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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The examiner finds support for all claimed limitations in the provisional application No. 63203451, filed 07/23/2021, and is therefore considering the effective filing date of currently pending claims to be 07/23/2021.
Status of claims
Claims 1-4, 6-13, 15-26, 29, 34 and 43 are pending and are under examination on the merits in this office action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/24/2025 and 04/22/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because the figure labels are improper. Currently, the figure labels are Fig. 1, Fig. 2, etc.; however, proper figure labels should be FIG. 1, FIG. 2, etc. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 16, 20, and 23 objected to because of the following informalities: claim 16 recites “said DNA” and depends from claim 4 which recites “said DNA vector.” Applicant may remedy by amending claim 16 to recite “said DNA vector.” In interest of compact prosecution, the examiner is interpreting “said DNA” as “said DNA vector.” Appropriate correction is required.
Claims 20 and 23 are confusing because they recite both “said DNA” and “said DNA” vector, but they both depend from claim 4, which already limits to “said DNA vector.” Therefore, similarly to claim 16 above, the examiner is interpreting “said DNA” as “said DNA vector.” Applicant may remedy by amending claims 20 and 23 to recite “said DNA vector” only.
Markush Grouping
Claim 15 rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of “said transgene encodes a viral antigen, a bacterial antigen, a therapeutic protein, a short hairpin RNA (shRNA), a small interfering RNA (siRNA), a microRNA (miRNA), a ribozyme, an antisense RNA, a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 construct, a zinc finger nuclease (ZFN), or a transcription activator-like effector nuclease (TALEN)” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The alternatives are not all members of the same recognized physical or chemical class or the same art-recognized class. For example, a therapeutic protein is a polypeptide molecule consisting of amino acids and a small interfering RNA is a nucleic acid molecule consisting of ribonucleic acids.
The members are not considered to be functionally equivalent and have a common use. For example, a therapeutic protein is typically used to restore a deficiency in the native protein’s expression level or function due to mutation, whereas small interfering RNA (as well as shRNA, microRNA, and antisense RNA) are typically deployed to reduce the expression of a native RNA by targeting it for degradation.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11, 17, 23, and 29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 11 and 29 refer to tables contained in the specification. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parteFressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
The term “substantially” in claim 17 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The first and second nanoparticle compositions cannot be clearly ascertained in relation to one another.
The term “substantially” in claim 23 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The DNA vector structure cannot be clearly ascertained as it is unclear to what degree the DNA vector comprises double-stranded DNA.
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.
Claims 1, 3-4, 7, 10, 25-26, 29, 34, and 43 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Anderson DW. et al., (WO2021102182A1, published 05/27/2021, provided in IDS).
Regarding claims 1, 7, 10, 25, 27, 29, 34,and 43 Anderson teaches compositions (see [0102] and claims 49-53) and methods of intracellular delivery of a DNA to a subject (Para. [0062] “a method includes…administering an amount of the expression cassette, particle, pharmaceutical composition or LNP composition to the mammal;” Para. [0007] “expression cassettes comprising nucleic acids encoding fusion proteins;” Para. [0195] "nucleic acid”…”including deoxyribonucleic acid (DNA);” Para. [0221] “pharmaceutical formulations of the invention are additionally useful in a method of delivering, administering or providing a fusion protein encoded by a nucleic acid to a subject in need thereof, as a method of treatment. In this manner, the nucleic acid is transcribed, fusion protein expressed and secreted by cells in vivo in a subject;” claim 49 A pharmaceutical composition comprising … a biologically compatible carrier or excipient.) comprising administration of: (a) at least one of a cytosolic DNA-sensing inhibitor selected from the group consisting of a cyclic GMP-AMP synthase - stimulator of interferon genes (cGAS - STING) pathway inhibitor (Paras. [0266] and [0268]” an immunosuppressive agent is administered…an immunosuppressive agent… is tofacitinib”; see Para. [0027] of the instant application, cGAS-STING pathway inhibitor is a TBK1 inhibitor; Para. [0130] of the instant application, TBKT inhibitor is tofacitinib) and an inflammasome pathway inhibitor ([0286] anti-IL-lb mAb (e.g., canakinumah (Haris®)); and (b) a first nanoparticle comprising said DNA (Para. [0062] “administering the expression cassette;” Para. [0048]” the expression cassette is comprised in a lipid nanoparticle (LNP) composition;” Para. [0007] expression cassettes comprising nucleic acids encoding fusion proteins; Para. [0195] "nucleic acid" including deoxyribonucleic acid (DNA)), wherein step (b) can be performed prior to, concomitantly with, or after step (a) (Para. [0265] The compound…can be administered as a combination composition, or administered separately, such as concurrently or in series or sequentially (prior to or following) delivery or administration of…expression cassette, vector).
