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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/15/2025 has been entered.
Receipt is acknowledged of an amendment, filed on 12/15/2025, in which claim 1 was amended, claims 4-6 were previously presented, claim 3 was canceled and claim 30 was newly added. Claims 1, 4-6 and 30 are currently under examination.
Priority
Acknowledgment is made of applicant's claim for priority based on a foreign application filed as EP19199697.4 on 09/25/2019.
All claims are given the priority date of 09/25/2019.
Response to Amendments - Claim Rejections - 35 USC § 112
The previous rejection of claims 1 and 3-6 under 35 U.S.C. 112(b) has been withdrawn in view of Applicant’s amendments to claim 1 filed on 12/15/2025.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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, 6 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (WO 2019/104058 Al; cited in a prior action) in view of Gao et al (Biomacromolecules 2016, 17, 3640- 3647; cited in a prior action). This rejection was made in the Office action mailed 10/24/2025 and has been rewritten to address the amendment to the claims in the reply filed 12/15/2025.
The term “4-branching poly-beta amino ester polymer” is interpreted within the claims as a hydrophilic cationic polymer that contains addition elements that allow for parts of the cationic polymer to be hydrophobic, such as an amphiphilic polymer. The positive charge of the cationic polymer results in hydrophilic properties inherent to the polymer. It is possible to have a highly hydrophobic cationic polymer, however, it is not possible to have a fully hydrophobic cationic polymer without some hydrophilic properties. This would result in an amphiphilic cationic polymer comprising both hydrophilic and hydrophobic properties.
With regard to the term “ribosomal protein,” the specification defines the term as encompassing “a CRISPR nuclease protein, e.g. Cas9, Cas12a, Cas14 or a Cas variant, for example modified versions of nuclease dead (dCas9).” See page 12, lines 30-31.
Regarding claims 1 and 30, Chen teaches the introduction of a nucleic acid and/or protein into a host cell through nanoparticle-mediated nucleic acid delivery [00193]. Chen teaches the use of a CRISPR cas effector protein in the form of a ribonucleoprotein complex comprising guide RNA and a delivery particle such as a polymer [00194-00196]. Chen teaches the delivery system of the CRISPR/cas effector protein and/or guide RNA as a biodegradable core-shell structured nanoparticle with a poly (Beta-amino ester) (PBAE) core enveloped by a phospholipid bilayer shell [00197]. Chen teaches the delivery particle polymer is cationic and the cell penetrating peptides are positively charged and hydrophobic [00196 and 00199].
Chen does not teach the polymer is a 4-branching poly-beta amino ester hyperbranched polymer.
Gao teaches the use of highly branched poly-beta amino esters for gene delivery vectors (Abstract). Gao teaches the benefits could be obtained through the introduction of branched structures that give much higher transfection efficiency compared to the original LPAEs as well as the increased improvement of gene transfection efficiency of poly-beta amino esters (Page 3641, Column 1 and Page 4). Gao teaches the use of cationic polymers, such as poly-beta amino esters, that have shown to have higher transfection efficiency due to the branched structure of the HPAEs (Page 3641, Column 2). Gao teaches HPAE-4 as a 4-branching highly branched poly beta amino ester that has higher efficiency of gene transfection (Page 3642, Column 2 and Scheme 1). Gou teaches a four-branching poly-beta amino ester polymer with three reactive groups as shown below.
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The image presented in scheme 1 of Gou has been labeled by examiner to show the four branches of the four-branching poly-beta amino ester polymer.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Chen to substitute the unbranched polymer with the hyperbranched or multibranched structure of the 4-branching highly branched poly beta amino ester for delivery as taught by Gao because Chen teaches it is within the ordinary skill in the art to use poly-beta amino ester polymers with nanoparticles for CRISPR cas gene editing for delivery to a cell and Gao teaches multibranched or "highly branched" polymers have increased efficiency for gene transfection into a cell.
One would have been motivated to make such a modification in order to receive the expected benefit of providing a composition capable of a higher efficiency of gene transfer to the desired cell as taught by Gao.
Regarding claim 6, Chen does not teach the size of the nanoparticle complex.
Gao teaches the measured range of particle sizes were from 0.3nm to 10 micrometers (Page 3641, Column 2). Gao teaches that size of the complex influenced the cell and cytotoxicity, specifically that larger sized and aggregate morphology of HPAE would result in excessive interactions of polyplexes leading to increased cytotoxicity (Page 3645, Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Chen to include the size of the nanoparticle used to deliver to cells efficiently as taught by Gao because Chen teaches it is within the ordinary skill in the art to use poly-beta amino ester polymers with nanoparticles for CRISPR cas gene editing for delivery to a cell and Gao teaches the range of particle sizes were from 0.3nm to 10 micrometers.
One would have been motivated to make such a modification in order to receive the expected benefit of less possibility of interactions of polyplexes leading to less possibilities of cytotoxicity with smaller nanoparticle complex sizes as taught by Gao.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (WO 2019/104058 Al; cited in a prior action) in view of Gao et al (Biomacromolecules 2016, 17, 3640-3647; cited in a prior action) and in further view of Bonafont et al (Molecular Therapy Vol. 27, pages 986-998, March 15, 2019; cited in a prior action). This rejection was previously presented in an Office Action filed on 10/24/2025 and maintained here.
