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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed November 17, 2025.
Claims 1, 7, 9, 11-13, 15, 18, 19, 22, 34, 38, 47, 55, 64, 68, and 72-76 are pending in the application. Claims 1, 7, 22, 55 and 68 are independent. Claims 7, 9, 13, 34, 55, 72, 73, and 75 has been amended as set forth in the claim set filed 11/17/2025. No claims have been canceled and claim 76 has been added by Applicants’ amendment filed on 11/17/2025.
Claims 1, 22, 55 and 68 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. The restriction requirement was previously made final in the office action filed on 12/21/2023.
Therefore, claims 7, 9, 11-13, 15, 18, 19, 34, 38, 47, 64, and 72-76 are examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US19/24905, filed March 29, 2019.
Applicant’s claim for the benefit of a prior-filed parent provisional applications 62/650,977 filed 03/30/2018, and 62/650,973 filed 03/30/2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is March 30, 2018.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112(b)
The rejection of claims 7, 9, 11-13, 15, 18, 19, 34, 38, 47, 64, and 72-75 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn.
Applicant’s amendments filed 11/17/2025 correct the indefinite terminology and lack of antecedent basis.
Claim objection
The objections of claims 9 and 73 are withdrawn in light of Applicant’s amendments filed 11/17/2025.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 7, 9, 11-13, 15, 18-19, 47, and 72-75 remain rejected and claim 76 is newly rejected under 35 U.S.C. 103 as being unpatentable over Cannon (US20060019393A1; IDS Reference filed 11/23/2022) in view of Perkins (Molecular and Cellular Biology, June 1983, 1123-1132), Tolmachov (Viral Gene Therapy, InTech, 20 July 2011) and Mustafa (2005, JOURNAL OF VIROLOGY, Nov. 2005, p. 13817–13821) as evidenced by GenBank (GenBank (2017. Lentiviral vector pHIV-iRFP720-E2A-Luc, complete sequence, Accession Number: MF693179) and Stanford (Nolan Lab; Accessed 6/28/2024). The examiner notes that claim 9 was inadvertently not included in the heading of the claim rejection 35 U.S.C. 103 rejection of the non-final action filed on 6/17/2025. However, is clearly rendered obvious by the Cannon and the cited references, and directly addressed in the body of the previously set forth rejection.
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 11/17/2025.
Regarding claims 7 and 75-76, Cannon teaches nucleic acid in a lentiviral vector system comprising a vector and packaging construct (Abstract). The nucleic acid comprises a heterologous nucleic acid insert flanked by LTRs (i.e. TRs) (para. 0023, 0095-0096). Packing (ψ), nucleic export sequences (WPRE/RRE), and minimal intervening viral sequences are located between the first terminal repeat (5’ LTR) and the heterologous nucleic acid sequence (Abstract, para. 0075, 0093, 0115, Fig. 1). Cannon teaches that the vector components are a minimal lentiviral vector system and therefore are interpreted as having minimal intervening sequences (para. 0011). As seen in Figure 1, the vector of Cannon has an intervening sequence between Eagl and MCS which is 123nt long and comprises a cPPT element.
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880
283
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As evidenced by GenBank below, the cPPT (i.e. polypurine tract) is 15nt long (see Note=cppt). Therefore, the intervening sequence is 108 nt. The construct of the present invention measures intervening sequences from U5 to U3.
The first half of the sequence starts at 1 and arrives at 950 with eagl with packaging signals, CMV promoters and U5 in between as seen by the psi above.
After the MSCs at 1100 (MCS are not included in the present application as intervening sequences), U3 which comprises a deletion site is at approximately 1900 nt. This is approximately 800 nucleotides which encompass intervening sequences as well as the U3 element.
CMV to U3 = approximately 1900 nucleotides
MSC = 27nt
Cppt (as evidenced by Genbank below) = 15nt
U3 = approximately 1900-1800 = 100nt
Intervening sequences are at least about 1750 nucleotides minus the CMV nucleotide length, R and U5 length. As taught by Genbank below, promoters can be 576 (815-239) nt in length. If this is taken into account, the intervening sequences could be less than about 1182 nucleotides.
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However, Cannon does not teach that the intervening sequences are between 50-500 and even more specifically a total of 125-200 base pairs in length.
Perkins teaches a transfection vector wherein all but about 700 base pairs of the intervening sequences were removed (Abstract).
Moreover, Mustafa teaches that intervening sequences between the core packaging elements in vectors are dispensable and do not affect vector RNA significantly (Abstract). As taught by Mustafa, the knowledge of intervening sequences being dispensable should help streamline the design of transfer vectors for gene therapy as they would not be needed as spacers (p. 13821, 1st column; p. 13817, 2nd column)
Tolmachov teaches that typically optimization of the lentiviral vector set up is usually required when utilizing genetic elements (p. 274, 3rd paragraph). Tolmachov additionally states that RNA size packaging constraints are often an issue in lentiviral vector design (p. 265, 1st line). Because of lentiviral packaging size constraints, shorter versions of genes are normally preferable and one will only include an intron within the cargo if it provides an important regulatory function for the genes expression (p. 268, 1st paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to reduce the number of minimal intervening sequences in the viral vector of Cannon as taught by Perkins, Mustafa and Tolmachov with a reasonable expectation of success. Doing so would be routine optimization of the design of the vectors which Tolmachov teaches is usually required for factors such as cargo size.