Regarding claim 3, Anderson teaches the method of claim 1, wherein said DNA is a DNA vector comprising a transgene operatively linked to a regulatory element (Para. [0137] expression cassettes can be delivered in order to affect the methods of the invention by any means in which the nucleic acid is transduced into and fusion protein expressed…such means include vectors; Para [0078] a method includes introducing an AAV vector genome comprising an expression cassette as set forth herein; Para. [204] An expression construct or cassette may comprise regulatory elements which serve to drive expression; Para [210] The term "operably linked" means that the regulatory sequences necessary for expression of a nucleic acid sequence are placed in the appropriate positions relative to the sequence so as to effect expression of the nucleic acid sequence; Para. [0105] an expression cassette in which an expression control element is operably linked to the nucleic acid encoding the fusion protein).
Regarding claim 4, Anderson teaches the method of claim 3, wherein said transgene is operatively linked to a promoter; and said DNA vector comprises 5' to 3' said promoter, said transgene, and a polyadenylation and termination signal. (claim 46 “wherein said expression cassette comprises in 5’ ->3’ orientation … a promoter operable in mammalian cells; said nucleic acid; a polyadenylation signal…).
Regarding claim 26, Anderson teaches said DNA is a DNA vector comprising a transgene operatively linked to a regulatory element, wherein said DNA vector comprises 5' to 3' a promoter, said transgene, and a polyadenylation and termination signal (claim 46: “expression cassette comprises in 5’ ->3’ orientation a first AAV ITR; a promoter operable in mammalian cells; said nucleic acid; a polyadenylation signal; and optionally a second AAV ITR”)
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 6-11, 15-21, 23-26, 29, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Fu Y., et al., (iScience.; 23(4):101026, and supplemental information, published 2020, provided in IDS) as evidenced by CLONTECH LABORATORIES INC., (pEGFP-N1 Vector Information, protocol PT3027-5, version PR93634, Catalog #6085-1, GenBank Accession #U55762. Published 2019, provided in IDS) in view of Morrissey DV. Et al., (US20190136231A1).
Regarding claims 1 and 25, Fu teaches a method of intracellular delivery of a DNA to a cell (Pg. 1, Abstract, DNA transfection…Administration of chemical inhibitors that block cGAS-mediated signaling cascades improves the expression of transgenes by ~1.5- to 3-fold in multiple cell lines and primary cells; Pg. 5 pretreatment of MEFs with C-176 and C-178 (STING inhibitors) followed by transfection of pEGFP-N1 plasmid increased the percentage of GFP+ cells) comprising administration of: (a) at least one of a cytosolic DNA-sensing inhibitor selected from the group consisting of a cyclic GMP-AMP synthase - stimulator of interferon genes (cGAS - STING) pathway inhibitor and an inflammasome pathway inhibitor (Pg. 1 abstract, targeting the cGAS-STING pathway can improve transgene expression, and this strategy may be applied to gene therapy; Pg. 4, fourth paragraph, Since knockout of the DNA sensor cGAS improved expression of transfected genes, we next asked whether the same improvement could be achieved by blocking cGAS-induced signaling cascade with small molecule inhibitors…TBK1 inhibitor, BX795, in L929 cells; see Para. [0027] of the instant application, cGAS-STING pathway inhibitor is a TBK1 inhibitor; Pg. 5 fifth paragraph, we tested two JAK inhibitors, Ruxolitinib and Tofacitinib; Pg. 5 we also included the recently reported STING inhibitors C-176 and C-178); and (b) a first nanoparticle comprising said DNA (Pg. 2, second paragraph, transfected pEGFP-N1 plasmid DNA complexed with Lipofectamine 2000), wherein step (b) can be performed prior to, concomitantly with, or after step (a) (Pg. 5 pretreatment of MEFs with C-176 and C-178 followed by transfection of pEGFP-N1 plasmid increased the percentage of GFP+ cells).
