 5' group I intron fragment".” (emphasis added). See Figure 1 below from Umekage for illustration of natural and permuted group I introns that show that in permuted configuration (as claimed wherein introns flank the exons; right side of the figure), the circRNA comprises only portions of exons included in the linear precursor (blue, purple).
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Thus, based on the structure of the non-circularized precursor RNA used in the process of generating a circRNA product, the “post-splicing” fragments may comprise the optional exon sequence of at least 1nt; however if such an optional sequence is not included in the non-circularized precursor RNA, the “post-splicing” fragments may comprise zero nt. Thus, it is interpreted that the claimed “post-splicing” fragments comprise zero to any number of any nucleotides. Thus, when the “post-splicing” fragments comprise zero nucleotides, the structure of the circRNA of claim 145 is required to comprise (b) an IRES and (c) an expression sequence. Further, when the “post-splicing” fragments comprises 1 or more nucleotides of an optional exon, the structure of such “post-splicing” fragment could be provided by any nucleotide(s) in the circRNA of claim 145.
The circRNA of claim 146 that adds one or two “duplex forming regions” upstream of the IRES and/or downstream of the expressions sequence do not require any specific structure. As noted in the 112b rejection above, since these regions are not clearly duplexing with any other region in the circRNA, it appears that the structural limitation of claim 146 could be met by any sequence of any length either upstream of the IRES or downstream of the expressions sequence of circRNA of claim 145.
The circRNA of claim 147 adds “spacer” upstream and/or downstream of the “duplex forming region” of claim 146. Claim 148 limits the spacer to sequences of “about 10 to about 60 nucleotides” (see [0178] for definition for the term “about”). Thus, one embodiment of the circRNA of claim 147 and 148 is interpreted to comprise any 10 nucleotides (spacer) followed by any at least 1 nucleotide (duplex forming region) followed by IRES and expression sequence. Another embodiment could be IRES and expression sequence followed any at least 1 nucleotide (duplex forming region) followed by any 10 nucleotides (spacer).
Taken together, the only meaningful limitations to the structure of the claimed circRNA are the IRES and the expression sequence. Numerous prior art teaching such circRNA were available. Attempt is made to apply the closest recent prior art.
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.
Claim(s) 145-152, 154 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Goldberg et al (WO 2016/197121 A1; 8 December 2016).
Regarding claim 145, Goldberg discloses nucleic acid sequences that are circularized wherein the nucleic acid comprises a 5’ UTR comprising an IRES followed by an RNA sequence which in some embodiments encodes for polypeptides such as an antigen (= claimed (b)-IRES, (c)-expression sequence; [0007, 00014, 00015, 00018]). Per interpretation presented above, Goldberg’s circRNA comprises at least zero nucleotides as “post-splicing” fragments. However, since Goldberg’s circRNAs comprise 300-1000 nucleotides (See at least example 5), any nucleotides flanking the IRES and the expression sequence meet the limitations of options (a) and (b).
Regarding claim 146, Goldberg discloses their circRNA comprises 5’ and 3’ complement-reverse complement (CRC) sequences wherein the 5’ and 3’ are at least partially complementary such that they would form a duplex and are located upstream of the IRES sequence and downstream of the RNA sequence (=claimed duplex forming regions options 1-3; [0007, 00012, 00119]). Sequences for 5’ and 3’ CRC share 100% complementarity ([00012], [000118-119], Table 1, Example 6).
Regarding claim 147, Goldberg discloses their circRNA comprises 5 and 3’ random nucleotide sequences located upstream and downstream of the 5 and 3’ CRC (=claimed spacer options 1-3; [0009, 00010]).
Regarding claim 148, Goldberg discloses the random nucleotide sequences of 5-25 nucleotides in length [0009].
Regarding claim 149, Goldberg discloses IRES from an encephalomyocarditis virus (EMCV), Hepatitis C (HCV), Cricket paralysis virus (CrPV) and GB Virus, PPT19 IRES or any widely known IRES from ires.org [00015, 0082, 00159], Figure 19).
Regarding claims 150, Goldberg discloses circRNA wherein no nucleotide is modified (see unmodified in Figures 17, 18).
Regarding claims 151, Goldberg discloses circRNA with at least one modified nucleotide [0109-111, 0016].
