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 .
1. Claims 1 – 8, 10 – 13, 22, 26, 30 – 32, 34, and 39 -45 are pending.
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1 – 8, 10 – 13, 22, 26, 30 – 32, 34, and 39 -45) in the reply filed on 04/06/2026 is acknowledged.
3. Claims 33, 34,35, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/06/2026.
4. All non-elected claims have been cancelled.
Priority
5. This application claims the benefit of United States Provisional Application Number 63/188,294 filed 05/13/2021.
Information Disclosure Statement
6. The information disclosure statement (IDS) submitted on 04/06/2026 and 02/15/2024 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
7. The drawings filed on 11/13/2023 are acknowledged.
Specification
8. The use of the term pEMBR, Triton X-100, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
9. Claims 1 – 8, 10 – 13, 22, 26, 30 – 32, 34, and 39 – 45 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.
10. Regarding claim 1, the metes and bounds of “a L1-52/55K (Packaging Protein 3)” cannot be determined because it is unclear what the relationship is between L1-52/55K and Packaging Protein 3. It is unclear if L1-52/55K is an abbreviation for Packaging Protein 3 and if Packaging Protein 3 is limiting L1-52/55K or is broader than L1-52/55K. Claims 2 – 8, 10 – 13, 22, 26, 30 – 32, 34, and 39 – 45 are also rejected as they depend from claim 1 and do not clarify the grounds of rejection.
11. Regarding claim 6, the metes and bounds of “L4 (Hexon Assembly)” cannot be determined because it is unclear what the relationship is between L4 and Hexon Assembly. It is unclear if L4 is an abbreviation for Hexon Assembly and if Hexon Assembly is limiting L4 or is broader than L4.
12. Regarding claim 7, the metes and bounds of “a partial L4 (Hexon Assembly)” cannot be determined because it is unclear what the relationship is between a partial L4 and Hexon Assembly. It is unclear if a partial L4 is an abbreviation for Hexon Assembly and if Hexon Assembly is limiting a partial L4 or is broader than a partial L4.
13. Regarding claim 8, the metes and bounds of “a partial Hexon Associated Precursor (L4 pVIII)” cannot be determined because it is unclear what the relationship is between a partial Hexon Associated Precursor and L4 pVIII. It is unclear if L4 pVIII is an abbreviation for a partial Hexon Associated Precursor and if L4 pVIII is limiting a partial Hexon Associated Precursor is limiting a partial L4 and if a partial Hexon Associated Precursor is broader than L4 pVIII.
14. Claim 31 recites the limitation "the E4 mini promoter" in line 2. There is insufficient antecedent basis for this limitation in the claim.
15. Claim 32 recites the limitation "the SV40 promoter" in line 2. There is insufficient antecedent basis for this limitation in the claim.
16. Regarding claim 39, the metes and bounds of “L4 (Hexon Assembly)” cannot be determined because it is unclear what the relationship is between L4 and Hexon Assembly. It is unclear if L4 is an abbreviation for Hexon Assembly and if Hexon Assembly is limiting L4 or is broader than L4.
17. Regarding claim 40, the metes and bounds of “a partial L4 (Hexon Assembly)” cannot be determined because it is unclear what the relationship is between a partial L4 and Hexon Assembly. It is unclear if a partial L4 is an abbreviation for Hexon Assembly and if Hexon Assembly is limiting a partial L4 or is broader than a partial L4.
18. Regarding claim 41, the metes and bounds of “a partial Hexon Associated Precursor (L4 pVIII)” cannot be determined because it is unclear what the relationship is between a partial Hexon Associated Precursor and L4 pVIII. It is unclear if L4 pVIII is an abbreviation for a partial Hexon Associated Precursor and if L4 pVIII is limiting a partial Hexon Associated Precursor is limiting a partial L4 and if a partial Hexon Associated Precursor is broader than L4 pVIII.
19. Claim 42 recites the limitation "the nucleotide sequence encoding a partial DNA Terminal Protein" in line 3. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite “a partial DNA Terminal Protein”.
20. Claim 43 recites the limitation "the nucleotide sequence encoding a partial 23kDa endoprotease" in line 3. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite “a partial 23kDa endoprotease”.
Claim Interpretation
21. For the purpose of applying prior art, “a L1-52/55K (Packaging Protein 3)” of claim 1 is interpreted as L1-52/55 kDa protein.
22. For the purpose of applying prior art, “L4 (Hexon Assembly)” of claim 6 is interpreted as L4.
23. For the purpose of applying prior art, “a partial L4 (Hexon Assembly)” of claim 7 is interpreted as a partial L4.
24. For the purpose of applying prior art, “a partial Hexon Associated Precursor (L4 pVIII)” of claim 8 is interpreted as L4 pVIII.
Claim Rejections - 35 USC § 102
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.
25. Claim(s) 1, 11, and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Matsushita (Matsushita, T., et al. Gene therapy 5.7 (1998): 938-945.), hereinafter Matsushita which is cited on the IDS filed 02/15/2024.
Claim 1 is drawn to an adenoviral helper plasmid comprising a nucleotide sequence encoding: (a) E2a protein; (b) an E4 region; (c) a VA RNA region; and (d) an L4 region; wherein the adenoviral helper plasmid does not comprise a nucleotide sequence encoding one or more of: a Fiber protein or portion thereof; a L1-52/55K (Packaging Protein 3); and a Peripentonal Hexon-Associated Protein.
