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 .
Withdrawn Rejections
The rejection of claims 134-137, on the basis that it contains an improper Markush grouping of alternatives, is withdrawn. The amendments cancel these claims, rendering their rejection moot.
The rejection of claim(s) 134-137 is/are rejected under 35 U.S.C. 103 as being unpatentable over Livia (WO 2020/023595 effectively filed 7/24/2018; or record in IDS) as applied to claims 127-130, 132-138, 140-146, and 157-159 above, and further in view of Sadelain (WO2017/180989 pub date: 10/19/2017), is withdrawn. Claims 134-137 have been canceled rendering their rejection moot.
The rejection of claim(s) 134-137, under 35 U.S.C. 103 as being unpatentable over Livia (WO 2020/023595 effectively filed 7/24/2018; or record in IDS) as applied to claims 127-130, 132-138, 140-146, and 157-159 above, and further in view of Cheng (EP 3 041 490 B1), is withdrawn. Claims 134-137 have been canceled rendering their rejection moot.
Specification
The lengthy specification has still not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The following new rejections are necessitated by the amendments to the claims:
Claim Rejections - 35 USC § 112/ New Matter
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 127-130, 138-146 and 157-164 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.
When determining if a new recitation added by amendment to the claims has adequate written description, the claims are analyzed first for their broadest reasonable interpretation and second the specification and claims, as originally filed, are examiners for the presence of one of explicit or implicit support.
Independent claims 127 and 154 newly recite, “wherein the first expression sequence encodes a CD19 or BCMA antigen binding molecules and/or the second expression sequence encodes a CD19 or BCMA antigen binding molecule”. Issues of indefiniteness have been described above and the interpretation discussed above also applies here.
A search of the specification and claims as originally filed fails to provide a literal disclosure of the newly added recitation. As such, the specification and claims fails to provide explicit written description for the newly added recitation.
A review of the specification provide the following relevant descriptions (citations from the pregrant publication):
[0135] FIG. 44 depicts the cytotoxicity of two CARs (anti-human CD19 CAR and anti-human BCMA CAR) expressed from a single circular RNA in T cells.
[0245] An “antigen binding molecule,” “antigen binding portion,” or “antibody fragment” refers to any molecule that comprises the antigen binding parts (e.g., CDRs) of the antibody from which the molecule is derived. An antigen binding molecule may include the antigenic complementarity determining regions (CDRs). Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′).sub.2, Fv fragments, dAb, linear antibodies, scFv antibodies, and multispecific antibodies formed from antigen binding molecules. Peptibodies (i.e. Fc fusion molecules comprising peptide binding domains) are another example of suitable antigen binding molecules. In some embodiments, the antigen binding molecule binds to an antigen on a tumor cell. In some embodiments, the antigen binding molecule binds to an antigen on a cell involved in a hyperproliferative disease or to a viral or bacterial antigen. In some embodiments, the antigen binding molecule binds to BCMA. In further embodiments, the antigen binding molecule is an antibody fragment, including one or more of the complementarity determining regions (CDRs) thereof, that specifically binds to the antigen. In further embodiments, the antigen binding molecule is a single chain variable fragment (scFv). In some embodiments, the antigen binding molecule comprises or consists of avimers.
[0331] In some embodiments, the CAR comprises an antigen binding domain specific for an antigen selected from the group CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA).
Example 22 Specific Lysis of Raji Cells by T Cells Expressing an Anti-CD19 CAR or an Anti-BCMA CAR
[1340] Constructs including Anabaena intron/exon regions, anti-CD19 or anti-BCMA CAR expression sequence, and a CVB3 IRES were circularized and reaction products were purified by size exclusion HPLC. 150,000 primary human CD3+ T cells were electroporated with 500 ng of circRNA, then were co-cultured with Raji cells at an E:T ratio of 2:1. % Specific lysis was measured 12 hours after electroporation (FIG. 24).
