DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-25 and 29, drawn to a recombinant adenovirus genome comprising a synthetic transcriptional circuit in the reply filed on 03/12/2026 is acknowledged.
Applicant’s election without traverse of species a recombinant adenovirus genome comprising a synthetic transcriptional circuit inserted between (i) L5 and E4 in the reply filed on 03/12/2026 is acknowledged.
Claims 26-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 03/12/2026.
Claims 1-25 and 29 are under examination in this Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/048651, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Instant Claim 29 recites “A recombinant adenovirus genome having a nucleotide sequence at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 1, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17.” However, the earlier filed provisional application, 63/048651, provided disclosure for SEQ ID NOs: 1 and 14 only. Therefore, SEQ ID NOs: 15-17 do not find support in the provisional application. Accordingly, claim 29 will have an effective filing date corresponding the earlier filed PCT Application No. PCT/US21/40586 filed 07/23/2021.
All other claims 1-25, under examination in this action appear to find support in the earlier filed provisional application, and thus are being examined with an effective filing date of 07/06/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/06/2023, 02/10/2023, and 10/28/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 29 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 29 recites a recombinant adenovirus genome having a nucleotide sequence at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 1, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17.
Adequate written description support for a claimed genus may be provided by describing sufficient identifying characteristics, describing a representative number of species, actual reduction to practice, disclosure of drawings or structural chemical formulas, complete or partial structure, physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure and any working examples, method of making the claimed invention, level of skill and knowledge in the art as well as predictability in the art are other determinants that are used to analyze whether applicants had possession of the claimed genus. The present specification fails to meet these requirements for several reasons.
The sequences for these SEQ ID Nos. range from 36,270 (SEQ ID No. 1) to 40,542 (SEQ ID No. 17) nucleotides. The limitation of “at least 90% identical” permits up to a 10% variance in the underlying nucleotide sequence. For example, regarding SEQ ID No. 1, up to 3,627 bases can be arbitrarily substituted, deleted, or inserted, or a combination thereof, resulting in an astronomical number of potential sequence variants. However, the specification does not provide a representative number of species, structural guidance, or working examples (other than insertions at three very specific regions as recited in claim 1) delineating which nucleotides or regions may be mutated without destroying the critical functional limitation of independent claim 1 (i.e., that the insertion “does not have substantially altered replication kinetics”).
Crucially, the unpredictability of making arbitrary modifications across this genome is explicitly acknowledged by the inventors themselves in paragraph [0140] of the specification, which states: “most modifications to the highly complex and optimized viral transcriptional units and promoters either fail to achieve sufficient control or severely impact and attenuate virus replication and yield, impacting maximal efficacy.”
This lack of unpredictability is further corroborated by established adenoviral engineering principals in the prior art, which demonstrated that the physical integrity and replication fitness of the adenovirus are tightly constrained by its genome size and structure. As taught by Saha B, et al., (Viruses. 6(9):3563-83, published 2014), “radical modifications to the genome size significantly decreases virion stability, suggesting that the virus genome plays a role in maintaining the physical stability of the Ad virion,” see abstract. Thus, arbitrary variations, deletions, or insertions spanning up to 10% of the sequence landscape inevitably alter these critical genome size and structure parameters, leading to structural instability of the virion and a corresponding failure in replication kinetics and yield.
Give the state of the prior art and the inventors’ own teachings that minor modifications to the Adenovirus genome can attenuates replication and yield, and the specification providing only three very specific “safe” insertion sites, the specification fails to provide adequate structure-function correlation to inform a person having ordinary skill in the art which of the thousands of potential mutations within 10%, 5%, or 1% variance will successfully preserve replication kinetics and virion stability. Accordingly, the applicant has failed to demonstrate possession of the broad genus as claimed.
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.
Claims 1-15, 18-19, 21-25, and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Partlo, W. (UC San Diego. ProQuest ID: Partlo_ucsd_0033D_17604. Merritt ID: ark:/13030/m5062cd4. Retrieved from https://escholarship.org/uc/item/2k3957sr, published 2018, provided in IDS, herein “UCSD”).
Regarding all claims, UCSD teaches synthetic adenovirus constructs comprising a synthetic transcriptional circuit, see Appendix B pgs. 171-206.
