DETAILED ACTION
Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of Group I claims 65, 74, and 96-97 and elected species AAV particle and compound X3 (table 1 of specification) in the reply filed on 10/23/2025 is acknowledged. The search results found additional species retroviral particle. For compact prosecution the claims are also examined for the additional species of retroviral particle found. With respect to the remaining species, the election of species is maintained.
Modified Group I (modified): Applicant added new claims to the elected invention Group I on 03/16/2026. The Group I now consist of claims 74, 97, and 123 – 125.
The election/restriction is made final.
Status of Claims (updated)
3. Claims 74, 97, 99, 110 and 123 - 127 as per claim listing filed on 03/16/2026 are pending.
4. Claims 99, 110, and 126-127 are withdrawn from examination due to restriction/election.
5. Claims 1-3, 6, 11, 13, 20-21, 24, 29, 32-34, 65, 96 are canceled by the applicant.
6. Claims 74, 97, and 123 - 125 are under examination in this office action.
Priority
7. This application is a 371 National Stage of International Application No.
PCT/US2021/039011, filed on June 24, 2021, which claims the benefit of U.S. Provisional Application No. 63/043,764, filed June 24, 2020, U.S. Provisional Application No. 63/043,767, filed June 24, 2020, U.S. Provisional Application No. 63/135,527, filed January 8, 2021, and U.S. Provisional Application No. 63/214,015, filed June 23, 2021.
Information Disclosure Statement
8. The information disclosure statement (IDS) submitted on 10/23/2025 and 03/16/2026 is filed in time and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Claim Rejection
9. Withdrawn rejection of claim 96 under 35 U.S.C. 112(b) because applicant cancelled the claim.
Claim Objections
10. Claim 125 is objected to because of the following informalities:
The claim 125 recited “an adeno-associate viral (AAV) particle”. The correction is required to “an adeno-associated viral (AAV) particle”
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (New)
11. 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.
Claim 124 is 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.
The instant claim 124 recited added limitation, wherein the cell surface binding moiety is a ligand capable of binding to an internalizing receptor and is selected from Tables 1-3.
The claim 124 fails to clearly set the boundaries of the invention, because referencing a table in the claim to recite a claim limitation as a Markush listing leaves the exact scope of the claim ambiguous and therefore the claim 124 is indefinite. Additionally, “[W]here 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. “ See e.g. MPEP 2173.05 (s).
Applicant is required to amend the claim to list the Markush limitations.
Claim Interpretation (modified)
12. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 74: The instant claim 74 is interpreted to be directed to a modified viral particle, comprising a viral particle covalently attached to a heterologous cell surface binding moiety that is capable of binding to a cell surface receptor, wherein the modified viral particle is of formula (I): [Xn-L-Z]m-P
or a pharmaceutically acceptable salt thereof,
wherein: X is the heterologous cell surface binding moiety capable of binding to the cell surface receptor; L is an optional linker; and Z is a residual moiety resulting from the attachment of Xn (or L, if present) to P; and P is a viral particle.
A heterologous cell surface binding moiety is interpreted to comprise a ligand that binds to a cell receptor.
Claim Rejections - 35 USC § 102 (New)
13. 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.
14. Claims 74, 97, and 123 - 125 are rejected under 35 U.S.C. 102(a)(1)/ (a)(2) as being anticipated by Mevel et al 2017 (WO2017212019A1 published 12/14/2017, cited on IDS filed on 10/23/2025).