Example 45 Functional Expression of Two CARs from a Single Circular RNA
[1440] Circular RNA encoding chimeric antigen receptors were electroporated into human peripheral T cells to evaluate surface expression and CAR-mediated cytotoxicity. The purpose of this study is to evaluate if circular RNA encoding for two CARs can be stochastically expressed with a 2A (P2A) or an IRES sequence. For electroporation, CD3+ T cells were commercially purchased (Cellero) and stimulated with anti-CD3/anti-CD28 (Stemcell Technologies) and expanded over 5 days at 37° C. in complete RPMI containing 10% FBS, IL-2 (10 ng/mL), and 50 uM BME. Four days post stimulation, T cells were electroporated with circular RNA encoding anti-human CD19 CAR, anti-human CD19 CAR-2A-anti-human BCMA CAR, and anti-human CD19 CAR-IRES-anti-human BCMA CAR using ThermoFisher's Neon Transfection System then rested overnight. For the cytotoxicity assay, electroporated T cells were co-cultured with Fluc+K562 cells expressing human CD19 or BCMA antigens at 1:1 ratio in complete RPMI containing 10% FBS, IL-2 (10 ng/mL), and 50 uM BME and incubated overnight at 37° C. Cytotoxicity was measured using a luciferase assay system 24 hours post-co-culture (Promega BrightGlo Luciferase System) to detect lysis of Fluc+ target cells.
[1441] Representative data are presented in FIG. 44, showing that two CARs can be functionally expressed from the same circular RNA construct and exert cytotoxic effector function.
So while the claims as amended broadly recite, “wherein the first expression sequence encodes a CD19 or BCMA antigen binding molecules and/or the second expression sequence encodes a CD19 or BCMA antigen binding molecule”, the disclosure and claims solely describe anti-CD19 CAR and anti-BMCA coding sequence used together as the first and second expression sequences. As such, the disclosure and claims as originally filed are much narrower in scope than that of the newly added recitations. As such, the specification and claims originally filed fails to provide adequate written description for the breadth of the newly added recitations as well.
In conclusion, the newly added recitation is deemed to be new matter because the specification and claims as originally filed fails to provide adequate explicit or implicit description for the new recitation. The scope of the newly added recitation is much broader than that of the application. Therefore, the newly added recitation and the disclosure are not commensurate in scope. Claims 128-130, 138-146, 158-164 are dependent upon the independent claims discussed above. As such, the dependent claims also comprise the new matter of their base claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 127-130, 138-146 and 157-164 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.
Amended claims 127 and 157 recite, “a CD19 or BCMA antigen-binding molecule”. The scope of this recitation is not apparent because it is not apparent if this recitation intends to mean “a CD19 or a BCMA antigen-binding molecule” or “a CD19 antigen-binding molecule or a BCMA antigen-binding molecule”. For purposes of identifying relevant art, the recitation will be interpreted both ways.
Claims 128-130, 138-146 and 158-164 depend upon either claim 127 or claim 157. As such, these dependent claims also comprise the identified indefinite subject matter.
The rejections of record are modified to take the amendments to the claims into consideration:
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)(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) 127-130, 138, 140-146, and 157-160, as amended, previously presented, or newly added, is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Livia (WO 2020/023595 effectively filed 7/24/2018; or record in IDS).
Regarding claim 127, Figure 1 discloses a circular RNA polynucleotide comprising in the following order a Td intron second half (i.e. post splicing group I intron fragment) a first IRES, coding sequence A (i.e. a first expression sequence), a second IRES, coding sequence B (i.e. a second expression sequence), and a Td Intron first half (i.e post splicing group I intron fragment).
The amendment to claim 127 specifies that the first expression sequences encodes a CD19 or BCMA antigen-binding molecule and/or the second expression sequence encodes a CD19 or BCMA antigen-binding molecule. The breadth of this recitation encompasses a first expression sequences encoding a CD19 and a second expression sequence encoding any expression sequence because the limitations of the first and sequence expression sequences are recited as “and/or” meaning alternative or both.
Livia discloses that the coding region may encode any suitable protein whose expression is desired such as, for example CD19 (p. 6, lines 26-31). As such, Livia discloses claim 127 as amended.
Regarding claim 128, Figure 1 show an IRES sequence between coding sequence A and B.
Regarding claims 129 and 130, Livia discloses that coding regions may be separated by a self-cleaving 2A peptide (p. 6, line 16-25).
Regarding claim 138, Livia discloses the spacers before the first IRES sequence and a spacer after coding sequence B (Figure 1 and 6). Livia also discloses one can include additional complementary sequences at each end of the linear RNA, which can bring the donor and acceptor sites into closer opposition for more efficient splicing (i.e. 5’ and 3’ duplex forming regions). See page 5, last paragraph.