Regarding claim 1, UCSD teaches a recombinant adenovirus genome, comprising a Two-Step Transcriptional Activation (TSTA) circuit that employs “TRE3G activated by the Tet-On transcription factor,” which is a form/species of a synthetic transcriptional circuit, see pgs. 78 and 84. UCSD teaches the synthetic transcriptional circuit is located between a modified L5 transcript unit and an E4 transcript unit; the E1A transcript unit and the E1B transcript unit; or the E1B transcript unit and the U gene transcript unit of the adenovirus genome, wherein insertion of the synthetic transcriptional unit does not substantially alter the kinetics of genome replication: “For our case, we are attempting to retain the kinetics of a replication competent Ad5 and thus both the E1 and E4 regions are still part of the genome. This gene-within-a-gene design rule is highly constraining, with only 3 possible locations available, as shown in fig 4.8. The three locations are; between the E1A and E1B transcripts, between the E1B transcript and the U gene transcript, and between the MLT and the E4 transcript,” page 83 and FIG 4.8. UCSD further teaches “a closer look at the sequence data of this region reveals that the full length L5 poly-A of the MLT and the full length E4 poly-A overlap, as shown in fig 4.9,” and that “given this overlap in poly-A sequences, inserting an exogenous gene between the AATAAA signals of the L5 poly-A and the E4 poly-A would destroy the full-length poly-A sequences of both.” Thus, UCSD teaches that “a solution to this problem is to add a new poly-A sequence to the right or left of the overlapping L5 and E4 poly-As.” UCSD teaches cloning a minimal SV40 poly-A sequence “to the left of the overlapping poly-As” (thereby generating a modified L5 transcript) and inserting “the payload and Tet-On genes into the space between.” UCSD teaches that “there is no significant loss of kinetics” when inserting the synthetic transcriptional unit into this region, see pgs. 83-84, FIG. 4.10 and 4.11.
Regarding claims 2-5, UCSD teaches the synthetic adenovirus construct, CMBT-933,
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which comprises a first exogenous nucleic acid sequence comprising a regulatable promoter operably linked to a payload open reading frame (ORF) - TRE3G::DNA Binding Protein (DBP) - and a second exogenous nucleic acid sequence comprising a heterologous promoter operably linked to a sequence encoding a composite DNA binding protein with a transcription activation or repression domain ORF - CMV::Tet-On. UCSD defines the DNA Binding Protein (DBP) “as the control protein” (i.e., the payload) because “its absence prevents efficient genome replication since this protein is responsible for protecting the single-stranded Ad genomes generated by the Ad DNA polymerase during the genome replication cycle. DNA Binding Protein (DBP) is defined in claims 4 and 5 of the instant case as the payload. While in the instant claim, “a composite DNA binding protein with a transcription activation or repression domain ORF” refers to a different DNA binding protein, for example a Tet-On transcription factor that binds to the regulatable promoter controlling the expression of DBP. Thus, CMBT-933 comprises the payload, DBP-an adenovirus protein essential for virus replication, under the control of a regulatable promoter, TRE3G, that is in turn bound by Tet-On transcription factor that is expressed by the heterologous constitutive CMV promoter. The instant specification also discloses CMBT-933 and its corresponding SEQ ID NO,
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Regarding claim 6, the CMBT-933 construct taught by UCSD further comprises an E2A region comprising a deletion of the DNA binding protein (DBP) ORF, see screen shot above.
Regarding claims 7-8, UCSD teaches wherein the heterologous promoter comprises a constitutive promoter or a selective promoter (claim 7), and further wherein (claim 8) the constitutive promoter is a CMV promoter or an EF1α promoter; or the selective promoter is a tissue-specific promoter, a tumor-specific promoter, or a promoter comprising microRNA (miR) binding sites (Pg 81-82: “We cloned three different promoters to drive expression of the Tet-On ORF; E2F1, CMV, and EF1α. We chose these three promoters because they are considered constitutive and represent three different levels of promoter strength with EF1α > CMV > E2F1.”). As shown above, CMBT-933 comprises the constitutive CMV promoter.
Regarding claim 9, UCSD teaches numerous constructs that comprise a tumor-selective promoter, wherein the tumor-selective promoter comprises an E2F transcription factor 1 (E2F1) promoter, a baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) promoter, an L-plastin (LP) promoter, a mucin 1 (MUC1) promoter, an alpha-fetoprotein (AFP) promoter, a cholecystokinin A receptor (CCKAR) promoter or a hypoxia inducible factor (HIF)-1α promoter; the tissue-selective promoter comprises a glial fibrillary acidic protein (GFAP) promoter, a surfactant protein B (SP-B) promoter, a tyrosinase promoter, or an osteocalcin promoter; or the promoter comprising miR binding sites comprises miR-122 binding sites (see for example constructs CMBT-755, CMBT-760, among many others, which comprise an E2F1 promoter).
