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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 18 February 2026 has been entered.
Response to Amendment
The amendment filed 18 February 2026 is acknowledged. Claims 1, 8, 10, 16, 20, 22, 26, 34, 35 are amended. Claims 13-15, 17, and 33 are canceled. Claims 36-40 are new.
Election/Restriction
As previously noted, Applicant's election with traverse of Group II (nucleic acid and nucleic acid composition) and species of (i) lipid nanoparticle; (ii) miR-142 target sequence; (iii) transthyretin promoter; (iv) nucleic acid encoding IL-2; (v) lentiviral vector in the reply filed on 24 February 2025 is acknowledged.
The requirement was deemed proper and was therefore made FINAL in the Office Action mailed 26 March 2025.
In regards to new claims 36-40, Applicant notes the mRNA vector is not a species of viral vector per se and therefore that the species election (v) is unclear, but request that these claims be considered along with the previously presented claims. For clarity of the record, the Examiner will consider the species election of lentiviral vector to read as an election of all types of vectors, but will rejoin the species of mRNA vectors for expedited prosecution; therefore claims 1, 8, 10, 16, 20, 21, and 36-40 read on an elected or rejoined species.
Claim Status
Claims 1, 8, 10, 16, 20-22, 26, and 34-40 are pending. Claims 22, 26, 34, 35 are withdrawn as directed towards an unelected invention or species, there being no allowable generic or linking claim. Claims 1, 8, 10, 16, 20, 21, and 36-40 are under examination in the instant office action.
Withdrawal of Objections
For clarity of the record, the Examiner notes that the objection to the Drawings in the Final dated 18 August 2025 was overcome in the after-final amendment dated 20 January 2026 as noted in the PTOL-303 dated 28 January 2026.
For clarity of the record, the Examiner notes that the objection to the Specification in the Final dated 18 August 2025 was overcome in the after-final amendment dated 20 January 2026 as noted in the PTOL-303 dated 28 January 2026.
Withdrawal of Rejections
For clarity of the record, the Examiner notes that the rejection of claims 1, 8, 10, 13-17, 20-21, and 33 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite in the Final dated 18 August 2025 was withdrawn in response to the after-final amendment dated 20 January 2026 as noted in the PTOL-303 dated 28 January 2026.
The rejection of claims 1, 8, 10, 13-14, 16 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over He et. al. “The Targeted Expression of the Human Interleukin-2/Interferon Α2b Fused Gene in α-Fetoprotein-Expressing Hepatocellular Carcinoma Cells.” Journal of cancer research and clinical oncology 125.2 (1999): 77–82. Web (Of record, cited in IDS dated 21 June 2022 NPL No: 34) in view of Annoni A, et. al. In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic tolerance. Blood. 2009 Dec 10;114(25):5152-61. doi: 10.1182/blood-2009-04-214569. PMID: 19794140; PMCID: PMC2792211 (Of record, 892) as evidenced by Brown BD, et. al. A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice. Blood. 2007 Dec 15;110(13):4144-52. doi: 10.1182/blood-2007-03-078493. Epub 2007 Aug 28. PMID: 17726165 (Of record, 892) is withdrawn in view of the amendment to the claims.
The rejection of claim 15 under 35 U.S.C. 103 as being unpatentable over He et. al. in view of Annoni et. al. as evidenced by Brown et. al. as applied to claim 1, above, and further in view of Mátrai J, et. al. Hepatocyte-targeted expression by integrase-defective lentiviral vectors induces antigen-specific tolerance in mice with low genotoxic risk. Hepatology. 2011 May;53(5):1696-707. doi: 10.1002/hep.24230. PMID: 21520180; PMCID: PMC3112259 (Of record, cited in IDS dated 6/21/2022) is withdrawn in view of the amendment to the claims.
The rejection of claim 21 under 35 U.S.C. 103 as being unpatentable over He et. al. in view of Annoni et. al. as evidenced by Brown et. al. as applied to claims 1 and 20 above, and further in view of Mazzolini G, et. al. Adenoviral gene transfer of interleukin 12 into tumors synergizes with adoptive T cell therapy both at the induction and effector level. Hum Gene Ther. 2000 Jan 1;11(1):113-25. doi: 10.1089/10430340050016201. PMID: 10646644 (Of Record, 892) is withdrawn in view of the amendment to the claims.
The rejection of claim 33 under 35 U.S.C. 103 as being unpatentable over He et. al. in view of Annoni et. al. as evidenced by Brown et. al. as applied to claim 1, above, and further in view of Cullis PR, Hope MJ. Lipid Nanoparticle Systems for Enabling Gene Therapies. Mol Ther. 2017 Jul 5;25(7):1467-1475. doi: 10.1016/j.ymthe.2017.03.013. Epub 2017 Apr 13. PMID: 28412170; PMCID: PMC5498813 is withdrawn in view of the amendment to the claims.