Regarding claim 140, Livia discloses the IRES can be selected from any class of IRESes-i.e., any one of Group IIV. In some embodiments, the IRES can be cricket paralysis virus IRES (CrPV-IRES) or Plautia stali intestine virus IRES (PSIV-IRES), each of which initiates translation in mammalian cells and requires minimal use of the cellular machinery for translation. the reduced reliance on the cellular machinery compared to other IRES sequences means that translation from CrPV-IRES and PSIV-IRES can be more efficient that when using other IRES sequences Exemplary alternative IRES suitable for use in a ceRNA construct include, but are not limited to, IRES from hepatitis C Virus (HCV), classical swine fever virus (CSFV), foot-and-mouth disease virus (FMDV), encephalomyocarditis virus (EMCV), polio virus, or hepatitis A virus. See page 6, lines 6-15.
Regarding claim 141, the circular RNA of Livia has no synthetic RNA elements.
Regarding claim 142, Livia does not expressly state that the expression sequences are codon optimized. However, codon optimization is relative to the host cell. Since the host cell is not recited, any coding sequence is codon optimized for coding sequence of origin. As such, Livia’s disclosure also meets the limitations of the claim given its broadest reasonable interpretation.
Regarding claim 143, Livia discloses an miRNA bind sequence can be present in the circular RNA (p. 8, last paragraph).
Regarding claims 145 and 146, these claims recite functional limitations of the claimed circular RNA of claim 127. As discussed above, all of the structural limitations of this claim are expressly present in Figures 1 and 6 of Livia. As such, these functional inherently must be present.
Regarding claim 157, the vector as claimed has the structural limitation found in figure 1 and 6 and additional can comprise the duplex forming regions as discussed above and discussed above in the discussion of claim 127. As such, Livia discloses claim 127 as amended.
Regarding claim 158, the cleavage site between the first and second expression sequences are disclosed by Livia as discussed above.
Regarding claim 159, Livia discloses the circular RNA can comprise circularization element for expressing eukaryotic cells (p. 5, lines 22-25).
Regarding claim 160, Livia discloses transfecting 293T cells (i.e. an immune cell) with ceRNA (p. 4, lines 1-3).
Response to Arguments
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive.
Applicant traverses the 102 rejection. Applicant submits that the amendments to the claims are not disclosed by Livia. In response, Applicant is not giving the claims their broadest reasonable interpretation and the claims as amended continue to be disclosed by Livia for reasons discussed above.
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.
(1) Claim(s) 127-130, 138, 140-146, and 157-164, as amended, previously presented or newly added, is/are rejected under 35 U.S.C. 103 as being unpatentable over Livia (WO 2020/023595 effectively filed 7/24/2018; or record in IDS) as applied to claims 127-130, 132-138, 140-146, and 157-159 above, and further in view of Sadelain (WO2017/180989 pub date: 10/19/2017).
Regarding amended claims127-130, 138, 140-146, and 157-159, Livia teaches the claims as discussed above. Livia does not teach that the embodiments that the first expression sequence and or the second expression sequence encodes a CD19 antigen-binding molecule as newly recited by the claims.
However, Sadelain teaches [0044] a T cell wherein a first transgene is integrated at a first site within the genome and a second transgene is integrated at a second site within the genome of the cell, the first transgene and/or second transgene each encodes a molecule independently selected from the group consisting of a CAR and other immune cell function related transgenes. Sadelain teaches a constitutive transcription unit that expresses a cell-surface CD19-specific scFV- FAT fusion protein that upon binding to B cells the FAT moiety is released, it translocates to the nucleus, and binds to its cognate DNA sequence in the second transcription unit, from which a chimeric immune receptor ligand is expressed. This second gene encodes a fusion protein composed on an extracellular antigen (that is recognized by a specific immunoglobulin receptor on the target B cell) and intracellular signaling domain(s) that activates the engineered T cell, resulting in target B-cell death. Thus, in this particular embodiment, expression of a first transgene is under the control of an endogenous constitutive promoter, which first transgene encodes the cell-surface CD19-specific scFv-NFAT fusion protein (i.e. a CD19 antigen binding molecule), and expression of a second transgene is under the control of an endogenous inducible promoter that is induced by binding of the cell-surface CD19-specific scFv-NFAT fusion protein to B cells, and the second transgene encodes a fusion protein comprising (i) an extracellular antigen (that is recognized by an immunoglobulin receptor on the target B cell), and (ii) at least one intracellular signaling domain that activates the engineered T cell, resulting in target B-cell death (for example, due to cytolytic activity of the activated T cell) (see [00303]). Further Sadelain further teaches he most successful CARs used to date are those targeting CD19, which offer the prospect of complete remissions in patients with chemorefractory/relapsed B cell malignancies [0010].