Regarding claim 10, as explained in regards to claim 2 above, the CMBT-933 construct comprises the first exogenous nucleic acid sequence comprises a TRE3G promoter operably linked to an adenovirus DBP ORF (the TRE3G::DBP domain), and the second exogenous nucleic acid sequence comprises a heterologous promoter operably linked to a reverse tetracycline-responsive transactivator (rtTA) ORF (the CMV::Tet-On). The instant specification establishes that “Tet-on” is used interchangeably with rtTA: “FIG. 3. Schematic representation of the rtTA ("Tet-On") gene placed in the adenovirus E3 region.”
Regarding claim 11, UCSD teaches the recombinant adenovirus genome further comprises an E3 region comprising an adenovirus death protein (ADP) ORF and comprises a deletion of the 12.5k, 6.7k, 19k, RIDa, RIDP and 14.7k ORFs (Pg. 32: ““As a final example, Fig 2.15 shows a comparison between wt Ad5 and an Ad5 virus deleted for expression of all of the E3 genes except ADP (DE3-12.5k, DE3-6.7k, DE3-19k, DE3-RIDα, DE3-RIDβ, E3-14.7k). The explanation for the significantly faster kinetics of the E3-deleted virus is unknown at this time. This result is included as an example of a virus engineered to be faster than wildtype and may have clinical applications as a more potent oncolytic.” See also construct CMBT-933, which comprises the same E3 deletions and comprises ADP.
Regarding claims 12-13, as shown above in the CMBT-933 screenshot, the structure of the construct comprises the first exogenous nucleic acid sequence preceding the second exogenous nucleic acid sequence (i.e., TRE3G::DNA Binding Protein (DBP), CMV::Tet-On) and the second exogenous nucleic acid sequence further comprises a second heterologous polyA sequence following the synthetic transcription factor ORF (i.e., Tet-On Poly-A). Furthermore, construct CMBT-933 comprises a third heterologous polyA sequence (i.e., an SV-40 Poly-A) preceding the first and second exogenous nucleic acid sequences, a schematic of which is presented in FIG 4.10 and provided below for convenience.
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Regarding claims 14-15, UCSD teaches the recombinant adenovirus genome further comprises a reporter gene; for example, the construct CMBT-933 taught by UCSD comprises mCherry. Furthermore, the CMBT-933 construct is “constructed to express mCherry-P2A-ADP,” see pg. 30, wherein P2A is a self-cleaving peptide.
Regarding claims 18-19, UCSD provides Table 3.3: shaft/Knob chimeras which teaches the recombinant adenovirus genome encodes a chimeric fiber protein comprising a fiber shaft from a first adenovirus serotype and a fiber knob from a second adenovirus serotype (claim 18) and further wherein the first adenovirus serotype is Ad5 and the second adenovirus serotype is Ad3, Ad9, Ad 11, Ad12, Ad34 or Ad37 (claim 19).
Regarding claim 21, UCSD teaches several recombinant adenovirus genomes further comprising an E1A region encoding a modified E1A protein; an E3 region encoding an adenovirus death protein (ADP) and comprising a modification in the coding sequences of at least three E3 genes selected from 12.5k, 6.7k, 19k, RIDa, RIDP and 14.7k, wherein the modification prevents expression of the encoded protein; and an E4 region comprising a deletion of the E4orf6/7 coding sequence; for example, the construct PCMN-1037 comprises E1A[DLXCXE], hexon[E451Q], D12.5k, D6.7k, D19k, YPet-P2A-ADP, DRIDα, DRIDβ, D14.7k, E3B::EGFRVHH, and DE4-ORF6/7, see Appendix B.
Regarding claims 22-25, UCSD teaches transfecting the recombinant adenovirus genomes into for example A546 cells (see pages 116, 121, 144, and xi). Thus, UCSD teaches an isolated cell comprising the recombinant adenovirus (rAd) genome (claim 22); a composition comprising the recombinant adenovirus genome (claim 23); an isolated adenovirus comprising the recombinant adenovirus genome (claim 24), and the compositions further comprising a pharmaceutically acceptable carrier because transfecting the rAd genome into a mammalian cell necessarily requires first isolation the virus into a composition in which it is stable and ready for further downstream applications, creating a composition comprising the isolated rAd virus and a pharmaceutically acceptable carrier such as Tris and finally transfecting cells to obtain an isolated cell comprising the rAd genome. See chapter 6: Experimental Procedures, particularly cell culture, virus expansion, virus harvest, virus purification, pages 128-145.
Regarding claim 29, as detailed above, UCSD teaches the recombinant adenovirus genome, CMBT-933, which has an identical name and structure (in terms of elements and order thereof) to SEQ ID No: 1 of the instant application as demonstrated below for convenience.