The combined teachings of Chen and Gao as discussed and applied above.
Regarding claim 4, Chen and Gao do not teach the CRISPR cas system configured to excise an exon in a gene.
Bonafont teaches the single-guided RNA -guided Cas9 nuclease delivered as a ribonucleoprotein complex by electroporation to precisely excise COL7Al exon 80 carrying c.6527insC mutation in RDEB patient keratinocytes (Page 987, Column 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Chen and Gao to include the specifics of the CRISPR cas 9 as the gene editing ribonucleoprotein for excision of COL7Al exon 80 as taught by Bonafont because Chen teaches it is within the ordinary skill in the art to use a CRISPR system within a nanoparticle complex to be delivered to a cell via a polymer, Gao taches the use of the highly branched poly-beta amino ester polymer for delivery to a cell and Bonafont teaches the use of the cas 9 ribonucleoprotein within a particle complex to excise the COL7A1 exon 80.
One would have been motivated to make such a modification in order to receive the expected benefit of excision of the mutation causing the genetic disorder such as in this case RDEB as taught by Bonafont.
Regarding claim 5, Chen and Gao do not teach the CRISPR cas system configured to excise exon 80 of the COL7 Al gene which codes for the collagen VII protein.
Bonafont teaches that using a dual single-guide RNA (sgRNA)-guided Cas9 nuclease delivered as a ribonucleoprotein complex through electroporation, we have achieved very efficient targeted deletion of COL 7 Al exon 80 in recessive dystrophic epidermolysis bullosa (RDEB) patient keratinocytes carrying a highly prevalent frameshift mutation (Abstract). This ex vivo non-viral approach rendered a large proportion of corrected cells producing a functional collagen VII variant (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Chen and Gao to include the specifics of the CRISPR cas 9 as the gene editing ribonucleoprotein for excision of COL7Al exon 80 as taught by Bonafont because Chen teaches it is within the ordinary skill in the art to use a CRISPR system within a nanoparticle complex to be delivered to a cell via a polymer, Gao taches the use of the highly branched poly-beta amino ester polymer for delivery to a cell and Bonafont teaches the use of the cas 9 ribonucleoprotein within a particle complex to excise the COL7A1 exon 80.
One would have been motivated to make such a modification in order to receive the expected benefit of excision of the mutation causing the genetic disorder such as in this case RDEB as taught by Bonafont.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claim 3 under 35 U.S.C. 103 as being unpatentable by Chen et al (WO 2019/104058 Al) in view of Gao et al (Biomacromolecules 2016, 17, 3640- 3647) is moot in view of the cancellation of the claims.
The previous rejection of claims 1 and 6 under 35 U.S.C. 103 as being unpatentable by Chen et al (WO 2019/104058 Al) in view of Gao et al (Biomacromolecules 2016, 17, 3640- 3647) has been maintained in view of Applicant’s amendments.
Applicant's arguments filed 12/15/2025 have been fully considered but they are not persuasive. Applicant’s arguments are not persuasive because Applicant argues the highly branched poly beta-amino ester (HPAE) is formed from a trimethylolpropane triacrylate (TMPTA) monomer, which only has three reactive groups and therefore forms a 3-branching highly branched polymer and cannot form a 4-branching polymer and therefore, Gao does not teach or suggest a 4-branching poly-beta amino ester polymer. Applicant continues to argue it follows that a skilled artisan would not have been led by Gao to modify the Chen nanoparticle by substituting a 4-branching poly-beta amino ester polymer for the unbranched polymer, as, contrary to the Examiner’s assertion, the 4-branching poly-beta amino ester polymer featured in amended claim 1 is not taught or suggested by Gao.
The current claim recites a four-branching poly-beta amino ester polymer and does not specify four reactive groups with one or more reactive group to each branch. Gou teaches a four-branching poly-beta amino ester polymer with three reactive groups as shown below.
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The image presented in scheme 1 of Gou has been labeled by examiner to show the four branches of the four-branching poly-beta amino ester polymer. Therefore, the rejection is proper and all elements of the claim are taught by Chen in view of Gou.
The previous rejection of claims 4 and 5 under 35 U.S.C. 103 as being unpatentable by Chen et al (WO 2019/104058 Al) and Gao et al (Biomacromolecules 2016, 17, 3640- 3647) further in view of Bonafont et al (Molecular Therapy Vol. 27, pages 986-998, March 15, 2019) has been maintained in view of Applicant’s amendments.
Applicant's arguments filed 12/15/2025 have been fully considered but they are not persuasive. Applicant’s arguments are not persuasive because Applicant simply argues that because the claim 1 is patentable due to the teachings not teaching all the elements of claim 1 renders claims 4 and 5, as dependent upon claim 1, as patentable.
This argument is not persuasive because Chen and Gou teach all the elements of claim in combination as presented above and Bonafort teaches the additional limitations set forth within claims 4 and 5.
Conclusion
No claims are allowed.
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/ALEXANDRA ROSE LIPPOLIS/ Examiner, Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637