It is well settled that routine optimization is not patentable, even if it results in significant improvements over the prior art. In support of this position, attention is directed to the decision in In re Aller, Lacey, and Haft, 105 USPQ 233 (CCPA 1955): Normally, it is to be expected that a change in temperature, or in concentration, or in both, would be an unpatentable modification. Under some circumstances, however, changes such as these may impart patentability to a process if the particular ranges claimed produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. In re Dreyfus, 22 C.C.P.A. (Patents) 830, 73 F.2d 931,24 USPQ 52; In re Waite et al., 35 C.C.P.A. (Patents) 1117, 168 F.2d 104, 77 USPQ 586. Such ranges are termed "critical" ranges, and the applicant has the burden of proving such criticality. In re Swenson et al., 30 C.C.P.A. (Patents) 809, 132 F.2d 1020, 56 USPQ 372; In re Scherl, 33 C.C.P.A. (Patents) 1193, 156 F.2d 72, 70 USPQ 204. However, even though applicant's modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art. In re Sola, 22 C.C.P.A. (Patents) 1313, 77 F.2d 627, 25 USPQ 433; In re Normann et al., 32 C.C.P.A. (Patents) 1248, 150 F.2d 708, 66 USPQ 308; In re Irmscher, 32 C.C.P.A. (Patents) 1259, 150 F.2d 705, 66 USPQ 314. More particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Swain et al., 33 C.C.P.A. (Patents) 1250, 156 F.2d 239, 70 USPQ 412; Minnesota Mining and Mfg. Co. v. Coe, 69 App. D.C. 217, 99 F.2d 986, 38 USPQ 213; Allen et al. v. Coe, 77 App. D. C. 324, 135 F.2d 11,57 USPQ 136. (Emphasis added). With regards to determining experimental parameters, such as time in culture, the court has held that "[d]iscovery of optimum value of result effective variable in known process is ordinarily within skill of art (In re Boesch and Slaney, 205 USPQ 215 (CCPA 1980)).
The adjustment of particular conventional working conditions is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan having the cited reference before him/her. In fact, the applicant is on record as stating that the ordinary artisan would have recognized that intervening sequences are noncoding viral nucleic acid segments between elements of the packageable vector RNA, such as integration, replication and packaging and are well known in the art (page 6 of Applicants’ remarks filed on 01/03/2025) .
Regarding claim 9, Cannon teaches that there is an internal promoter operably linked to the heterologous nucleic acid insert between the TRs (para. 0069, figure 1).
Regarding claim 11, Cannon teaches that the 5’LTR comprises a U5 region (para. 0054, Figure 1). As evidenced by Stanford, 5’LTRs inherently normally act as RNA pol II promoters (2nd paragraph).
Regarding claim 12, Cannon teaches that the 3’TR comprises a repeat region and a U3 region and that the U3 region enhances termination (transcription termination) (para. 0055-56, 0022)
Regarding claim 13, Cannon teaches that the packaging sequence has a psi sequence which is before the polypurine tract sequence (Figure 1)
Regarding claim 15 and 72, Cannon teaches a nucleic acid sequence which comprises nucleic export sequences such as a Rev protein response element or PRE (WPRE/RRE) which is located between the psi and polypurine tract (Figure 1, para. 0073, 0115).
Regarding claim 18, Cannon teaches that the heterologous coding sequence encodes a protein, peptide or RNA (Abstract, para. 0023, 0098).
Regarding claim 19, Cannon teaches that the constitutive promoter is CMV or SV40 at the 5’ end upsteam of the 5’ TR (Fig. 1, para. 0086).
Regarding claim 47, Cannon teaches that the vector is utilized to produce a transcribed proviral sequence (i.e. a transcribed nucleic acid) (para. 0026, Claim 19).
Regarding claim 73, Cannon teaches a lentiviral nucleic acid encoding Gag (Abstract).
Regarding claim 74, Cannon teaches a that the terminal repeats are LTRs (Abstract, Figure 1).
Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 34 and 38 remain rejected under 35 U.S.C. 103 as being unpatentable over Cannon (supra) in view of Perkins (supra), Tolmachov (supra) and Mustafa (supra) as applied to claim 7 above, and in further view of Choi (Gene Therapy (2016) 23, 627–633; previously cited) as evidenced by GenBank (GenBank (2017. Lentiviral vector pHIV-iRFP720-E2A-Luc, complete sequence, Accession Number: MF693179) and Stanford (Nolan Lab; Accessed 6/28/2024)
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 11/17/2025.