The provisional rejections of claims 1, 10-17, 20-21, and 33 on the ground of nonstatutory double patenting over copending Application No. 18038140 (“the ‘140 application”) in view of Annoni et. al., Brown et. al., He et. al., Matrai et. al., and Cullis et. al. are withdrawn in view of the amendment to the claims.
Claim Rejections - 35 USC § 103- New, necessitated by Amendment
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 8, 10, 16, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2012143401 to Ferry et. al. published 26 October 2012 in view of He et. al. “The Targeted Expression of the Human Interleukin-2/Interferon Α2b Fused Gene in α-Fetoprotein-Expressing Hepatocellular Carcinoma Cells.” Journal of cancer research and clinical oncology 125.2 (1999): 77–82. Web (Of record, cited in IDS dated 21 June 2022 NPL No: 34).
Claim interpretation: Instant claim 1 is directed towards a lentiviral vector comprising a nucleotide sequence encoding IL-2, wherein the nucleotide sequence is adapted to be targeted to the liver, wherein the nucleotide sequence is operably linked to a liver-specific promoter and/or enhancer and to one or more miR-142 and/or miR-126 target sequences. Regarding the phrase “operably linked”, the examiner notes that there is no special definition of “operably linked” in the instant specification. A person of ordinary skill in the art would understand that “operably linked” means that the nucleotide sequences are linked in a manner which connects their functions such that they operate together.
Ferry et. al. teaches nucleic acid constructs and vector for use in gene transfer and gene therapy applications for obtaining tissue-specific expression of a transgene of interest. Ferry et. al. teaches the lentiviral vector PTKM12 designed for liver-specific transgene expression (reads on “adapted to be targeted to the liver”) comprising the transgene of interest controlled by a Tet-On transthyretin promoter (mTTR) operably linked to four target sequences of miR-142 and TetR-KRAB (Figure 2; p. 15 lines 15-30) (reads on claims 1, 8, 10).
Regarding claim 16, Ferry et. al. teaches vectors comprising the nucleic acids of the invention including viruses (p. 12 lines 20-30) and lentiviral vectors (p. 13 line 8) (reads on viral particle comprising the nucleotide sequences).
Regarding claim 20, Ferry et. al. teaches a pharmaceutical composition for treating a patient by gene therapy comprising a therapeutically effective amount of a vector of the present invention (p. 14 line 30- p. 15 line 4).
Ferry et. al. teaches that the transgene of interest is selected from a group wherein the group includes interleukins (p. 14 lines 2-5).
Ferry et. al. does not explicitly teach that the gene of interest is interleukin 2 (IL-2).
This deficiency is resolved by He et. al.
He et. al. teaches the use of a liver-specific promoter and a tumor-specific ɑ-fetoprotein (AFP) enhancer to achieve regulated expression of the cytokine interleukin-2/interferon ɑ2b fused gene for the treatment of hepatocellular carcinoma (equivalent to targeted to the liver). Specifically, He et. al. teaches a retroviral vector comprising a liver-specific albumin promoter and IL-2/IFNɑ2b fusion (Fig. 1).
Regarding claim 16, He et. al. teaches packaging of viral particle with the L(FL-IL-2/IFNɑ2b)SN retrovirus and transfection of the recombinant retrovirus into HCC cells (p 78 Col. 2-p 79 Col. 1 “Packaging of viral particles” and “Transfection of recombinant retrovirus into HCC cells” sections).
Regarding claim 20, He et. al. teaches that a composition of cells infected with the IL-2/IFNɑ fused gene in hepatoma cells (equivalent to a pharmaceutical composition comprising the instant nucleic acid and a carrier, diluent, or excipient because the living cells require a buffer (reads on carrier or diluent) to remain alive) stimulated anti-tumor immunity against the tumor cells after they were administered to nude mice (See Fig. 6, Discussion p. 81-82).
