Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
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 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.
Response to Amendments
Applicant’s IDS and response filed Jul. 23, 2026 have been received and entered into the case.
Status of the Claims
Claims 1-2, 6-7, 10, 13-15, 19, 46, 47, and 49-53 are currently pending.
Claims 15, 19 and 50 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species or Invention, there being no allowable generic or linking claim.
Claims 3-5, 8-9, 11-12, 16-18, 20-45 and 48 are cancelled.
Claims 51-53 are new.
Claims 1-2, 6-7, 10, 13-14, 46, 47, 49, and 51-53 have been considered on the merits.
Claim Suggestion
Claim 1 is missing a comma after “CCL5” in line 5. It is suggested that a comma be added.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are maintained for 1-2, 6-7, 10, 13-14, 46, 47, and 49. New claim rejections under 35 USC § 103 have been added to address the new claims 51-53.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 2, 10, 13, 46, 47, 49 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Chakraborty et al. (WO 2016/011306 A1) (ref. of record) in view of Huang et al. (US 2018/0311343 A1) (ref. of record).
With respect to claims 1, 49 and 51, Chakraborty teaches isolated nucleic acid molecules that encode one or more peptides or polypeptides of interest where the nucleic acid is mRNA (00050-00051 and 00058). With respect to claims 1, 49 and 51, Chakraborty teaches that the polynucleotides or the mRNA sequence can encode a cytokine including IL-12 (0001234 and 0001305). Chakraborty further teaches the polynucleotide encoding where the protein of interest is an antigen and where the antigen of interest is TNFα, TNFβ, IFNα, IFNβ, IFNγ, IL-I, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, and IL-12 (0001015, 0001221, and 0001305).
With respect to claims 1 and 49, Chakraborty teaches the mRNA contains an untranslated region (UTR) sequence (0065). With respect to claims 1, 2, and 49, Chakraborty teaches the polynucleotide may contain one or more microRNA target sequences (000475) and further teaches the polynucleotide can include at least one or three miRNA-binding sites in the 3’UTR to direct cytotoxic or cytoprotective mRNA therapeutics to specific cells including normal or cancerous cells (000487-000488 and 000529-000530). Additionally, Chakraborty teaches the microRNA sequences can be within the 5’UTR (000541). With respect to claims 1 and 49, Chakraborty teaches the polynucleotide expression can be determined by the miRNA expressed in the cells and miRNA binding sites in the polynucleotide (000528). Chakraborty teaches that polynucleotides can be engineered for targeted expression in specific cell types by understanding of the expression patterns of micro RNA in different cell types and that through the introduction of tissue-specific microRNA binding sites, polynucleotides can be designed for protein expression a tissue or for a biological condition (000483-000484 and 000532). Accordingly, Chakraborty teaches the miRNA targeting sequences allow for the different expression of the coding sequences in different cells types within the target organ or tissue. With respect to claims 1 and 49, Chakraborty teaches that the polynucleotide can be engineered to include microRNA sites that are expressed in different tissues and can be engineered to include both miRNA-192 and miRNA-122 to regulated the expression of the polynucleotide in the liver and kidneys of the subject (00527).
Chakraborty does not explicitly teach at least three of the miRNA binding sites are not the same as recited in claims 1 and 49. Additionally, Chakraborty does not explicitly teach where the at least three miRNA binding site sequences provide multi-organ protection by reducing expression of the cytokine polypeptide in at least three organs selected from the group consisting of liver, brain, lung, breast, pancreas, kidney, and colon as recited in claims 1 and 49.
However, Huang teaches an isolated mRNA sequence with at least three micro-RNA (miRNA) binding sites where the miRNA are the same or different (0603 and 0608). Huang teaches the miRNA can be the same or any combination from those in table 3 which includes miRNA-122 (0603). Huang teaches that the miRNA binding sites incorporated into a polynucleotide can target the same or different tissues in the body (0608).