Regarding claim 1, Matsushita teaches a plasmid (pVAE2AE4 – 5) encoding E2A, E4 regions, VA RNA I and II, and L4 region (page 939, right col. para. 3; page 942, right col. last para.; page 943, left col. para. 1). Matsushita does not teach that pVAE2AE4 – 5 comprises a nucleotide sequence encoding a Fiber protein or portion, a L1-52/55K or a Peripentonal Hexon-Associated Protein.
Regarding claim 11, Matsushita does not teach the plasmid comprises a nucleotide sequence encoding DNA Terminal protein.
Regarding claim 13, Matsushita teaches plasmid pVAE2AE4-2 that comprises a nucleotide sequence encoding E2a protein, an E4 region, a VA RNA region, an L4 region and does not comprise a sequence encoding 23kDa protease (page 939, right col. para. 3; page 943, left col. para. 2 and right col. para. 1).
Therefore, Matsushita anticipates claims 1, 11, and 13.
26. Claim(s) 1 – 5, 8, 11, 34, and 41 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Choi (US-20210275614-A1; Filed 10/24/2019; Published 09/09/2021), hereinafter Choi.
Claim 1 is drawn to an adenoviral helper plasmid comprising a nucleotide sequence encoding: (a) E2a protein; (b) an E4 region; (c) a VA RNA region; and (d) an L4 region; wherein the adenoviral helper plasmid does not comprise a nucleotide sequence encoding one or more of: a Fiber protein or portion thereof; a L1-52/55K (Packaging Protein 3); and a Peripentonal Hexon-Associated Protein.
Regarding claim 1, Choi teaches an adenoviral helper plasmid comprising a nucleotide sequence encoding an E2a protein, an E4 region, a VA RNA region, and an L4 region (pVIII) in Figure 5 where the helper plasmid does not comprise a sequence encoding L1-52/55K or a peripentonal hexon-associated protein (page 4, para. 0053; page 12, para. 0132 – 0135; page 13, para. 0136 – 0140).
Regarding SEQ ID NO: 14 of claim 2 and SEQ ID NOs: 16 and 18 of claim 3, Choi teaches the helper plasmid comprises a VA RNA sequence that is SEQ ID NO: 16 (page 13, para. 0137), which is at least 80% identical to SEQ ID NO: 14 of claim 2 and comprises sequences that are at least 80% identical to SEQ ID NO: 16 and 18 of claim 3 as shown below.
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Regarding SEQ ID NO: 15 of claim 4 and SEQ ID NO: 17 and SEQ ID NO: 19 of claim 5, Choi teaches the sequence of the VA RNA region is SEQ ID NO: 48 (page 12, para. 0132 – 0135; page 13,, para. 0135 – 0137; page 94, SEQ ID NO: 48; Figure 5) which is at least 80% identical to SEQ ID NO: 15 of claim 4 and comprises SEQ ID NO: 17 and SEQ ID NO: 19 of claim 5 as shown below.
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Regarding claim 8 and 41, Choi teaches a helper plasmid that comprises incomplete L4 pVIII (SEQ ID NO: 54) that is the claimed SEQ ID NO 12 of claim 41 as shown below (page 12 – 13, para. 0135; Table 3; page 97; Figure 5) and encodes an amino acid sequence that is at least 80% identical to SEQ ID NO: 13 of claim 8.
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Regarding claim 11, Choi does not teach the helper plasmid comprises a sequence encoding DNA Terminal Protein (Figure 5).
Regarding claim 34, Choi teaches the sequence of pHelper that is SEQ ID NO: 45 (page 16, para. 0160) that has at least 80% sequence identity to SEQ ID NO: 41 of claim 34 as shown below.
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Therefore, Choi anticipates claims 1 – 5, 8, 11, 34, and 41.
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 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.
27. Claim(s) 1 – 3, 6, 7, 11 – 13, 39, 40, and 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsushita (Matsushita, T., et al. Gene therapy 5.7 (1998): 938-945.), hereinafter Matsushita which is cited on the IDS filed 02/15/2024 in view of GenBank2 (GenBank2. Human adenovirus type 5 strain NHRC Ad5FS 7151, complete genome; GenBank: AY601635.1; https://www.ncbi.nlm.nih.gov/nucleotide/AY601635.1; 04/12/2006), hereinafter GenBank2.
Matsushita anticipates claim 1, 11, and 13 as set forth above.
Regarding claims 2 and 3, Matsushita teaches the helper plasmid pVAE2AE4 – 5 encodes the VA RNA I and II genes of adenovirus 5 (page 942, right col. last para.) but does not teach the nucleotide or sequences.
Regarding claims 6, 7, 39, and 40, Matsushita teaches the helper plasmid pVAE2AE4 – 5 encodes the L4 region of 100-Mr, 33-Mr, VIII genes of adenovirus 5 (page 942, right col. last para.) but does not teach the nucleotide or amino acid sequences.
Regarding claim 12 and 43, Matsushita teaches the helper plasmid pVAE2AE4 – 5 encodes adenovirus 5 protease gene (page 942, right col. last para.) but does not teach the nucleotide or amino acid sequences.