He et. al. further teaches “compared with general cytokine biotherapy, gene therapy has not only fewer side-effects, but also a stronger antitumor response because of the high concentration of cytokines at a local tumor site […] Thus, our study of the targeted expression of the IL-2/IFNɑ fused cDNA in human HCC cells cannot only provide experimental data for treatment of HCC but may also pave the way for the use of the IL-2/IFNɑ fused gene in prevention and treatment of metastasis of HCC” (p 82, Col. 1, Discussion).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the IL-2 transgene of He et. al. in the liver-specific vector of Ferry et. al. in order to benefit from the inducible liver-specific expression for improved gene therapy as taught by Ferry et. al combined with the benefits of local IL-2 treatment with fewer side effects. This would have a reasonable expectation of success because Ferry et. al. teaches that the target gene may be an interleukin and He et. al. teaches gene therapy using a liver-specific promoter controlling IL-2 expression.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2012143401 to Ferry et. al. published 26 October 2012 in view of He et. al. (cited in IDS dated 21 June 2022 ) applied to claims 1 and 20 above, and further in view of Mazzolini G, et. al. Adenoviral gene transfer of interleukin 12 into tumors synergizes with adoptive T cell therapy both at the induction and effector level. Hum Gene Ther. 2000 Jan 1;11(1):113-25. doi: 10.1089/10430340050016201. PMID: 10646644 (Of Record, 892 dated 3/26/2025).
Claim 21 recites a pharmaceutical composition of claim 20, wherein the pharmaceutical composition further comprises a population of T cells.
The teachings of Ferry et. al. in view of He et. al. are in the 103 rejection above.
Ferry et. al. in view of He et. al. does not teach the pharmaceutical composition further comprising T cells.
Mazzolini et. al. teaches a method and composition for the gene therapy of a hepatic tumor comprising and adenoviral vector expressing IL-12 and adoptive transfer of CD8+ T cells (Abstract, entire document). Mazzolini et. al. further teaches that adenoviral transfer of IL-12 into CT26 (hepatic) tumors has a synergistic effect with adoptive transfer of antitumor T lymphocytes (Fig. 4 and 5, p 119-121). Mazzolini et. al. teaches that “we postulate that protocols of adoptive immunotherapy will benefit from previous active immunotherapy approaches performed on the same patient, which thereby augment the number of responding T cells available for their subsequent in vitro expansion. Among the candidates for those active therapy procedures are the gene transfer of cytokines or costimulatory molecules (p 122 Col. 2). Mazzolini et. al. also teach that IL-2 alone delivered in the adoptive transfer process did not display anti-tumor activity by themselves (p 123 Col. 1).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the IL-2 expressing cytokine gene therapy of Ferry et. al. in view of He et. al. in a composition with the adoptive T cell therapy as taught by Mazzolini et. al., resulting in a composition of retroviruses targeting hepatic cellular carcinoma with IL-2/IFNɑ expressing retroviral vector and anti-tumor CD8+ T cells. This would have a predictable effect because He et. al. teach that tumor-locally expressed IL-2 stimulates anti-tumor T-cell activity better than systemic IL-2, and Mazzolini et. al. teaches that cytokine therapy in combination with adoptive T cell transfer has a synergistic effect.
Claims 36-39 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2012143401 to Ferry et. al. published 26 October 2012 in view of He et. al. (Of record, cited in IDS dated 21 June 2022 NPL No: 34), and further in view of Cullis PR, Hope MJ. Lipid Nanoparticle Systems for Enabling Gene Therapies. Mol Ther. 2017 Jul 5;25(7):1467-1475. doi: 10.1016/j.ymthe.2017.03.013. Epub 2017 Apr 13. PMID: 28412170; PMCID: PMC5498813 (Of record, 892 dated 3/26/2025).
Claim interpretation: Instant claim 36 is directed towards an mRNA vector comprising a nucleotide sequence encoding IL-2, wherein the nucleotide sequence is adapted to be targeted to the liver, wherein the nucleotide sequence is operably linked to a liver-specific promoter and/or enhancer and to one or more miR-142 and/or miR-126 target sequences. Regarding the phrase “operably linked”, the examiner notes that there is no special definition of “operably linked” in the instant specification. A person of ordinary skill in the art would understand that “operably linked” means that the nucleotide sequences are linked in a manner which connects their functions such that they operate together.
Ferry et. al. teaches nucleic acid constructs and vector for use in gene transfer and gene therapy applications for obtaining tissue-specific expression of a transgene of interest. Ferry et. al. teaches the lentiviral vector PTKM12 designed for liver-specific transgene expression (reads on “adapted to be targeted to the liver”) comprising the transgene of interest controlled by a Tet-On transthyretin promoter (mTTR) operably linked to four target sequences of miR-142 and TetR-KRAB (Figure 2; p. 15 lines 15-30) (reads on claims 36, 37). Ferry et. al. teaches that the vector for delivery of the nucleic acid may be a non-viral delivery system (p. 13 lines 1-5).
