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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 5, 2026 has been entered.
Applicants' arguments, filed March 5, 2026, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Claim Objections
Claim 22 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. The sequence of the interleukin 6 receptor is not known in the art.
Response to Amendment
The declaration under 37 CFR 1.132 filed March 5, 2026 is sufficient to overcome the rejection of claims 1 - 4 and 7 - 22 based upon Chen et al. (US 8,158,601) in view of He et al. (Pharmaceutics, 2022) further in view of Kim et al. (J Control Rel, 2018) and Wang et al. (Molecular Therapy, 2017) as the data established unexpected behavior of formulations comprising 78.8 mol% DOTAP and 10 mol% ionizable cationic lipid compared to those with 50 mol% DOTAP and 25 mol% ionizable cationic lipid which differentiates the claims over the Chen et al. reference relied upon to reject the claims previously.
However, the data relating to the targeting peptides is not persuasive as statistically significance is stated compared to the control only, not the two ligands individually. It appears that the overall area of the violin plot for the combination of collagen IV (Col-IV) targeting peptide and interleukin 6 receptor (IL-6R) targeting peptide and apparent average intensity for the combined ligands is less than each peptide individually. The nature of the plot makes determination of exact average fluorescence intensity values difficult to determine but the unexpected effect from the combined targeting ligands that is reasonably commensurate in scope with the claims has not been demonstrated. Note also that in some cases, a synergistic effect can be the expected result so even the demonstration of synergy in binding may not be sufficient when the expected result is a synergistic interaction.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 1 - 4, and 9 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over Patil et al. (WO 2022/132926; Patil-926) in view of Patil et al. (WO 2020/226139; Patil-139), Kim et al. (J Control Rel, 2018) and Wang et al. (Molecular Therapy, 2017).
Patil-926 discloses nucleic acid-lipid particles having 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) that preferentially localise to the lung, various lung tissues and tissues to which the particles are directly injected, that can optionally be associated with a therapeutic agent such as therapeutic mRNA and/or nucleic acid controller system (whole document, e.g., abstract). The nucleic acid-lipid particle for delivering a nucleic acid cargo to a lung tissue of a subject can include 20 mol % to 80 mol % DOTAP of the total lipid present in the nucleic acid-lipid particle (p 3, ¶ 2) and about 75% DOTAP is also disclosed (p 5, ¶ 4). The LNPs (lipid nanoparticles) may also comprise other cationic lipids such as MC3 (p 32, ¶ 2). A conjugated lipid such as a PEG (polyethyleneglycol)-lipid can be present in certain embodiments and optionally in amounts of about 0.5 mol % of the total lipid present in the nucleic acid-lipid particle, of about 1.0 mol % of the total lipid present in the nucleic acid-lipid particle, or of about 1.5 mol % of the total lipid present in the nucleic acid-lipid particle (p 3, ¶ 4). One or more non-cationic lipids such as cholesterol or non-cationic lipids other than cholesterol can also be present at a concentration in one embodiment of from 20 mol % to 80 mol % of the total lipid present in the lipid-nucleic acid particle (p 4, ¶¶ 1 and 2). Neutral lipids such as DOPE can also be included (¶ bridging p 32 and 33). Amphipathic lipids such phosphatidylcholine and phosphatidylethanolamines can be present (p 33, ¶ 3). The nucleic acid cargo can be synthetic or naturally occurring RNA such as modified mRNA (p 4, ¶ 4 onward). The formulations in Table 2 (p 59) comprise 25, 50 or 75 mol% DOTAP; varying amounts of cholesterol; 10 mol% DOPC, a neutral lipid; and 0, 0.5 or 1.5 mol% PEG2k-DMG (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000) and were loaded with RNA.
Explicit examples with a combination of DOTAP and another cationic lipid such as DLlin-MC3-DMA (MC3) are not set forth.