Regarding claim 152, Goldberg discloses the following modified nucleotides “In embodiments, the nucleic acid may comprise a modified nucleotide, e.g., 5-propynyluridine, 5-propynylcytidine, 6-methyladenine, 6-methylguanine, N ,N ,dimethyladenine, 2-propyladenine, 2-propylguanine, 2-aminoadenine, 1-methylinosine, 3-methyluridine, 5-methylcytidine, 5-methyluridine, 5-(2-amino )propyl uridine, 5-halocytidine, 5-halouridine, 4-acetylcytidine, 1-methyladenosine, 2-methyladenosine, 3-methylcytidine, 6-methyluridine, 2-methylguanosine, 7-methylguanosine, 2,2-dimethylguanosine, 5-methylaminoethyluridine, 5-methyloxyuridine, 7-deaza-adenosine, 6-azouridine, 6-azocytidine, 6-azothymidine, 5-methyl-2-thiouridine, 2-thiouridine, 4-thiouridine, 2-thiocytidine, dihydrouridine, pseudouridine, queuosine, archaeosine, naphthyl substituted naphthyl groups, an 0- and N-alkylated purines and pyrimidines, N6-methyladenosine, 5-methylcarbonylmethyluridine, uridine 5-oxyacetic acid, pyridine-4-one, pyridine-2-one, aminophenol, 2,4,6-trimethoxy benzene, modified cytosines that act as G-clamp nucleotides, 8-substituted adenines and guanines, 5-substituted uracils and thymines, azapyrimidines, carboxyhydroxyalkyl nucleotides, carboxyalkylaminoalkyl nucleotides, or alkylcarbonylalkylated nucleotides” ([00016], Figure 17, 18).
Regarding claim 154, Goldberg discloses RNA sequences encode at least the following polypeptides: antigen, antibodies, cytokines, chemokines, chimeric proteins [00014].
Therefore, Goldberg anticipates the claimed invention.
Claim(s) 145, 146, 149-150 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wesselhoeft et al (Engineering circular RNA for potent and stable translation in eukaryotic cells. Nature Comm. July 2018, 9:2629; IDS 8/30/2024).
Regarding claim 145, Wesselhoeft discloses a circRNAs with the E2 3’ exon fragment of the group I intron (=post-splicing 3’ group I intron fragment), an IRES, an expression sequence encoding proteins (=an antigen since antibodies against these proteins could be produced, used in Figure 3) and E1 5’ exon fragment of the group I intron (=a post-splicing 5’ group I intron fragment ) (Figure 1, 3). Gaussia luciferase, human Epo, EGFP, firefly luciferase and Cas9 enzyme were encoded by the circRNA (Figure 3).
Regarding claim 146, Wesselhoeft discloses circRNA further comprising 5’ and 3’ internal homology arm that form duplex with each other (Figure 3A)
Regarding claim 149, Wesselhoeft discloses several IRES: CVB3, EV71, EMCV, PV, CSFV, HRV2, ABPV, HAV, HTLV, HCV, GTX, Rbm3, FMD, HHV5, PPV, CPRV, HPV31,IAPV, NRF (Figure 4, Supplementary figure 4)
Regarding claim 150, Wesselhoeft discloses circRNA with unmodified i.e. naturally occurring nucleotides.
Therefore, Wesselhoeft anticipates the claimed invention.
Claim Rejections - 35 USC § 102/103
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.
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) 153 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Goldberg.
The teachings of Goldberg as applied to claims 145-152 are applicable to the instant rejection.
Regarding claim 153, Goldberg discloses circRNA with 25-100% of uridines substituted with pseudouridine or 25-75% of cytidines substituted with 5methyl-cytidine or combinations of the two ([00174-177], Figure 18). Goldberg teaches the utility of retaining unmodified nucleotides in their circRNA by showing that circRNA with 100% modified uridines or 75% modified cytidines do not perform better than circRNA with 50% or less modified uridines or cytidines (Figure 18).
Goldberg does not explicitly state the % of nucleotides in their circRNA that are modified or % of nucleotides in their circRNA that are uridine or cytidine.
Thus, Goldberg is silent as to the % of nucleotides in their circRNA that are naturally occurring/unmodified. The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not the circRNA of Goldberg that comprises 25-75% modified cytidines or 25-100% modified uridines is patentable distinct, and if so to what extent, from applicant’s circRNA that comprises at least about 80% unmodified nucleotides.