Regarding claim 38, Ferry et. al. teaches vectors comprising the nucleic acids of the invention including viruses (p. 12 lines 20-30)
Regarding claim 39, Ferry et. al. teaches a pharmaceutical composition for treating a patient by gene therapy comprising a therapeutically effective amount of a vector of the present invention (p. 14 line 30- p. 15 line 4).
Ferry et. al. teaches that the transgene of interest is selected from a group wherein the group includes interleukins (p. 14 lines 2-5).
Ferry et. al. does not explicitly teach that the gene of interest is IL-2.
This deficiency is resolved by He et. al.
He et. al. teaches the use of a liver-specific promoter and a tumor-specific ɑ-fetoprotein (AFP) enhancer to achieve regulated expression of the cytokine interleukin-2/interferon ɑ2b fused gene for the treatment of hepatocellular carcinoma (equivalent to targeted to the liver). Specifically, He et. al. teaches a retroviral vector comprising a liver-specific albumin promoter and IL-2/IFNɑ2b fusion (Fig. 1).
Regarding claim 16, He et. al. teaches packaging of viral particle with the L(FL-IL-2/IFNɑ2b)SN retrovirus and transfection of the recombinant retrovirus into HCC cells (p 78 Col. 2-p 79 Col. 1 “Packaging of viral particles” and “Transfection of recombinant retrovirus into HCC cells” sections).
Regarding claim 20, He et. al. teaches that a composition of cells infected with the IL-2/IFNɑ fused gene in hepatoma cells (equivalent to a pharmaceutical composition comprising the instant nucleic acid and a carrier, diluent, or excipient because the living cells require a buffer (reads on carrier or diluent) to remain alive) stimulated anti-tumor immunity against the tumor cells after they were administered to nude mice (See Fig. 6, Discussion p. 81-82).
He et. al. further teaches “compared with general cytokine biotherapy, gene therapy has not only fewer side-effects, but also a stronger antitumor response because of the high concentration of cytokines at a local tumor site […] Thus, our study of the targeted expression of the IL-2/IFNɑ fused cDNA in human HCC cells cannot only provide experimental data for treatment of HCC but may also pave the way for the use of the IL-2/IFNɑ fused gene in prevention and treatment of metastasis of HCC” (p 82, Col. 1, Discussion).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the IL-2 transgene of He et. al. in the liver-specific vector of Ferry et. al. in order to benefit from the inducible liver-specific expression for improved gene therapy as taught by Ferry et. al combined with the benefits of local IL-2 treatment with fewer side effects. This would have a reasonable expectation of success because Ferry et. al. teaches that the target gene may be an interleukin and He et. al. teaches gene therapy using a liver-specific promoter controlling IL-2 expression.
Ferry et. al. in view of He et. al. do not explicitly teach wherein the vector is an mRNA vector.
This deficiency is resolved by Cullis et. al.
Cullis et. al. teaches that LNP systems are designed to solved the problem of delivery of genetic drugs such as mRNA to treat diseases. Cullis et. al. teaches that LNP systems has been designed to contain siRNA to silence genes in hepatocytes following i.v. administration (p 1468 Col. 2-1470 Col. 1 “LNP siRNA Systems: Liver Targets”. Cullis et. al. further teaches that these LNP siRNA systems can be applied to load LNP mRNA systems, and that additional optimization changes can be made to the LNP mRNA systems: “Thus, while LNP mRNA systems containing MC3 exhibit appreciable gene expression in hepatocytes following i.v. administration, cationic lipids optimized for maximum mRNA delivery can result in 20-fold higher expression levels (see https://acuitastx.com). These expression levels are sufficiently high that therapeutic levels of proteins such as erythropoietin can be achieved at dose levels as low as 0.03 mg mRNA/kg body weight in non-human primates.34 These results indicate the potential for utilizing the liver as a factory for protein replacement protocols or as a way to introduce therapeutic proteins, such as monoclonal antibodies, to target malignancies or other pathologies” (p 1471 Col. 1-2 “LNP mRNA and Plasmid DNA Systems”). Cullis et. al. teaches that LNP technology has advantages of “potency, payload, and design flexibility” (Abstract, see also Future perspectives p. 1473).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to apply the LNP mRNA technology for as an alternate vector for delivery of the nucleic acid of Ferry et. al. in view of He et. al. in order to design a gene therapy to deliver the nucleic acid of Ferry et. al. with to express the fusion cytokine of He et. al. to the liver in LNPs as taught by Cullis et. al. and to benefit from the potency, payload, and design advantages as taught by Cullis et. al. This would have a predictable effect because both He et. al. and Cullis et. al. teach liver-targeted gene therapy for expression of therapeutic proteins.