In further support, Chakraborty teaches RNA sequence where at least two of the miRNA binding sites are not the same and that these sequences may down-regulate the expression of the polynucleotide in different tissues or organs (000558-000559). Chakraborty teaches that polynucleotides can be engineered for targeted expression in specific cell types by understanding of the expression patterns of miRNA in different cell types and that through the introduction of tissue-specific miRNA binding sites, polynucleotides can be designed for protein expression a tissue or for a biological condition (000483-000484 and 000532) and teaches that the differential expression of microRNA occurs in various cancer cells/tissues and other diseases (000518-000519). Chakraborty further teaches examples of tissues where microRNAs are known to regulate mRNA including liver (miRNA-122), muscle (miRNA-133, miRNA-206, miRNA-208), endothelial cells (miRNA-17-92, miRNA-126), myeloid cells (miRNA-142-3p, miRNA-142-5p, miRNA-16, miRNA-21, miRNA-223, miRNA-24, miRNA-27), adipose tissue (let-7, miRNA-30c), heart (miRNA-1d, miRNA-149), kidney (miRNA-192, miRNA-194, miRNA-204), lung epithelial cells (let-7, miRNA-133, miRNA-126), and pancreas (miRNA-375) (000480 and 000505). Additionally, Chakraborty teaches that the polynucleotide can be engineered to include microRNA sites that are expressed in different tissues and can be engineered to include miRNA-192 and miRNA-122 to regulated the expression of the polynucleotide in the liver and kidneys of the subject (00527). Chakraborty further teaches that miRNA-122 is abundant in the liver and it can be used to inhibit the expression of the gene of interest if it is not intended to be targeted to the liver (000480 and 000483-000484).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the isolated mRNA sequence of Chakraborty to include at least three miRNA binding sites that are different from one another for the benefit of targeting the same or different tissues in the body as taught by Huang and Chakraborty. It would have been obvious to one of ordinary skill in the art based on the teachings of Huang and Chakraborty that more than two miRNA binding sites can be included in the isolated mRNA and all three can be different, since Huang teaches Huang teaches an isolated mRNA sequence with at least three micro-RNA (miRNA) binding sites where the miRNA are different and Chakraborty teaches RNA sequences where at least two of the miRNA binding sites are not the same. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the isolated mRNA sequence of Chakraborty to include at least three miRNA binding sites, since isolated mRNA sequences were known to contain three different miRNA binding sites as taught by Huang and Chakraborty teaches the mRNA sequence containing at least three miRNA binding sites and where at least two are different.
Similarly, one of ordinary skill in the art would have been motivated to modify the isolated mRNA sequence of Chakraborty to include at least three different miRNA binding sites that prevent or reduce the expression of mRNA sequence in at least three different organs including liver, brain, lung, breast, pancreas, kidney, and colon, for the benefit of targeting the expression to the particular organ and tissue in need of treatment and preventing expression in organs or tissues which are not the targeted organ. It would have been obvious one of ordinary skill in the art that at least three different organs, including the claimed organs, could have reduced expression of the mRNA by incorporating different miRNAs reducing in the expression in those organs, since Huang teaches similar isolated mRNA sequence with at least three micro-RNA (miRNA) binding sites where the miRNA are the same or different and Chakraborty teaches the RNA sequence where at least two of the miRNA binding sites are not the same and that these sequences may down-regulate the expression of the polynucleotide in different tissues or organs. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the isolated mRNA sequence of Chakraborty to include at least three miRNA binding sites, since isolated mRNA sequences were known to contain three different miRNA binding sites as taught by Huang and Chakraborty teaches the mRNA sequence containing at least two miRNA binding sites and where at least two are different and down-regulate the expression in at least two organs where the organs are at least the liver, lung, pancreas and/or kidney (000559). Additionally, it was known that particular miRNA sequences could be used to prevent off-target or particular organ expression of mRNA as taught by Chakraborty.
Chakraborty does not explicitly teach the isolated mRNA sequence where the first and cell types are different selections from non-neoplastic cells, a transformed cell phenotype, a pre-cancerous phenotype and/or a neoplastic phenotype as recited claim 1. However, Chakraborty teaches that the differential expression of microRNA occurs in various cancer cells/tissues and other diseases (000518-000519). Additionally, Chakraborty teaches the polynucleotide expression can be determined by the miRNA expressed in the cells and miRNA binding sites in the polynucleotide (000528). Chakraborty teaches that polynucleotides can be engineered for targeted expression in specific cell types by understanding of the expression patterns of miRNA in different cell types and that through the introduction of tissue-specific miRNA binding sites, polynucleotides can be designed for protein expression a tissue or for a biological condition (000483-000484 and 000532). In addition, Chakraborty teaches that the polynucleotide can be engineered to include microRNA sites that are expressed in different tissues and can be engineered to include miRNA-192 and miRNA-122 to regulated the expression of the polynucleotide in the liver and kidneys of the subject (00527). Accordingly, at the effect time of filing of the claimed invention, it would have been obvious to one of ordinary skill in the art to modify the isolated RNA sequence of Chakraborty so that the miRNA binding sites allow for differential expression in the cell types listed in claim 9 based on the teachings in Chakraborty that different cell types can be targeted based on the miRNAs in mRNA. Furthermore, one would have been motivated to modify the isolated RNA sequence of so that the miRNA binding sites allow for differential expression in the cell types listed in claim 1, since these are known cell types and Chakraborty teaches using miRNA sequences to control expression in cancer cells and different cell types within a tissue. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the isolated RNA sequence of Chakraborty so that the miRNA binding sites allow for differential expression in the cell types listed in claim 1 for these reasons.
