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 .
Claims 1, 2, 4-13, 15, 17, 18, 21, 29, 30, 40, 41, 158-161 are pending and under examination.
This office action is in response to the amendment filed on 4/29/2026.
All previous rejection not reiterated in this office action are withdrawn.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, 4-8, 10, 11, 15, 17, 18, 21, 29, 30, 40, 41 and 158-161 is/are rejected under 35 U.S.C. 102(a1)(a2) as being anticipated by Huang (IDS). This rejection is rewritten to address the amendment.
Huang teaches an antigen of interest encoded by an mRNA, provided on the same mRNA as the immune potentiator construct or a different mRNA construct, wherein said construct are formulated to be administered to a subject in need thereof to stimulate an immune response against the antigen in the subject (paragraph [0016] and [0034]). Huang teaches the mRNA construct can further include an open reading frame (ORF) encoding a polypeptide of interest and further comprises one or more miRNA binding sites provides for regulation based on tissue specific and/or cell type specific expression of naturally-occurring miRNAs (paragraph [0564]), wherein the construct may include at least two, three, four…miRNA-binding sites in the UTR in order to regulate cytotoxic or cytoprotective mRNA therapeutics to specific cells (paragraph [0575]), wherein the miRNA binding sites may be same or different (paragraph [0603]). Huang teaches the antigen of interest may be bacterial antigen (paragraph [0031]). Huang teaches the composition further comprises delivery vehicle such as a lipid nanoparticle (paragraph [0172]). Therefore, the teaching from Huang anticipates the claimed invention of claim 1.
Regarding claim 2 and claim 7, Huang teaches that the mRNA construct may be encapsulated in lipid nanoparticles (paragraph [0650]), which meets the limitation of “comprised within.”
Regarding claims 4, 29 and 30, Huang teaches the antigen may be at least one bacterial antigen and viral antigen (paragraph [0026] and [0027]). The viral antigen may be an influenza antigen (paragraph [0474]).
Regarding claims 5 and 6, Huang teaches the immunopotentiator mRNA comprises stimulating type I interferon (IFN) (paragraph [0212]).
Regarding claim 8, Huang teaches mRNA construct encoding cytokine including IL-12 to induce T cell activation (paragraph [0520]).
Regarding claims 10, 11 and 15, Huang teaches the construct may include at least two, three, four…miRNA-binding sites in the UTR in order to regulate cytotoxic or cytoprotective mRNA therapeutics to specific cells (paragraph [0575]), wherein the miRNA binding sites may be same or different (paragraph [0603]).
Regarding claims 17 and 18, Huang teaches miRNA sequences corresponding to different tissues and/or cell types including liver (miR-122), muscle (miR-133, miR206, miR208), kidney (miR-192, miR-194)…etc (paragraph [0578]) may be included in the construct for cytotoxic or cytoprotective mRNA therapies.
Regarding claim 21, SEQ ID NO: 47, the elected sequence, having 100% sequence homology with miR-192 (see attached alignment), which is taught by Huang to be liver specific miR (paragraph [0578]).
Regarding claims 158-161, Huang teaches the antigen of interest may be one or more tumor antigens specific for the subject (one or more neoepitopes), wherein said antigens may be encoded by one or more mRNAs, same or different mRNA construct (paragraph [0028]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huang, in view of the sequence having accession number (BFU97828).
The teaching from Huang has been discussed above.
However, Huang does not teach that the immunopotentiator IL-12 is encoded by a sequence having at least 90% identity with SEQ ID NO: 59.
The sequence having accession number BFU97828 has 100% homology with SEQ ID NO:59, and is a codon optimized human interleukin-12 transgene (alignment provided in previous OA).
It would have been obvious to an ordinary skilled in the art to make a composition as claimed to include IL-12 encoded by SEQ ID NO:59, which is known in prior art to be a codon optimized human interleukin-12 transgene. The ordinary skilled in the art would have been motivated to do so to ensure optimal expression in human cells, which is the intended utility of the composition taught by Huang. The ordinary skilled in the art would have reasonable expectation of success to make an RNA construct comprising said sequence because all claimed elements are known in prior art. Therefore, the claimed invention of claim 9 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 12 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huang.
