Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This Action is in response to the papers filed on February 17, 2026. Pursuant to the amendment filed on July 17, 2026, claims 1,3-11,13-15,19 and 49 are currently pending of which claims 1, 6-8, 10-11, and 19 have been amended, claims 16-18, and 20 have been cancelled, and claim 49 is newly filed.
Therefore, claims 1,3-11,13-15,19 and 49 are currently under examination to which the following grounds of rejection are applicable.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 6, 2026 was filed after the mailing date of the Non-Final Action on November 14, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 112
In view of Applicants’ amendment to the claims dated February 17, 2026, wherein claims 1, 6-8, 10-11, and 19 have been amended, the rejection to claims 7 and 11 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form, are withdrawn.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendment to the claims dated February 17, 2026, wherein claims 16-18, and 20 have been cancelled, the rejection to cancelled claims 16-18, and 20 rejected under 35 U.S.C. have been rendered moot.
Maintained Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 103
Claims 1, 3-7, 13, 19 remain rejected and claim 49 is newly rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Molecular Therapy-Nucleic Acids 7 (2017): 366-377; hereinafter ‘Chen’; of record IDS filed on December 21, 2022) in view of Zhang (U.S. Pub 2017/0152528 A1; hereinafter ‘Zhang-2’; of record) and in view of Chen et al. (Advanced functional materials 27.46 (2017): 1703036; hereinafter ‘Chen-2’; of record). This is a modified rejection necessitated by Applicants' amendments to the claims in the response filed on February 17, 2026.
Claim 1 is directed to a liposomal nanoparticle comprising: (a) a liposomal vehicle comprising:
(i) one or more liposome forming lipids; and (ii) one or more destabilizing agents capable of forming reactive oxygen species when exposed to an inducer; and (b) a genome editing agent, wherein: the one or more destabilizing agents are selected from the group consisting of photosensitizers, inorganic nanoparticles and metal nanoparticles; the inducer is electromagnetic radiation; and the genome editing agent is a Clustered Regularly Interspaced Short Palindromic repeats (CRISPR) complex comprising a CRISPR-associated protein and a guide RNA that specifically binds to a target DNA.
Regarding claim 1, Chen teaches methods of using light triggerable liposomes to deliver a gene to silence one of the pituitary adenylyl cyclase-activating polypeptide (PACAP) receptors (abstract). The liposomes are comprised of DOPC and DOTAP with verteporfin used as the destabilizing agent/photosensitizer (page 373, col 1, par 2; Fig. 1). Verteporfin (VP) when light stimulated with UV, generated reactive oxygen species (ROS) that destabilized the liposomal and endolysosomal membranes of the liposome (page 367, col 2, par 1; Fig. 1). Moreover, antisense oligodeoxynucleotide (asODN) molecules of PACAP receptor 1 (PAC1R) comprising a cationic polymer, were incorporated into the liposome and were released upon light illumination (page 367, col 2, par 1; page 373, col 1, par 2, and Fig. 1)
Chen teaches the liposome as including antisense RNA to control select mRNA expression, but does not teach a genome editing agent, in particular a CRISPR complex. Altogther, Chen teaches the claimed liposomal nanoparticle, except for the genome editing agent being CRISPR-Cas9.
Zhang-2 teaches the CRISPR-Cas9 complex, particularly gRNA and Cas9, can be packaged and delivered in vivo by liposomes, nanoparticles, e.g. gold nanoparticles (par 0029, 0261-0270; 0453, 0545-0546, 0869). Additionally, there is clear motivation to use CRISPR-Cas9 technology for gene editing by describing, “an advantage of the present methods is that the CRISPR system avoids off-target binding and its resulting side effects. This is achieved using systems arranged to have a high degree of sequence specificity for the target DNA.” (par 0160), and furthermore “The Cas9 enzyme is more efficient and more multiplexible, by which it is meant that one or more targets can be set at the same time. So far, efficient excision of genomic DNA>30% by Cas9 in human cells and may be as high as 30%, and may be improved in the future.” (0876).
Chen and Zhang-2 do not teach the genome editing complex comprises a CRISPR-associated protein, in particular the Cas9 protein.