Patil-139 discloses nucleic acid-lipid particles having DOTAP that preferentially localizes to the liver that can optionally be associated with a therapeutic agent such as therapeutic mRNA and/or nucleic acid controller system (whole document, e.g., abstract). The surprising discovery was made that the addition of a second ionizable or cationic lipid to the DOTAP containing nucleic acid-lipid nanoparticle formulation shifted the delivery location to the liver (p 2, ¶ 2). Paragraph 2 on p 12 lists various lipids that fall within the scope of “cationic lipid” and include a number of lipids from instant claim 12 including dilinoleylmethyl-3-dimethylaminopropionate (DLin-M-C2-DMA) (also known as MC2), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-l 9-yl 4-(dimethylamino) butanoate (DLin-MC3-DMA, MC3), 1,2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLinDMA) and 1,2-distearyloxy-N,N-dimethyl-3-aminopropane (DSDMA). Many of these lipids are also listed as examples of ionizable lipids (p 13, ¶ 2) given the pH dependent nature of the charge of such lipids. Based on the total amount of lipids in the composition, DOTAP can be at least about 50% (all percent are molar basis) and the amount of ionizable lipid can be at least about 10%, at least about 5% cholesterol, at least about 0.1% of other non-cationic lipids such as DOPE, DPOC and/or DSPE and at least about 1.0 mol% to about 1.5 mol% of a conjugated lipid that inhibits aggregation of particles (p 31, ¶ 3). Such conjugated lipids can be DMG-PEG2k (p 31, ¶ 3).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate a second non-ionizable/cationic lipid such as MC3 into the LNPs disclosed by Patil-926. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Patil-926 generally discloses that more than one cationic lipid can be present and Patil-139 discloses that the addition of a second cationic lipid alters the delivery location of the nanoparticles. Patil-139 provides mol percents for a combination of DOTAP and ionizable lipids that can be cationic. The amount of a specific lipid in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results based on the desired cellular target and cargo to be
The use of peptides to target the LNPs to collagen IV and IL-6R is not disclosed.
Kim et al. discloses that a major contributor of cardiovascular disease (CVD) is atherosclerosis which is an inflammation driven chronic condition that leads to plaque formation (p 337, col 1). Collagen type IV targeting peptides are an efficient ligand for targeting nanoparticles toward atherosclerosis (p 338, col 1, ¶¶ 4 and 5). A PEG with a maleimide group was used for peptide conjugation to the nanocarrier (p 338, col 2, ¶ 3).
Wang et al. discloses that receptor-targeted drug delivery has been demonstrated as a potential approach to achieve drug accumulation in glioma (p 1556, col 2, ¶ 2). The interleukin-6 receptor (IL-6R), a membrane bound glycoprotein, is expressed on the blood-brain barrier (BBB) and various brain tumors including glioblastoma, astrocytoma and pituitary tumors but not healthy astrocytes (p 1556, col 2, ¶ 2). The hexapeptide LSLITRL (I6P7) specifically binds to IL-6R, inhibits the binding of IL-6 to IL-6R, and could increase the BBB transport of therapeutic agents toward glioma and also inhibit tumor growth and progression (p 1556, col 2, ¶ 2). The cascade-targeting gene transfer system could not only demonstrate high transfection efficiency and low toxicity, but also improved brain-penetrating and glioma-targeting efficiency, as well as elevated transgene expression (p 1560, col 2, ¶ 4).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to attach a peptide targeting proteins such as those that bind to collagen IV and IL-6R to the lipid nanoparticles of Patil-926 and Patil-139. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success targeting ligands can add additional specificity to a broad level of tissue targeting disclosed by Patil-926 and Patil-139 by binding to cells within that tissue that have one or both of collagen IV and IL-6R. The selection of the target protein(s) and therefore which peptides must be attached to the LNPs to target that protein depends on the particular application and targeting peptide are known for collagen IV and IL-6R as taught by Kim et al. and Wang et al. Those targeting peptides can be readily conjugated to the lipid nanostructures via a maleimide group using the conjugation reaction well-known to those of ordinary skill in the art using PEG with maleimides groups as disclosed by Kim et al.