Claim 74. Mevel et al 2017 is in the art directed to a virus, a modified adeno-associated virus (AAV), a recombinant Adeno- Associated Virus (rAAV) vector particles chemically coupled by covalent attachment on their capsid with at least one ligand (a ligand reads on heterologous cell surface binding moiety) and to a method for producing said recombinant Adeno-Associated Virus (rAAV) vector particle. The ligand (a heterologous cell surface binding moiety) is capable of binding to a cell surface receptor (see, abstract, claims 1-20). According to a more specific aspect of the present embodiment, galactose- derived ligands, which are recognized by asialoglycoprotein receptor (ASPGPr), can be used to specifically target hepatocytes (see, page 32 lines 25-29). The chemical modification considered in the framework of the present invention may therefore be carried out by formation of a covalent bond directly to the amino groups present on the AAV capsid without requirements of previous genetic modifications to the capsid sequence (see, page 7 lines 7-10). Mevel et al 2017 anticipated the instant claimed modified viral particle of formula (I): [Xn-L-Z]m-P; because Mevel et al 2017 teaches an AAV particle (P) capsid protein covalently attached to a heterologous cell surface binding moiety (L , ligand), X as a spacer, the claimed Z Z is a residual moiety resulting from the attachment may be inherently present as not explicitly disclosed (see, claims 12-13, see description, entire prior art).
Claim 97. Mevel et al 2017 anticipated the added limitation of instant claim 74, wherein the viral particle composition is an empty virus particle by disclosing labelling of empty capsids (see, page 5 line 5). Although the empty capsids is labeled with FITC, the empty capsid can also be labeled in view of claim 74 with the ligand.
Claim 123. Mevel et al 2017 anticipated the added limitation of instant claim 123, wherein the cell surface receptor is mannose 6 phosphate receptor (M6PR), asialoglycoprotein receptor (ASGPR), or folate receptor by disclosing the introduction of a ligand, a N-acetylgalactosamine (GalNAc) derivative, such as compound 6 and 13 as described above, on the AAV2 particle surface increases the selective transduction of hepatocytes via the asialo glycoprotein receptor (ASPGr) (see, page 32 lines 25-27). Figure 3 represents covalent coupling of GalNAc ligands on the capsid of AAV2 via primary amino groups (see, page 48, lines 5-6). Figure 4 represents the transduction of human primary hepatocytes with AAV2 and AAV2 vectors chemically modified with GalNAc ligands (see, page 51, lines 18-25).
Claim 124. Mevel et al 2017 anticipated the added limitation of instant claim 124, wherein the cell surface binding moiety is a ligand capable of binding to an internalizing receptor and is selected from Tables 1-3 by disclosing GalNAc ligands (see, page 32 lines 25-27). According to one embodiment, a cell-type specific ligand may be derived from vitamins such as folates (see, page 14 lines 17-18). Mannose ligands (see, page 54, lines 30-31, page 55 lines 15-19).
Claim 125. Mevel et al 2017 anticipated the added limitation of instant claim 125, wherein the viral particle is an adenoviral (AV) particle, an adeno-associated viral (AAV) particle, or a lentiviral (LV) particle (see, page 1, lines 21-23, abstract, claims 1-25).
Claim Rejections - 35 USC § 103
15. 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.
16. Claims 74, 97, and 123 - 125 are rejected under 35 U.S.C. 103 as being unpatentable over Mevel et al 2017 (WO2017212019A1 published 12/14/2017, cited on IDS filed on 10/23/2025) as applied to claims 74, 97, and 123 – 125 above and further in view of Mingozzi et al 2013 (Science translational medicine, 5(194), p. 1-9).
Claims 74, 97, and 123 - 125: The teachings of Mevel et al 2017 (WO2017212019A1) that anticipated claims 74, 97, and 123 - 125 as recited supra are incorporated here in entirety.
Claim 97: Mevel et al 2017 do not explicit express or teach the claim 97 added limitation regarding covalent attachment of the ligand to virus particle empty capsid (AAV capsid).
Mingozzi et al 2013 is in the art and is directed to overcoming preexisting humoral immunity to AAV using capsid decoys. Mingozzi et al 2013 disclosed that adeno-associated virus (AAV) vectors delivered through the systemic circulation successfully transduce various
target tissues in animal models. However, similar attempts in humans have been hampered by the high prevalence of neutralizing antibodies to AAV, which completely block vector transduction. We show in both mouse and nonhuman primate models that addition of empty capsid to the final vector formulation can, in a dose dependent manner, adsorb these antibodies, even at high titers, thus overcoming their inhibitory effect. To further enhance the safety of the approach, we mutated the receptor binding site of AAV2 to generate an empty capsid mutant that can adsorb antibodies but cannot enter a target cell. Optimizing the ratio of full/empty capsids in the final formulation of vector, based on a patient’s anti-AAV titers, maximize the efficacy of gene transfer after systemic vector delivery (see, abstract, entire article).