The teaching from Huang has been discussed above. Huang teaches at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more miRNA binding site may be engineered into a 3’ UTR of a polynucleotide, wherein said miRNA binding sites may be same or different, so that targeted expression in same or different tissues in the body may be achieved. Huang teaches introduction of different combination of cell type specific, tissues specific and/or disease specific miRNA binding sites into the construct so that expression of the polypeptide of interest may be regulated (paragraph [0608]).
However, Huang does not specifically teach the at least 3 miRNA binding sequence in the first mRNA construct is same or different from the 3 miRNA binding sequence in the second mRNA construct.
It would have been obvious to an ordinary skilled in the art whether the miRNA binding sites in the first mRNA construct encoding an antigen, and the second mRNA construct encoding the immunopotentiator are same or different depends on the type of what tissue/cell the antigen is intended to be expressed based on the teaching from Huang. The ordinary skilled in the art would use different combination of miRNA binding sites when the antigen is intended to be expressed in a tumor cell, i.e. liver cancer, whereas the immunopotentiator is intended to be expressed in an immune cell. The ordinary skilled in the art would have recognized if both antigen and the immunopotentiator is intended to be expressed in hematopoietic cells, same combination of miRNA binding sites would be used for both mRNA construct. Since Huang teaches cell type/tissue or tumor specific miRNAs, the ordinary skilled in the art would have reasonable expectation of success to pick from said miRNA binding sites to regulate the expression of the antigen and immunopotentiator of interest at desired site in a subject. Therefore, the claimed invention of claims 12 and 13 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 40 and 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huang, in view of Tupin (US 2015/0165014).
The teaching from Huang has been discussed above. Huang gave some example of bacterial antigen including antigens from S. aureus (paragraph [0466]), and Chlamydia (paragraph [0470]).
However, Huang did not give an example of bacterial antigen being from Mycobacterium tuberculosis (claim 40), wherein the protein may be one of ESAT-6, Ag85b (claim 41).
Tupin teaches mycobacterial antigen vaccine (title). Tupin teaches the antigen may be obtained from Mycobacterium tuberculosis (paragraph [0045]). Tupin teaches the antigenic protein may include ESAT-6, Ag85B and TB10.4 (paragraph [0056]).
It would have been obvious to an ordinary skilled in the art that the composition taught by Huang is not limited to bacterial antigen from S. aureus and Chlamydia. It would have been obvious to an ordinary skilled in the art that antigen vaccine from M. tuberculosis (taught by Tupin) would also benefit from the inclusion of miRNA binding sites to achieve tissue/cell specific protection based on combined teaching from Huang and Tupin. The ordinary skilled in the art would have reasonable expectation of success to replace the bacterial protein in the composition taught by Huang with M. tuberculosis protein such as ESAT-6, Ag85B and TB10.4 taught by Tupin following combined teaching from Huang and Tupin. Therefore, the claimed invention of claims 40 and 41 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Response to Arguments
In response to the rejection, Applicant argues that Huang does not teach “optimized” miRNA target sequences as claimed. Applicant alleges Huang only teaches its miRNA binding sites as requiring “sufficient complementary” to facilitate miRNA-mediated regulation, and states “a miRNA binding site can be complementary to only a portion of a miRNA, e.g., to a portion less than 1, 2, 3 or 4 nucleotides of the full length of a naturally-occurring miRNA sequence (paragraph [0567]), and “the degree of match or mis-match between miRNA binding site and the miRNA seed can act as a rheostat to more finely tune the ability of the miRNA to modulate protein expression.” (paragraph [0615]). Applicant alleges that this “rheostat” approach deliberately introducing mismatches to tune expression levels is contradictory to the claimed optimized sequences that minimize mismatches for maximum silencing efficiency. Applicant argues that the present specification defines “optimize” with precision and demonstrates its functional significance in paragraph [0097], which describes an embodiment of the invention a single base mismatch is limited to the 5’ or 3’ end of the target sequence, and this experimentally validated design criterion that is absent from Huang. Applicant argues that Huang’s disclosure of multiple miRNA binding sites is centered primarily on oncology-related application citing paragraph [0575] that states “a polynucleotide of the disclosure can include two, three, five…ten or more miRNA binding sites in the 5’ UTR and/or 3’ UTR in order to regulate cytotoxic or cytoprotective mRNA therapeutics to specific cells such as, but not limited to, normal and/or cancerous cells.” Applicant argues such teaching means the context of this disclosure is regulating of therapeutics directed to cancer cells, not organ protection in the context of infectious disease vaccines. Applicant argues that Huang does not teach the combination of a pathogenic microbial antigen-encoding mRNA constructs with at least three different optimized miRNA target sequences in the UTR, because in paragraph [1401] only states “the mmRNA further comprises one or more microRNA binding sites.” Applicant argues that the combination of all claimed elements is not found in any single passage or unified teaching, but the rejection is pieces together disparate teaching scattered across Huang’s voluminous specification.