Chen-2 teaches liposome-templated hydrogel nanoparticles (LHNPs) are optimized for efficient co-delivery of Cas9 protein and nucleic acids (comprises gRNA sequences), in which the Cas9 is delivered as a protein, “making it possible to maximize the efficiency and specificity of CRISPR/ Cas9 and minimize the undesired side effects associated with constitutive activation of Cas9.” (page 6, col 1, par 2). The lipid nanoparticles consist of cationic 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) lipids, cholesterol, and 1,2-distearroyl-sn-glycero-3-phosphoethanolamine (DSPE)-polyethylene glycol (PEG)2000-maleimide (MAL) (page 7, col 1, par 1). Chen-2 describes the advantage of delivering the Cas9 protein in which undesired side-effects are reduced and efficiency is increased in comparison to constitutive activation of Cas9 is in DNA form (Discussion, par 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the light-triggerable liposomes taught by Chen comprising verteporfin as the destabilizing agent/photosensitizer to incorporate the CRISPR complex as its cargo because it would have been obvious to combine prior art elements according to known methods to yield predictable results. In particular Chen teaches applying the known technique of using a destabilizing agent within liposomal nanoparticles for controlled temporal and spatial release of cargo, and Zhang-2 and Chen-2 teach the packaging and release of CRISPR complex in DNA and protein complex forms respectively, and therefore the combination of teachings would have led one of ordinary skill to arrive at the claimed invention of a light-triggered liposomal nanoparticle for genome editing.
Moreover, there is motivation to use the CRISPR-Cas9 technology as opposed to the RNAi technology taught by Chen, as seen by Zhang-2 describing the high specificity for editing with reduced side effects when targeting a specific DNA sequence. Secondly, Chen-2 describes the advantage of delivering the Cas9 protein in which undesired side-effects are reduced and efficiency is increased in comparison to constitutive activation of Cas9 in DNA form (Discussion, par 1).
Therefore, this further supports it would be obvious to swap out the RNAi technology used by Chen in the liposomal nanoparticle comprising a photosensitizer with CRISPR-Cas9, and furthermore it may be more appropriate for the CRISPR Complex to include Cas9 as a protein. A skilled artisan would have had a reasonable expectation of success as controlling gene delivery comprising via liposomal nanoparticle comprising liposomal vehicles and a genome editing agent was known in the art before the effective filing date of the claimed invention.
Regarding claim 3, dependent on claim 1, Zhang-2 teaches wherein the liposomal vehicle further comprises cholesterol (“Several other additives may be added to liposomes in order to modify their structure and properties. For instance, either cholesterol or sphingomyelin may be added to the liposomal mixture in order to help stabilize the liposomal structure and to prevent the leakage of the liposomal inner cargo.” (par 0264)).
Regarding claim 4, dependent on claim 1, Chen teaches wherein the one or more liposome forming lipids are phospholipids (“When preparing lipVP-DNA complexes, DOTAP, DOPC, and VP were mixed in 500 mL of chloroform with a molar ratio (DOTAP:DOPC:verteporfin) of 1:0.94:0.06.8” (p 373, col 1); DOPC is considered a phospholipid).
Regarding claim 5, dependent on claim 4, Chen teaches the liposomes comprise DOPC and DOTAP (“To prepare the liposomes, we chose 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) as a neutral lipid and 1, 2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP) as a cationic lipid. The latter can enhance gene delivery because it is able to freely pass through negatively charged cell membranes.” (page 367, col 1, par 2)).
Regarding claim 6, dependent on claim 1, and claim 7, dependent on claim 1, the rejection above to claim 1 makes obvious wherein the one or more destabilizing agents is a photosensitizer, i.e. verteporfin.
Regarding claim 13, dependent on claim 1, the rejection above to claim 1 makes obvious wherein the inducer is light (claim 13) based on using ultraviolet radiation which is a form of electromagnetic radiation that light comprises.
Regarding claim 19, dependent on claim 1, Chen-2 teaches wherein the CRISPR-associated protein is cas9, or a variant thereof.” (page 6, col 1, par 2).
Regarding claim 49, dependent to claim 1, Chen-2 in view of Zhang-2 and Chen teach a method of modifying the genome of a cell, comprising administering the liposomal nanoparticle of claim 1 to a cell, and exposing the liposomal nanoparticle to the inducer to thereby destabilize the liposomal nanoparticle and release the genome editing agent based on the rejection to claim 1 described above.
Claims 8-11 remain rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Molecular Therapy-Nucleic Acids 7 (2017): 366-377; hereinafter ‘Chen’; of record IDS filed on December 21, 2022) in view of Zhang (U.S. Pub 2017/0152528 A1; hereinafter ‘Zhang-2’; of record) and in view of Chen et al. (Advanced functional materials 27.46 (2017): 1703036; hereinafter ‘Chen-2’; of record) as applied to claim 1 above, and further in view of Miranda et al. (Bioengineering & translational medicine 1.3 (2016): 267-276; of record). This is a modified rejection necessitated by Applicants' amendments to the claims in the response filed on February 17, 2026.
The combined teachings of Chen, Zhang-2, and Chen-2 render obvious claim 1 as stated in the paragraphs above.