Thus it would have been obvious to an artisan of ordinary skill in the art before the time of filing to use transgene encoding CD19-specific scFv-NFAT fusion protein taught by Saldelain in the ceRNA of Livia in immune cells to predictably arrive at the limitations of the claims. The artisan would have a reasonable expectation of success in introducing the transgene enoding CD19-spicific scFv-NFAT of Sadelain into the ceRNA of Livia because Sadlelain teaches its successful use in bi-cistronic expression constructs and Livia provide methods of introducing such sequences into ceRNA expression constructs. Further, the artisan would be motivated to incorporate a transgene encoding CD19-spicific scFv-NFAT of Sadelain into the ceRNA of Livia for use in immune cells because Salelain teaches it is a targeting molecule which offers the propects of compete remission in patients with chemrefractory/relapsy B cell malignancies.
Regarding claims 160, Livia teaches the claimed eukaryotic cell comprising circular RNA polynucleotide and describes using a 293T cell line. Further Sadelain further teaches other types of CAR-T cells and immune cells can be used in their invention.
Regrading claim 161-162, 163(a) and (b), and 164, Sadelain teaches a CD19 ScFv fragment as discussed above. Further, Sadelain teaches in certain embodiments of a T cell wherein a first transgene is integrated at a first site within the genome and a second transgene is integrated at a second site within the genome of the cell, as described above, the first transgene and/or second transgene each encodes a molecule independently selected from the group consisting of a CAR, a CCR, a cytokine, a dominant negative, a microenvironment modulator, an antibody, a biosensor, a chimeric receptor ligand (CRL), a chimeric immune receptor ligand (CIRL), a soluble receptor, a solute transporter, an enzyme, a ribozyme, a genetic circuit, an epigenetic modifier, a transcriptional activator, a transcriptional repressor, and non-coding RNA. In certain embodiments of a T cell wherein a first transgene is integrated at a first site within the genome and a second transgene is integrated at a second site within the genome of the cell, as described above, the first transgene and/or second transgene encodes a cytokine. In certain embodiments wherein the first and/or second transgene encodes a cytokine, the cytokine preferably is immunostimulatory. In certain embodiments where the cytokine is immunostimulatory, the cytokine is selected from the group consisting of IL2, IL12, IL15, and IL18. In certain embodiments wherein the first transgene and/or second transgene encodes a cytokine, the cytokine preferably is immunoinhibitory. In certain embodiments where the cytokine is immunoinhibitory, the cytokine is selected from the group consisting of TGFBeta and IL10. In certain embodiments of a T cell wherein a first transgene is integrated at a first site within the genome and a second transgene is integrated at a second site within the genome of the cell, as described above, the first transgene and/or second transgene encodes an antibody. In certain embodiments, the antibody is an immunoglobulin, a Bi-specific T-cell engager (BiTE), a diabody, a dual affinity re-targeting (DART), a Fab, a F(ab'), a single chain variable fragment (scFv), and a nanobody. In certain embodiments of a T cell wherein a first transgene is integrated at a first site within the genome and a second transgene is integrated at a second site within the genome of the cell, as described above, the first transgene and/or second transgene encodes a CAR. In a particular embodiment, the CAR binds to a cancer antigen. In certain embodiments of a T cell wherein a first transgene is integrated at a first site within the genome and a second transgene is integrated at a second site within the genome of the cell, as described above, the T cell is sensitized to a target antigen. [0046]- [0048]. In certain embodiments of a T cell wherein a first transgene is integrated at a first site within the genome and a second transgene is integrated at a second site within the genome of the cell, and wherein the first endogenous promoter is constitutive, and the second endogenous promoter is inducible, the first transgene encodes a CAR. In a particular embodiment where the first transgene encodes a CAR, the first endogenous promoter is a T cell receptor promoter. In certain embodiments, the T cell receptor promoter is selected from the group consisting of T cell receptor alpha chain promoter, T cell receptor beta chain promoter, CD3 gamma chain promoter, CD3 delta chain promoter, CD3 epsilon chain promoter, and CD3 zeta chain