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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 04, 2026 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on June 04, 2026. Claims 1, 3-6, 8, 10, 14, 16. 18-21, 23, 25, 29, 31 and 33-37 are pending. Claims 3-4, 18-19, 31 and 33-37 are withdrawn. Claims 1, 5-6, 8, 10, 14, 16, 20-21, 23, 25 and 29 are currently examined.
Claim Rejections - 35 USC § 102
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.
(Previous rejection- maintained with edition) Claims 1, 5-6, 8, 10, 14, 16, 20-21, 23, 25 and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Situ et al. ( Virology. 2018 Dec; 525:170-181).
The base claim 1 is directed to a gene delivery system comprising a lentiviral gene delivery vector particle comprising a polynucleotide encoding at least one gene-of-interest, wherein the lentiviral gene delivery vector comprises a modified Sindbis virus envelope protein comprising at least one mutation that renders the Sindbis virus envelope protein unable to bind a cell surface protein on a target cell; and at least one bispecific polypeptide comprising a first binding domain for the modified Sindbis virus envelope protein and a second binding domain for a target cell-specific receptor protein.
The base claim 16 is directed to a composition comprising a lentiviral gene delivery vector particle comprising a polynucleotide encoding at least one gene-of-interest, wherein the lentiviral gene delivery vector comprises a modified Sindbis virus envelope protein comprising at least one mutation that renders the Sindbis virus envelope protein unable to bind a cell surface protein on a target cell; and at least one bispecific polypeptide comprising a first binding domain for the Sindbis virus envelope protein and a second binding domain for a target cell-specific receptor protein.
Situ et al. discloses two lentiviral vectors system by pseudotyping the vectors with modified Sindbis virus envelope proteins, where the antibody such as anti-hTfR1 antibody can bind both lentiviral pseudoparticle and the target cell expressing the cell surface protein hTfR1 simultaneously. One of the systems Situ et al. taught is the 2.2 pseudotype that contains the ZZ peptide inserted into the E2 protein of the Sindbis virus. The ZZ peptide binds the Fc region of antibodies and the antibody can bind to a receptor such as hTfR1 of a target-cell. Another system Situ et al. taught is the E2 71 AV, STAV, eMA, and mSAH pseudotypes that are inserted with avidin streptavidin, monomeric rhizavidin, and the monomeric streptavidin/rhizavidin, respectively, in E2. These molecules are known to bind biotin. Therefore, the E2 71 AV, STAV, eMA, and mSAH pseudotypes are expected to be conjugated with biotinylated antibodies and the antibody such as anti-hTfR1 antibody to bind to the target-cell receptor (See page 4, paragraph 5; Fig. 1, page 20 and below). Situ et al. also teaches the “gene-of-interest” is a reporter gene of EGFP (See e.g. page 6, paragraph 2 and Fig. 3).
Furthermore, Situ et al. teaches that they have successfully used targeting lentiviral vector system with the ZZ domain for specific transduction of desired cell types in immunodeficient mice, demonstrating the proof of principle of the targeted lentiviral transduction. High stability of binding between E2 71 eMA and mSAH and biotinylated ligands will enable this targeting lentiviral transduction system to be applicable to immunocompetent animal experimental settings, facilitating application of targeted lentiviral transduction to broad fields of research (See page 11, paragraph 2). Here the animal transduction experiment indicates an administration of a composition of the pseudotyped lentiviral vector to the subject, which teaches claim 16 for “a composition comprising a viral gene delivery vector particle” as claimed.
Accordingly, Situ et al. anticipates the amended base claims 1 and 16 by teaching a gene delivery system/composition comprising a lentiviral gene delivery vector, a modified Sindbis virus envelope protein being unable to bind its original receptor-binding regions through E2 insertion, and a bispecific antibody that can bind the viral vector and a target cell-specific protein (See Fig. 1 below). Here the target-cell specific receptor protein is hTfR1, the viral gene delivery vector particle is a lentivirus and the bispecific polypeptide is an anti-hTfR1 antibody. Although Situ et al. does not explicitly adopt the term “bispecific polypeptide” as claimed, the teaching of the antibody in Situ is actually a “bispecific polypeptide” because the anti-hTfR1 antibody applied in the Situ’s study is used to bind both the target-cell receptor hTfR1 and the modified E2 of Sindbis virus, where the E2 is inserted with ZZ peptide or conjugated with a biotin-binding protein (See page 28). As for the newly added limitation at” mutations in the E2 domain that ablate native receptor binding, wherein the modified Sindbis virus envelope protein lacks integrated biotin-binding domains” in the base claims 1 and 16, the 2.2 design of Situ in Fig. 1 below teaches that the ZZ peptide, IgG Fc-binding peptide derived from protein A, as an adaptor molecule fused with the mutated Sindbis virus envelope protein to non-covalently conjugate targeting antibodies to lentiviral vectors. Lentiviral vectors pseudotyped with 2.2 can be easily conjugated with antibodies against various target molecules, including CD4, Transferrin receptor 1 (TfR1), PSCA, CD19, CD20, DC-SIGN, CD34, and P-glycoprotein, by simply mixing the vectors with antibodies. The vectors specifically transduce cell types recognized by the conjugated antibodies (see page 3, paragraph 3), here the ZZ insertion in E2 is a type of mutation and the 2.2 construct does not integrated biotin-binding domains (See Fig. 1 below), and the mutation/insertion in E2 domain eliminate/ablate the native receptor binding region (See page 2, paragraph 4; page 3, paragraph 1).