Canon, Perkins, Tolmachov and Mustafa teach a heterologous nucleic acid in a lentiviral vector flanked by ITRs with packaging and nuclear export sequences and intervening viral sequences which are routinely optimized to a total between 50 and 500 base pairs, as discussed in the 103 above and referenced herein in its entirety.
Regarding claim 34 and 38, Cannon further teaches that the nucleic acid encodes siRNA, structural RNAs, anti-sense RNAs and therapeutic polypeptides (para. 0098).
However, Cannon does not teach that the heterologous nucleic acid encodes a Cas nuclease gene such as cas9 nuclease.
Choi teaches fusing a Cas9 sequence into a heterologous nucleotide in a lentiviral vector and through this method, off-target editing of chromosomes were reduced when compared with an expression vector (p. 628, 1st column).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to fuse a cas9 sequence into a heterologous nucleotide as taught by Choi in the lentiviral vector of Cannon, Tolmachov, Mustafa, and Perkins in place of the anti-sense RNA technology with a reasonable expectation of success. An artisan would be motivated to utilize Cas9 in the lentiviral technology of Cannon instead of RNAi methods as unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, gene-editing technologies such as Cas9/CRISPR allow permanent disruption/deletion of the targeted gene after a single treatment (p. 628).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 64 remain rejected under 35 U.S.C. 103 as being unpatentable over Cannon (supra) in view of Perkins (supra), Tolmachov (supra) and Mustafa (supra) as applied to claim 7 above, and in further view of Liu (MOLECULAR MEDICINE REPORTS 17: 835-842, 2018; previously cited) as evidenced by GenBank (GenBank (2017. Lentiviral vector pHIV-iRFP720-E2A-Luc, complete sequence, Accession Number: MF693179) and Stanford (Nolan Lab; Accessed 6/28/2024)
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 11/17/2025.
Canon, Perkins, Tolmachov and Mustafa teach a heterologous nucleic acid in a lentiviral vector flanked by ITRs with packaging and nuclear export sequences and intervening viral sequences which are routinely optimized to a total between 50 and 500 base pairs, as discussed in the 103 above and referenced herein in its entirety.
While Cannon teaches that the nucleic acid encodes siRNA, structural RNAs, anti-sense RNAs and therapeutic polypeptides (para. 0098), Cannon does not teach that the heterologous nucleic acid encodes a microRNA that targets a specific gene as in claim 64. As described in the specification mir-30 is utilized to create shRNA in the vector.
Liu teaches stable silencing of TRIM28 expression by a specific siRNA (a more specific microrna) lentivirus vector which inhibited the growth and exerted obvious anti-tumor effects in mice (Abstract).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize a microRNA which targets genes such as TRIM28 in a heterologous nucleotide as taught by Liu in the lentiviral vector of Cannon as the anti-sense and siRNA molecules with a reasonable expectation of success. An artisan would be motivated to utilize siRNA which targets TRIM28 in the lentiviral technology of Kafri instead of RNAi methods as siRNA which targets TRIM28 in lentiviral vectors is known in the art to inhibit tumor growth in vivo (p. 837, bridging paragraph).
Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments and amendments filed 11/18/2025 regarding the 103 rejections,
Applicant’s arguments and amendments filed 11/18/2025 have been considered, however they are not persuasive.
Applicant argues against the references individually based on their disclosure of base pairs and nucleotide sequences of intervening sequences and states that based on the evidence found within the references, there is no motivation to further remove elements from the primary reference and no disclosure of a process to do so. Moreover, Applicant argues that routine optimization was not employed and that the invention amounts to more than routine optimization.
In response to applicant's argument that there is no process shown to reduce the intervening sequences of Cannon to a minimal amount within the references, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In response to applicant’s argument that there is no motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the motivation arises from Tolmachov teaching that typically optimization of the lentiviral vector set up is usually required when utilizing genetic elements (p. 274, 3rd paragraph). Tolmachov additionally states that RNA size packaging constraints are often an issue in lentiviral vector design (p. 265, 1st line). Because of lentiviral packaging size constraints, shorter versions of genes are normally preferable and one will only include an intron within the cargo if it provides an important regulatory function for the genes expression (p. 268, 1st paragraph). This provides a suggestion or motivation to reduce the size of intervening sequences.
Applicant briefly states that the references cited demonstrate the unexpected results of the instant application, however does not indicate how. Furthermore, the unexpected results should be in commensurate with the scope of the invention and therefore if this is the case, the minimal intervening sequences of the invention at certain critical range should be present within the independent claims as critical elements. If Applicant is suggesting the RNA propagation is the unexpected result which is inherent from the construct itself and not a method of use of the construct, it would be beneficial to disclose the evidence in a Declaration specifically or point to where the unexpected results are in the specification.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634