Matsushita teaches AAV vectors are being used for gene therapy (page 938). Matsushita teaches AAV vectors require adenovirus infection of the producer cells in order to replicate (page 939, left col. para. 3). Matsushita teaches AAV vectors are typically produced by cotransfecting separate plasmids encoding the AAV vector and the AAV genome into 293 cells followed by infection with adenovirus (page 939, left col. para. 3). Matsushita teaches even after purifying the AAV vectors by cesium chloride density centrifugation, the AAV vector preparations are still substantially contaminated with adenoviral structural proteins (page 939, left col. para. 3). Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity (page 939, right col. para. 1; page 942, right col. para. 3). Matsushita teaches pVAE2AE4 – 5 was able to produce AAV vector a few-fold more efficient than adenovirus infection (page 939, right col. para. 3; Figure 1).
Regarding claims 2 and 3, GenBank2 teaches the nucleotide sequence of the VA RNA region of a human adenovirus 5 genome (GenBank: AY601635.1) that is at least 80% identical to SEQ ID NO: 14 of claim 2 and comprises SEQ ID NOs: 16 and 18 of claim 3 as shown below.
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Regarding claim 6 and 39, GenBank2 teaches the nucleotide sequence of human adenovirus 5 genome that comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO: 3 of claim 39 and encodes an amino acid sequence of L4 that is at least 80% identical to SEQ ID NO: 4 of claim 6. when translated. A portion of the alignment between the nucleotide sequences is shown below with 100% identity.
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Regarding claims 7 and 40, GenBank2 teaches the nucleotide sequence of a human adenovirus 5 genome (GenBank: AY601635.1) that comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO: 5 of claim 40 and encodes an amino acid sequence of partial L4 that is at least 80% identical to SEQ ID NO: 6 of claim 7. The alignment between the nucleotide sequences is shown below with 100% identity.
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Regarding claim 12 and 43, GenBank2 teaches the nucleotide sequence of a human adenovirus 5 genome (GenBank: AY601635.1) that comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO: 22 of claim 43 and encodes an amino acid sequence of 23kDa endoprotease that is at least 80% identical to SEQ ID NO: 23 of claim 12. The alignment between the nucleotide sequences is shown below with 100% identity. The alignment of the nucleotide sequences is shown below.
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It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Matsushita regarding a helper plasmid encoding an E2a protein, an E4 region, a VA RNA region, and an L4 region from human adenovirus 5 and that does not encode a Fiber protein or a L1-52/55K, or a Peripentonal Hexon-Associated Protein with the teachings of GenBank2 regarding the genome sequence of human adenovirus 5 to arrive at the claimed adenoviral helper plasmid where the plasmid encodes a VA RNA region that is at least 80% identical to SEQ ID NO: 14, a L4 region nucleotide sequence that is at least 80% identical to SEQ ID NO: 3 that encodes an amino acid sequence of L4 region that is at least 80% identical to SEQ ID NO: 4, a partial L4 that is at least 80% identical to SEQ ID NO: 5 that encodes an amino acid sequence of partial L4 that is at least 80% identical to SEQ ID NO: 6, and a partial 23kDa endoprotease nucleotide sequence that is at least 80% identical to SEQ ID NO: 22 that encodes an amino acid sequence of a partial 23kDa endoprotease that is at least 80% identical to SEQ ID NO: 23. One would have been motivated to combine the teachings of Matsushita and GenBank2 in a helper plasmid to produce AAV vectors without using virus as Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity. One would have a reasonable expectation of success in combining the teachings as Matsushita teaches the sequences of the helper plasmid are from human adenovirus 5 and Matsushita teaches pVAE2AE4 – 5 was able to produce AAV vector a few-fold more efficient than adenovirus infection.
28. Claim(s) 1, 10, 11, 13, and 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsushita (Matsushita, T., et al. Gene therapy 5.7 (1998): 938-945.), hereinafter Matsushita which is cited on the IDS filed 02/15/2024 in view of Mitani (Mitani, Kohnosuke, et al. Proceedings of the National Academy of Sciences 92.9 (1995): 3854-3858.), hereinafter Mitani in view of GenBank3 (GenBank3. Human adenovirus C, complete genome NCBI Reference Sequence: NC_001405.1; https://www.ncbi.nlm.nih.gov/nuccore/9626158; 08/13/2018), hereinafter GenBank3.
Matsushita anticipates claim 1, 11, and 13 as set forth above. Matsushita does not teach the plasmid encodes a partial DNA Terminal Protein with an amino acid sequence that is at least 80% identical to SEQ ID NO: 21 of claim 10 or comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO: 20 of claim 42.
Matsushita teaches AAV vectors are being used for gene therapy (page 938). Matsushita teaches AAV vectors require adenovirus infection of the producer cells in order to replicate (page 939, left col. para. 3). Matsushita teaches AAV vectors are typically produced by cotransfecting separate plasmids encoding the AAV vector and the AAV genome into 293 cells followed by infection with adenovirus (page 939, left col. para. 3). Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity (page 939, right col. para. 1; page 942, right col. para. 3). Matsushita teaches pVAE2AE4 – 5 and pVAE2AE4 – 2 was able to produce AAV vector a few-fold more efficient than adenovirus infection (page 939, right col. para. 3; Figure 1).