promoter. In a particular embodiment, the promoter is T cell receptor alpha chain promoter. In certain embodiments of a T cell described above, except insofar as the foregoing embodiments relate to a transgene encoding a cytokine that is immunoinhibitory, for example, TGFbeta or IL10, the T cell is an immunostimulatory T cell. In certain embodiments where the T cell is an immunoinhibitory T cell, the T cell is selected from the group consisting of cytotoxic T lymphocyte (CTL), CD4+ subtype, CD8+ subtype, central memory T cell (TCM), stem memory T cell (TSCM), effector memory T cell, effector T cell, Thl cell, Th2 cell, Th9 cell, Thl7 cell, Th22 cell, and Tfh (follicular helper) cell. In a specific embodiment, the T cell is CD4+. In a specific embodiment, the T cell is CD8+. In certain embodiments of a T cell described above, except insofar as the foregoing embodiments relate to a transgene encoding a cytokine that is immunostimulatory, for example, the cytokine is selected from the group consisting of IL2, IL12, IL15, and IL18, the T cell is an immunoinhibitory T cell. In a specific embodiment, the T cell is a regulatory T cell. [0154]-[0156].
The combination of prior art cited above in all rejections 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. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A, E and G are applicable. The claimed method was known in the art at the time of filing as indicated by Livia in view of Sadelain. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Response to Arguments
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive.
Applicant traverses this 103 rejection with Livia in view of Sadelian and submits that Livia does not teach the CD19 or BCMA antigen binding molecules now claimed. In response, Applicant’s arguments are not persuasive for reasons discussed above in the 102 rejection. Examiner acknowledges in the modified 103 rejection above that Livia does not teach a CD19 antigen-binding molecule embodiment, but as discussed above the claim is being interpreted more broadly than this embodiment.
Applicant submits that Sadelain describes transgenes is the genome of T cells and does not teach any circular RNA. In response, Applicant’s is not considered the teaches of Livia and Sadelain as a whole. Livia provide adequate guidance to taking the sequence information for a CD19-scFv fusion protein fragment from Sadelian and making an expression sequence to place in the circular RNA construct of Livia as claimed.
Applicant submits there would be no reasonable expectation of success. In response Applicant makes this statement but does not provide any evidence to demonstrate that one could not use well established recombinant molecular biology techniques with the teaches of circular RNA construct construction detailed in Livia with the specific sequence information of Salelain for the CD19 ScFv fusion protein fragment predictably. To the contrary Livia demonstrates executes the use of similar sequence information for expression sequences in their circular RNA construct construction. As such, Applicant’s argument is not persuasive.
(2) Claim(s) 140, as previously presented, is/are rejected under 35 U.S.C. 103 as being unpatentable over Livia (WO 2020/023595 effectively filed 7/24/2018; or record in IDS) as applied to claims 127-130, 132-138, 140-146, and 157-159 above, and further in view of Bonnal (Bonnal et al. Nucleic Acids Research 2003 31(1):427-428).
Livia teaches some of the species of IRES sequences claimed as discussed above. Livia does not teach most of the IRES species claimed. All or most of the claimed IRES species are disclosed and publicly available it the website taught by Bonnal (abstract) and can be used in the circular RNA as claimed.
As such before the time of effective filing, it would have been obvious to choose any IRES species available in the prior art, as taught by Bonnal in the circular RNA of Livia to predictable arrive at the limitations of claim 140.
The combination of prior art cited above in all rejections 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. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and E are applicable. The claimed method was known in the art at the time of filing as indicated by Livia in view of Bonnal. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Response to Arguments
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive.
Applicant traverses this 103 rejection with Livia in view of Bonnal and submits that Livia does not teach the CD19 or BCMA antigen binding molecules now claimed. Applicant’s argument are not found persuasive because Livia does teach the limitations as discussed above.