UCSD disclosure:
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Instant specification disclosure:
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Absent evidence to the contrary, the examiner is considering the CMBT-933 of UCSD to comprise at least 90% nucleotide sequence identity to SEQ ID No: 1 of the instant application if not 100% identity.
Claims 1-15, 21-25, and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Partlo, W. ("Progress Toward Engineered Adenovirus for Selective Replication in Tumors and Druggable Control of Virus Progression," Oral Presentation, January 26, 2018, provided in IDS, herein “Partlo”).
Regarding claim 1, Partlo teaches a recombinant adenovirus genome, comprising a Two-Step Transcriptional Activation (TSTA) circuit that employs “TRE3G activated by the Tet-On transcription factor,” which is a form/species of a synthetic transcriptional circuit, see slides 9 and 47-54. Partlo teaches the synthetic transcriptional circuit is located between a modified L5 transcript unit and an E4 transcript unit; the E1A transcript unit and the E1B transcript unit; or the E1B transcript unit and the U gene transcript unit of the adenovirus genome, wherein insertion of the synthetic transcriptional unit does not substantially alter the kinetics of genome replication (slides 38: “design rule: do not place a gene within a gene…where is a ‘safe’ place to insert a gene within the Ad5 genome…three possible locations: between E1A poly-A and E1B promoter, between E1B poly-A and E2B poly-A, between L5 poly-A and E4 poly-A.” Slide 39: “gene placement between L5 and E4 leads to much improved performance…only very strong promoter, EF1α, shows notable decrease in kinetics.”)
Regarding claims 2-5, Partlo teaches the synthetic adenovirus construct, CMBT-933 (DE2-DNA Binding Protein, D12.5k, D6.7k, D19k, mCherry-P2A-ADP, DRIDα, DRIDβ, D14.7k, SV40 Poly-A on L5 side, TRE3G:: DNA Binding Protein (for), CMV::Tet-On (for), Tet-On Poly-A), which comprises a first exogenous nucleic acid sequence comprising a regulatable promoter operably linked to a payload open reading frame (ORF) - TRE3G::DNA Binding Protein (DBP) - and a second exogenous nucleic acid sequence comprising a heterologous promoter operably linked to a sequence encoding a composite DNA binding protein with a transcription activation or repression domain ORF - CMV::Tet-On - see slides 55-59. Partlo teaches that E2A DNA Binding Protein “DBP” is an exceptional candidate as a single gene to place under the control of TSTA based on several criteria as detailed on slides 47-56, one of which being that it “must be critical to viral life cycle.” DNA Binding Protein (DBP) is defined in claims 4 and 5 of the instant case as the payload. While in the instant claim, “a composite DNA binding protein with a transcription activation or repression domain ORF” refers to a different DNA binding protein, for example a Tet-On transcription factor that binds to the regulatable promoter controlling the expression of DBP. Thus, CMBT-933 comprises the payload, DBP-an adenovirus protein essential for virus replication, under the control of a regulatable promoter, TRE3G, that is in turn bound by Tet-On transcription factor that is expressed by the heterologous constitutive CMV promoter.
Regarding claim 6, the CMBT-933 construct taught by Partlo further comprises an E2A region comprising a deletion of the DNA binding protein (DBP) ORF, see CMBT-933 description above.
Regarding claims 7-8, Partlo teaches wherein the heterologous promoter comprises a constitutive promoter or a selective promoter (claim 7), and further wherein (claim 8) the constitutive promoter is a CMV promoter or an EF1α promoter; or the selective promoter is a tissue-specific promoter, a tumor-specific promoter, or a promoter comprising microRNA (miR) binding sites. As shown above, Partlo teaches CMBT-933m which comprises the constitutive CMV promoter. Furthermore, Partlo teaches using EF1α promoter in construct CMBT-704, see slide 46.
Regarding claim 9, Partlo further teaches constructs that comprise a tumor-selective promoter, wherein the tumor-selective promoter comprises an E2F transcription factor 1 (E2F1) promoter, a baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) promoter, an L-plastin (LP) promoter, a mucin 1 (MUC1) promoter, an alpha-fetoprotein (AFP) promoter, a cholecystokinin A receptor (CCKAR) promoter or a hypoxia inducible factor (HIF)-1α promoter; the tissue-selective promoter comprises a glial fibrillary acidic protein (GFAP) promoter, a surfactant protein B (SP-B) promoter, a tyrosinase promoter, or an osteocalcin promoter; or the promoter comprising miR binding sites comprises miR-122 binding sites (see for example construct CMBT-702 on slide 46, which comprise an E2F1 promoter).