The above arguments have been fully considered but deemed unpersuasive. Applicant’s characterization of the teaching from Huang is incomplete because the statement “a miRNA binding site having sufficient complementary to a miRNA refers to a degree of complementarity sufficient to facilitate miRNA-mediated translational repression or degradation of the polynucleotide” is followed by the statement “full or complete complementarity is preferred when the desired regulation is mRNA degradation.”(last 5 lines from paragraph [0567]). Huang went on to teach “in some embodiments, the miRNA binding site includes a sequence that has complete complementarity with a miRNA sequence” (paragraph [0568], lines 9-11). As such, the disclosure from Huang encompasses miRNA binding site having full or complete complementarity, which meets the limitation of “optimized miRNA target sequences have no more than a single bp mismatch across the length of the target sequence.” It is incorrect to ignore some embodiments that meets the limitation of the claim, but cites other embodiments that does not meet the limitation of the claim. Similarly, the argument directed to Rheostat in paragraph [0615] is based on incomplete information because that sentence is explaining that the degree of match can be used to finely tune the ability of miRNA to modulate protein expression, whereas embodiments for designing a polynucleotide comprising miRNA binding sites that has 100% identity to miRNA sequence is also included in that paragraph (see lines 1-4 of paragraph [0615]). Applicant’s interpretation for the statement in paragraph [0575] that “a polynucleotide of the disclosure can include two, three, five…ten or more miRNA binding sites in the 5’ UTR and/or 3’ UTR in order to regulate cytotoxic or cytoprotective mRNA therapeutics to specific cells such as, but not limited to, normal and/or cancerous cells” is only in the context of oncology related therapy is incorrect because it clearly encompasses both “cytotoxic” or “cytoprotective” mRNA to specific cells. Although Huang does not use the term “organ protection sequence,” protecting normal cells in a subject is protecting normal organs. In response to the argument directed to teaching of all elements are not in a single passage, it is noted that this is not a requirement for anticipatory rejection as long as the entire reference teaches each and every limitation of the claim. Therefore, for reason discussed in previous rejection and set forth above, this rejection is still considered proper and thus maintained.
With regard to the obviousness rejection, Applicant provides same argument as above and indicates the secondary reference does not make up the deficiency.
Since there is no deficiency in Huang for reason discussed above, this argument is not persuasive.
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 1, 2, 4-8, 10, 14, 18, 21, 29 and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2-6, 9, 10, 13, 14 and 16 of U.S. Patent No. 11,596,685. Although the claims at issue are not identical, they are not patentably distinct from each other because the composition claimed in claim 1 of the ‘685 patent anticipates claims 1, 2, 4-7, 29 of the present application.
Claims 2-5 of ‘685 patent recites same limitation as claim 30 of present application that the viral antigen is from a coronavirus spike protein.
Claim 6 of the ‘685 patent recites the same limitation as claim 14 of the present application, wherein the composition includes a delivery vehicle being lipid nanoparticle.
Claim 9 of the ‘685 patent recites same limitation as claim 18 of present application, wherein the OPS comprises at least three miRNA target sequence including miRNA-122, miRNA-125…etc.
Claim 10 of the ‘685 patent recites same limitation as claim 21 of the present application, wherein the miRNA target sequences are selected from one or more SEQ ID NO: 44-57.
Claim 13 of the ‘685 patent recites same limitation as claim 8 of the present application, wherein the second ORF codes for IL-12 protein, subunit, derivative agonist or homologue thereof.
Claim 14 of ‘685 patent recites same limitation as claim 6 of the present application, wherein the first mRNA further comprises a second ORF that encodes a proinflammatory cytokine including IL-1…GM-CSF.