(3) Claim(s) 138-140 and 144, as previously presented, is/are rejected under 35 U.S.C. 103 as being unpatentable over Livia (WO 2020/023595 effectively filed 7/24/2018; or record in IDS) as applied to claims 127-130, 132-138, 140-146, and 157-159 above, and further in view of Wesselhoeft (Wesselhoeft et al. Nature communications DOI: 10.1038/s41467-018-05096-6; (2018) 9:2629; pages 1-10).
Livia teaches the claims as discussed above. Livia does not teach the following:
Livia does not teach the use of spacers sequences (claim 138), particularly of the claimed length (claim 139). However, Wesselhoeft teaches various means of improving circular RNA design including the use of spacers. Wesselhoeft teaches in order to further improve the efficiency of circRNA generation from the self-splicing precursor RNA, we considered other factors that may influence successful circularization. The 3′ PIE splice site is proximal to the IRES, and because both sequences are highly structured, we hypothesized that sequences within the IRES may interfere with the folding of the splicing ribozyme, either proximally at the 3′ splice site or distally at the 5′ splice site through long-distance contacts. In order to allow these structures to fold independently, we designed a series of spacers between the 3′ PIE splice site and the IRES that we predicted would either permit or disrupt splicing (Fig. 2a, Supplementary Data 1). Permissive spacers were designed to conserve secondary structures present within intron sequences that may be important for ribozyme activity, while the disruptive spacer was designed to disrupt sequences in both intron halves, especially the 5′ half. The addition of spacer sequences predicted to permit splicing increased splicing efficiency from 46 to 87% (P1 and P2), while the addition of a disruptive spacer sequence completely abrogated splicing (Fig. 2b). This improved construct, containing both homology arms and rationally designed spacers, was able to circularize RNA approaching 5 kb in length (Supplementary Fig. 1b). See page 2, col 2.
As such, it would have been obvious before effective filing of the instant application to include spacer sequences of the claimed length as taught by Wesselhoeft to the circular RNA of Livia to predictably arrive at the limitations of claims 138 and 139. An artisan would have a reasonable expectation of success because Wesselhoeft provides guidance to designing effective spacer sequences and means of introducing them into circular RNA. Further an artisan would be motivated to add spacer sequences because improves circularization efficiency by increasing splicing efficiency, as taught by Wesslehoeft.
Regarding claim 140, Livia discloses the use of IRES sequence but does not provide teachings to all the possible IRES sequences. However, Wesselhoeft teaches IRES sequences from EMCV, CVB3, EV71, PV, CSFV, HVR2 that are successfully used with circular RNA (fig 4.).
As such, it would have been obvious to an artisan of ordinary skill before effective filing to choose any of the IRES sequence taught by Wesselhoeft in the circular RNA of Livia to predictable arrive at the limitations of claim 140. An artisan would have a reasonable expectation of success because Wesselhoeft demonstrates successful use with circular RNA. An artisan would be motivated to choose one of the IRES species of Wesselhoeft as well because they show that they can be used specifically with circular RNA constructs.
Regarding claim 144, Livia teaches the limitations of the circular RNA as discussed above. Livia does not teach the claimed size range of the circular RNA. However, Wesselhoeft teaches circularize RNA approaching 5 kb in length as discussed above. Further, it would have been obvious to an artisan of ordinary skill that one would make the any size length necessary to include at least all the requisite structural elements of the circular RNA. Further, method of optimizing length are would be routine optimization known to an artisan of ordinary skill in the field. As such, the claimed size range is obvious.
The combination of prior art cited above in all rejections 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. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A, B, E and G are applicable. The claimed method was known in the art at the time of filing as indicated by Livia in view of Wesselhoeft. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Response to Arguments
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive.
Applicant traverses this 103 rejection with Livia in view of Wesselhoeft and submits that Livia does not teach the CD19 or BCMA antigen binding molecules now claimed. Applicant’s argument are not found persuasive because Livia does teach the limitations as discussed above.
The following new 103 rejection is necessitated by the amendments to the claims:
(4) Claim(s) 127-130, 138, 140-146, and 157-164, as amended, previously presented or newly added, is/are rejected under 35 U.S.C. 103 as being unpatentable over Livia (WO 2020/023595 effectively filed 7/24/2018; or record in IDS) as applied to claims 127-130, 138, 140-146, and 157-159 above, and further in view of Ma (US2019/0135894 pub date:5/9/2019).