Claims 40 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2012143401 to Ferry et. al. published 26 October 2012 in view of He et. al. (Of record, cited in IDS dated 21 June 2022 NPL No: 34), and further in view of Cullis PR, Hope MJ. Lipid Nanoparticle Systems for Enabling Gene Therapies. Mol Ther. 2017 Jul 5;25(7):1467-1475. doi: 10.1016/j.ymthe.2017.03.013. Epub 2017 Apr 13. PMID: 28412170; PMCID: PMC5498813 (Of record, 892 dated 3/26/2025), and in further view of Mazzolini G, et. al. Adenoviral gene transfer of interleukin 12 into tumors synergizes with adoptive T cell therapy both at the induction and effector level. Hum Gene Ther. 2000 Jan 1;11(1):113-25. doi: 10.1089/10430340050016201. PMID: 10646644 (Of record, 892 dated 3/26/2025).
The teachings of Ferry et. al., He et. al., and Cullis et. al. in regards to claims 36-39 are in the 103 rejection above.
Ferry et. al. in view of He et. al. and Cullis et. al. does not teach the pharmaceutical composition further comprising T cells.
This deficiency is resolved by Mazzolini et. al.
Mazzolini et. al. teaches a method and composition for the gene therapy of a hepatic tumor comprising and adenoviral vector expressing IL-12 and adoptive transfer of CD8+ T cells (Abstract, entire document). Mazzolini et. al. further teaches that adenoviral transfer of IL-12 into CT26 (hepatic) tumors has a synergistic effect with adoptive transfer of antitumor T lymphocytes (Fig. 4 and 5, p 119-121). Mazzolini et. al. teaches that “we postulate that protocols of adoptive immunotherapy will benefit from previous active immunotherapy approaches performed on the same patient, which thereby augment the number of responding T cells available for their subsequent in vitro expansion. Among the candidates for those active therapy procedures are the gene transfer of cytokines or costimulatory molecules (p 122 Col. 2). Mazzolini et. al. also teach that IL-2 alone delivered in the adoptive transfer process did not display anti-tumor activity by themselves (p 123 Col. 1).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the IL-2 expressing cytokine gene therapy of Ferry et. al. in view of He et. al. and Cullis et. al. in a composition with the adoptive T cell therapy as taught by Mazzolini et. al., resulting in a composition of retroviruses targeting hepatic cellular carcinoma with IL-2/IFNɑ expressing retroviral vector and anti-tumor CD8+ T cells. This would have a predictable effect because He et. al. teach that tumor-locally expressed IL-2 stimulates anti-tumor T-cell activity better than systemic IL-2, and Mazzolini et. al. teaches that cytokine therapy in combination with adoptive T cell transfer has a synergistic effect.
Response to Arguments
The arguments filed 18 February 2026 have been fully considered but are not persuasive. The examiner notes that the instant arguments are in regards to He et. al. in view of Annoni et. al. as evidenced by Brown et. al., and therefore are in regards to a different combination of references. However, to the extent possible the Examiner has addressed the arguments as they might read on the new 103 rejection, above.
Applicant argues that He’s retroviral system does not suggest or make obvious a substitution to a lentiviral or mRNA vector of the instantly amended claims because He et. al. teaches that the retroviral system is superior; therefore, He et. al. is fundamentally technically incompatible with the present applications targeting of IL-2 expression to the liver (Remarks 2/18/26 p. 5-6). First, this is not persuasive in view of the new 103 rejection above. As described, Ferry et. al. explicitly discloses lentiviral vectors comprising all of the claimed elements except for the explicit recitation of interleukin-2; however, Ferry et. al. teaches the target transgene make be an interleukin, but does not specifically teach IL-2. He et. al. resolves this deficiency because He et. al. teaches and motivates the liver-specific expression of IL-2 for cytokine-based gene therapy (See 103 rejection above).
Next, the Examiner would like to note that this argument is unpersuasive because lentiviruses are retroviruses (Milone, Michael C., and Una O’Doherty. "Clinical use of lentiviral vectors." Leukemia 32.7 (2018): 1529-1541; see p. 1529 right column, ¶2).
Further, the full quote from He et. al. at the end of the abstract is “Therefore, this study illustrates the superiority of using transcriptionally targeted recombinant retrovirus vectors in cytokine-based gene therapy” (emphasis is the Examiner’s). Rather than emphasizing that no other vectors other than the particular MLV viral vector of He et. al. would be appropriate, He et. al. use the generic term retrovirus. Understood in the context of the entirety of He et. al., which emphasizes the use of liver-specific promoters for gene therapy, a person of ordinary skill in the art would not be discouraged from trying alternative embodiments of the vector. In fact, as described in the 103 above, He et. al. describe their study as “paving the way” for gene therapy in HCC and a person of ordinary skill in the art would understand that moving from a mouse in vivo model of HCC to other models or to gene therapy for the treatment of HCC in humans could require alternative embodiments such as retroviruses or non-viral vectors.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., suitability to express in slowly dividing non-cancerous liver cells) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The instant limitations “adapted to be targeted to the liver” and “liver-specific promoter and/or enhancer” do not limit the instant vector to use in slowly dividing liver cells.