Claim 16 of the ‘685 patent recites same limitation as claim 10 of the present application, wherein the second UTR that comprises at least 3 miRNA target sequences all different from each other.
Claims 11-13, 15, 17, 158-161 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,596,685, in view of Huang.
As discussed above, claim 1 of ‘685 patent anticipates the claimed invention of claim 1 of present application. The minor variation recited in the following claims would have been obvious in view of the teaching from Huang (set forth above).
Regarding claims 11 and 15, Huang teaches the construct may include at least two, three, four…miRNA-binding sites in the UTR in order to regulate cytotoxic or cytoprotective mRNA therapeutics to specific cells (paragraph [0575]), wherein the miRNA binding sites may be same or different (paragraph [0603]).
Regarding claim 17, Huang teaches miRNA sequences corresponding to different tissues and/or cell types including liver (miR-122), muscle (miR-133, miR206, miR208), kidney (miR-192, miR-194)…etc (paragraph [0578]) may be included in the construct for cytotoxic or cytoprotective mRNA therapies.
Regarding claims 158-161, Huang teaches the antigen of interest may be one or more tumor antigens specific for the subject (one or more neoepitopes), wherein said antigens may be encoded by one or more mRNAs, same or different mRNA construct (paragraph [0028]).
Regarding claims 12 and 13, Huang teaches at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more miRNA binding site may be engineered into a 3’ UTR of a polynucleotide, wherein said miRNA binding sites may be same or different, so that targeted expression in same or different tissues in the body may be achieved. Huang teaches introduction of different combination of cell type specific, tissues specific and/or disease specific miRNA binding sites into the construct so that expression of the polypeptide of interest may be regulated (paragraph [0608]).
However, Huang does not specifically teach the at least 3 miRNA binding sequence in the first mRNA construct is same or different from the 3 miRNA binding sequence in the second mRNA construct.
It would have been obvious to an ordinary skilled in the art whether the miRNA binding sites in the first mRNA construct encoding an antigen, and the second mRNA construct encoding the immunopotentiator are same or different depends on the type of what tissue/cell the antigen is intended to be expressed based on the teaching from Huang. The ordinary skilled in the art would use different combination of miRNA binding sites when the antigen is intended to be expressed in a tumor cell, i.e. liver cancer, whereas the immunopotentiator is intended to be expressed in an immune cell. The ordinary skilled in the art would have recognized if both antigen and the immunopotentiator is intended to be expressed in hematopoietic cells, same combination of miRNA binding sites would be used for both mRNA construct. Since Huang teaches cell type/tissue or tumor specific miRNAs, the ordinary skilled in the art would have reasonable expectation of success to pick from said miRNA binding sites to regulate the expression of the antigen and immunopotentiator of interest at desired site in a subject. Therefore, the claimed invention of claims 12 and 13 would have been prima facie obvious to an ordinary skilled in the art in view of claim 1 of ‘685 patent and teaching from Huang.
Claims 40 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,596,685 in view of Tupin.
Claim 1 of ‘685 patent differs from claim 40 and 41 of present application for not specifying the bacterial antigen being from Mycobacterium tuberculosis (claim 40), wherein the protein may be one of ESAT-6, Ag85b (claim 41).
Tupin teaches mycobacterial antigen vaccine (title). Tupin teaches the antigen may be obtained from Mycobacterium tuberculosis (paragraph [0045]). Tupin teaches the antigenic protein may include ESAT-6, Ag85B and TB10.4 (paragraph [0056]).
It would have been obvious to an ordinary skilled in the art that the composition claimed in claim 1 of ‘685 patent encompasses many bacterial protein. It would have been obvious to an ordinary skilled in the art that antigen vaccine from M. tuberculosis (taught by Tupin) would also benefit from the inclusion of miRNA binding sites to achieve tissue/cell specific protection based on combined claim 1 of ‘685 patent and Tupin. The ordinary skilled in the art would have reasonable expectation of success to place the bacterial protein from M. tuberculosis protein such as ESAT-6, Ag85B and TB10.4 taught by Tupin in the claimed composition. Therefore, the claimed invention of claims 40 and 41 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim 1, 2, 5, 6-8, 10, 11, 14, 15, 17 and 18 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-5, 7 and 8 of U.S. Patent No. 12,195,746. Although the claims at issue are not identical, they are not patentably distinct from each other because the composition claimed in claim 1 of the ‘746 patent anticipates the claimed invention of claims 1, 2, 5, 7, 10, 11 of the present application.