The prior art of Goldberg discloses circRNA that comprise modified nucleotides which is patentably similar to applicant’s circRNA with atmost about 20% modified nucleotides (= at least about 80% unmodified) for these reasons: Goldberg discloses that in their circRNA anywhere from 25-100% of one type of nucleotides could be modified. Even in the unlikely circumstance that the entire circRNA of Goldberg is made up of one type of nucleotide; in teaching a range of 25-100% modified nucleotides, Goldberg still discloses a circRNA that is at most 25% modified (= at most about 20%). However, since it is improbable that the entire circRNA of Goldberg is made up of one type of nucleotide, it is likely that Goldberg’s circRNA comprises at most about 20% modified nucleotides. Thus, Goldberg circRNA is likely to be at least about 80% unmodified. Where an examiner cannot determine whether or not the reference inherently possesses properties which anticipate, or render obvious, the claimed invention a rejection under §§102/103 is appropriate. See MPEP §§ 2112-2112.02.
The cited art taken as a whole demonstrates a reasonable probability that the modified circRNA of Goldberg is either identical or sufficiently similar to the claimed modified circRNA that whatever differences exist, they are not patentably significant. Therefore, the burden of establishing novelty or non-obviousness by objective evidence is shifted to applicants. See MPEP § 2112(v). Clear evidence that Goldberg’s circRNA does not and could not comprises at least about 80% unmodified nucleotides would advance prosecution and might permit allowance of claims to applicant’s circRNA of claim 153. Furthermore, clear evidence that Goldberg’s circRNA does not possess a critical characteristic that is possessed by the claimed circRNA would advance prosecution and might permit allowance of claims to applicant’s circRNA of claim 153. Applicant is requested to specifically point out the support for any amendments made to the disclosure and arguments in response to this Office Action, including the claims. See MPEP §§ 714.02 and 2163.06. Applicant is also requested to refer to pages and line numbers in the as-filed specification. It is noted that other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Therefore, Goldberg anticipates and/or renders obvious the claimed invention.
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.
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) 147, 148, 151-154 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wesselhoeft as applied to claims 145, 146 above, and further in view of Goldberg.
The teachings of Wesselhoeft as applied to claims 145, 146, 149 and 150 are pertinent to the instant rejection.
The teachings of Goldberg as applied to claims 145-154 are pertinent to the instant rejection.
Regarding claim 147 and 148, Wesselhoeft teaches a spacer between the 5’ internal homology arm and the IRES and a spacer between the coding region and the 3’ internal homology arm. Wesselhoeft does not teach a spacer upstream of the 5’ internal homology arm and downstream of the 3’ internal homology arm, as claimed.
Regarding claims 151-153, Wesselhoeft does not teach a circRNA with modified nucleotides such a circRNA with at least about 80% unmodified nucleotides is produced.
Regarding claim 154, Wesselhoeft teaches circRNA capable of encoding a range of proteins (Gaussia luciferase, human Epo, EGFP, firefly luciferase and Cas9 enzyme were encoded by the circRNA in Figure 3). Wesselhoeft does not teach circRNA encoding the recited adjuvants.
Goldberg rectifies these deficiencies.
Regarding claim 147 and 148, Goldberg teaches the inclusion of the random nucleotide sequence (=spacer) upstream of their 5’ CRC (=5’ internal homology arm of Wesselhoeft and claimed duplex forming region) and downstream of their 3’CRC, wherein the random nucleotide sequence is 5-25 nucleotides in length (as required by claim 148; [0009, 00010]).
Regarding claims 151-153, Goldberg teaches circRNA with modified nucleotides wherein the modified nucleotides are the following: “In embodiments, the nucleic acid may comprise a modified nucleotide, e.g., 5-propynyluridine, 5-propynylcytidine, 6-methyladenine, 6-methylguanine, N ,N ,dimethyladenine, 2-propyladenine, 2-propylguanine, 2-aminoadenine, 1-methylinosine, 3-methyluridine, 5-methylcytidine, 5-methyluridine, 5-(2-amino )propyl uridine, 5-halocytidine, 5-halouridine, 4-acetylcytidine, 1-methyladenosine, 2-methyladenosine, 3-methylcytidine, 6-methyluridine, 2-methylguanosine, 7-methylguanosine, 2,2-dimethylguanosine, 5-methylaminoethyluridine, 5-methyloxyuridine, 7-deaza-adenosine, 6-azouridine, 6-azocytidine, 6-azothymidine, 5-methyl-2-thiouridine, 2-thiouridine, 4-thiouridine, 2-thiocytidine, dihydrouridine, pseudouridine, queuosine, archaeosine, naphthyl substituted naphthyl groups, an 0- and N-alkylated purines and pyrimidines, N6-methyladenosine, 5-methylcarbonylmethyluridine, uridine 5-oxyacetic acid, pyridine-4-one, pyridine-2-one, aminophenol, 2,4,6-trimethoxy benzene, modified cytosines that act as G-clamp nucleotides, 8-substituted adenines and guanines, 5-substituted uracils and thymines, azapyrimidines, carboxyhydroxyalkyl nucleotides, carboxyalkylaminoalkyl nucleotides, or alkylcarbonylalkylated nucleotides” ([00016], Figure 17, 18; [0109-111, 0016]. Goldberg teaches circRNA with 25-100% of uridines substituted with pseudouridine or 25-75% of cytidines substituted with 5methyl-cytidine or combinations of the two ([00174-177], Figure 18).