With respect to claims 1 and 49, for immune specific miRNAs, Chakraborty teaches miRNA-125b; miRNA-148a; and miRNA-30 (000497) and for liver specific miRNAs, Chakraborty teaches miRNA-122; miRNA-199; miRNA-194. Chakraborty teaches additional miRNA binding sites are disclosed in provisional applications No. 61/753661 Table 9, No. 61/754159 Table 9, and No. 61/758921 Table 7. Table 9 of No. 61/753661 includes miRNA-122; miRNA-125a; miRNA-125b; miRNA-199, miRNA-124; Let-7; miRNA-148a; miRNA-148b; miRNA-375; miRNA-143; miRNA-145; miRNA-192; miRNA-194; miRNA-204; miRNA-215; and miRNA-30.
With respect to claim 10, Chakraborty teaches engineering mRNA sequence so that there is differential expression of the coding sequence including liver and lung (00019 and 000431). With respect to claim 13, Chakraborty teaches the mRNA contains at least one open reading frame encoding at least one polypeptide of interest and teaches a construct can include more than one open reading frame (00071, 000368, and 000370).
Chakraborty does not teach the isolated mRNA sequence where the three miRNA binding site sequences are complementary to miRNA-122, Let-7b, and miRNA-192 as recited claim 46 or where the miRNA binding site sequences are complementary to miRNA-124a and miRNA-375 as recited claim 47. However, Chakraborty teaches miRNA binding sites that can be included in isolate mRNA sequence are disclosed in provisional applications No. 61/753661 Table 9, No. 61/754159 Table 9, and No. 61/758921 Table 7. Table 9 of No. 61/753661 includes miRNA-122; miRNA-125a; miRNA-125b; miRNA-199, miRNA-124; Let-7; miRNA-148a; miRNA-148b; miRNA-375; miRNA-143; miRNA-145; miRNA-192; miRNA-194; miRNA-204; miRNA-215; and miRNA-30. Additionally, Chakraborty teaches the polynucleotide expression can be determined by the miRNA expressed in the cells and miRNA binding sites in the polynucleotide (000528). Chakraborty teaches that polynucleotides can be engineered for targeted expression in specific cell types by understanding of the expression patterns of micro RNA in different cell types and that through the introduction of tissue-specific microRNA binding sites, polynucleotides can be designed for protein expression a tissue or for a biological condition (000483-000484 and 000532). Chakraborty further teaches Let-7b is expressed in adipose tissue, miRNA-122 is expressed in liver, miRNA-192 is expressed in kidney, and miRNA-375 is expressed in the pancreas (000480 and 000505). Accordingly, at the effect time of filing of the claimed invention, it would have been obvious to one of ordinary skill in the art to modify the isolated RNA sequence of Chakraborty so that the miRNA binding sites are those listed in claims 46 and 47 based on the teachings in Chakraborty that different cell types can be targeted based on the miRNAs in mRNA and Chakraborty teaches the listed miRNAs. Furthermore, one would have been motivated to modify the isolated RNA sequence of so that the miRNA binding sites are those listed in the claims 46 and 47 to control the expression in different cell types, Chakraborty teaches using different miRNA sequences to control expression in cancer cells and different cell types within a tissue. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the isolated RNA sequence of Chakraborty so that the miRNA binding sites are those listed in claims 46 and 47 for these reasons and these miRNAs and their effects on tissue/cell type specific expression were known and the effects would be predictable.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 6 and 7 are rejected under 35 U.S.C. 103(a) as being unpatentable over Chakraborty in view of Huang (as applied to claims 1, 2, 10, 13, 46, 47, 49 and 51 above), and further in view of Califano et al. (US 2010/0197772 A1) (ref. of record).