Claim 2 of the ‘746 patent recites same limitation as claim 15 of the present application, wherein the first OPS comprises at least 4 miRNA binding sites.
Claim 3 of the ‘746 patent recites same limitation as claim 17 of the present application for protect one or more organ including liver, brain, lung, breast and pancreas.
Claim 4 of ‘746 patent and claim 18 of the present application recite the one of the miRNA binding site comprises miR-122.
Claim 5 of the ‘746 patent recites delivery particle comprise aminoalcohol lipidoids, which anticipates the lipidoid particle recited in claim 14 of the present application.
Claim 7 of the ‘746 patent recites same limitation as claim 6 of the present application, wherein the second mRNA codes cytokines including IL-1, IL-2…IL-12.
Claim 8 of ‘746 patent recites same limitation as claim 8 of the present application, wherein the second ORF codes for IL-12.
Claims 12-13, 21, 42-44 and 158-161 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12/195,746 in view of Huang.
As discussed above, claim 1 of ‘746 patent anticipates the claimed invention of claim 1 of present application. The minor variation recited in the following claims would have been obvious in view of the teaching from Huang (set forth above).
Regarding claim 21, SEQ ID NO: 47, the elected sequence, having 100% sequence homology with miR-192 (see attached alignment), which is taught by Huang to be liver specific miR (paragraph [0578]).
Regarding claims 42, 43 and 44, Huang teaches the antigen is a tumor associated antigen that is a neoantigen (paragraph [0447]) or MUC1 (paragraph [0425]). Since MUC1 is commonly expressed in liver, lung, breast and pancreas, it is considered as liver antigen, lung antigen, breast antigen and pancreas antigen.
Regarding claims 158-161, Huang teaches the antigen of interest may be one or more tumor antigens specific for the subject (one or more neoepitopes), wherein said antigens may be encoded by one or more mRNAs, same or different mRNA construct (paragraph [0028]).
Regarding claims 12 and 13, Huang teaches at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more miRNA binding site may be engineered into a 3’ UTR of a polynucleotide, wherein said miRNA binding sites may be same or different, so that targeted expression in same or different tissues in the body may be achieved. Huang teaches introduction of different combination of cell type specific, tissues specific and/or disease specific miRNA binding sites into the construct so that expression of the polypeptide of interest may be regulated (paragraph [0608]).
However, Huang does not specifically teach the at least 3 miRNA binding sequence in the first mRNA construct is same or different from the 3 miRNA binding sequence in the second mRNA construct.
It would have been obvious to an ordinary skilled in the art whether the miRNA binding sites in the first mRNA construct encoding an antigen, and the second mRNA construct encoding the immunopotentiator are same or different depends on the type of what tissue/cell the antigen is intended to be expressed based on the teaching from Huang. The ordinary skilled in the art would use different combination of miRNA binding sites when the antigen is intended to be expressed in a tumor cell, i.e. liver cancer, whereas the immunopotentiator is intended to be expressed in an immune cell. The ordinary skilled in the art would have recognized if both antigen and the immunopotentiator is intended to be expressed in hematopoietic cells, same combination of miRNA binding sites would be used for both mRNA construct. Since Huang teaches cell type/tissue or tumor specific miRNAs, the ordinary skilled in the art would have reasonable expectation of success to pick from said miRNA binding sites to regulate the expression of the antigen and immunopotentiator of interest at desired site in a subject. Therefore, the claimed invention of claims 12 and 13 would have been prima facie obvious to an ordinary skilled in the art in view of claim 1 of ‘746 patent and teaching from Huang.
Claim 1, 2, 4-8, 10-14, 15, 17, 18, 21, 29, 30, 158-161 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 9, 10-15 and 18 of U.S. Patent No. 11,931,409 in view of Huang.
The composition claimed in claim 1 of the present application overlaps in scope with the composition claimed in claim 1 of the ‘409 patent. The only difference is that the miRNA binding sequences claimed in claim 1 of the ‘409 patent is in the second mRNA construct that encodes the proinflammatory cytokine instead of the first construct encoding the bacterial and/or viral antigen.