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Regarding claims 5, 6, 8, 20-21 and 23, Situ et al. teaches that the bispecific polypeptide is an anti-hTfR1 antibody (See page 28 and below), which teaches claims 5 and 20. Here the hTfR1 antibody is an anti-human TfR1 antibody (claims 6 and 21). Because the E2 of Situ et al. is modified, the anti-hTfR1 antibody is considered to bind the Sindbis virus envelope protein in the E2 domain of the modified Sindbis virus envelope protein, which teaches claims 8 and 23.
Regarding claims 10 and 25, Situ et al. teaches that they used the ZZ peptide, IgG Fc-binding peptide derived from protein A, as an adaptor molecule fused with the mutated Sindbis virus envelope protein (2.2, Fig. 1A and B) to non-covalently conjugate targeting antibodies to lentiviral vectors. Lentiviral vectors pseudotyped with 2.2 can be easily conjugated with antibodies against various target molecules, including CD4, Transferrin receptor 1 (TfR1), PSCA, CD19, CD20, DC-SIGN, CD34, and P-glycoprotein, by simply mixing the vectors with antibodies (See page 3, paragraph 3, and Fig. 1 above).
Regarding claim 14 and 29, Situ et al. teaches the gene-of-interest is a marker gene, EGFP. For example, Situ et al. teaches that since the titers are exceptionally high, it is possible that the EGFP expression of the cells transduced by the E2 71 eMA and SAH pseudotypes is mediated by pseudo-transduction, which is the binding of the EGFP protein associated with the vectors (See e.g., page 8, paragraph 2).
Responses to Applicant’s Remarks
Applicant’s arguments filed on June 04, 2026 has been received and fully considered.
Applicant’s arguments for the rejection under 35 U.S.C. § 102 is not found persuasive for the following reasons:
1). Applicant argued that Situ's system requires insertion of adapter molecules, such as avidin, streptavidin, eMA, mSAH, into the E2 domain to enable targeting, whereas Applicant's invention achieves targeting through ablative mutations in the E2 domain that preserve the domain's native structure, allowing direct bispecific antibody binding without adapter intermediaries (See Remarks, page 7).
Applicant’s argument is not persuasive because the mutation as claimed at “…comprising mutations in the E2 domain…” does not exclude the insertion, which is one type of mutations.
Also, the instant base claims do not cite a limitation on preserving a E2 native structure. Therefore, the insertion in E2 of Situ teaches the mutation of E2 domain as claimed.
2). Applicant argued that “Situ's system conjugates biotinylated antibodies to the
vectors through the biotin-binding molecules (avidin/streptavidin binding). The targeting antibody binds indirectly through biotin-streptavidin/rhizavidin interactions, not by direct engagement with the E2 domain itself (See Remarks, page 8).
Applicant’s argument is not persuasive.
(i). Situ displays a biotin-binding molecules (avidin/streptavidin binding) in their article, but also discloses another construct 2.2 with a ZZ domain inserting into the E2 (See Fig. 1, page 20 and above), the ZZ peptide can bind to the Fc region of antibodies without integrating biotin-binding (See page 21 and Fig. 1). Thus, Situ teaches the newly added limitation at “wherein the modified Sindbis virus envelope protein lacks integrated biotin-binding domains”.
(ii). The instant base claim 1 requires the binding is for “… the modified Sindbis virus envelope protein…”, which does not limit the binding is directly to E2.
Here, the above responses to the instant remarks also extent to applicant’s arguments on claims 1 and 16 at page 8, paragraphs 3-6.
3). Applicant argued the term "mutation/insertion” used in the office action (See page 8, paragraphs 7-8).
Applicant’s argument is not persuasive.
The instant claims do not limit the mutation types. Insertion is also a type of mutation. This can be evidenced by iNHGRI’s description (https://www.genome.gov/genetics-glossary/Insertion). NHGRI teaches that an insertion, as related to genomics, is a type of mutation that involves the addition of one or more nucleotides into a segment of DNA (See page 1).
4). Applicant argued that applicant's invention uses mutations alone to ablate native receptor binding while explicitly excluding integrated biotin-binding domains. Situ does not contemplate or teach this approach. Situ's focus is entirely on using
mutations as a stepping stone to enable safe insertion of adapter molecules, not as a standalone targeting mechanism (See Remarks, page 9).
Applicant’s argument is not persuasive.
Based on the description above, the instant claims do not cite limitation for the mutation types, and the insertion is a type of mutations. Also, Situ discloses another construct 2.2 that insert the ZZ into the E2 domain, where the ZZ can bind antibody without integrating biotin-binding domains. In addition, the instant claims used the term “comprising’ mutations in the E2 domain that does not require the mutation needed is “alone” to ablate native receptor binding.
Conclusion
No claims are allowed.
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/RUIXUE WANG/ Examiner, Art Unit 1672
i NHGRI is cited only to response to applicant’s argument and not to reject any claim.
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