Claim(s) 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Patil-926 and Patil-139 as applied to claims 1 - 4, and 9 – 13 above, and further in view of Jiang et al. (Nephr Dialysis Transplant, 2022) or Anananuchatkul et al. (ACS Omega, 2020).
Patil-926 and Patil-139 are discussed above.
The use of peptides to also target the LNPs to CD63 or GAL-3 is not disclosed.
Jiang et al. discloses a novel kidney MSC (mesenchymal stem cell) exosomes (MSC-exos) that were loaded with a kidney targeting peptide and a CD63 targeting peptide (Background and method section).
Anananuchatkul et al. discloses that galectin-3 (Gal-3) is a galactose-binding protein and is expressed in the cytoplasm and nucleus and secreted from cells and elevated Gal-3 expression levels is the evidence of its ability to enhance tumor cell adhesion to common extracellular matrix proteins, to increase lung carcinoma metastasis, and to help cancer cells resist apoptosis, rendering Gal-3 an important target for cancer treatment and diagnosis (p 5667, col 1, ¶ 3). A peptide phage library was used to screen for α-helical peptides that bind to Gal-3 (p 5667, col 2, ¶ 1). Peptides that bound to Gal-3 were identified and a stapled peptide ligand could be conjugated with nanoparticles for drastic improvement in the binding affinity to Gal-3 (p 5670, col 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to attach a peptide targeting proteins such as those that bind to CD63 and/or GAL-3 to the lipid nanoparticles of Patil-926 and Patil-139. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because such ligands will provide targeting of the cargo such as plasmids or other nucleic acids to cells expressing the targeted protein. The selection of the target protein and therefore which peptides to attach to the LNPs to target that protein depends on the particular application and targeting peptide are known for collagen IV, IL-6R, CD63 and GAL-3 as taught by the applied prior art. Those targeting peptides can be readily conjugated to the lipid nanostructures via a maleimide group using the conjugation reaction well-known to those of ordinary skill in the art.
Claim(s) 14 – 21 are rejected under 35 U.S.C. 103 as being unpatentable over Patil-926 and Patil-139 as applied to claims 1, 4, and 9 – 13 above, and further in view of Sun et al. (AAPS PharmSciTech, 2022) and Jungles (WO 2020/150716; cited on IDS filed May 2, 2025).
Patil-926 and Patil-139 are discussed above.
The delivery of an mRNA nucleic acid cargo encoding portions of the membrane protein ENPP1 comprising SEQ ID NO: 1 such as the soluble portion of ENPP1, a gene for rescuing gene expression in a smooth muscle cell, is not disclosed.
Sun et al. examined the effect of the molar ratio of DOTAP/chol, PEGylation and lipid to mRNA ratio on mRNA transfection (whole document, e.g., abstract). The molar ratio of cationic lipid to neutral lipid usually plays an important part in determining the optimal transfection efficiency for many liposomal formulations (p 135, col 1, ¶ 1). While mRNA is less stable than DNA, it causes fewer immune responses and is directly delivered and expressed in the cytoplasm without requiring nuclear localization for expression, there is no potential for mutagenesis due to genomic integration (p 135, col 1, ¶ 1).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use mRNA as the nucleic acid cargo in the cationic lipid nanoparticle delivery system of Patil-926, Patil-139, Kim et al. and Wang et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Patil-926 and Patil-139 discloses that a variety of nucleic acids can be delivered and Sun et al. discloses that mRNA can be delivered using such particles while causing fewer immune responses and lack of nuclear localization for expression eliminates the potential for mutagenesis due to genomic integration. One of ordinary skill in the art can determine the optimal nucleic acid cargo depending on the desired effect of nucleic acid delivery to a particular target cell based on the polypeptide on the surface provided for targeting purposes.