Regarding “partial DNA Terminal Protein” of claims 10 and 42, Mitani teaches a pKM74 having L1, L2, VA I and II and terminal protein partially or completely deleted did not produce virus when transfected into 293 cells (page 3856, left col.). Mitani teaches mixing pKM74 with Ad2 DNA/terminal protein complex and cotransfecting into 293 cells produced virus (page 3856, left col.). Mitani teaches the replication origins in the ITRs should allow pKM74 to be replicated in the transduced cells as a result of expression of Ad2 proteins including pTP supplied by the helper Ad2 (page 3858, left col. para. 1). Mitani teaches by improving vector design and using a better helper virus, it might be possible to develop a safe adenoviral vector system with a large cloning capacity (page 3858, right col. para. 1). Mitani teaches adenoviruses are attracting increasing attention as expression vectors for human gene therapy (page 3854, left col.). Mitani does not teach SEQ ID NO: 21 of claim 10 or SEQ ID NO: 20 of claim 42.
Regarding SEQ ID NO: 21 of claim 10 and SEQ ID NO: 20 of claim 42, GenBank3 teaches the nucleotide sequence of adenovirus 2 that comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO: 20 and encodes an amino acid sequence of pTP of adenovirus 2 that is at least 80% identical to SEQ ID NO: 21 (page 5). The alignment of the pTP from GenBank3 and SEQ ID NO: 21 is shown below.
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It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Matsushita regarding a helper plasmid encoding an E2a protein, an E4 region, a VA RNA region, and an L4 region from human adenovirus 5 and that does not encode a Fiber protein or a L1-52/55K, or a Peripentonal Hexon-Associated Protein with the teachings of Mitani regarding mixing pKM74 with Ad2 DNA/terminal protein complex and cotransfecting into 293 cells produced virus with the teachings of GenBank3 regarding the nucleic acid and amino acid sequence of Ad2 partial terminal protein to arrive at the claimed helper plasmid wherein the adenoviral helper plasmid comprises a nucleotide sequence encoding a partial DNA Terminal Protein having an amino acid sequence that is at least 80% identical to SEQ ID: No 21 and wherein the adenoviral helper plasmid comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO: 20, the nucleotide sequence encoding a partial DNA Terminal Protein. One would have been motivated to combine the teachings of Matsushita, Mitani, and GenBank3 in a helper plasmid to produce AAV vectors without the need of a helper virus as Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity. One would have a reasonable expectation of success in combining the teachings as Matsushita teaches pVAE2AE4 – 5 and pVAE2AE4 – 2 was able to produce AAV vector a few-fold more efficient than adenovirus infection and Mitani teaches pTP supplied by the helper Ad2 produced virus.
29. Claim(s) 1, 11, 13, 22, 26, 44 and 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsushita (Matsushita, T., et al. Gene therapy 5.7 (1998): 938-945.), hereinafter Matsushita which is cited on the IDS filed 02/15/2024 in view of Stutika (Stutika, C. et. al. Journal of General Virology (2015), 96, 1 – 11), hereinafter Stutika as evidenced by Alazard-Dany (Alazard-Dany, Nathalie, et al. PLoS Pathogens 5.3 (2009): e1000340.), hereinafter Alazard-Dany in view of GenBank (GenBank. Human herpesvirus 1 strain 17, complete genome, NCBI Reference Sequence: NC_001806.2; https://www.ncbi.nlm.nih.gov/nuccore/nc_001806; 08/13/2018), hereinafter GenBank in view of Kim (Kim JH, et. al. PLoS One. 2011;6(4):e18556), hereinafter Kim.
Matsushita anticipates claim 1, 11, and 13 as set forth above. Matsushita does not teach the helper plasmids further comprises nucleotide sequences of HSV-1 UL30 and HSV-1 UL42 of claims 22 and 44 or further comprises a nucleotide sequence encoding HSV-1 UL29 of claims 26 and 45. Matsushita teaches AAV vectors are being used for gene therapy (page 938). However, Matsushita teaches AAV vectors require adenovirus infection of the producer cells in order to replicate (page 939, left col. para. 3). Matsushita teaches AAV vectors are typically produced by cotransfecting separate plasmids encoding the AAV vector and the AAV genome into 293 cells followed by infection with adenovirus (page 939, left col. para. 3). Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity (page 939, right col. para. 1; page 942, right col. para. 3). Matsushita teaches pVAE2AE4 – 5 and pVAE2AE4 – 2 produced AAV vector a few-fold more efficient than adenovirus infection (page 939, right col. para. 3; Figure 1).
Regarding claims 22 and 44, Stutika teaches the HSV1 helper genes UL30 and UL42 aid in the replication of AAV5 and AAV2 (page 5; page 6, left col. para. 1 – 3; Figure 3a,b). Stutika teaches the plasmid comprising UL30/42 was that of Alazard-Dany (page 9, left col. para. 1). This plasmid comprises the sequences of UL30 and UL42 genes from wt HSV-1 (17 syn+) linked through the FMDV2A auto-protease peptide as evidenced by Alazard-Dany (page 3, right col. last para.; page 4, left col. para. 1; page 9, left col. para. 2). The GenBank accession no. of HSV-1 from which the genes were amplified is NC_001806 where the positions of the amplified sequence of UL30 is 62,755 – 66,512 bp and the positions of the amplified sequence of UL42 is 93,113 – 94,617 bp as evidenced by Alazard-Dany (page 9, right col. para. 2). The plasmid comprising UL30 and UL42 are separated by a sequence encoding an FMDV2A sequence (page 9, left col. para. 1 as evidenced by Alazard-Dany at page 9, right col. last para.) but not a P2A cleavage site.