Regarding claim 127-130, 138, 140-146, and 157-159, Livia teaches the circular RNA construct and the T cells comprising said circular RNA construct as discussed above. Livia does not teach the embodiments wherein the first expression vector encodes a CD19 antigen binding molecule and the second expression vector encodes a BCMA antigen binding molecule.
However, Ma teaches while killing multiple myeloma cells can provide short-term relief, LSCs (myeloma leukemic stem cells), if not destroyed, will always re-grow, causing the patient to relapse. It is imperative that LSCs be destroyed to achieve durable cures for multiple myeloma disease. Without wishing to be bound by theory, it is believed that a small subset of multiple myeloma cells is stem cells that are CD19 positive and associated with disease progression and relapses, and a bulky myeloma cell population is BCMA positive. Therefore, it is critical to develop new therapies that can specifically target both the myeloma stem cell population and the bulky myeloma population. A compound CAR in the present disclosure targets BCMA+ and/or CD19+ positive populations of multiple myeloma cells and is embodied herein ([0488]). In some embodiments, the present disclosure provides a method of eradicating or killing myeloma stem cells (LSCs) or bulk myeloma cells expressing CD19 and/or BCMA. In this embodiment, a T or NK engineered cell having a BCMA unit and a CD19 unit is administered to a patient in need thereof. [0489] In some embodiments, the disclosed disclosure comprises methods and compositions of deleting both BCMA and CD19 populations in multiple myeloma to prevent relapses using a BCMA-CD19 cCAR. CAR is more powerful in eliminating myeloma cells when combination of two units of BCMA and CD19 (BCMA-CD19) together in a vector or a cell. [0490] In further embodiments, a compound CAR, BCMA-CD19 cCAR in a T or NK cell may be used to eradicate or kill BCMA+CD19+ or BCMA+CD19− or BCMA−CD19+ populations. [0491] In some embodiments, the disclosed disclosure comprises methods and compositions of deleting both BCMA and CD19 populations in multiple myeloma to prevent relapses using a BCMA-CD19 cCAR. CAR is more powerful in eliminating myeloma cells when combination of two units of BCMA and CD19 (BCMA-CD19) together in a vector or a cell. [0492]
As such, it would have been obvious to an artisan of ordinary skill before the time of incorporate the BCMA CAR expression sequence in the first or the second expression sequence and the CD19 CAR expression sequence in the second or first expression sequence taught by Ma into the circular RNA constructed introduce into T cells taught by Livia to predictable arrive at the limitations of the claims. The artisan would have a reasonable expectation of success because Ma provides the two sequence units for BCMA CAR and CD19 CAR that can be used in the methodologies of Livia to successfully make the circular RNA construct of the claims. Further, one would be motivated to use the BCMA CAR and CD19 CAR sequences in the circular RNA construct of Livia because the T cells comprising these two expression sequences and expressing the two CARs can be used to treat myeloma known to relapse, as taught by Ma.
Regarding claims 160, the combined art as discussed above would result in a T cell (i.e. immune cell ) comprising the claimed circular RNA construct as discussed above.
Regarding claim 161-162 and 164, Ma teaches CARs as discussed above.
Regarding claim 163. Livia in view of Ma teaches the claimed construct variants of a-d as discussed above.
The combination of prior art cited above in all rejections 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. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A, B, E and G are applicable. The claimed method was known in the art at the time of filing as indicated by Livia in view of Ma . Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
(5) Claim(s) 140 is/are rejected under 35 U.S.C. 103 as being unpatentable over Livia (WO 2020/023595 effectively filed 7/24/2018; or record in IDS) in view of Ma (US2019/0135894 pub date:5/9/2019)., as applied to claims 127-130, 132-138, 140-146, and 157-159 above, and further in view of Bonnal (Bonnal et al. Nucleic Acids Research 2003 31(1):427-428).
Livia in view of Ma teaches the claims as discussed above Livia also teaches some of the species of IRES sequences claimed as discussed above. Livia in view of Ma does not teach most of the IRES species claimed. All or most of the claimed IRES species are disclosed and publicly available it the website taught by Bonnal (abstract) and can be used in the circular RNA as claimed.