Regarding claims 3 -4, 23, and 26, Fu further teaches wherein said DNA is a DNA vector comprising a transgene operatively linked to a regulatory element and wherein said transgene is operatively linked to a promoter; and said DNA vector comprises 5' to 3' said promoter, said transgene, and a polyadenylation and termination signal (Pg. 1, Plasmid DNA pEGFP-N1; see CLONTECH pEGFP-N1 Vector Information, Pg. 2, second paragraph, Human cytomegalovirus (CMV) immediate early promoter: 1-589; enhancer regions 59-465; Enhanced green fluorescent protein (EGFP) gene Start codon (ATG): 679-681); SV40 early mRNA polyadenylation signal 1552–1557 & 1581–1586; Pg. 2 transfected pEGFP-N1 plasmid DNA complexed with Lipofectamine 2000 into wild-type and Cgas-/- L929 cells and examined the GFP protein expression). Fu teaches pEGFP-N1, which us a double-stranded DNA vector, see Pgs2-4 and CLONTECH pEGFP-N1 vector information.
Regarding claims 6-7 and 9, Fu teaches “since knockout of the DNA sensor cGAS improved expression of transfected genes,” the logical next question was whether small molecule inhibitors of the cGAS-STING pathway could serve as cytosolic DNA-sensing inhibitors. Fu reports “small molecule inhibitors targeting cgas-induced signaling improve expression of transfected genes,” see page 4 fourth paragraph. Fu further teaches administering to primary mouse embryonic fibroblast (MEF) cells the STING inhibitors C-176 and C-178 followed by transfection of a pEGFP-N1 plasmid DNA, see page 5 last paragraph. Fu reports a marked increase in GPF+ MEF cells compared to control MEF cells not treated with the STING inhibitors and further reports cGAS knockout in the MEFS did not further increase the population of GFP+ cells under STING inhibitor treatment, indication that the effect is exclusively attributed to STING.
Regarding claim 8, Fu teaches administering to L929 cells a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 vector construct as a cGAS inhibitor, i.e., knockout (KO), followed by transfection of a pEGFP-N1 plasmid DNA, see page 2 second paragraph. Fu reports a marked increase in GPF+ cells in cGAS KO L929 cells compared to wild-type L929 cells.
Regarding claims 10, Fu teaches using a TBK1 inhibitors (BX795 and MRT67307) and describes TBK1 inhibitors as cGAS-STING pathway inhibitor, see graphical abstract and reproduced below for convenience:
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Regarding claims 11 and 29, Fu teaches administering a compound recited in Table 2, Tofacitinib.
Regarding claim 16, Fu teaches transfection of a plasmid (i.e., circular DNA), see Pg. 2 para 2 and CLONTECH pEGFR-N1.
Regarding claim 21, Fu teaches cytosolic DNA-sensing inhibitor is administered at about the same time up to about 4 hours prior to administration of said DNA vector (Pg. 8, last paragraph, “to test the effect of inhibitors of cGAS-induced signaling cascade on RNaseL activation, BJ-5ta cells were transfected with pCMV-RNaseL-Flag in the presence of TBK1 inhibitor BX795 or DMSO.”). Fu also teaches administering the inhibitor prior to the DNA vector, see Pgs. 4-7.
While Fu teaches generating CRISPR/Cas9 KO mice and isolating and treating primary cells from said KO mice, Fu does not teach administering to “a subject” (e.g., a human patient). While Fu teaches using Lipofectamine (i.e., a liponanoparticle composition) to facilitate the transfection of transgenes, Fu does not teach encapsulating the DNA and/or inhibitor in a first nanoparticle (e.g., lipid nanoparticle, LNP) per se and/or a second nanoparticle. Fu also does not teach wherein said first nanoparticle (e.g., LNP) is configured to release said cytosolic DNA-sensing inhibitor prior to the release of said DNA or said DNA vector.
Morrissey teaches “in vitro and in vivo delivery and editing using LNPs with sgRNA expressed from DNA expression cassettes;” thus, Morrissey “demonstrates gene editing using LNPs loaded with Cas9 mRNA and an expression cassette encoding an sgRNA,” and/or further loaded with a transgene template expression cassette, see example 11, [0257][0057][101-110]. Morrissey further teaches the sgRNA expression cassette DNA is not closed-ended DNA ([0258]: “amplicons encoding sgRNA were prepared by PCR amplification of a DNA sequence containing a U6 promoter linked to an sgRNA;” [0110]: the template contains ssDNA or dsDNA containing flanking invert-terminal repeat (ITR) sequences… the template is supplied as a plasmid, minicircle, nanocircle, or PCR product.”). Morrissey further teaches “Co-delivery of Cas9 mRNA and sgRNA expression cassette; sgRNA expression cassette administered 2 hours prior to Cas9 mRNA; and Cas9 mRNA administered 2 hours prior to sgRNA expression cassette,” see [0259].