Regarding “SEQ ID NO: 30” of claim 22 and “SEQ ID NO: 29” of claim 44, GenBank teaches the nucleotide sequence of UL30 from NC_001806 comprises codons 62807 – 66553 which is at least 80% identical to SEQ ID NO: 29 of claim 44 and encodes a UL30 that has an amino acid sequence that is at least 80% identical to SEQ ID NO: 30 of claim 22 (page 14). A portion of the alignment of the amino acid sequence of SEQ ID NO: 30 and UL30 from NC_001806 is shown below indicating 100% identity between the sequences.
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Regarding “SEQ ID NO: 32” of claim 22 and “SEQ ID NO: 31” of claim 44, GenBank teaches the nucleotide sequence of UL42 from NC_001806 comprises codons 93112 - 94578 which is at least 80% identical to SEQ ID NO: 31 of claim 44 and encodes a UL42 that has an amino acid sequence that is at least 80% identical to SEQ ID NO: 32 of claim 22 (page 19). A portion of the alignment of the amino acid sequence of SEQ ID NO: 32 and UL42 from NC_001806 is shown below indicating 100% identity between the sequences.
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Regarding claims 26 and 45, Stutika teaches HSV1 UL29 co-localizes with AAV5 Rep and AAV2 Rep (page 6, left col. last para. and right col. para. 1). Stutika teaches AAV5 and AAV2 Rep can be recruited by HSV to nuclear replication compartments (page 6, right col. para. 1; Figure 4). Stutika teaches UL29 and the helicase-primase complex are required to initiate the formation of the replication compartments, which further mature when the two-component HSV polymerase (UL30/42) is co-expressed (page 6, left col. last para.). Stutika teaches UL29 is part of a minimal set of helper genes (UL29, UL5, UL52) for AAV replication (page 7, right col. last para.; page 8, left col. para. 1). Stutika teaches HSV-induced AAV2 DNA replication is initiated by AAV ssDNA-dependent ternary complex formation of Rep78 and UL29 on the hairpin-structured AAV ITR and this may be true for AAV5 (page 8, left col. para. 3 and right col. para. 1). The GenBank accession no. of HSV-1 from which the genes were amplified is NC_001806 where the positions of the amplified sequence of UL29 is 62,091 – 58,431 bp as evidenced by Alazard-Dany (page 9, right col. para. 2).
Regarding “SEQ ID NO: 38” of claim 26 and “SEQ ID NO: 37” of claim 45, GenBank teaches the nucleotide sequence of UL29 from NC_001806 comprises codons 58464 – 62054 which is at least 80% identical to SEQ ID NO: 37 of claim 45 and encodes a UL29 that has an amino acid sequence that is at least 80% identical to SEQ ID NO: 38 of claim 26 (page 13 – 14). A portion of the alignment of the amino acid sequence of SEQ ID NO: 38 and UL29 from NC_001806 is shown below indicating 100% identity between the sequences.
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Stutika as evidenced by Alazard-Deny does not teach “a P2A cleavage site” of claims 22 and 44. However, the plasmid comprising UL30 and UL42 are separated by a sequence encoding an FMDV2A sequence (page 9, left col. para. 1 as evidenced by Alazard-Dany at page 9, right col. last para.) However, Stutika teaches UL30, UL42, and UL29 provide helper functions for productive AAV2 and AAV5 replication (page 6, right col. para. 2 – 3). Stutika teaches the AAVs are small, replication-deficient, apathogenic viruses that require co-infection with an unrelated helper virus for productive infection and HSV has been shown to support productive AAV2 replication (page 1, left col. para. 2).
Regarding “P2A cleavage site” and “SEQ ID NO: 34” of claim 22 and “P2A cleavage site” and “SEQ ID NO: 33” of claim 44, Kim teaches a nucleotide sequence encoding and amino acid sequence for P2A (Figure 1B; page 2, left col. last para. and right col. para. 1) that are at least 80% identical to SEQ ID NO: 33 and SEQ ID NO: 34, respectively. Kim teaches constructing plasmids with each harboring different 2A peptides and evaluating their cleavage efficiency in human cell lines including 293 cells where P2A showed the highest cleavage efficiency (Abstract; Figure 2). Kim teaches a self-cleaving 2A peptide could be used when expression of more than one gene is required in cells because of its small size and high cleavage efficiency between the genes upstream and downstream of the 2A peptide (Abstract; page 7, left col. last para.).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Matsushita regarding a helper plasmid encoding an E2a protein, an E4 region, a VA RNA region, and an L4 region from human adenovirus 5 where the plasmid comprises an E4 promoter and does not encode a Fiber protein or a L1-52/55K, or a Peripentonal Hexon-Associated Protein with the teachings of Stutika regarding the HSV1 helper genes UL30 and UL42 aid in the replication of AAV5 and AAV2 and UL29 is part of a minimal set of helper genes (UL29, UL5, UL52) for AAV replication with the teachings of Kim regarding P2A has a higher cleavage efficiency than F2A to arrive at the claimed plasmid further comprising HSV-1 UL30 and HSV-1 UL42 wherein the nucleotide sequences of UL30 and UL42 are at least 80% identical to SEQ ID NO: 29 and 31, respectively and encode amino acid sequences that