Huang teaches an antigen of interest encoded by an mRNA, provided on the same mRNA as the immune potentiator construct or a different mRNA construct, wherein said construct are formulated to be administered to a subject in need thereof to stimulate an immune response against the antigen in the subject (paragraph [0016] and [0034]). Huang teaches the mRNA construct can further include an open reading frame (ORF) encoding a polypeptide of interest and further comprises one or more miRNA binding sites provides for regulation based on tissue specific and/or cell type specific expression of naturally-occurring miRNAs (paragraph [0564]). Huang teaches the construct may include at least two, three, four…miRNA-binding sites in the UTR in order to regulate cytotoxic or cytoprotective mRNA therapeutics to specific cells (paragraph [0575]), wherein the miRNA binding sites may be same or different (paragraph [0603]).
It would have been obvious to an ordinary skilled in the art that the miRNA binding sites may be present in either the first construct, the second construct or both as taught by Huang based on which tissue and/or cell specific expression is intended for the antigen and/or the immunopotentiator. The ordinary skilled in the art would recognize that the claimed composition of claim 1, 2, 4-7 and 29 would have been an obvious variant of the composition of claim 1 of the ‘409 patent.
Claims 2 and 3 of ‘409 patent recites same limitation as claim 8 of present application, wherein the second ORF codes for IL-12.
Claims 9 and 21 of ‘409 patent recites same limitation of as claim 18 of present application, wherein at least 3 different miRNA target sequence includes miRNA-122…miRNA-6761.
Claim 10 of ‘409 patent recites same limitation as claim 21 of present application, wherein the OPS comprises SEQ ID NO: 44-57.
Claim 11-13 of ‘409 patent recites same limitation as claim 15 of present application that the OPS comprises 4, 5 and 6 miRNA target sequences.
Claim 14 and 15 of ‘409 patent recites same limitation as claim 30 of present application that the antigen include coronavirus spike protein.
Claim 18 of ‘409 patent recites same limitation as claim 14 of present application that the delivery composition comprises a lipid nanoparticle.
Regarding claims 10, 11 and 17, Huang teaches the construct may include at least two, three, four…miRNA-binding sites in the UTR in order to regulate cytotoxic or cytoprotective mRNA therapeutics to specific cells (paragraph [0575]), wherein the miRNA binding sites may be same or different (paragraph [0603]). Huang teaches miRNA sequences corresponding to different tissues and/or cell types including liver (miR-122), muscle (miR-133, miR206, miR208), kidney (miR-192, miR-194)…etc (paragraph [0578]) may be included in the construct for cytotoxic or cytoprotective mRNA therapies.
Regarding claims 158-161, Huang teaches the antigen of interest may be one or more tumor antigens specific for the subject (one or more neoepitopes), wherein said antigens may be encoded by one or more mRNAs, same or different mRNA construct (paragraph [0028]).
Regarding claims 12 and 13, Huang teaches at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more miRNA binding site may be engineered into a 3’ UTR of a polynucleotide, wherein said miRNA binding sites may be same or different, so that targeted expression in same or different tissues in the body may be achieved. Huang teaches introduction of different combination of cell type specific, tissues specific and/or disease specific miRNA binding sites into the construct so that expression of the polypeptide of interest may be regulated (paragraph [0608]).
However, Huang does not specifically teach the at least 3 miRNA binding sequence in the first mRNA construct is same or different from the 3 miRNA binding sequence in the second mRNA construct.
It would have been obvious to an ordinary skilled in the art whether the miRNA binding sites in the first mRNA construct encoding an antigen, and the second mRNA construct encoding the immunopotentiator are same or different depends on the type of what tissue/cell the antigen is intended to be expressed based on the teaching from Huang. The ordinary skilled in the art would use different combination of miRNA binding sites when the antigen is intended to be expressed in a tumor cell, i.e. liver cancer, whereas the immunopotentiator is intended to be expressed in an immune cell. The ordinary skilled in the art would have recognized if both antigen and the immunopotentiator is intended to be expressed in hematopoietic cells, same combination of miRNA binding sites would be used for both mRNA construct. Since Huang teaches cell type/tissue or tumor specific miRNAs, the ordinary skilled in the art would have reasonable expectation of success to pick from said miRNA binding sites to regulate the expression of the antigen and immunopotentiator of interest at desired site in a subject. Therefore, the claimed invention of claims 12 and 13 would have been prima facie obvious to an ordinary skilled in the art in view of claim 1 of ‘409 patent and teaching from Huang.