Goldberg teaches the utility of retaining unmodified nucleotides in their circRNA by showing that circRNA with 100% modified uridines or 75% modified cytidines do not perform better than circRNA with 50% or less modified uridines or cytidines (Figure 18).
Regarding claim 154, Goldberg teaches RNA sequences encode at least the following polypeptides: antigen, antibodies, cytokines, chemokines, chimeric proteins [00014].
The combination of prior art cited above under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S., 82 USPQ2d 1385 (2007): Exemplary rationales that may support a conclusion of obviousness are in MPEP 2143.
In the present situation, rationale A is applicable. MPEP 2143 guides that for rationale A Combining prior art elements according to known methods to yield predictable results “Office personnel must articulate the following: (1) a finding that the prior art included each element claimed, although not necessarily in a single prior art reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference; (2) a finding that one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately; (3) a finding that one of ordinary skill in the art would have recognized that the results of the combination were predictable; and (4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness”.
(1) The prior arts of Wesselhoeft and Goldberg teach each of the claimed elements. Wesselhoeft teaches the base circRNA of claims 145 and 146 while Goldberg provides the additional elements of spacers upstream and downstream of duplex forming regions (claims 147, 148), modified nucleotides (claims 151-153) and specific encoded polypeptides (claims 154).
(2) An ordinary artisan would combine the elements of Wesselhoeft and Goldberg using standard cloning methods or by synthetically deriving the entire polynucleotide. Both Wesselhoeft and Goldberg teach methods for making RNA constructs. For example Wesselhoeft uses a combination of cloning methods and also artificially synthesizing entire sequence of interest such as the IRES sequence, homology sequences etc. (Cloning and mutagenesis). Similar methods are used by Goldberg (Example 1, 2).
An ordinary artisan recognizes the function of these elements in a nucleic acid construct and expects these elements to perform the known functions when included in a construct. An ordinary artisan recognized the function of spacer sequences in constructs is to introduce gap between structures to reduce stearic hinderances and improve function. To this end, Wesselhoeft uses spacers to reduce interaction between regions of RNA with critical secondary structures thus improving circularization (page 2, col. 2, para 2) and Goldberg also shows that inclusion of the spacer improves circularization (Figure 11). Similarly, an ordinary artisan recognizes the function of modified nucleotides. Wesselhoeft teaches modified nucleotides improved translation of linear RNA (Figure 6) and that “To further suppress an immune response directed against circRNA, methods such as nucleoside modification could potentially be incorporated into circRNA design” (page 8, col. 1, para1). While Goldberg, shows that inclusion of some modified nucleotides in circRNA also improves translation efficiency (Figure 17, 18). Finally, an ordinary artisan recognizes the function of various expression sequences in constructs. Substitution of Wesselhoeft’s expression sequences with Goldberg’s expression sequences in Wesselhoeft’s construct would result in a circRNA that expresses the claimed sequences of claim 154.
(3) Considering Goldberg produces circRNA with spacers, modified nucleotides and expression sequences of claim 154, an ordinary artisan would predict that inclusion of these elements taught by Goldberg in a circRNA of Wesselhoeft would result in circRNA comprising each of the claimed elements i.e. post-splicing fragments, duplex forming regions, spacers, IRES and expressions sequences with some modified nucleotides.