As such before the time of effective filing, it would have been obvious to choose any IRES species available in the prior art, as taught by Bonnal in the circular RNA of Livia in view of Ma to predictable arrive at the limitations of claim 140.
The combination of prior art cited above in all rejections 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. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and E are applicable. The claimed method was known in the art at the time of filing as indicated by Livia in view of Ma in further view of Bonnal. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
(6) Claim(s) 138-140 and 144is/are rejected under 35 U.S.C. 103 as being unpatentable over Livia (WO 2020/023595 effectively filed 7/24/2018; or record in IDS) in view of Ma (US2019/0135894 pub date:5/9/2019), as applied to claims 127-130, 138, 140-146, and 157-159 above, and further in view of Wesselhoeft (Wesselhoeft et al. Nature communications DOI: 10.1038/s41467-018-05096-6; (2018) 9:2629; pages 1-10).
Livia in view of MA teaches the claims as discussed above. Livia in view of MA does not teach the following:
Livia in view of MA does not teach the use of spacers sequences (claim 138), particularly of the claimed length (claim 139). However, Wesselhoeft teaches various means of improving circular RNA design including the use of spacers. Wesselhoeft teaches in order to further improve the efficiency of circRNA generation from the self-splicing precursor RNA, we considered other factors that may influence successful circularization. The 3′ PIE splice site is proximal to the IRES, and because both sequences are highly structured, we hypothesized that sequences within the IRES may interfere with the folding of the splicing ribozyme, either proximally at the 3′ splice site or distally at the 5′ splice site through long-distance contacts. In order to allow these structures to fold independently, we designed a series of spacers between the 3′ PIE splice site and the IRES that we predicted would either permit or disrupt splicing (Fig. 2a, Supplementary Data 1). Permissive spacers were designed to conserve secondary structures present within intron sequences that may be important for ribozyme activity, while the disruptive spacer was designed to disrupt sequences in both intron halves, especially the 5′ half. The addition of spacer sequences predicted to permit splicing increased splicing efficiency from 46 to 87% (P1 and P2), while the addition of a disruptive spacer sequence completely abrogated splicing (Fig. 2b). This improved construct, containing both homology arms and rationally designed spacers, was able to circularize RNA approaching 5 kb in length (Supplementary Fig. 1b). See page 2, col 2.
As such, it would have been obvious before effective filing of the instant application to include spacer sequences of the claimed length as taught by Wesselhoeft to the circular RNA of Livia in view of MA to predictably arrive at the limitations of claims 138 and 139. An artisan would have a reasonable expectation of success because Wesselhoeft provides guidance to designing effective spacer sequences and means of introducing them into circular RNA. Further an artisan would be motivated to add spacer sequences because improves circularization efficiency by increasing splicing efficiency, as taught by Wesslehoeft.
Regarding claim 140, Livia discloses the use of IRES sequence but does not provide teachings to all the possible IRES sequences. However, Wesselhoeft teaches IRES sequences from EMCV, CVB3, EV71, PV, CSFV, HVR2 that are successfully used with circular RNA (fig 4.).
As such, it would have been obvious to an artisan of ordinary skill before effective filing to choose any of the IRES sequence taught by Wesselhoeft in the circular RNA of Livia in view of Ma to predictable arrive at the limitations of claim 140. An artisan would have a reasonable expectation of success because Wesselhoeft demonstrates successful use with circular RNA. An artisan would be motivated to choose one of the IRES species of Wesselhoeft as well because they show that they can be used specifically with circular RNA constructs.
Regarding claim 144, Livia in view of Ma teaches the limitations of the circular RNA as discussed above. Livia in view of Ma does not teach the claimed size range of the circular RNA. However, Wesselhoeft teaches circularize RNA approaching 5 kb in length as discussed above. Further, it would have been obvious to an artisan of ordinary skill that one would make the any size length necessary to include at least all the requisite structural elements of the circular RNA. Further, method of optimizing length are would be routine optimization known to an artisan of ordinary skill in the field. As such, the claimed size range is obvious.
The combination of prior art cited above in all rejections 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. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A, B, E and G are applicable. The claimed method was known in the art at the time of filing as indicated by Livia in view of Ma in further view of Wesselhoeft. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
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 MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632