Regarding claims 8-11, dependent on claim 1, Chen teaches a liposome comprising DOTAP, DOPE and cholesterol, loaded with a photosensitizer verteporfin (VP), and Zhang-2 teaches liposomes packaged with CRISPR-Cas9 in DNA form, and Chen-2 teaches liposomes packaged with CRISPR-Cas9 in protein form, particular Cas9 protein with gRNAs in DNA form.
Chen teaches, as described in the claim 1 rejection above, wherein the one or more destabilizing agents is a photosensitizer, particularly verteporfin. Chen-2 states, “Delivery of Cas9 in the form of protein has been previously attempted by other groups using lipid nanoparticles, gold nanoparticles,” (p 6, col 1).
The combined teachings of Chen, Zhang-2, and Chen-2 do not teach wherein the one or more destabilizing agents is a metal nanoparticle, that is a gold nanoparticle.
Miranda teaches a liposomal nanoparticle that comprises gold nanoparticles that are either embedded within the bilayer, encapsulated in the core, or tethered to the membrane (Fig. 1). Moreover, Miranda describes the role gold nanoparticles have in liposomal cargo release by acting as a destabilizing agent through photothermal release, “gold nanoparticles (AuNPs) can be used to enhance light triggered release due to their suitability for photothermal conversion based on surface plasmon resonance and hot electron mechanisms. AuNPs are able to rapidly and efficiently absorb visible, UV and NIR light and release energy as heat on the scale of picoseconds… When proximal to liposomes, the high temperatures achieved by AuNPs can induce membrane stress and rupture, followed by cargo release.” (page 271, col 2, par 1). Furthermore, Miranda describes the known role of verteporfin as a successful example of a light-activated agent used in a known therapeutic ( page 274, col 1, par 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have employed liposomal nanoparticle that comprise gold nanoparticles based on the teaching of Miranda that describes this product, and the motivation for including gold based on its photothermal properties that aid in cargo release. Therefore, at the time of filing the combination of references to arrive at the claimed invention would have been obvious. Moreover, it would have been obvious to include gold with the photosensitizer of verteporfin (VP) as taught by Chen based on the known role of VP as photosensitizer for photodynamic therapy as previously described, and further mentioned by Miranda.
Claims 14-15 remain rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Molecular Therapy-Nucleic Acids 7 (2017): 366-377; hereinafter ‘Chen’; of record IDS filed on December 21, 2022) in view of Zhang (U.S. Pub 2017/0152528 A1; hereinafter ‘Zhang-2’; of record) and in view of Chen et al. (Advanced functional materials 27.46 (2017): 1703036; hereinafter ‘Chen-2’; of record) as applied to claim 1 above, and further in view of Clement et al. (Sci Rep 6, 19954 (2016); of record). This is a modified rejection necessitated by Applicants' amendments to the claims in the response filed on February 17, 2026.
The combined teachings of Chen, Zhang-2, and Chen-2 render obvious claim 1 as stated in the paragraphs above.
Regarding claims 14-15, Chen teach the use of UV to generate ROS based on the presence on verteporfin (VP). The UV used fell in the UVA wavelength, 315-400 nm at a power density of 1.25 mW/cm2 with an illumination time no longer than 5 minutes (Chen’s page 371, col 1, par 2). The instant specification states that “High energy electromagnetic radiation typically has energy higher than about 5 keV,” (Instant Specification page 13, par 1). Therefore, by using Planck's energy equation, E = h × c / λ; wherein Planck's constant (h = 6.6261 × 10⁻³⁴ J⋅s), and speed of light (c = 299792458 m/s), and the wavelength at 400 nm are inputted the maximum electron voltage produced by the UV is only 0.0031 keV or 3.1 eV. Based on this calculation and in view of the full disclosure, Chen does not teach wherein the inducer is high energy electromagnetic radiation.
Clement teaches nanoparticles comprising Verteporfin were able to generate reactive oxygen species as a result of UV light and 8 keV of X-ray irradiation; additionally, the amount of ROS produced per cell is then estimated based on using energy as high of 30keV. Clements describes both X-ray or gamma rays can be used for these outcomes (abstract; Fig. 1; page 3, par 2; page 8, par 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have claimed the inducer as being a form of high energy electromagnetic radiation being that the prior art shows photosensitizer, in particular verteporfin, capable of causing ROS within a cell; and therefore such outcome would be expected to be maintained when integrated into the claimed liposomal nanoparticle being that the structure is the same, and the outcome being presented across UV to X-rays, and finally gamma-rays.