Regarding claim 10, as explained in regards to claim 2 above, the CMBT-933 construct comprises the first exogenous nucleic acid sequence comprises a TRE3G promoter operably linked to an adenovirus DBP ORF (the TRE3G::DBP domain), and the second exogenous nucleic acid sequence comprises a heterologous promoter operably linked to a reverse tetracycline-responsive transactivator (rtTA) ORF (the CMV::Tet-On). The instant specification establishes that “Tet-on” is used interchangeably with rtTA: “FIG. 3. Schematic representation of the rtTA ("Tet-On") gene placed in the adenovirus E3 region.”
Regarding claim 11, Partlo teaches the recombinant adenovirus genome further comprises an E3 region comprising an adenovirus death protein (ADP) ORF and comprises a deletion of the 12.5k, 6.7k, 19k, RIDa, RIDP and 14.7k ORFs See also construct CMBT-933 on slides 55-59, which comprises the same E3 deletions and comprises ADP.
Regarding claims 12-13, as shown above in the CMBT-933 description, the structure of the construct comprises the first exogenous nucleic acid sequence preceding the second exogenous nucleic acid sequence (i.e., TRE3G::DNA Binding Protein (DBP), CMV::Tet-On) and the second exogenous nucleic acid sequence further comprises a second heterologous polyA sequence following the synthetic transcription factor ORF (i.e., Tet-On Poly-A). Furthermore, construct CMBT-933 comprises a third heterologous polyA sequence (i.e., an SV-40 Poly-A) preceding the first and second exogenous nucleic acid sequences.
Regarding claims 14-15, Partlo teaches the recombinant adenovirus genome further comprises a reporter gene; for example, the construct CMBT-933 taught by Partlo comprises mCherry. Furthermore, the CMBT-933 construct comprises mCherry-P2A-ADP,” see slide 46 and 55-59, wherein P2A is a self-cleaving peptide.
Regarding claim 21, Partlo; an E3 region encoding an adenovirus death protein (ADP) and comprising a modification in the coding sequences of at least three E3 genes selected from 12.5k, 6.7k, 19k, RIDa, RIDP and 14.7k, wherein the modification prevents expression of the encoded protein; and into recombinant adenovirus genomes. As detailed above, CMBT-933 already comprises an E3 region encoding an adenovirus death protein (ADP) and comprising a modification in the coding sequences of at least three E3 genes selected from 12.5k, 6.7k, 19k, RIDa, RIDP and 14.7k, wherein the modification prevents expression of the encoded protein; however, Partlo teaches further incorporating an E1A region encoding a modified E1A protein and an E4 region comprising a deletion of the E4orf6/7 coding sequence into the recombinant adenovirus genome, see slide 56. Partlo teaches by further including both the modified E1A protein and deletion of the E4orf6/7, cell viability of Ad infected cells dramatically increases.
Regarding claims 22-25, Partlo teaches assembly of viral genome, transfecting the recombinant adenovirus genomes into for example A546 cells, purifying viral particles, and infecting cell typed of interest (see slides 18-22). Thus, Partlo teaches an isolated cell comprising the recombinant adenovirus (rAd) genome (claim 22); a composition comprising the recombinant adenovirus genome (claim 23); an isolated adenovirus comprising the recombinant adenovirus genome (claim 24), and the compositions further comprising a pharmaceutically acceptable carrier because transfecting the rAd genome into a mammalian cell or infecting cell type of interest necessarily requires first isolation the virus into a composition in which it is stable and ready for further downstream applications, creating a composition comprising the isolated rAd virus and a pharmaceutically acceptable carrier such as Tris, and finally infecting cells to obtain an isolated cell comprising the rAd genome.
Regarding claim 29, as detailed above, Partlo teaches the recombinant adenovirus genome, CMBT-933, which has an identical name and structure (in terms of elements and order thereof) to SEQ ID No: 1 of the instant application as demonstrated below for convenience.
Partlo disclosure:
CMBT-933 (DE2-DNA Binding Protein, D12.5k, D6.7k, D19k, mCherry-P2A-ADP, DRIDα, DRIDβ, D14.7k, SV40 Poly-A on L5 side, TRE3G:: DNA Binding Protein (for), CMV::Tet-On (for), Tet-On Poly-A)
Instant specification disclosure:
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Absent evidence to the contrary and given that the oral presentation (i.e., “Partlo”) was disseminated by the same research group who are also the inventors on the current application, the examiner is considering CMBT-933 of Partlo to comprise at least 90% nucleotide sequence identity to SEQ ID No: 1 of the instant application if not 100% identity.