Jungles discloses vectors for the expression of ENPP1 in vivo and methods for the treatment of diseases of calcification and ossification in a subject (whole document, e.g., abstract). The recombinant polynucleotide encodes human ENPP1 (p 2, ¶ 4). In some embodiments a signal peptide fused to ENPP1 that is secreted into the cytosol (p 3, last ¶), reading on a soluble ENPP1 molecule. In some embodiments the ENPP1 can be membrane bound and not secreted (p 4, ¶ 1). In some embodiments the ENPP1 encodes a polypeptide of SEQ ID NO: 1 (p 4, ¶ 2), and SEQ ID NO:1 of Jungles is identical to SEQ ID NO: 1 of the instant application including amino acids 97 - 925. Upon administration, the constructs can be used to prevent or reduce the progression of a condition or disease in a mammal such as those with a deficiency of NPP1, and the pathological calcification or ossification of soft tissue (p 7, ¶¶ 3 and 4).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use a nucleic cargo encoding ENPP1 into the lipid nanoparticles of Patil-926, Patil-139, Kim et al. and Wang et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the formulations of Patil-926 and Patil-139 be used to deliver various nucleic acid cargoes and Jungles discloses the use of nucleic acids encoding ENPP1 such as SEQ ID NO:1 for treat conditions associated with a deficiency of NPP1 by expressing ENPP1. One of ordinary skill in the art can determine the optimal nucleic acid cargo depending on the desired effect of nucleic acid delivery to a particular target cell based on the polypeptide on the surface provided for targeting purposes. Both membrane bound and secreted (soluble) forms of ENPP1 are disclosed by Jungles as encoded proteins to be delivered to cells to bring about expression of ENPP1 to treat a variety of conditions.
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 – 4 and 7 – 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 21 and 22 of copending Application No. 19/171,179 in view of Kim et al. (J Control Rel, 2018) and Wang et al. (Molecular Therapy, 2017) and optionally further in view of Patil et al. (WO 2022/132926; Patil-926), Jiang et al. (Nephr Dialysis Transplant, 2022) or Anananuchatkul et al. (ACS Omega, 2020) and Sun et al. (AAPS PharmSciTech, 2022).
The claims of US’179 recited a particle comprising ionizable lipid (such as about 10% MC3 ionizable lipid), a neutral lipid (such as about 2.1% DOPE), cholesterol (such as about 7.6%), one or more PEG-lipids (such as about 1.5%) and DOTAP (such as about 78.8%); a peptide conjugated to a linker in the particle and a construct for expressing either a full-length or truncated extracellular domain of human ENPP1 and a promotor to drive expression of the gene (claims 21 and 22). These are the same lipid particle structure as claimed in the instant application.
Specific MC3 ionizable lipids, specific PEG-lipids and targets for the targeting peptides are not claimed. mRNA as the expression construct is not claimed.
Kim et al., Wang et al., Patil-926, Jiang et al., Anananuchatkul et al. and Sun et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to optimize the specific ingredients and amounts of each ingredient in the lipid nanoparticles of US’179 and the targeting peptide such as for collagen IV and IL-6R on the surface of the nanoparticle depending on the particulars of the nucleic acid cargo contained in the lipid nanoparticle. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the lipid nanoparticles of US’179 comprise a construct to express a particular gene but other materials expressing other proteins can also be included as taught by the applied prior art and known to one of ordinary skill in the art. One of ordinary skill in the art would routinely optimize the amounts of each of the components of the lipid delivery structure and there is no evidence of record as to the amounts of the various components. By conjugating a targeting moiety to the lipid structures, the cargo can be delivered preferentially to cells having the specific target. One of ordinary skill in the art can readily determine the best targeting ligand to conjugate to the lipid particles via a maleimide-bearing lipid based on the desired cellular target and known targeting ligands for those targets.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618
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