In response to applicant's argument that "the present claims are directed to different vector systems with different functionalities to effectuate the inventive contribution of allowing IL-2 expression in liver cells to achieve the combined benefit of increased effector response and avoidance of IL-2 toxicity" (Remarks 2/18/26, p. 7), the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Further, as described in the 103 rejection above, He et. al. teaches that localized expression of IL-2 would reduce systemic toxicity.
In response to the arguments regarding Matrai et. al., the arguments are moot due to the cancellation of claim 15 (Remarks 2/18/26 p. 7-8).
In regards to the argument regarding Annoni/Brown and Mazzolini et. al., 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). These rejections are moot in view of the new 103 rejection above.
Double Patenting- New, necessitated by amendment
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, 8, 10, 16 and 20-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 18038140 (“the ‘140 application”) in view of WO 2012143401 to Ferry et. al. published 26 October 2012.
This is a provisional nonstatutory double patenting rejection.
The ‘140 application teaches a method of therapy by increasing liver immune response comprising administering an agent, or a nucleic acid comprising a nucleotide sequence encoding the agent that increases the number of Kupffer cells (claim 1) and wherein the agent is administered simultaneously, sequentially, or separately with an interleukin that binds to IL-2R or a nucleic acid comprising a nucleotide sequence encoding the interleukin (claim 2, regarding instant claim 1); wherein the interleukin is IL-2, IL-7, or IL-15 (claim 7, regarding instant claims 1). Claim 13 teaches wherein the agent or nucleic acid is administered as part of an adoptive T cell therapy; Claim 14 teaches wherein the agent is administered simultaneously with a population of T cells (reads on the composition further comprising T cells, instant claim 21). Claim 15 teaches a product comprising the agent that increases the number of Kupffer cells and an interleukin that binds to IL-2 receptor, or a nucleic acid comprising the nucleotide sequence encoding the interleukin (regarding instant claim 1). Claim 17 teaches the method of claim 2 wherein the interleukin or encoding nucleic acid is adapted to be targeted to the liver (regarding instant claim 1 and 20), claim 18 teaches the method of claim 2 wherein the interleukin or encoding nucleotide sequence is comprised in a nanoparticle. Claim 19 teaches the method of claim 2 wherein the nucleic acid is the form of a vector adapted for liver-specific expression of the nucleotide sequence (Regarding instant claim 1). Claim 20 teaches the method wherein the nucleic acid encoding the interleukin is operably linked to one or more expression control sequences for liver-specific expression (regarding instant claim 1). Claim 19 teaches wherein the one of more vectors comprises a liver-specific promoter or enhancer encoding the interleukin (regarding instant claim 1 and 10).
The claims of the ‘140 application partially render obvious the composition of the instant claims because a method of treating comprising administering a composition is not patentably distinct from the composition comprising a nucleic acid encoding an interleukin targeted to the liver of the instant claims.
Regarding claim 21, ‘140 application claim 14 teaches the method of claim 1 wherein the agent that increases Kupffer cells is administered with a population of T cells.
The ‘140 application does not explicitly teach the method comprising the agent to increase Kupffer cells, the nucleic acid encoding an interleukin, and a population of T cells. However, it would have been obvious to combine the method comprising the population of T cells of claim 14 with the method comprising the nucleic acid encoding an interleukin of claim 15 to predictable effect because the claims teach that both the T cells and the interleukin can be administered with the Kupffer agent.
Thus, the difference between the ‘140 application and the instant claims is that the ‘140 application does not teach that the nucleic acid is a lentiviral vector, comprising a particular liver-specific promoter and wherein the nucleic acid is operably linked to more than one miR-142 target sequence. The deficiency is resolved by Ferry et. al.
Ferry et. al. teaches nucleic acid constructs and vector for use in gene transfer and gene therapy applications for obtaining tissue-specific expression of a transgene of interest. Ferry et. al. teaches the lentiviral vector PTKM12 designed for liver-specific transgene expression (reads on “adapted to be targeted to the liver”) comprising the transgene of interest controlled by a Tet-On transthyretin promoter (mTTR) operably linked to four target sequences of miR-142 and TetR-KRAB (Figure 2; p. 15 lines 15-30) (reads on claims 1, 8, 10).
