DETAILED ACTION
Claims 1-8, 10, 12-14, 17-18, 20, 22, 24, 26, 28, 31 and 34 are pending and under examination in the instant application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/21/24 and 10/30/25 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner, and initialed and signed copies of the 1449s are attached to this action.
Claim Objections
Claim 17 is an improper claim as it depends on canceled claim 15. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 17-18 are 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.
Claim 17 depends on a canceled claim, claim 15. As such the limitations of an adenovirus of claim 15 cannot be determined since claim 15 is canceled, the metes and bounds of the claim as a whole cannot be known. Claim 18 depends on claim 17 and thus is also indefinite as it too ultimately depends on a canceled claim.
Due to the unknown features of the adenovirus as claimed in claims 17 and 18, further examination of these claims under 35 U.S.C. 112(a), 102, and 103 is precluded.
Claim 26 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.
Claim 26 depends on claim 24 and recites, “wherein the capsid modification is substitution of a fiber gene or a part thereof with a homologous part derived from another serotype of adenovirus to form a chimeric adenovirus…”. Claim 24, however, recites that the capsid modification is insertion of an RGD within an H1 loop of an adenovirus fiber protein. Thus, it is unclear whether the modification of claim 26 is a further modification in addition to the previous recitation of insertion of an RGD within an H1 loop of adenovirus fiber protein, or whether claim 26 conflicts with the limitation of claim 24. Thus, the metes and bounds of the claim cannot be determined.
In the interest of compact prosecution, claim 26 has been interpreted as encompassing but not limited to the addition of an RGD to the fiber gene from a different serotype virus.
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.
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.
Claims 1, 4-8, 10, 12-14, 20, 22, 24, 26, 28, 31 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Rojas et al. (2016) J. Control. Rel., Vol. 237, 78-88, in view of U.S. Patent 7,279,318 (2007), hereafter referred to as Seymour et al., Vonder Haar et al. (1994), J. Bacteriol., Vol. 176(20), 6207-6213, Niemann et al. (2020) Oncolytic Viruses, Methods in Molecular Biology, Vol. 2058, Chapter 3, pages 31-49, WO 2009/098492 (2009), hereafter referred to as Baker et al., Dias et al. (2012) Gene Therapy, Vol. 19, 988-998, and Gao et al. (2020) Cancers, Vol. 12, 1139;doi:10.3390/cancers12051139, pages 1-25.
Rojas et al. teaches that the efficacy of using recombinant adenoviruses as vaccines, gene therapy vectors, and oncolytic viruses is limited by pre-existing neutralizing antibodies (Rojas et al., page 78). Rojas et al. teaches to protect adenovirus against pre-existing neutralizing antibodies by inserting an albumin-binding domain (ABD) in the main adenovirus capsid protein, the hexon, such that the modified hexon protein comprises an albumin-binding domain and binds serum albumin to shield the virus upon systemic administration (Rojas et al., page 78). More specifically, Rojas et al. teaches that the albumin-binding domain from the protein G of Streptococcus was inserted in the HVR1 of hexon in the oncolytic virus ICOVIR15, and Ad5 adenovirus, generating the oncolytic adenovirus ICOVIR15-ABD, and that the binding domain was flanked by GSGS-linkers and centered in HVR1 after the D150 amino acid with out deleting any hexon sequence (Rojas et al., Fig. 1B). In Figure 1, Rojas et al. provides a partial diagram of the ICOVIR15 viral genome which comprises 5' and 3' ITS flanking a partially deleted E1A sequence, the hexon sequence and insertion point of the ABD (Rojas et al., Figure 1B). Rojas et al. further teaches that the ABD-modified adenoviruses bind human and mouse albumin and maintain their infectivity and replication capacity in presence of pre-existing neutralizing antibodies (Rojas et al., page 78 and Figures 4 and 6). Rojas et al. concludes that coating of the virus capsid with serum protein represents an effective approach to evade pre-existing neutralizing antibodies (Rojas et al., page 78).
Rojas et al. differs from the instant invention by not teaching to coat the adenovirus with the serum protein transferrin, or to modify hexon sequence of an adenovirus to comprise a transferring binding protein. Seymour et al. supplements Rojas et al. by teaching the generation of transferrin coated adenovirus. Seymour et al. teaches various modifications to adenovirus in order to avoid serum antibodies and/or increase gene expression in target cells (Seymour et al., paragraphs 13, 43, and 58). Seymour et al. teaches coating adenovirus with the serum protein transferrin using a chemical linker, and demonstrates increasing cellular uptake of the transferrin coated adenovirus (Seymour et al., Examples 2-3). It is also noted that Seymour et al. also shows other coated adenoviruses exhibit reduced neutralizing antibody activity (Seymour et al., Examples 12 and 21). Vonder Haar et al. further supplements Rojas et al. and Seymour et al. by teaching that bacterial transferring binding proteins were known at the time of filing, including transferring binding proteins tbp1 and tbp2 from the bacteria Neisseria meningitidis which are capable of binding to human transferrin (Vonder Haar et al., page 6207). Vonder Haar et al. further teaches using progressive deletions of the tbp2 sequence to determine the human transferrin binding domain (Vonder Haar et al., page 6209, Figure 2).