are at least 80% identical to SEQ ID NO: 30 and SEQ ID NO: 32, respectively, and wherein UL30 and UL42 are separated by a P2A cleavage site encoded by a nucleic acid sequence that is at least 80% identical to SEQ ID NO: 33 and having an amino acid sequence that is at least 80% identical to SEQ ID NO: 34, and to arrive at the claimed plasmid further comprising HSV-1 UL29 wherein the nucleotide sequence is at least 80% identical to SEQ ID NO: 37 and wherein UL29 has an amino acid sequence that is at least 80% identical to SEQ ID NO: 38. One would have been motivated to combine the teachings of Matsushita, Stutika, and Kim in a helper plasmid for producing AAV vectors without the use of virus as Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity and Stutika teaches UL30, UL42, and UL29 provide helper functions for productive AAV2 and AAV5 replication, and Kim teaches a self-cleaving 2A peptide could be used when expression of more than one gene is required in cells because of its small size and high cleavage efficiency between the genes upstream and downstream of the 2A peptide. One would have a reasonable expectation of success in combining the teachings as Matsushita teaches pVAE2AE4 – 5 and pVAE2AE4 – 2 produced AAV vector a few-fold more efficient than adenovirus infection and Stutika teaches the HSV1 helper genes UL30 and UL42 aid in the replication of AAV5 and AAV2 and Stutika teaches HSV1 UL29 co-localizes with AAV5 Rep and AAV2 Rep Stutika teaches UL29 and the helicase-primase complex are required to initiate the formation of the replication compartments, which further mature when the two-component HSV polymerase (UL30/42) is co-expressed and Kim teaches P2A showed the highest cleavage efficiency.
30. Claim(s) 1 – 5, 8, 11, 30, 34, and 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Choi (US-20210275614-A1; Filed 10/24/2019; Published 09/09/2021), hereinafter Choi in view of Matsushita (Matsushita, T., et al. Gene therapy 5.7 (1998): 938-945.), hereinafter Matsushita which is cited on the IDS filed 02/15/2024.
Choi anticipates claims 1 – 5, 8, 11, 34, and 41 as set forth above.
Choi does not teach the E4 region does not comprise E4orf1 and E4orf2 of the helper plasmid of claim 30. However, Choi teaches a long Ad helper plasmid and a short helper plasmid in Figure 5. Choi teaches an embodiment where the helper plasmid only comprises orf6 of E4 (page 3, para. 0029; page 12, para. 0132 and 0134). Choi teaches a shorter plasmid to reduce “plasmid load” during transfection so that the overall copy number of plasmids of all three plasmids in the three-plasmid system can be increased to give higher number of plasmid templates for gene expression and replication for rAAV production and the reduced plasmid load is surprisingly useful for larger batches (page 12, para. 0135). Choi teaches the short and long helper plasmids each produce AAV (page 17, para. 0164 – 0166).
Matsushita teaches combining individual plasmids pVAE2A with pCMVE4orf6 (only orf6 of E4) acted together as helper plasmids and had AAV helper function and was essentially equivalent to pVAE2AE4 – 2 that comprises all orfs of E4 (Figure 1; page 940, left col. para. 2 and right col. para. 1). Matsushita teaches only the E4orf6 is thought to contribute to AAV2 production (page 940, left col. para. 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to delete E4orf1 and E4orf2 of the long helper plasmid of Choi to arrive at the claimed helper plasmid wherein the E4 region does not comprise E4orfl, and wherein the E4 region does not comprise E4orf2. One would have been motivated to delete E4orf1 and E4orf2 in Choi’s long Ad helper plasmid to increase rAAV production because Choi teaches a shorter plasmid to reduce “plasmid load” during transfection so that the overall copy number of plasmids of all three plasmids in the three-plasmid system can be increased to give higher number of plasmid templates for gene expression and replication for rAAV production and the reduced plasmid load is surprisingly useful for larger batches. One would have a reasonable expectation of success as Choi teaches an embodiment where the helper plasmid only comprises orf6 of E4 and Choi teaches the short helper plasmid produces AAV and Matsushita teaches combining individual plasmids pVAE2A with pCMVE4orf6 (only orf6 of E4) acted together as helper plasmids and had AAV helper function and was essentially equivalent to pVAE2AE4 – 2 that comprises all ORFs of E4.
31. Claim(s) 1 – 5, 8, 11, 13, 31, and 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsushita (Matsushita, T., et al. Gene therapy 5.7 (1998): 938-945.), hereinafter Matsushita which is cited on the IDS filed 02/15/2024 as evidenced by GenBank2 (GenBank2. Human adenovirus type 5 strain NHRC Ad5FS 7151, complete genome; GenBank: AY601635.1; https://www.ncbi.nlm.nih.gov/nucleotide/AY601635.1; 04/12/2006), hereinafter GenBank2 in view of Choi (US-20210275614-A1; Filed 10/24/2019; Published 09/09/2021), hereinafter Choi in view of Raychaudhuri (Raychaudhuri, P. et. al. The EMBO journal 6.13 (1987): 4073-4081.), hereinafter Raychaudhuri.
Matsushita anticipates claim 1, 11, and 13 as set forth above.