In addition to Morrissey teaching the transgene may be a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 construct as discussed above, Morrissey also teaches the transgene encodes a therapeutic protein ([0108]: “the template sequence may comprise an exogenous sequence,” and “the integration of the exogenous sequence may result in restored gene function” by “a gene knock-in.”).
Morrissey teaches “the Class 2 Cas nuclease mRNA is formulated in a first LNP composition and the guide RNA nucleic acid is formulation in a second LNP composition,” or “the Class 2 Cas nuclease mRNA and the guide RNA nucleic acid are formulated together in a LNP composition,” see [0011] and that the LNP are substantially the same, claim 5. Morrissey further teaches “are formulated in a single LNP composition,” see claims 5 and 19.
Morrissey teaches the first nanoparticle is configured to release one component prior to the release of a second component (see [0181]: “The LNP compositions will generally, but not necessarily, be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” includes any ingredient other than the compound(s) of the disclosure, the other lipid component(s) and the biologically active agent. An excipient may impart either a functional (e.g. drug release rate controlling) and/or a non-functional (e.g. processing aid or diluent) characteristic to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.”).
Morrissey teaches wherein the subject is a human subject, see [0187], claim 5 – claim 15.
Morrissey further teaches the LNPs are administered in “a pharmaceutically acceptable buffer, e.g., for in vivo administration of LNPs,” see [0163]. Morrissey further teaches “The LNP compositions will generally, but not necessarily, be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” includes any ingredient other than the compound(s) of the disclosure, the other lipid component(s) and the biologically active agent. An excipient may impart either a functional (e.g. drug release rate controlling) and/or a non-functional (e.g. processing aid or diluent) characteristic to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form,” see [0181].
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify the methods of Fu by formulation the DNA vector and/or cytosolic DNA-sensing inhibitor in the lipid nanoparticle (LNP) delivery systems taught by Morrissey and administering the resulting compositions to a subject, including a human subject, with the components provided in the same or different LNPs and, where desired, with controlled or sequential release. A PHOSITA would have been motivated to do so because Fu expressly teaches that inhibition of cGAS-mediated signaling improves expression of delivered transgenes and suggest that such inhibition may be applied to gene therapy, while Morrissey teaches that LNPs are suitable vehicles for in vivo delivery of DNA expression cassettes and other gene-editing components to subjects. Thus, a PHOSITA would have looked to employ Fu’s DNA-sensing inhibitor strategy in the LNP delivery platforms of Morrissey in order to improve intracellular delivery, transgene expression, and gene-therapy efficacy following administration to a subject. A PHOSITA would have had a reasonable expectation of success because Fu demonstrates the benefit of inhibiting the innate inflammatory response when introducing transgenes into cells and Morrissey demonstrates successful in vitro and in vivo delivery of RNA and DNA expression cassettes and gene editing components using LNPs.
Claims 12-13, 22, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Fu Y., et al., (iScience.; 23(4):101026, and supplemental information, published 2020, provided in IDS) as evidenced by CLONTECH LABORATORIES INC., (pEGFP-N1 Vector Information, protocol PT3027-5, version PR93634, Catalog #6085-1, GenBank Accession #U55762. Published 2019, provided in IDS) in view of Morrissey DV. Et al., (US20190136231A1) as applied to claims 1-4, 6-11, 15-21, 23-26, 29, and 43 above, and further in view of Kaminski, et al., (J. Immunol. Vol. 191, pp 3876-83, publishes 2013, provided in IDS) and Steinhagen F, et al., (Eur J Immunol.;48(4):605-611, published 2018).
The teachings of Fu and Morrissey are incorporated herein by reference to the preceding 103 rejection.
Neither Fu nor Morrissey teach administering an inflammasome inhibitor (e.g., AIM2 inhibitor) or in combination with a cytosolic DNA-sensing inhibitor.