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.
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 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Partlo, W. ("Progress Toward Engineered Adenovirus for Selective Replication in Tumors and Druggable Control of Virus Progression," Oral Presentation, January 26, 2018, provided in IDS) as applied to claims 1-15, 21-25, and 29 above, and further in view of Qiao C, et. al., (Gene Ther.;18(4):403-10, published 2011).
The teachings of Partlo are herein incorporated by reference to the 102 rejection above.
Partlo does not teach recombinant adenovirus genome of claim 1 further comprising at least one modification to detarget an adenovirus from the liver not such modification being one or more binding sites for a liver-specific microRNA.
Qiao teaches “liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver,” see title. Qiao further teaches that “aberrant liver expression of transgenes may result in side-effects or even immune responses,” see introduction third paragraph. Thus, Qiao teaches that the research group “intended to improve controlled gene expression by exploiting post-transcriptional regulation via endogenous tissue-specific microRNA systems, thus, to inhibit transgene expression in undesired tissues by incorporating tissue-specific miRNA target sequences into the 3′untranslated region (UTR) of an AAV vector cassette,” see introduction last paragraph.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to incorporate a liver detargeting modification, such as one or more miR122 binding sites, into the recombinant adenovirus genomes of Partlo. A PHOSITA would have been motivated to do so in order to improve controlled gene expression, thereby reducing side-effects or even immune responses. A PHOSITA would have had a reasonable expectation of success because incorporating such proven techniques would be accomplished using standard recombinant genetic cloning techniques and the strategy was already proven successful for the intended purpose.
Claims 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Partlo, W. ("Progress Toward Engineered Adenovirus for Selective Replication in Tumors and Druggable Control of Virus Progression," Oral Presentation, January 26, 2018, provided in IDS) as applied to claims 1-15, 21-25, and 29 above, and further in view of Krasnykh VN., et al., (JOURNAL OF VIROLOGY, Vol. 70, No. 10, p. 6839–6846, published 1996).
The teachings of Partlo are herein incorporated by reference to the 102 rejection above.
Partlo does not teach recombinant adenovirus genome of claim 1 further comprising nucleic acid sequence encoding a chimeric fiber protein comprising a fiber shaft from a first adenovirus serotype and a fiber knob from a second adenovirus serotype. Furthermore, while Partlo does teach the Ad5 genome, which comprises the Ad5 serotype for the fiber shaft, Partlo does not teach the second adenovirus serotype for the Knob is Ad3, Ad9, Ad 11, Ad12, Ad34 or Ad37.
Krasnykh teaches “generation of recombinant adenovirus vectors with modified fibers for altering viral tropism,” see title. Specifically, Krasnykh teaches generating “an adenovirus vector containing chimeric fibers composed of the tail and shaft domains of adenovirus serotype5 and the knob domain of serotype 3,” see abstract. Krasnykh teaches that this chimeric fiber protein was consistent with reports in the art that it has altered tropism, determined by the knob, and further teaches “that the chimeric Ad5/Ad3 fiber is also capable of being incorporated into mature viral particles,” see discussion second and third paragraphs. Krasnykh teaches that chimeric fiber proteins “allow cell-specific targeting,” a utility that would be beneficial to overcome the limitations of adenoviruses have faced in vivo, see abstract.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify the recombinant adenovirus genome of Partlo to encode a chimeric fiber protein comprising the shaft domain of adenovirus serotype 5 and the knob domain of adenovirus serotype 3, thereby arriving at a recombinant adenovirus genome comprising a chimeric fiber protein having a fiber shaft from a first adenovirus serotype and a fiber knob from a second adenovirus serotype. A PHOSITA would have been motivated to do so because Krasnykh teaches that the fiber knob domain determined viral tropism and that replacement of the Ad5 knob with the Ad3 knob produces a vector with altered tropism, is capable of being incorporated into mature viral particles, and permits cell-specific targeting. Therefore, a PHOSITA would have been motivated to incorporate the known Ad5/Ad3 chimeric fiber protein into the recombinant adenovirus of Partlo in order to modify viral tropism, improve targeting of desired cells, and overcome limitations associated with native Ad5-mediated infection. A PHOSITA would have had a reasonable expectation of success because krasnykh experimentally demonstrated that adenovirus vectors containing chimeric fibers composed of the Ad5 tail and shaft domains and the Ad3 knob domain could be successfully generated and that the chimeric fiber was incorporated in to mature viral particles while retaining infectivity. Accordingly, a PHOSITA would have a reasonably expected that incorporation of the known Ad5/Ad3 chimeric fiber in to the recombinant adenovirus of Partlo would likewise yield a functional adenovirus exhibiting the altered tropism associated with the Ad3 knob domain.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Partlo, W. ("Progress Toward Engineered Adenovirus for Selective Replication in Tumors and Druggable Control of Virus Progression," Oral Presentation, January 26, 2018, provided in IDS) as applied to claims 1-15, 21-25, and 29 above, and further in view of Bayo-Puxan N, et. al., (Hum. Gene Ther.; 20:1214-1221, published 2009)
The teachings of Partlo are herein incorporated by reference to the 120 rejection above.