The teachings of Chakraborty and Huang can be found in the previous rejection above.
Chakraborty does not teach that the miRNA binding sequence is SEQ ID NO: 1 as recited in claims 6 and 7. However, Califano teaches isolated nucleic acid sequences of micro RNAs (abstract) including a miRNA-122 sequence with 100% homology with SEQ ID NO: 1 (abstract, Table 1 and SEQ ID NO. 3048). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Chakraborty such that the miRNA-122 sequence has the sequence of SEQ ID NO: 1 for the purpose being able to have a mRNA construct containing a miRNA binding sequence. Furthermore, it would have been obvious to one skilled in the art to have further modified Chakraborty such that the miRNA-122 sequence has the sequence of SEQ ID NO: 1, since the particular miRNA-122 binding sequence was known as taught by Califano. Such a modification merely involves the substitution of one known binding sequence for miRNA-122 for another. Additionally, the substitution of one known material (i.e. binding sequence) for another known material (i.e. binding sequence) would have yielded predictable results (e.g. the manufacture of a mRNA with miRNA-122 binding sequence) to one of ordinary skill in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 52 and 53 are rejected under 35 U.S.C. 103(a) as being unpatentable over Chakraborty in view of Huang (as applied to claims 1, 2, 10, 13, 46, 47, 49 and 51 above), and further in view of Hyde et al. (US 2010/0136094 A1).
The teachings of Chakraborty and Huang can be found in the previous rejection above.
Chakraborty does not teach the isolated mRNA sequence where the first coding sequence encoding a first cytokine polypeptide is IL-12 and a second coding sequence encodes CXCL9 as recited in claims 52 and 53.
However, Hyde teaches a therapeutic composition that is configured to modulate one or more cytokines where the cytokines include TNFα, TNFβ, IFNα, IFNβ, IFNγ, IL-I, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, CCL2, CCL3, CCL4, CCL5, CXCL9 and CXCL10 (0026-0027 and 0123-124).
In further support, Chakraborty teaches that the isolated mRNA molecules can encode one or more peptides or polypeptides of interest (00050-00051 and 00058), that the mRNA sequence can encode a cytokine including TNFα, TNFβ, IFNα, IFNβ, IFNγ, IL-I, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, and IL-12 (0001015, 0001221, 0001234, and 0001305).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Chakraborty such that the isolated mRNA sequence includes one coding sequence for IL12 and a second coding sequence for CXCL9 for the purpose being able to have a mRNA construct containing multiple sequences encoding for known cytokine polypeptides as taught by Hyde. Furthermore, it would have been obvious to one skilled in the art to have further modified Chakraborty such that the isolated mRNA sequence includes one coding sequence for IL12 and a second coding sequence for CXCL9, since Chakraborty teaches the mRNA containing more than one polypeptide sequence and where the sequence is a cytokine including IL12, and Hyde teaches CXCL9 is another known cytokine included in a therapeutic compositions or modulated by therapeutic compositions. Such a modification involves the inclusion of another known cytokine.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Allowable Subject Matter
Claim 14 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Response to Arguments
Applicant's arguments filed Jul. 23, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that the reference, Brook (Exhibit A), provides evidence demonstrating the unexpected results achieved by the claimed invention (Remarks pg. 7 para. 2). However, this argument was not found to be persuasive, since the evidence or data presented in Brook is not commensurate in scope with the claimed invention. The mRNA construct taught by Brook encodes for specific polypeptides, and contains a sequence of miRNA binding sites which is referred to as the multiorgan protection (MOP) sequence (abstract). Brook does not disclose which or how many miRNA binding sites form the MOP sequence. Therefore, it is unclear whether the miRNA sequences are commensurate in scope with the claims.