Regarding claim 16, Ferry et. al. teaches vectors comprising the nucleic acids of the invention including viruses (p. 12 lines 20-30) and lentiviral vectors (p. 13 line 8) (reads on viral particle comprising the nucleotide sequences).
Regarding claim 20, Ferry et. al. teaches a pharmaceutical composition for treating a patient by gene therapy comprising a therapeutically effective amount of a vector of the present invention (p. 14 line 30- p. 15 line 4).
Ferry et. al. teaches that the transgene of interest is selected from a group wherein the group includes interleukins (p. 14 lines 2-5).
Ferry et. al. does not explicitly teach that the gene of interest is IL-2.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the lentiviral vector of Ferry et. al. and add the four copies of the miR-142 target sequence of Ferry et. al. to the method of interleukin gene therapy of the ‘140 patent in order to benefit from the restriction of expression to liver cells in order benefit from an improved regulatable vector for gene therapy with tissue-specific expression as taught by Ferry et. al. This would have a predictable effect because both Ferry et. al. and the ‘140 patent are using gene therapy for liver cells.
Claims 36-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7, 14-15, and 17-21 of copending Application No. 18038140 (“the ‘140 application”) in view of WO 2012143401 to Ferry et. al. published 26 October 2012 and Cullis PR, Hope MJ. Lipid Nanoparticle Systems for Enabling Gene Therapies. Mol Ther. 2017 Jul 5;25(7):1467-1475. doi: 10.1016/j.ymthe.2017.03.013. Epub 2017 Apr 13. PMID: 28412170; PMCID: PMC5498813 (Of record, 892 dated 3/26/2025).
This is a provisional nonstatutory double patenting rejection.
The ‘140 application teaches a method of therapy by increasing liver immune response comprising administering an agent, or a nucleic acid comprising a nucleotide sequence encoding the agent that increases the number of Kupffer cells (claim 1) and wherein the agent is administered simultaneously, sequentially, or separately with an interleukin that binds to IL-2R or a nucleic acid comprising a nucleotide sequence encoding the interleukin (claim 2, regarding instant claim 36); wherein the interleukin is IL-2, IL-7, or IL-15 (claim 7, regarding instant claims 36). Claim 13 teaches wherein the agent or nucleic acid is administered as part of an adoptive T cell therapy; Claim 14 teaches wherein the agent is administered simultaneously with a population of T cells (reads on the composition further comprising T cells, instant claim 21). Claim 15 teaches a product comprising the agent that increases the number of Kupffer cells and an interleukin that binds to IL-2 receptor, or a nucleic acid comprising the nucleotide sequence encoding the interleukin (regarding instant claim 36). Claim 17 teaches the method of claim 2 wherein the interleukin or encoding nucleic acid is adapted to be targeted to the liver (regarding instant claim 36), claim 18 teaches the method of claim 2 wherein the interleukin or encoding nucleotide sequence is comprised in a nanoparticle (regarding instant claims 38). Claim 19 teaches the method of claim 2 wherein the nucleic acid is the form of a vector adapted for liver-specific expression of the nucleotide sequence (Regarding instant claim 36). Claim 20 teaches the method wherein the nucleic acid encoding the interleukin is operably linked to one or more expression control sequences for liver-specific expression (regarding instant claim 36). Claim 19 teaches wherein the one of more vectors comprises a liver-specific promoter or enhancer encoding the interleukin (regarding instant claim 36).
The claims of the ‘140 application partially render obvious the composition of the instant claims because a method of treating comprising administering a composition is not patentably distinct from the composition comprising a nucleic acid encoding an interleukin targeted to the liver of the instant claims.
Regarding claim 21, ‘140 application claim 14 teaches the method of claim 1 wherein the agent that increases Kupffer cells is administered with a population of T cells.
The ‘140 application does not explicitly teach the method comprising the agent to increase Kupffer cells, the nucleic acid encoding an interleukin, and a population of T cells. However, it would have been obvious to combine the method comprising the population of T cells of claim 14 with the method comprising the nucleic acid encoding an interleukin of claim 15 to predictable effect because the claims teach that both the T cells and the interleukin can be administered with the Kupffer agent.
Thus, the difference between the ‘140 application and the instant claims is that the ‘140 application does not teach that the nucleic acid is an mRNA and wherein the nucleic acid is operably linked to more than one miR-142 target sequence. The deficiency is resolved by Ferry et. al. and Cullis et. al.