Regarding an E4 promoter of claim 31, Matsushita teaches the genes in pVAE2AE4 – 5 and pVAE2AE4 – 2 are arranged such that the 5’ ends of the E2A and E4 promoters abut (page 943, left col. para. 1 – 2). The sequence of the E4 promoter of human adenovirus 5 is shown below aligned with SEQ ID NO: 1 of claim 31 as evidenced by GenBank2.
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Matsushita does not teach sequence of the E4 promoter is a E4 mini promoter. However, Matsushita teaches AAV vectors are being used for gene therapy (page 938). Matsushita teaches AAV vectors require adenovirus infection of the producer cells in order to replicate (page 939, left col. para. 3). Matsushita teaches AAV vectors are typically produced by cotransfecting separate plasmids encoding the AAV vector and the AAV genome into 293 cells followed by infection with adenovirus (page 939, left col. para. 3). Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity (page 939, right col. para. 1; page 942, right col. para. 3). Matsushita teaches pVAE2AE4 – 5 and pVAE2AE4 – 2 was able to produce AAV vector a few-fold more efficient than adenovirus infection (page 939, right col. para. 3; Figure 1).
Choi anticipates claim 1 as set forth above. Choi teaches a long Ad helper plasmid and a short helper plasmid in Figure 5. Choi teaches an embodiment where the helper plasmid only comprises orf6 of E4 (page 3, para. 0029; page 12, para. 0132 and 0134). Choi teaches a shorter plasmid to reduce “plasmid load” during transfection so that the overall copy number of plasmids of all three plasmids in the three-plasmid system can be increased to give higher number of plasmid templates for gene expression and replication for rAAV production and the reduced plasmid load is surprisingly useful for larger batches (page 12, para. 0135). Choi teaches the short and long helper plasmids each produce AAV (page 17, para. 0164 – 0166; Figure 9). Choi does not teach an E4 mini promoter having a nucleotide sequence that is at least 80% identical to SEQ ID NO: 1 of claim 31. One would have been motivated to combine Matsushita and Choi because both teach adenoviral helper plasmids that comprise nucleic acid sequences encoding E2a, an E4 region, a VA region and an L4 region.
Regarding SEQ ID NO: 1 of claim 31, Raychaudhuri teaches a sequence of the adenovirus E4 promoter in Figure 5 in which a smaller region (beginning at the region indicated by “[d]” on the top strand and reading from right to left) has 100% identity to SEQ ID NO: 1. Raychaudhuri teaches at least 180 nucleotides of the E4 promoter are required for full promoter activity (Abstract). Raychaudhuri teaches a probe containing all of the E4 sequences previously shown to be critical for transcription in Figure 1 and smaller versions to identify proteins that interact with the E4 promoter (page 4074, left col. para. 1 – 3 and right col. last para.; page 4076, left col. and right col. para. 1). Raychaudhuri teaches a factor designated E4F that is critical for E4 transcription is substantially increased in extracts of adenovirus-infected cells (page 4076, right col. last para.; page 4077, left col. para. 1; page 4078, left col.). Raychaudhuri teaches the binding site for E4F includes the sequence GACGTAAC in the E4 promoter ([e] in Figure 5) (page 4077, left col. last para.).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Matsushita regarding a helper plasmid encoding an E2a protein, an E4 region, a VA RNA region, and an L4 region where the plasmid comprises an E4 promoter and does not encode a fiber protein, L1-52/55K, or a Peripentonal Hexon-Associated Protein with the teachings of Choi regarding a long helper plasmid encoding an E2a protein, an E4 region, a VA RNA region, and an L4 region where the plasmid does not encode a L1-52/55K, or a Peripentonal Hexon-Associated Protein and a short helper plasmid encoding E2A, and E4 region, and a VA RNA region where the plasmid does not encode does not encode a fiber protein, L1-52/55K, or a Peripentonal Hexon-Associated Protein with the teachings of Raychaudhuri regarding protein binding sequences in the E4 promoter to arrive at the claimed adenoviral helper plasmid wherein the E4 region is operably linked to the E4 mini promoter having a nucleotide sequence that is at least 80% identical to SEQ ID NO: 1. A rationale for arriving at SEQ ID NO: 1 through routine optimization comes from the teachings of Choi and Raychaudhuri where Choi teaches a shorter plasmid is desirable in the three-plasmid system for gene expression and replication for rAAV production and is useful for larger batches and Raychauduri teaches a method for identifying the regions of the E4 promoter necessary for promoter activity and for binding E4F which closely corresponds to transcription of the E4 gene and Raychaudhuri teaches at least 180 nucleotides of sequence of the E4 promoter are required for full promoter activity. Taken together, Choi and Raychaudhuri provide a rationale for one of ordinary skill in the art to arrive at the claimed E4 mini promoter having a nucleotide sequence that is at least 80% identical to SEQ ID NO: 1 with a reasonable expectation of success starting with the E4 promoter of Matsushita as Choi teaches a shorter plasmid is capable of producing rAAV and Raychaudhuri teaches binding sites for E4F and at least 180 nucleotides of sequence are required for full promoter activity. One would have been motivated to combine the teachings of Matsushita, Choi, and Raychaudhuri in a helper plasmid with reduced size to produce AAV vectors without the need of a helper virus as Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity and Choi teaches a shorter plasmid to reduce “plasmid load” during transfection so that the overall copy number of plasmids of all three plasmids in the three-plasmid system can be increased to give higher number of plasmid templates for gene expression and replication for rAAV production and the reduced plasmid load is surprisingly useful for larger batches. One would have a reasonable expectation of success in combining the teachings as Matsushita teaches pVAE2AE4 – 5 was able to produce AAV vector and Choi teaches the short helper plasmid produces AAV and Raychaudhuri teaches a factor designated E4F that is critical for E4 transcription is substantially increased in extracts of adenovirus-infected cells and the binding site for E4F includes the sequence GACGTAAC in the E4 promoter.