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the prior art teachings of Mevel et al 2017 with additional teachings of Mingozzi et al 2013 on empty capsid as a decoy for overcoming preexisting humoral immunity to AAV to develop efficacious modified AAV gene therapy for treatment or therapeutic purpose and for commercial success. There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 97. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see, MPEP § 2143, example of rationales, A -G).
Response to Arguments
17. Applicant’s arguments with respect to the rejected claims in the prior non-final rejection office action and in response filed amended claims 74, 97 and new claims 123 - 125 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant’s arguments:
In summary, applicant argued that rejection of claims under 35 USC 102 and 103 are improper and requires withdrawal of rejection.
In Response:
Applicant’s arguments with respect to the rejected claims in the prior non-final rejection office action and in response filed amended claims 74, 97 and new claims 123 - 125 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Please see office action as recited supra.
18. Relevant Prior Arts:
Gary-Bobo M, Nirdé P, Jeanjean A, Morère A, Garcia M. Mannose 6-phosphate receptor targeting and its applications in human diseases. Curr Med Chem. 2007;14(28):2945-53.
Mével et al 2019. Chemical modification of the adeno-associated virus capsid to improve gene delivery. Chem Sci. 2019 Dec 9;11(4):1122-1131.
Michelfelder S, Varadi K, Raupp C, Hunger A, Körbelin J, Pahrmann C, Schrepfer S, Müller OJ, Kleinschmidt JA, Trepel M. Peptide ligands incorporated into the threefold spike capsid domain to re-direct gene transduction of AAV8 and AAV9 in vivo. PLoS One. 2011;6(8):e23101.
Büning H, Srivastava A. Capsid Modifications for Targeting and Improving the Efficacy of AAV Vectors. Mol Ther Methods Clin Dev. 2019 Jan 26; 12:248-265.
Ponnazhagan S, Mahendra G, Kumar S, Thompson JA, Castillas M Jr. Conjugate-based targeting of recombinant adeno-associated virus type 2 vectors by using avidin-linked ligands. J Virol. 2002 Dec;76(24):12900-7.
Stachler MD, Chen I, Ting AY, Bartlett JS. Site-specific modification of AAV vector particles with biophysical probes and targeting ligands using biotin ligase. Mol Ther. 2008 Aug;16(8):1467-73.
Sanhueza et al 2017. Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor. J Am Chem Soc. 2017 Mar 8;139(9):3528-3536. (Year: 2017).
Kay t al 2018. US20180163229A1. Novel recombinant adeno-associated virus capsids containing a designed ankyrin repeat protein (darpin) or fragment thereof. The present invention relates to variant AAV capsid polypeptides containing designed ankyrin repeat proteins (DARPins), wherein the variant capsid polypeptides exhibit an enhanced neutralization profile, increased transduction, and/or tropism in human liver and/or hepatocyte cells, or human pancreas and/or pancreatic cells, as compared to capsid polypeptides that do not include DARPins.
Rigo et al 2018. (WO2018057837A1, 03/29/2018). Gene therapy and targeted delivery of conjugated compounds.
Deniaud et al 2021 (WO 2021005210 A1, 01/14/2021, priority to EP19185879.4, 07/11/2019). Chemically modified adeno-associated virus. The invention relates to chemically modified adeno-associated (AAV) virus and their use in gene therapy.
Kay et al 2017. (WO2017096164A1, 06/08/2017). Novel recombinant adeno-associated virus capsids with enhanced human skeletal muscle tropism. Variant AAV capsid polypeptides, wherein the variant AAV capsid polypeptides exhibit increased transduction and/or tropism in human muscle tissue or cells as compared non-variant parent capsid polypeptides.
Conclusion
19. No claim is allowed.
20. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
21. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J Visone can be reached at 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600
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