Kaminski and Steinhagen both teach synthetic oligodeoxynucleotides (ODNs) comprised of the immunosuppressive motif TTAGGG and a specific suppressive ODN-A151. Kaminski teaches A151 abrogated type I IFN, TNF-α, and ISG induction in response to cytosolic dsDNA and A151 abrogated caspase-1–dependent IL-1β and IL-18 maturation in dendritic cells stimulated with dsDNA, see abstract. Kaminski further teaches A151 mediates these effects by binding to AIM2 in a manner that is competitive with immune-stimulatory DNA and as a consequence prevents AIM2 inflammasome complex formation, see abstract. Thus, Kaminski teaches that suppressive ODNs modulate the immune system and unveil novel applications for suppressive ODNs in the treatment of infectious and autoimmune diseases, see abstract. Similarly, Steinhagen also teaches A151 and reports that the suppressive ODN A151 effectively inhibits activation of cGAS in response to cytosolic DNA, thereby inhibiting type I IFN production by human monocytes and A151 abrogated cGAS activation in response to endogenous accumulation of DNA, see abstract. Thus, Steinhagen teaches that suppressive ODNs are new therapeutics against IFN-driven pathologies due to cGAS activation, see abstract.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to further modify Fu in view of Morrissey by employing the suppressive oligodeoxynucleotide A151 taught by Kaminski and Steinhagen as an inflammasome pathway inhibitor (i.e., an AIM2 inhibitor) and/or as an additional cytosolic DNA-sensing inhibitor in combination with the GAS-STING pathway inhibitors taught by Fu. A PHOSITA would have been motivated to do so because Fu expressly teaches that activation of cytosolic DNA-sensing pathways by delivered DNA limits transgene expression and that inhibition of such pathways improves transgene expression following DNA delivery. Kaminski teaches that A151 inhibits AIM2 inflammasome activation induced by cytosolic DNA by preventing AIM2 inflammasome complex formation, while Steinhagen teaches that the same suppressive oligodeoxynucleotide inhibits cGAS activation induced by cytosolic DNA. Thus, a PHOSITA would have looked at the AIM2 and cGAS inhibitor, A151, in order to further suppress DNA-induced innate immune responses associated with delivered DNA and thereby improve intracellular delivery and expression of a transgene. A PHOSITA would have had a reasonable expectation of success because Kaminski demonstrates that A151 successfully inhibits AIM2 inflammasome signaling in response to cytosolic DNA, Steinhagen demonstrates that A151 successfully inhibits cGAS activation on response to cytosolic DNA, and Fu demonstrates that inhibition of DNA-sensing pathways improves transgene expression Furthermore, Morrissey successfully demonstrates that LNP are optimal delivery vehicles for multiple polynucleotides and/or transgenes. Accordingly, the use of A151 as an AIM2 inhibitor alone or in combination with other cytosolic DNA-sensing inhibitors in the DNA-delivery system of Fu and Morrissey would have been a predictable use of known DNA-sensing inhibitors for their established purpose of reducing DNA-induces innate immune activation.
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, 3-4, 6-12, 13, 15-16, 19, and 21-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-7, 15, 19-23, and 25 of copending Application No. 18258981 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application claims methods of delivering a transgene to a subject using a non-viral vector, including nanoparticle-based delivery systems such as lipid nanoparticles, in combination with administration of an immunosuppressant. The instant claims differ primarily in specifying that the immunosuppressant is a cytosolic DNA-sensing inhibitor, such as a cGAS-STING pathway inhibitor or an inflammasome pathway inhibitor. Selection of a particular immunosuppressant from among known immunosuppressive agents for use in the otherwise same non-viral transgene delivery methods would have been an obvious variation and does not render the instant claimed subject matter patentably distinct from that claimed in the reference application. Furthermore, because the instant claims are open-ended (i.e., comprising), the methods of the reference application, which additionally require administration of a phagocyte-depleting agent, encompass all the limitations of the instant claimed methods together with an additional step.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1-4, 6-13, 15-26, 29, 34 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 77-15, and 18-41 of copending Application No. 19109831 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application and the instant application are directed to the same invention, namely intracellular delivery of a DNA (wherein a DNA is a DNA vector) using nanoparticles while concomitantly administering inhibitors of innate immune signaling pathways to improve transgene delivery and expression. The claims substantially if not identically overlap in DNA cargo, transgene constructs, nanoparticle compositions, subject limitations, administration regimens, and pharmaceutical compositions. Furthermore, the reference application expressly recites administration of JAK inhibitors to serve as type 1 interferon receptor pathway inhibitors, while the instant application expressly claims Tofacitinib, a JAK inhibitor, as a cGAS-STING pathway inhibitor. Accordingly, the claimed subject matter merely represents an anticipated version of the patentably indistinct subject matter claimed in the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/COREY LANE BRETZ/Patent Examiner, 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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