Response to Applicants' Arguments as they apply to rejection of 1, 3-7, 11, 13, and 17-20 rejected under 35 USC § 103
In relation to claim 1, Applicants states:
“The suggested modification of Chen's liposome would not have been expected by one of ordinary skill in the art to yield predictable results, as the Examiner alleges; Applicant submits one of ordinary skill in the art would not have considered that such a modification would have yielded a triggerable liposome capable of releasing the CRISPR complex in a manner where it would retain its gene editing functionality.”
“None of Chen, Zhang-2, nor Chen-2 teach or suggest that a CRISPR-Cas9, or other gene editing complex, could be delivered using an electromagnetic radiation-triggerable liposome, let alone the liposome described in Chen… In contrast, none of the liposomes disclosed in Zhang-2 or Chen-2 rely on the formation of ROS to release their payload. In fact, there is no teaching, suggestion, or motivation in Zhang-2 or Chen-2 that payloads may be incorporated into a triggerable liposome.”
“In addition, an ordinarily skilled person would further appreciate that delivery of a small antisense oligonucleotide (as taught in Chen) would be significantly different from delivery of a large ribonucleoprotein complex (e.g., a CRISPR complex). Accordingly, an ordinarily skilled person would appreciate the entirely different formulation and stability challenges associated with the delivery of a large ribonucleoprotein complex.”
“Finally, for reasons discussed at length in the previous response, an ordinarily skilled person would expect that the use of ROS (as used to trigger Chen's liposomes) could potentially disrupt components essential to a CRISPR-based gene editing system.”
Applicant’s arguments, starting on page 5 of the Remarks filed on February 17, 2026, with respect to the rejection(s) of the claims under 35 USC § 103 have been fully considered but are not persuasive for the following reasons:
1st Argument: In response to applicant's argument that it would not be predictable to have yielded a triggerable liposome capable of releasing the CRISPR complex in a manner where it would retain its gene editing functionality, the examiner disagrees because Chen-2 establishes that the claimed liposomal nanoparticle is capable of cargo release due integration of verteporfin. Since the liposomal taught and claimed are identical, except for the gene editing technologies, and it is reasonably expected that the claimed gene editing technology would similarly be released when stimulated with an inducer. Furthermore, the claim does not recite whether the CRISPR-Cas9 is functional, and therefore this is not a limitation that is given weight. Regardless, the Applicant has not provided any data that there is an expectation that the CRISPR-Cas9 would not be released and functional, for example the ROS being released as impacting the catalytic domain of the nuclease.
2nd Argument: In response to applicant's argument that none of the liposomes disclosed in Zhang-2 or Chen-2 rely on the formation of ROS to release their payload, and that there is no teaching, suggestion, or motivation in Zhang-2 or Chen-2 that payloads may be incorporated into a triggerable liposome, the examiner disagrees because it is clearly described in Chen-2 of photoresponsive liposomal nanoparticles that have cargo, e.g. antisense RNA, that are released when exposed to UV light due to ROS generation “destabilizing the endolysosomal membranes and enhancing the liposomal release of antisense DNA into the cytoplasm.” (abstract). Furthermore, the teaching of Zhang-2 and Chen is to establish that CRISPR-Cas9 can be incorporated into liposomes; and the teaching of the particular liposomal nanoparticles claimed is provided by Chen-2.
3rd Argument: In response to applicant's argument that is in reference to the size difference between the antisense oligonucleotide (as taught in Chen) and the claimed CRISPR-Cas9 (Cas9 protein with gRNAs), the examiner disagrees with this argument in view of Chen teaching liposomal nanoparticles that are capable of encapsulating Cas9 proteins (p 7, col 1, par 1-2). The liposomal nanoparticle of Chen is similar to that claimed except for not comprising a destabilizing agent capable of forming reactive oxygen species when exposed to an inducer, and therefore unless the verteporfin significantly impacts the size restriction of the liposomal nanoparticle it remains expected the liposomal nanoparticle taught by Chen-2 can comprise the claimed gene editing technology.
4th Argument: In response to applicant's argument that ROS “could potentially disrupt components essential to a CRISPR-based gene editing system” the Examiner disagrees as there is no evidence or indication that ROS would impact the gene editing technology, and moreover this is supported by Chen-2 teaching the ROS generated as not disrupting the antisense oligonucleotides. Chen-2 describes “VP has a broad absorption band between 300 and 500 nm with one absorption peak at 350 nm, which can be activated to generate ROS with a UV light source.”, and how DNA is sensitive to UV and therefore dosage and exposure time were optimized to minimize light toxicity (p 371, col 1, par 2). Altogether, there is no indication that the CRISPR-Cas9 technology would be impacted by the ROS production due to the oligonucleotides not being negatively impacted, and moreover it being taught that dosage of UV can be altered to minimize toxic effects.
Conclusion
Claims 1, 3-11, 13-15, 19 and 49 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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