Partlo does not teach the genome encodes a fiber protein modified to include an RGD peptide.
Bayo-Puxan teaches “replacement of adenovirus type 5 fiber shaft heparan sulfate proteoglycan-binding domain with RGD for improved tumor infectivity and targeting,” see title. Bayo-Puxan further teaches that “mutation of the KKTK heparin sulfate-binding domain of the fiber shaft to GATK results in liver transduction detargeting, but it is not compatible with otherwise useful HI-loop tumor-targeting ligand insertions such as the insertion of Arg-Gly-Asp (RGD),” see abstract. To circumvent this problem, Bayo-Puxan teaches mutating “the KKTK domain to RGDK,” see abstract. Bayo-Puxan teaches that “similar to RGD at the HI-loop, RGD at this new shaft location efficiently enhances the infectivity of adenovirus and improves the tumor-to-liver transduction ratio in vivo,” see abstract.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify the fiber of Partlo to include an RDG peptide. A PHOSITA would have been motivated to do so in order to enhance the infectivity of adenovirus and improve the tumor-to-liver transduction ratio. A PHOSITA would have had a reasonable expectation of success because incorporating such proven modification would be accomplished using standard recombinant genetic cloning techniques.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-2, 4-8, 11-20, and 22-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 18/151,081 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application explicitly claims an engineered oncolytic adenovirus genome comprising identical genetic modifications, synthetic transcriptional circuit design, and structural parameters that encompass or render obvious every limitation of claims 1-2, 4-8, 11-20, and 22-25 the instant application.
Independent claim 1 of the reference application established the genomic backbone deletions by reciting an engineered adenovirus genome comprising an E2A region comprising a deletion of the DNA binding protein (DBP) open reading frame (ORF), and an E3 region comprising an adenovirus death protein (ADP) ORF and comprising a deletion of the 12.5k, 6.7k, 19k, RIDa, RIDP and 14.7k ORFs. Furthermore, claim 1 recites the additional features a first exogenous nucleic acid sequence comprising a CMV-Tet-O promoter operably linked to an adenovirus DBP ORF; and a second exogenous nucleic acid sequence comprising a p53-responsive promoter operably linked to a tetracycline repressor (TetR) protein ORF, while dependent claim 2 recites the first and second exogenous nucleic acid sequences are located between the L5 and E4 regions of the adenovirus genome. Thus, taken together, claims 1 and 2 read on claims 1-2, 4-8, and 11 of the instant application and are merely a species of the broader instant claims.
Dependent claims 3-6 of the reference application read on instant claims 12-13, both reciting orientation of the exogenous nucleic acid sequences to one another and number and position of heterologous Poly A sequences.
Dependent claims 9-10 of the reference application read on instant claims 14-15, as they are word for word.
Dependent claims 11-13 of the reference application read on instant claims 16-17, as they are word for word and further recite miR122 as a specific species of micoRNA.
Dependent claims 14-16 of the reference application read on instant claims 18-20, as they are word for word.
Dependent claims 18-21 of the reference application read on instant claims 22-25, as they are word for word.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
It is noted that the claims of reference application received a notice of allowance, 06/01/2026, and thus if the reference application issues, the provisional double patenting rejection herein will convert to a double patenting rejection in the following office action.
Claims 1, 14-16, 18-19, 21, and 24-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 5, 8-9, 11, 13-14, and 17-18 of U.S. Patent No. US12365878B2. Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of US12365878B2 recites a recombinant adenovirus genome comprising an E1A modification, a specific 6-ORF E3 deletion/modification, and an E4orf6/7 deletion. Instant claim 21 recites the identical E1A, and E4orf6/7 modifications, and a broader genus of the E3 modification (requiring a modification of “at least three” of the same six E3 ORFs). Thus, the structural backbone modifications of US12365878B2 claim 1 represents a species configuration of the backbone recited in instant claim 21.