Ferry et. al. teaches nucleic acid constructs and vector for use in gene transfer and gene therapy applications for obtaining tissue-specific expression of a transgene of interest. Ferry et. al. teaches the lentiviral vector PTKM12 designed for liver-specific transgene expression (reads on “adapted to be targeted to the liver”) comprising the transgene of interest controlled by a Tet-On transthyretin promoter (mTTR) operably linked to four target sequences of miR-142 and TetR-KRAB (Figure 2; p. 15 lines 15-30) (reads on claims 1, 8, 10).
Regarding claim 16, Ferry et. al. teaches vectors comprising the nucleic acids of the invention including viruses (p. 12 lines 20-30) and lentiviral vectors (p. 13 line 8) (reads on viral particle comprising the nucleotide sequences).
Regarding claim 20, Ferry et. al. teaches a pharmaceutical composition for treating a patient by gene therapy comprising a therapeutically effective amount of a vector of the present invention (p. 14 line 30- p. 15 line 4).
Ferry et. al. teaches that the transgene of interest is selected from a group wherein the group includes interleukins (p. 14 lines 2-5).
Ferry et. al. does not explicitly teach that the gene of interest is IL-2.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the lentiviral vector of Ferry et. al. and add the four copies of the miR-142 target sequence of Ferry et. al. to the method of interleukin gene therapy of the ‘140 patent in order to benefit from the restriction of expression to liver cells in order benefit from an improved regulatable vector for gene therapy with tissue-specific expression as taught by Ferry et. al. This would have a predictable effect because both Ferry et. al. and the ‘140 patent are using gene therapy for liver cells.
‘140 in view of Ferry et. al. does not teach the vector is an mRNA vector contained with a lipid nanoparticle.
This deficiency is resolved by Cullis et. al.
Cullis et. al. teaches that LNP systems are designed to solved the problem of delivery of genetic drugs such as mRNA to treat diseases. Cullis et. al. teaches that LNP systems has been designed to contain siRNA to silence genes in hepatocytes following i.v. administration (p 1468 Col. 2-1470 Col. 1 “LNP siRNA Systems: Liver Targets”. Cullis et. al. further teaches that these LNP siRNA systems can be applied to load LNP mRNA systems, and that additional optimization changes can be made to the LNP mRNA systems: “Thus, while LNP mRNA systems containing MC3 exhibit appreciable gene expression in hepatocytes following i.v. administration, cationic lipids optimized for maximum mRNA delivery can result in 20-fold higher expression levels (see https://acuitastx.com). These expression levels are sufficiently high that therapeutic levels of proteins such as erythropoietin can be achieved at dose levels as low as 0.03 mg mRNA/kg body weight in non-human primates.34 These results indicate the potential for utilizing the liver as a factory for protein replacement protocols or as a way to introduce therapeutic proteins, such as monoclonal antibodies, to target malignancies or other pathologies” (p 1471 Col. 1-2 “LNP mRNA and Plasmid DNA Systems”). Cullis et. al. teaches that LNP technology has advantages of “potency, payload, and design flexibility” (Abstract, see also Future perspectives p. 1473).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to apply the LNP mRNA technology for as an alternate vector for delivery of the nucleic acid of ‘140 in view of Ferry et. al. in order to design a gene therapy to deliver the nucleic acid of ‘140 in view of Ferry et. al. with to express IL-2 in the liver in LNPs as taught by Cullis et. al. and to benefit from the potency, payload, and design advantages as taught by Cullis et. al. This would have a predictable effect because both ‘140 and Cullis et. al. teach liver-targeted gene therapy for expression of therapeutic proteins.
Response to Arguments
Applicant’s arguments dated 2/18/2026 have been fully considered but are not persuasive. Applicant’s arguments that the rejections are moot in view of the amendments to claims are moot in view of the new rejection above. Applicant argues that the secondary references have deficiencies relevant to motivation to combine and obviousness as discussed above. In as far as the reply to the 103 arguments above is relevant to the new rejections, this is unpersuasive. The Examiner also notes that the arguments in regards to He et. al. are not relevant to the new NSDP rejection above because ‘140 in view of Annoni et. al. and ‘120 in view of Annoni et. al. and Cullis et. al. teaches all of the limitations of the claims. Applicant argues that a terminal disclaimer is not appropriate because the ‘140 application has not been examined for patentability. The Examiner notes that ‘140 is the later-filed application, and if there is a time such that the provisional NSDP rejection is the last remaining rejection, it will be withdrawn pursuant to MPEP 804.I.B.1.b. Non-statutory patenting may not be held in abeyance.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kathleen CunningChen whose telephone number is (703)756-1359. The examiner can normally be reached Monday - Friday 11-8:30 ET.
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, Gregory Emch can be reached at (571) 272-8149. 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.
/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights