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 .
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5, 6, 8, 11, 14, 25, 26, 31, 35, 36, 38, 41, 44, and 55-56 are rejected under 35 U.S.C. 103 as being unpatentable over Ying et al. (Histone deacetylase inhibitor Scriptaid reactivates latent HIV-1 promoter by inducing histone modification in in vitro latency cell lines, 2010) in view of Breuel et al. (Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation, 2019), Jaalouk et al. (Inhibition of histone deacetylation in 293GPG packaging cell line improves the production of self-inactivating MLV-derived retroviral vectors, 2006) Luznik et al. (Tat-independent Replication of human Immunodeficiency Viruses, 1994) and Al-Rubeai, Viral Vectors for Gene Therapy, 2011)
Regarding Claims 1 and 31: Ying teaches a method of culturing A7 cells which harbored a latent HIV-1 viral transcript visualized by a green fluorescent protein (GFP) which were treated with Scriptaid with or without the PKC activator Prostratin to test the impact on HIV-1 production. (Pg 265, Abstract and pg 268, Results) It was shown that Scriptaid (HDAC inhibitor) when combined with Prostratin resulted in a higher percentage of GFP expression than Scriptaid alone, which is a visualization for how much HIV-1 production occurred within the A7 cells as GFP expression was correlated to viral production. (Pg 268, Fig 3 and Results) This reads on the claimed method of a PKC inhibitor (Prostratin) being present in the cell culture medium at a concentration that increases the viral titer within a viral vector production culture system and also reads on a viral vector production comprising a cell comprising nucleic acid sequences encoding viral vector components (HIV-1).Ying fails to teach use of a self-inactivating viral vector and use of a tat-independent lentiviral vector.
Luznik et al. teaches that tat-defective HIV-1 can replicate without any stimulation in MT-4 cells, and with the presence of TNF-a and PMA in U937 cells, demonstrating that inhibitory effects of tat antagonists can be overridden by TNF-a. (Pg 1, Introduction) One skilled in the art would understand that not being dependent on stimulation of the cells, as is required in tat-driven replication, would be preferable over tat-driven activation due to the virus not needing stimulation to activate in MT-4 cells. As such, this would also give motivation to a person skilled in the art to carry out the replication itself in MT-4 cells in place of the A7 cells as taught by Ying, thereby giving reason to modify the protocol.
Jaalouk teaches use of self-inactivating retroviral vectors (SIN) and that they have been used successfully to drive upregulated transgene expression by inducible promoters in addition to allowing for regulated or targeted gene expression.(Pg 2, Background)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jaalouk and Luznik with the teachings of Ying. A person of ordinary skill in the art would have had motivation and a reasonable expectation of success at doing so based on the teachings of Jaalouk, who detail that SINs allow for regulated, targeted gene expression and Luznik, who demonstrate tat-independent HIV replication without the need for a stimulant.
Regarding Claims 5 and 35: Breuel teaches a method of producing engineered U1 lentiviral shuttles which are used to transfect exon 5 of BBS1 in HEK293T cells. In addition to this, two packaging plasmids were transfected along with the modified U1 snRNA cassette. (Pg 128, Treatment with Engineered U1 snRNA and/or AONs) This reads on the claimed method of a modified U1 snRNA being co-expressed with lentiviral components which binds to the packaging region of the lentiviral vector genome sequence. This is performed in vitro (pg 127, Cell Culture of Patient-Derived Fibroblasts and Treatment with AONs), which further reads on the method of claim 35 of a viral vector production system.
Regarding Claims 6 and 36: Breuel teaches that incorporation of the modified U1 snRNA led to an increased amount of correctly spliced BBS1 transcripts without elevated levels of apoptic cell death. (Pg 123, Abstract) Breuel further teaches that manipulation of pre-mRNA processing is a promising approach to overcoming diseases caused by genetic mutations. (pg 123, Abstract) In addition to this, Breuel teaches that the modified U1 snRNA is inserted into the mutated splice donor site (exon 5). (Pg 128, Treatment with Engineered U1 snRNA and/or AONs) This reads on the claimed method of the major splice donor region of the lentiviral vector genome comprising a functional mutation.
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to use the method of increasing viral titer by use of a PKC activator (prostratin) as taught by Ying with the modified U1 snRNA transfection method taught by Breuel to create a modified U1 snRNA binding to a nucleotide sequence within the packaging region of the lentiviral vector genome sequence. One would have had motivation and a reasonable expectation of success at doing so based on the teachings of Breuel, who teach an engineered U1 snRNA inserted with packaging vectors into exon 5 of BBS1 in HEK293T cells and that manipulation of pre-mRNA processing is promising regarding treating genetic diseases.
Regarding Claims 8 and 38: Jaalouk teaches a method of transfection of a pJ6ΩBleo plasmid into 293GPG cells (pg 9, Methods) which resulted in the generation of SINCMV retroviral producers which had stable viral production. (pg 2, Results) The SINCMV retroviral producing cells were then treated with sodium butyrate, which resulted in a dose-dependent increase in viral titer when compared to non-treated culture conditions. (Pg 4, Results) This reads on the claimed method of use of an HDAC inhibitor, specifically sodium butyrate.
Regarding claims 11 and 41: Ying teaches a method of culturing A7 cells which harbored a latent HIV-1 viral transcript which when treated with prostratin and a HDAC inhibitor, had an increased viral titer than when treated with just the HDAC inhibitor alone. (Pg 268, Results) This reads on use of prostratin as the PKC activator within a viral vector production system. Ying fails to teach use of sodium butyrate as the specified HDAC inhibitor.
Jaalouk teaches use of sodium butyrate (HDAC inhibitor) to increase viral titer levels in the culture of SINCMV cells in vitro. (Pg 4, Results). This reads on the claimed method of use of sodium butyrate as an HDAC inhibitor within a viral vector production system.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine use of sodium butyrate as an HDAC inhibitor along with use of a self-inactivating vector as taught by Jaalouk with the teachings of Ying of prostratin as a PKC activator with the transfection method as taught by Breuel to create a viral vector production system which uses prostratin as the PKC activator and sodium butyrate is the HDAC inhibitor. One would have had a reasonable expectation of success and motivation of doing so based on the teachings of Ying, who demonstrates that use of prostratin increases viral titer and Jaalouk, who demonstrates that use of sodium butyrate increases viral titer and that self-inactivating lentiviral vectors allow for regulated or targeted gene expression.
Regarding Claims 14 and 44: Ying discloses use of A7 cells, which is a Jurkat cell line encoding Tat-driven HIT LTR expression. (Pg 266, Materials and Methods) This reads on the claimed method of use of a stable producer cell line.
Regarding claims 25 and 55: Ying teaches use of HIV-1 transfected Jurkat cell line which is used to study latent HIV-1 transmission. (Pg 266, Materials and Methods) This reads on the claimed method of use of HIV-1 as the lentiviral vector used in the viral vector production system.
Regarding claims 26 and 56: Breuel teaches transfection of a nucleotide sequence which results in correct splicing of the BBS1 protein. (Pg 12, Abstract) This reads on the claimed method of delivery of a nucleotide of interest.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the use of an HIV-1 lentiviral vector with the modified U1 snRNA transfection method taught by Breuel to create a modified lentiviral U1 snRNA vector used in a vector production system. One would have had a reasonable expectation of success and motivation at doing so based on the teachings of Breuel who teaches use of a lentivirus, Ying who further specifies use of HIV-1, and Al-Rubeai, who teaches that lentiviral vectors are safe, powerful, and reliable.
Claims 12 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Ying et al. (Histone deacetylase inhibitor Scriptaid reactivates latent HIV-1 promoter by inducing histone modification in in vitro latency cell lines, 2010) in view of Breuel et al. (Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation, 2019), Jaalouk et al. (Inhibition of histone deacetylation in 293GPG packaging cell line improves the production of self-inactivating MLV-derived retroviral vectors, 2006) Luznik et al. (Tat-independent Replication of human Immunodeficiency Viruses, 1994) and Al-Rubeai, Viral Vectors for Gene Therapy, 2011) and José et al. (Reactivation of latent HIV-1 by new semi-synthetic ingenol esters, 2014)
The teachings of Ying, Breuel, Jaalouk, Luznik, and Al-Rubeai are disclosed above. All fail to teach use of ingenol as a PKC activator.
Regarding claims 12 and 42: José teaches a method of exposing cells in culture to various ingenols and ingenol derivatives due to ingenols having the ability to reactivate latent HIV-1. (Pg 329, Results) José demonstrated that the addition of ingenol derivatives to the culture media increased transcription and activated latent HIV expression and transcription in PBMC donor-derived cells. (Pg 332-333, results) This reads on use of ingenol as the PKC activator within the viral vector production system, but fails to teach use of sodium butyrate as an HDAC inhibitor.
Jaalouk teaches use of sodium butyrate (HDAC inhibitor) to increase viral titer levels in the culture of SINCMV cells in vitro. (Pg 4, Results). This reads on the claimed method of use of sodium butyrate as an HDAC inhibitor within a viral vector production system.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine use of sodium butyrate as an HDAC inhibitor as taught by Jaalouk with the teachings of José of ingenol as a PKC activator with the transfection method as taught by Breuel to create a viral vector production system which uses sodium butyrate as the PKC activator and sodium butyrate is the HDAC inhibitor. One would have had a reasonable expectation of success and motivation of doing so based on the teachings of José, who demonstrates that use of ingenol reactivates latent HIV transcription and Jaalouk, who demonstrates that use of sodium butyrate increases viral titer.
Response to Arguments
Applicant's arguments filed 03/26/2026 have been fully considered but they are not persuasive.
Applicant has amended claims 1 and 31 to require use of a tat-independent lentiviral vector. This overcomes the previous 35 U.S.C. 103 rejection of Ying in view of Jaalouk and Al-Rubeai, but as necessitated by amendment, Luznik et al. has been incorporated into the amendment. Luznik teaches the benefit of use of a tat-independent replication system for HIV-1 as it allows replication to be carried out without the need for stimulation in MT-4 cells, giving a person of ordinary skill in the art to modify the protocol taught by Ying to make use of MT-4 cells, as they are already widely used in HIV research. This further renders the argument of Ying depending on tat-mediated LTR activation irrelevant, as Luznik provides an assay for measuring viral titer that does not depend on tat-driven replication, as illustrated in Figure 1.
Applicant further argues that Ying uses non-producer cells harboring a wild-type virus, which is different than the producer cells of the claimed invention. Again, Examiner points out that this is not reflected in the claims regardless of the point of use, but has incorporated the teachings of Luznik of use of MT-4 cells, which is a known producer cell line commonly used in the study of HIV, and would be known to a person of ordinary skill in the art.
Furthermore, Applicant argues that a person skilled in the art would have no motivation to combine the teachings of the secondary references in their respective 35 U.S.C. 103 rejections. However, per MPEP 2141.03.I, "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.”
As such, the 35 U.S.C. 103 rejections regarding claims 1, 5, 6, 8, 11, 12, 14, 25-26, 31, 32, 35, 36, 38, 41, 42, 44, and 55-56 are upheld.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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