The primary difference between the two independent backbones is that instant claim 1 requires a synthetic transcriptional circuit inserted at a specific genomic rejoin (e.g., between a modified L5 transcript unit and an E4 transcript unit), which is not explicitly recited in US12365878B2.
It would have been obvious to a person having ordinary skill in the art to incorporate the synthetic transcriptional circuit, reporter elements, and targeting modifications of the instant claims into the backbone claimed in US12365878B2. The specification of US12365878B2 explicitly contemplates modifying and expanding this exact adenovirus backbone stating: “the recombinant adenovirus genome further encodes a targeting ligand, further encodes a chimeric fiber protein, further includes at least one modification to detarget an adenovirus from the liver, further includes a heterologous open reading frame (ORF), further includes a deletion of E4orf3, or any combination thereof.
When considering the applicant’s own teaching to introduce heterologous ORFs, targeting modifications, and chimeric fibers into the backbone, a PHOSITA would look to insert the synthetic transcriptional circuit of instant claim 1 (which functions as a regulatable heterologous regulatory ORF) into stable intergenic boundaries like the L5/E4 junction. Furthermore, the addition of the specific modifications recited in the instant dependent claims (14-16, 18-19, and 24-25) are also claimed in US12365878B2: reporter genes and 2A peptides (claims 13 and 14 US12365878B2), liver detargeting (claim 5 of US12365878B2), chimeric fiber proteins (claims 8-9 and 11 of US12365878B2), and isolated virus and compositions comprising the virus (claims 17-18 of US12365878B2).
Claims 1, 14-16, 18-19, 21, and 24-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-45, 52-54, 57-64, 70, and 73-74 of copending Application No. 19261101 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 41 and 45 of the reference application recites a recombinant adenovirus genome comprising an E1A modification, a specific 6-ORF E3 deletion/modification, and an E4orf6/7 deletion. Instant claim 21 recites the identical E1A, and E4orf6/7 modifications, and a broader genus of the E3 modification (requiring a modification of “at least three” of the same six E3 ORFs). Thus, the structural backbone modifications of the reference application claims 41 and 45 represents a species configuration of the backbone recited in instant claim 21.
The primary differences between reference application and the instant application is that the reference application recites method claims employing the backbone structure of the instant application and that instant claim 1 requires a synthetic transcriptional circuit inserted at a specific genomic rejoin (e.g., between a modified L5 transcript unit and an E4 transcript unit) in the genetic backbone, which is not explicitly recited in the reference application.
It would have been obvious to a person having ordinary skill in the art to incorporate the synthetic transcriptional circuit, reporter elements, and targeting modifications of the instant claims into the backbone claimed in the reference application. The specification of the reference application explicitly contemplates modifying and expanding this exact adenovirus backbone stating: “the recombinant adenovirus genome further encodes a targeting ligand, further encodes a chimeric fiber protein, further includes at least one modification to detarget an adenovirus from the liver, further includes a heterologous open reading frame (ORF), further includes a deletion of E4orf3, or any combination thereof. It would have further been obvious to employ an rAAV comprising the recombinant genome in methods to inhibit tumor cell viability and treating cancer in a subject as the logical next step as the rAAV composition is specifically designed for this purpose.
When considering the applicant’s own teaching to introduce heterologous ORFs, targeting modifications, and chimeric fibers into the backbone, a PHOSITA would look to insert the synthetic transcriptional circuit of instant claim 1 (which functions as a regulatable heterologous regulatory ORF) into stable intergenic boundaries like the L5/E4 junction. Furthermore, the addition of the specific modifications recited in the instant dependent claims (14-16, 18-19, and 24-25) are also claimed in the reference application: reporter genes and 2A peptides (claims 61-64 70, and 73-74 the reference application), liver detargeting (claim 54 of the reference application), chimeric fiber proteins (claims 57-58 of the reference application), and isolated virus and compositions comprising the virus (claims 41 and 45 of the reference application).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Requirement for Information
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
Acknowledging the submission of Partlo, W. ("Progress Toward Engineered Adenovirus for Selective Replication in Tumors and Druggable Control of Virus Progression," Oral Presentation, January 26, 2018), filed on 01/06/2023 within the IDS, the examiner has determined that additional factual information is reasonably necessary to properly examine the claims in this application. The file is a redacted copy of the slide deck used during the oral presentation given at Genomics Institute of the Novartis Research Foundation (GNF) on January 26, 2018. The examiner request a non-redacted copy of this slide deck. Specifically, redacted text in text boxes, gene arrows, and/or shapes on slides 9, 21, 25-26, 34, 41-46, 48-55, and 61.
Conclusion
No claims are allowed
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/COREY LANE BRETZ/Patent Examiner, 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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