Applicant argues that additional experimental data presented in Exhibit B demonstrates the anti-tumor efficacy of IL-12-MOP and the synergistic anti-tumor effects of IL-12-MOP combined with CXCL9-MOP where both constructs contain miR-122-5P, miR-192-5P, and miR-30a-5P (Remarks pg. 7 para. 3). Although the data shows the anti-tumor efficacy of IL-12-MOP and the synergistic anti-tumor effects of IL-12-MOP combined with CXCL9-MOP where both constructs contain miR-122-5P, miR-192-5P, and miR-30a-5P, the data is not commensurate in scope with the claim invention. The claimed mRNA sequence is broader than the mRNA sequences for generating the data in Exhibit B. Additionally, miR-30a-5P is not being claimed as one of the miRNAs. In addition, as stated in the MPEP 716.01(c) I, “Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant.” Attorney statements or arguments cannot take the place of evidence which must be supported by an appropriate affidavit or declaration. MPEP 716.01(c) II
Applicant argues that the claimed invention is directed to requiring at least three different miRNA binding site sequences that prevent the unwanted expression of the cytokine polypeptide in multiple organs and is not directed to the general concept of using individual miRNA binding site sequences to regulate expression in specific tissues (Remarks pg. 8 para. 2). Applicant further argues that Chakraborty broadly discloses including one or miRNA binding sites in the polynucleotides to direct targeting to specific cells, but not protection against unwanted expression across multiple different organs and does not teach the claimed combination of miRNAs (Remarks pg. 8 para. 3). This argument was not found to be persuasive, since Chakraborty teaches a RNA sequence where at least two of the miRNA binding sites are not the same and that these sequences may down-regulate the expression of the polynucleotide in different tissues or organs (000558-000559). Chakraborty teaches that polynucleotides can be engineered for targeted expression in specific cell types by understanding of the expression patterns of miRNA in different cell types and that through the introduction of tissue-specific miRNA binding sites, polynucleotides can be designed for protein expression a tissue or for a biological condition (000483-000484 and 000532) and teaches that the differential expression of microRNA occurs in various cancer cells/tissues and other diseases (000518-000519). Therefore, it was known that particular miRNA sequences could be used to prevent off-target or particular organ expression of mRNA. It is maintained it would have been obvious to one of ordinary skill in the art based on these teachings that multiple organs, not just two, can have the mRNA expression reduced by the inclusion of multiple specific miRNA binding site sequences in the mRNA sequence.
Applicant argues that Chakraborty only discloses organ-level regulation with two organs, the liver and kidney, with two miRNA binding sites and does not teach additional organs such as the lungs, pancreas, and heart which Brook demonstrates are subject to off-target expression (Remarks pg. 8-9 bridging para.). These arguments were not found to be persuasive, since one of ordinary skill in the art could have easily conceived of multiple organs based on the disclosure of Chakraborty including additional organs such as the lungs, pancreas, and heart.
It is maintained that it would have been obvious one of ordinary skill in the art that at least three different organs, including the claimed organs, could have reduced expression of the mRNA by incorporating different miRNAs reducing in the expression in those organs, since Huang teaches similar isolated mRNA sequence with at least three micro-RNA (miRNA) binding sites where the miRNA are the same or different and Chakraborty teaches the RNA sequence where at least two of the miRNA binding sites are not the same and that these sequences may down-regulate the expression of the polynucleotide in different tissues or organs Chakraborty further teaches examples of tissues where microRNAs are known to regulate mRNA including liver, muscle, endothelial cells, myeloid cells, adipose tissue, heart kidney, lung epithelial cells and pancreas (000480 and 000505).
Applicant argues that Huang does not remedy the deficiencies of Chakraborty, since Huang is directed to STING pathway activation and the induction of natural interferon production, Huang does not address the toxicity of systemic cytokine exposure, and Huang does not provide any motivation to select three different miRNA binding sites targeting different organs for multi-organ protection (Remarks pg. 9 para. 2). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Chakraborty is being relied upon for a mRNA encoding a cytokine polypeptide and Huang is being relied upon for further support of mRNA sequences encoding polypeptides with at least three different miRNA sequences was known. Additionally, Chakraborty provides motivation for including multiple miRNA sequences to down-regulated the mRNA in different organs (000558-000559). Chakraborty teaches that polynucleotides can be engineered for targeted expression in specific cell types by understanding of the expression patterns of miRNA in different cell types and that through the introduction of tissue-specific miRNA binding sites, polynucleotides can be designed for protein expression a tissue or for a biological condition (000483-000484 and 000532) and teaches that the differential expression of microRNA occurs in various cancer cells/tissues and other diseases (000518-000519). Based the teachings of Huang and Chakraborty, one of ordinary skill in the art could have easily conceived an mRNA with at least three different miRNAs to down-regulate the expression in at least three different organs that are not the target of the mRNA. Applicant addressed each prior art reference separately and only with regard to the specific limitations of that reference. However, when the prior art references are taken as a whole, they teach that the skilled artisan knows each limitation as currently claimed.