Thus, based on the teaching of Seymour et al. that coated adenovirus can be used to reduce neutralizing anti-adenovirus antibody activity, that adenovirus can be coated with the serum proteins transferrin, and that transferrin coated serum exhibited increased cellular uptake and thus increased expression in target cells, and the teaching of Vonder Haar et al. for bacteria Neisseria meningitidis transferrin binding proteins which bind to human transferrin, it would have been prima facie obvious to the skilled artisan at the time of filing to modify the adenovirus taught by Rojas et al. to insert the transferrin-binding domain taught by Vonder Haar et al. in the HVR1 of adenoviral hexon in order to generate an adenoviral vector capable of being coated with transferrin in order to both increase cellular uptake of the adenovirus and reduce serum neutralizing antibody response with a reasonable expectation of success. Further based on the teachings of Rojas et al. to insert the binding protein after D150 of HVR1 of the hexon protein, it would have been prima facie obvious to the skilled artisan at the time of filing to insert the transferrin binding protein after D150, including between amino acids 154-155 with reasonable expectation of success.
While Rojas et al. teaches that the insertion of the binding domain included the insertion of a GSGS linker sequence into an Ad5 hexon sequence, Rojas et al. does not teach the use of a linker with the sequence of SEQ ID NO:5 which is GGGGSGGGGSGGGGS, or teach that the hexon sequence of Ad5 is SEQ ID NO:7. However, at the time of filing, the linker sequence GGGGSGGGGSGGGGS was a well known sequence for use in adenoviral genomic modifications. Neimann et al., for example teaches to use a functionally neutral spacer peptide for clear spatial separation of the two functional domains, such as a glycine-serine linker with the amino acid sequence GGGGSGGGGSGGGGS (Neimann et al., page 38). Further, the sequence of the Ad5 hexon polypeptide with the sequence of SEQ ID NO:7 was also known at the time of filing. Baker et al., for example, teaches an adenoviral hexon polypeptide sequence which is 100% identical to SEQ ID NO:7 (Baker et al., Figure 12).
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Therefore, in view of the motivation provided by Neimann et al. to use a linker with the sequence of SEQ ID NO:5 in adenovirus, and the teachings of Baker et al. for the well known sequence of Ad5 hexon which is a sequence 100% identical to SEQ ID NO:7, it would have been prima facie obvious to the skilled artisan at the time of filing make an adenoviral vector according to Rojas et al. in view of Seymour et al. and Vonder Haar et al. by inserting the transferrin binding protein with a linker domain of SEQ ID NO:5 into an adenoviral hexon protein with the sequence of SEQ ID NO:7 with a reasonable expectation of success.
While Rojas et al. teaches an adenoviral vector useful for treating cancer, Rojas et al., Seymour et al., and Vonder Haas et al. further differ from the instant claims by not teaching additional features of anti-cancer adenoviral vectors including the insertion of an RGD into the fiber loop, the replacement of the adenovirus fiber protein with a different serotype adenoviral fiber protein, the use specifically of Ad5/3, the inclusion of a therapeutic gene in E3, or the inclusion of a tissue or tumor specific promoter operably linked to an adenoviral gene. However, at the time of filing, number of antitumor adenoviral vectors were known in the prior art which could be used successfully in methods of treating cancer. Dias et al., for example, teaches an Ad5/3 adenovirus comprising an adenoviral genome comprising a partially deleted E1A sequence, a partial deletion of E3 in which a portion of E3 is replaced with a sequence encoding an anti-CTLA4 antibody, and a replacement of Ad5 fiber with Ad3 fiber (Dias et al., page 989, Figure 1). Gao et al. provides a list of anti-tumor and oncolytic adenoviral vectors that have been used in clinical trials to treat various cancers, including adenovirus in which an E2F-1 promoter drives expression of E1A, an adenovirus where a survivin promoter drives the expression of E1A, and an adenovirus where an RGD peptide motif has been inserted into the H1 loop of the Ad fiber protein (Gao et al., Table 2).
Therefore, based on the teachings of Gao et al. and Dias et al. for adenoviral vectors currently used in clinical trials which include the genomic features recites in the instant claims, it would have been prima facie obvious to the skilled artisan at the time of filing to use any of these clinically approved adenoviral vector as the starting adenoviral genome for the modified adenovirus comprising an insertion of a transferrin binding protein into the hexon HVR1 as taught by Rojas et al. in view of Seymour et al., and Vonder Haas et al. with a reasonable expectation of making the adenoviral vector and in using the vector in methods of treating cancer.
Allowable Subject Matter
Claims 2 and 3 are 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.
It is noted that the nucleic acid sequences and amino acid sequences for the transferrin binding protein recited in claims 2 and 3, SEQ ID NOS 1-4, 8, and 10, are not taught or suggested by the prior art of record. Each of these sequence differs from known transferrin binding nucleic acids or proteins by at least one nucleotide and amino acid.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