Claims 40 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,931,409 in view of Tupin.
Claim 1 of ‘409 patent differs from claim 40 and 41 of present application for not specifying the bacterial antigen being from Mycobacterium tuberculosis (claim 40), wherein the protein may be one of ESAT-6, Ag85b (claim 41).
Tupin teaches mycobacterial antigen vaccine (title). Tupin teaches the antigen may be obtained from Mycobacterium tuberculosis (paragraph [0045]). Tupin teaches the antigenic protein may include ESAT-6, Ag85B and TB10.4 (paragraph [0056]).
It would have been obvious to an ordinary skilled in the art that the composition claimed in claim 1 of ‘685 patent encompasses many bacterial protein. It would have been obvious to an ordinary skilled in the art that antigen vaccine from M. tuberculosis (taught by Tupin) would also benefit from the inclusion of miRNA binding sites to achieve tissue/cell specific protection based on combined claim 1 of ‘409 patent and Tupin. The ordinary skilled in the art would have reasonable expectation of success to place the bacterial protein from M. tuberculosis protein such as ESAT-6, Ag85B and TB10.4 taught by Tupin in the claimed composition. Therefore, the claimed invention of claims 40 and 41 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claims 1, 4-8, 14, 15, 18, 21, 29, 42, 44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 8, 9, 10, 13, 14, 19, 26-28 of U.S. Patent No. 12,220,456 in view of Huang.
The composition claimed in claim 1 of the present application overlaps in scope with the composition claimed in claim 1 of the ‘456 patent. The only difference is that the miRNA binding sequences claimed in claim 1 of the ‘456 patent is in the second mRNA construct that encodes the proinflammatory cytokine instead of the first construct encoding tumor antigen
Huang teaches an antigen of interest encoded by an mRNA, provided on the same mRNA as the immune potentiator construct or a different mRNA construct, wherein said construct are formulated to be administered to a subject in need thereof to stimulate an immune response against the antigen in the subject (paragraph [0016] and [0034]). Huang teaches the mRNA construct can further include an open reading frame (ORF) encoding a polypeptide of interest and further comprises one or more miRNA binding sites provides for regulation based on tissue specific and/or cell type specific expression of naturally-occurring miRNAs (paragraph [0564]). Huang teaches the construct may include at least two, three, four…miRNA-binding sites in the UTR in order to regulate cytotoxic or cytoprotective mRNA therapeutics to specific cells (paragraph [0575]), wherein the miRNA binding sites may be same or different (paragraph [0603]).
It would have been obvious to an ordinary skilled in the art that the miRNA binding sites may be present in either the first construct, the second construct or both as taught by Huang based on which tissue and/or cell specific expression is intended for the antigen and/or the immunopotentiator. The ordinary skilled in the art would recognize that the claimed composition of claim 1, 2, 4-7 and 29 would have been an obvious variant of the composition of claim 1 of the ‘456 patent.
Claims 3 and 4 of the ‘456 patent recites same limitation as claim 8 of present application that the second ORF codes for IL-12 protein, derivative, agonist or homologue thereof.
Claim 8, 27 and 28 of the ’456 patent recites same limitation as claim 18 of present application that the first, second and third miRNA target sequence includes miRNA-122…miRNA-6761.
Claim 9 of ‘456 patent recites same limitation as claim 21 of present application that miRNA target sequence includes SEQ ID NO: 44-57.
Claim 10 of ‘456 patent recites same limitation as claim 15 of present application that OPS comprises at least 3, 4, and 5 miRNA target sequences.
Claim 13 of ‘456 patent recites same limitation as claim 42 of present application that the tumor antigen is a cancer specific antigen.
Claim 14 of ‘456 patent recites same limitation as claim 44 of present application that the tumor associated antigen is a neoantigen.
Claim 19 of ‘456 patent recites same limitation as claim 14 of present application that the delivery composition comprises lipid nanoparticle.