Applicant argues that the claim requires a specific combination of at least three different miRNA binding site sequences for controlling mRNA biodistribution which is a strategy that is different from Chakraborty and has unexpected functional outcomes as demonstrated in Brook (Remarks pg. 9 para. 3). Applicant argues that Brook demonstrates that mRNA encoding the firefly luciferase (Luc) without a multiorgan protection (MOP) sequence was administered intravenously, Luc protein activity was observed systemically and the inclusion of MOP sequences enable targeted transcription translation (Remarks pg. 9 para. 4). Applicant argues that the results of Brook show that mRNA based therapeutics inherently involve the exposure of the mRNA to multiple organs, Chakraborty’s two-miRNA approach would only address two organs, the liver and kidneys, protected, and for cytokine-encoding mRNA systemic expression poses significant toxicity risks (Remarks pg. 9 para. 5). Applicant argues that the Brook data demonstrates that MOP with gene silencing miRNAs enabled tissue-specific control of transcription translation and MOP sequences had significantly decreased transcript translation in all distal organs and expression of the Luc at the injection site was maintained (Remarks pg. 10 para. 1). However, these arguments were not found to be persuasive, since as stated previously, the evidence or data presented in Brook is not commensurate in scope with the claimed invention. The mRNA construct taught by Brook that produces these results encodes for the specific polypeptide, Luc, and contains miRNA binding sites which is referred to as the multiorgan protection (MOP) sequence (abstract). Brook does not disclose which or how many miRNA binding sites form the MOP sequence. Therefore, it is unclear whether the miRNA sequences are commensurate in scope with the claims.
Applicant argues that the inclusion of a third miRNA binding site enables suppression in and protection of multiple organs (Remarks pg. 10 para. 1). Applicant argues the breath of protection of three miRNA binding sites is unexpected, since Chakraborty only teaches protecting the liver and kidney and Huang does not address cytokine toxicity or the combination of miRNA binding sites being used to achieve simultaneous multi-organ suppression (Remarks pg. 10 para. 3). This argument was not found to be persuasive, since Chakraborty teaches that the polynucleotide can be engineered to include microRNA sites that are expressed in different tissues so that the mRNA can be down regulated in those tissues. Chakraborty further gives an example where the mRNA can be engineered to include miRNA-192 and miRNA-122 to regulated the expression of the polynucleotide in the liver and kidneys of the subject (00527). Chakraborty further teaches that miRNA-122 is abundant in the liver and it can be used to inhibit the expression of the gene of interest if it is not intended to be targeted to the liver (000480 and 000483-000484). Therefore, it was known that particular miRNA sequences could be used to prevent off-target or particular organ expression of mRNA. Further, Chakraborty teaches RNA sequence where at least two of the miRNA binding sites are not the same and that these sequences may down-regulate the expression of the polynucleotide in different tissues or organs (000558-000559).
Applicant argues that the skilled artisan would not expect by adding a third miRNA binding site to the system of Chakraborty, one would transform a two-organ regulatory approach to a comprehensive multi-organ protection strategy (Remarks pg. 10 para. 2 and pg. 13 last para.). However, this argument was not found to be persuasive, since Chakraborty provides motivation for including multiple miRNA sequences to down-regulated the mRNA in different organs (000558-000559). Specifically, Chakraborty teaches that polynucleotides can be engineered for targeted expression in specific cell types by understanding of the expression patterns of miRNA in different cell types and that through the introduction of tissue-specific miRNA binding sites, polynucleotides can be designed for protein expression a tissue or for a biological condition (000483-000484 and 000532) and teaches that the differential expression of microRNA occurs in various cancer cells/tissues and other diseases (000518-000519). Additionally, Huang teaches mRNA sequences encoding polypeptides with at least three different miRNA sequences was known. Based the teachings of Huang and Chakraborty, one of ordinary skill in the art could have easily conceived an mRNA with at least three different miRNAs to down-regulate the expression in at least three different organs that are not the target of the mRNA.