The cited prior art meets the criteria set forth in both Graham and KSR. Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Wesselhoeft and Goldberg to yield a predictable result of a circRNA comprising each of the claimed elements i.e. post-splicing fragments, duplex forming regions, spacers, IRES and expressions sequences with some modified nucleotides.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 145, 149, 150, 154 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 9-11 of U.S. Patent No. US 11352641 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1 and 8 of `641 is a method that produces and thus teaches the product of instant claims 145 and 154. Each of claims 1 and 8 render obvious a circRNA with the structure claimed in claims 145 and 154 because the circRNA of these claims is produced from a vector comprising a 3′ Group I self-splicing intron fragment containing a 3′ splice site dinucleotide, an internal ribosome entry site (IRES), a protein coding region encoding a chimeric antigen receptor (CAR), a 5′ Group I self-splicing intron fragment containing a 5′ splice site dinucleotide which inherently results in a circRNA with the instantly claimed structure. Claim 9-11 of `641 further recites IRES sequences that are the same as IRES sequences of instant claim 149. Further, claims in `641 do not recite any modified nucleotides, thus they implicitly teach circRNA with unmodified nucleotides of claim 150.
Claims 145, 149, 150, 154 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 16-18 of U.S. Patent No. US 11352640 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1 and 8 of `640 is a method that discloses the product of instant claims 145 and 154 since each recite a circRNA produced from a vector comprising a 3′ Group I self-splicing intron fragment containing a 3′ splice site dinucleotide, an internal ribosome entry site (IRES), a protein coding region encoding a chimeric antigen receptor (CAR), a 5′ Group I self-splicing intron fragment containing a 5′ splice site dinucleotide which inherently results in and thus teaches a circRNA with the structure claimed in claims 145 and 154. Claim 16-18 of `640 further recites IRES sequences that are the same as IRES sequences of instant claim 149. Further, claims in `640 do not recite any modified nucleotides, thus they implicitly teach circRNA with unmodified nucleotides of claim 150.
Claims 145, 149, 150-152, 154 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-7, 8-10, 29 of U.S. Patent No. US 11447796 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1,3 and 29 of `796 are methods that makes and thus discloses the product of instant claims 145 and 154 since the circRNA is produced from a vector comprising a 3′ Group I self-splicing intron fragment containing a 3′ splice site dinucleotide, an internal ribosome entry site (IRES), a protein coding region, a 5′ Group I self-splicing intron fragment containing a 5′ splice site dinucleotide, wherein the protein coding region encodes a CAR, which inherently result in a circRNA with the structure claimed in claims 145 and 154. Claim 6-7 of `796 further recites vector comprising modified nucleotides thus disclosing a circRNA product produced that has modified nucleotides, such as of instant claims 151, 152. Claim 8-10 of `796 further recites IRES sequences that are the same as IRES sequences of instant claim 149. Further, aside from claims 6-7, remainder of the claims in `796 do not recite any modified nucleotides, thus they implicitly teach circRNA with unmodified nucleotides of claim 150.
Claims 145, 149, 150, 154 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, of U.S. Patent No. US 11981909 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1, 5, 7, 10 of `909 are vectors that make and thus discloses the product of instant claims 145 and 154 since the circRNA is produced from a vector comprising a 3′ Group I self-splicing intron fragment containing a 3′ splice site dinucleotide, an internal ribosome entry site (IRES), a protein coding region, a 5′ Group I self-splicing intron fragment containing a 5′ splice site dinucleotide, wherein the protein coding region encodes human proteins or a CAR, which inherently result in a circRNA with the structure claimed in claims 145 and 154. Claim 4 of `909 further recites IRES sequences that are the same as IRES sequences of instant claim 149. Further, claims in `909 do not recite any modified nucleotides, thus they implicitly teach circRNA with unmodified nucleotides of claim 150.
Claims 145, 149, 150, 154 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 14, 15, 16 of U.S. Patent No. US 11603396 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1, 14 of `396 are pharmaceutical composition comprising circRNA comprising a 3′ group I intron fragment, an Internal Ribosome Entry Site (IRES), an expression sequence encoding a chimeric antigen receptor (CAR), and a 5′ group I intron fragment. This is identical to circRNA with the structure claimed in claims 145 and 154. Claim 2, 3, 15, 16 of `396 further recites IRES sequences that are the same as IRES sequences of instant claim 149. Further, claims in `396 do not recite any modified nucleotides, thus they implicitly teach circRNA with unmodified nucleotides of claim 150.
Claim 145, 149, 150, 154 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3, 4, 18, 19, 20, 23, 24, 25 of copending Application No. 18/069,621 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1, 18, 19, 23, 24, 25 of `621 are pharmaceutical compositions comprising circRNA comprising a 3′ group I intron fragment, an Internal Ribosome Entry Site (IRES), an expression sequence encoding a chimeric antigen receptor (CAR), and a 5′ group I intron fragment. T