32. Claim(s) 1, 11, 13, and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Matsushita (Matsushita, T., et al. Gene therapy 5.7 (1998): 938-945.), hereinafter Matsushita which is cited on the IDS filed 02/15/2024 in view of Sakaguchi (Sakaguchi, Masakiyo, et al. Molecular biotechnology 56.7 (2014): 621-630.), hereinafter Sakaguchi.
Matsushita anticipates claim 1, 11, and 13 as set forth above. Matsushita teaches the genes in pVAE2AE4 – 5 and pVAE2AE4 – 2 are arranged such that the 5’ ends of the E2A and E4 promoters abut (page 943, left col. para. 1 – 2). Matsushita teaches the CMV promoter can be substituted for the E4 regulatory regions suggest that intricate interplay that occurs between these adenoviral promoters and their gene products is probably irrelevant in the transfection-based helper system (page 942, left col. para. 3). Matsushita teaches plasmid pCMVE4orf6 that only expresses E4orf6 where E4orf6 is operably linked to the CMV IE promoter (page 943, right col. para. 4). Matsushita teaches pCMVE4orf6 combined with pVAE2A or pVA and pCMVE2A showed similar levels of AAV production as pVAE2A2AE4-2 and pVAE2AE4 – 5 in Figure 1. Matsushita teaches adenovirus mutants with defects in the E1A, E1B55-Mr, E2A, and E4orf6 genes do not support AAV2 replication (page 939, left col. para. 1). Matsushita does not teach the E4 region is operably linked to the SV40 promoter of claim 32. However, Matsushita teaches AAV vectors are being used for gene therapy (page 938). Matsushita teaches AAV vectors require adenovirus infection of the producer cells in order to replicate (page 939, left col. para. 3). Matsushita teaches AAV vectors are typically produced by cotransfecting separate plasmids encoding the AAV vector and the AAV genome into 293 cells followed by infection with adenovirus (page 939, left col. para. 3). Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity (page 939, right col. para. 1; page 942, right col. para. 3). Matsushita teaches pVAE2AE4 – 5 and pVAE2AE4 – 2 was able to produce AAV vector a few-fold more efficient than adenovirus infection (page 939, right col. para. 3; Figure 1).
Regarding “SV40 promoter” of claim 32, Sakaguchi teaches vectors for expression of genes in mammalian cells sometime fail to attain sufficient expression levels depending on the nature of the cargo genes and/or on host cell types (Abstract). Sakaguchi teaches insertion of an additional promoter downstream of a cargo gene greatly enhanced the expression levels (Abstract; page 2, left col. para. 2). Sakaguchi teaches promoters of viral origin have been widely used for high-level gene expression including SV40 (page 1, left col.). Sakaguchi teaches the SV40 promoter of Accession No. AY864928 (2156 – 2474 bp) was used (page 2, right col. para. 2) which is at least 80% identical to SEQ ID NO: 2 as shown below.
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Sakaguchi teaches constructing an adenovirus vector with a CMV promoter and SV40 promoter downstream of the transgene (page 2, right col. para. 3; Figure 3; page 7, left col.). Sakaguchi teaches potent gene expression was observed in an adenovirus vector in 293 cells (page 7, left col.; Figure 3).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Matsushita regarding a helper plasmid encoding an E2a protein, an E4 region, a VA RNA region, and an L4 region where the plasmid comprises an E4 promoter and does not encode a fiber protein, L1-52/55K, or a Peripentonal Hexon-Associated Protein and regarding plasmid pCMVE4orf6 that only expresses E4orf6 where E4orf6 is operably linked to the CMV IE promoter with the teachings of Sakaguchi regarding an adenovirus vector comprising a CMV promoter and a SV40 promoter where the SV40 promoter is downstream of the transgene to increase its expression to arrive at the claimed helper plasmid wherein the E4 region is operably linked to the SV 40 promoter, wherein the SV 40 promoter has a nucleotide sequence that is at least 80% identical to SEQ ID NO: 2. One would have been motivated to combine the teachings of Matsushita, and Sakaguchi in a helper plasmid with increased E4 expression to produce AAV vectors without the need of a helper virus as Matsushita teaches elimination of adenovirus from the AAV vector production protocol should result in a less complicated large-scale production procedure and a potentially safe preparation of higher purity and E4orf6 is required for AAV replication. One would have a reasonable expectation of success in combining the teachings as Matsushita teaches E4orf6 operably linked to a CMV promoter acts as a helper plasmid in AAV production and Matsushita teaches the CMV promoter can be substituted for the E4 regulatory regions suggest that intricate interplay that occurs between these adenoviral promoters and their gene products is probably irrelevant in the transfection-based helper system and Sakaguchi teaches potent gene expression was observed in an adenovirus vector with a CMV promoter and a SV40 promoter downstream of the transgene in 293 cells.
Conclusion
No claims allowed.
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