Applicant further argues that another critical and unexpected feature of the claimed invention is that the multiple binding sites do not compromise the expression at the intended site of administration as shown in Brook and that the skilled artisan might expect that the multiple miRNA binding sites would reduce the overall transcript stability or translation efficiency (Remarks pg. 10-11 bridging para.). Applicant argues that Brook demonstrates that the IL-12-MOP was able to effect a 67-fold enhancement in antibody response in adult mice (Remarks pg. 11 para. 2). Applicant further argues that this result is unexpected, since the skilled artisan would expect that the addition of multiple miRNA binding sites would attenuate cytokine expression at ineffective levels and the prior art does not teach or suggest that cytokine-encoding mRNA with three different miRNA binding sites would retain sufficient expression to achieve potent adjuvant effects (Remarks pg. 11 para. 3). Applicant argues that Brooks further shows an additional unexpected therapeutic benefit of amplifying the humoral immunity to levels observed in healthy young adult mice when IL-12-MOP is administered to aged mice (Remarks pg. 11 para. 3). Applicant argues another advantage of the IL-12p70 and IL-12-MOP adjuvants shown in Brook is that both maintained significantly elevated antibody response for over one year post-immunization and that the prior art does not teach or suggest that incorporating three different miRNA binding sites into cytokine-encoding mRNA would enhance immune durability (Remarks pg. 11-12 bridging para.). These arguments were not found to be persuasive, since, as stated previously, the evidence or data presented in Brook is not commensurate in scope with the claimed invention. The mRNA construct taught by Brook that produces these results encodes for the specific cytokine IL12, and containing miRNA binding sites which is referred to as the multiorgan protection (MOP) sequence (abstract). Brook does not disclose which or how many miRNA binding sites form the MOP sequence. Therefore, it is unclear whether the miRNA sequences are commensurate in scope with the claims.
Applicant argues that the data presented in Exhibit B further supports that the isolated mRNA sequence has unexpected results. Specifically, Example 1 shows that a single dose of DMPCTx-IL-12-MOP, encoding IL-12, induces a dose-dependent tumor growth delay, tumor regression and complete response in animals compared to saline. Applicant argues that these results would not be predicted to retain sufficient biological activity, since the construct has three miRNA binding sites which would be expected to attenuate cytokine expression (Remarks pg. 12 para. 2). Applicant argues that Example 2 of Exhibit B demonstrates that DMPCTx-CXCL9-MOP, encoding a different cytokine, CXCL9, also demonstrated anti-tumor activity in the cancer model confirming the effects of MOP extends across multiple cytokines and would not be predicted by the prior art (Remarks pg. 13 para. 1). Although the data shows the anti-tumor efficacy of IL-12-MOP and CXCL9-MOP where both constructs contain miR-122-5P, miR-192-5P, and miR-30a-5P, the data is not commensurate in scope with the claim invention. The claimed mRNA sequence is broader than the mRNA sequences for generating the data in Exhibit B. Additionally, miR-30a-5P is not being claimed as one of the miRNAs. In addition, as stated in the MPEP 716.01(c) I, “Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant.” Attorney statements or arguments cannot take the place of evidence which must be supported by an appropriate affidavit or declaration. MPEP 716.01(c) II
Applicant argues that Brook demonstrates that the claimed MOP architectures can be used as a generalizable delivery platform, and shows that it can be used for luciferase encoding, antigen encoding and cytokine encoding transcripts, and can be used in at least two different animal species (Remarks pg. 13 para. 2).
This arguments was not found to be persuasive, since, as stated previously, the evidence or data presented in Brook is not commensurate in scope with the claimed invention. The mRNA construct taught by Brook encodes for the specific multiorgan protection (MOP) sequence containing miRNA binding sites. Brook does not disclose which or how many miRNA binding sites form the MOP sequence. Therefore, it is unclear whether the miRNA sequences are commensurate in scope with the claims and whether the same effects would be predicted for the claimed miRNAs.
Applicant argues that Califano does not remedy the deficiencies of Chakraborty and Huang, since Califano merely disclosed the sequence of miRNA-122 and does not disclose or suggest the combination of at least three different miRNA binding site sequences or the motivation to combine three different miRNA binding sites for the purpose of achieving simultaneous protection across multiple organs (Remark pg. 14 para. 4). However, this argument was not found to be persuasive, since the arguments with respect to the rejections over Chakraborty and Huang were not found to be persuasive as explained above.
Additionally, the unexpected results demonstrated by Brook apply to claims 6 and 7 and would not been predicted by the teachings in Califano (Remarks pg. 14-15 bridging para.). However, this argument was not found to be persuasive, since the results presented in Brooks are not commensurate in scope with the claims as explained above.
Conclusion
No claims are allowed.
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 extension fee 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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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