Claim 26 of ‘456 patent recites same limitation as claim 1 of present application that the first mRNA comprises at least one miRNA target sequence.
Regarding claims 10, 11 and 17, Huang teaches the construct may include at least two, three, four…miRNA-binding sites in the UTR in order to regulate cytotoxic or cytoprotective mRNA therapeutics to specific cells (paragraph [0575]), wherein the miRNA binding sites may be same or different (paragraph [0603]). Huang teaches miRNA sequences corresponding to different tissues and/or cell types including liver (miR-122), muscle (miR-133, miR206, miR208), kidney (miR-192, miR-194)…etc (paragraph [0578]) may be included in the construct for cytotoxic or cytoprotective mRNA therapies.
Regarding claims 42, 43 and 44, Huang teaches the antigen is a tumor associated antigen that is a neoantigen (paragraph [0447]) or MUC1 (paragraph [0425]). Since MUC1 is commonly expressed in liver, lung, breast and pancreas, it is considered as liver antigen, lung antigen, breast antigen and pancreas antigen.
Regarding claims 158-161, Huang teaches the antigen of interest may be one or more tumor antigens specific for the subject (one or more neoepitopes), wherein said antigens may be encoded by one or more mRNAs, same or different mRNA construct (paragraph [0028]).
Regarding claims 12 and 13, Huang teaches at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more miRNA binding site may be engineered into a 3’ UTR of a polynucleotide, wherein said miRNA binding sites may be same or different, so that targeted expression in same or different tissues in the body may be achieved. Huang teaches introduction of different combination of cell type specific, tissues specific and/or disease specific miRNA binding sites into the construct so that expression of the polypeptide of interest may be regulated (paragraph [0608]).
However, Huang does not specifically teach the at least 3 miRNA binding sequence in the first mRNA construct is same or different from the 3 miRNA binding sequence in the second mRNA construct.
It would have been obvious to an ordinary skilled in the art whether the miRNA binding sites in the first mRNA construct encoding an antigen, and the second mRNA construct encoding the immunopotentiator are same or different depends on the type of what tissue/cell the antigen is intended to be expressed based on the teaching from Huang. The ordinary skilled in the art would use different combination of miRNA binding sites when the antigen is intended to be expressed in a tumor cell, i.e. liver cancer, whereas the immunopotentiator is intended to be expressed in an immune cell. The ordinary skilled in the art would have recognized if both antigen and the immunopotentiator is intended to be expressed in hematopoietic cells, same combination of miRNA binding sites would be used for both mRNA construct. Since Huang teaches cell type/tissue or tumor specific miRNAs, the ordinary skilled in the art would have reasonable expectation of success to pick from said miRNA binding sites to regulate the expression of the antigen and immunopotentiator of interest at desired site in a subject. Therefore, the claimed invention of claims 12 and 13 would have been prima facie obvious to an ordinary skilled in the art in view of claim 1 of ‘456 patent and teaching from Huang.
Claims 1, 4-6, 8, 14, 18, 21 and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5, 9-11, 13-15 of copending Application No. 19/048760 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 5 of ‘760 application anticipates the claimed composition of claims 1, 4, 5 of the present application.
Claim 9 of ‘760 application recites same limitation as claim 44 of present application that the antigen is a neoantigen.
Claim 10 of ‘760 application recites same limitation as claim 6 of present application that the proinflammatory cytokine includes IL-1…GM-CSF.
Claim 11 of ‘760 application recites same limitation as claim 8 of present application that the proinflammatory cytokine is IL-12.
Claim 13 of ‘760 application recites same limitation as claim 18 of present application that the miRNA target sequence binds to miRNA-122…miRNA-6761.
Claim 14 of ‘760 application recites same limitation as claim 21 of present application that OPS comprises SEQ ID NO: 44-57.
Claim 15 of ‘760 application recites same limitation as claim 14 of present application that the delivery composition comprises a lipid nanoparticle.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant requests the rejection be held in abeyance until claims are otherwise determined to be allowable.
Applicant is reminded that NDP can only be overcome by filing a TD, or amending the claim so that it is no longer overlap in scope. Therefore, the above rejection is maintained for reason set forth in previous office action and reiterated above.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637
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