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 on 08/05/2026. Claims 1-5, 7-19, and 21-24 are currently pending. Claims 1, 10, 15, 17, and 24 have been amended and claim 6 has been cancelled by Applicant’s amendment filed on 08/05/2026.
Election/Restrictions
Applicants’ election of Group I, claims 1-18, drawn to a retroviral RNA vector comprising a 5’ cap, transgene, 3’ long terminal repeat and an RNA packaging sequence was previously acknowledged.
Claims 19 and 22-24 were previously withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. The requirement for restriction was previously made final.
Therefore, claims 1-5, 7-18 are currently under examination to which the following grounds of rejection are applicable. Claims 1, 15, and 17-19 are independent claims.
Priority
The instant application a 371 of PCT/GB2021/053169 filed 12/03/2021, which claims priority to UNITED KINGDOM 2019084.9 filed 12/03/2020.
Thus, the earliest possible priority for the instant application is 12/03/2020.
Withdrawn Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112(b)
The rejection of claim 10 under 35 USC § 112(b) is withdrawn in view of the amendments in the response filed on 08/05/2026. The recitation of “…such as…” has been removed. Applicants’ arguments with regard to a withdrawn objection/rejection are moot.
Claim Rejections - 35 USC § 102
The rejection of claims 1-5, 7, 9, and 11-18 under 35 USC § 102 as being unpatentable over Vink et al. (WO 2015/056014 Al, IDS filed 06/01/2023) as evidenced by Chameettachal et al. (Chameettachal A et al., J Mol Biol. 2023) is withdrawn in view of the amendments in the response filed on 08/05/2026. Applicants’ arguments with regard to a withdrawn rejection are moot.
Claim Rejections - 35 USC § 103
The rejection of claim 6 (now cancelled) under 35 USC § 103 as being unpatentable over Vink et al. (WO 2015/056014 Al, IDS filed 06/01/2023) as evidenced by Chameettachal et al. (Chameettachal A et al., J Mol Biol. 2023) and Mock et al. (Mock U et al., Sci Rep. 2014) and in view of Galla et al. (Galla M et al., Mol Cell. 2004) is withdrawn in view of the amendments in the response filed on 08/05/2026. Applicants’ arguments with regard to a withdrawn rejection are moot.
New rejections/objections in response to Applicants’ arguments or amendmentsClaim 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 1-5, 7, 9, and 10-18 ARE rejected under 35 U.S.C. 103 as being unpatentable over Vink et al. (WO 2015/056014 Al, IDS filed 06/01/2023) as evidenced by Chameettachal et al. (Chameettachal A et al., J Mol Biol. 2023, of record) in view of Galla et al. (Galla M et al., Mol Cell. 2004, of record).
This rejection is necessitated in response to the claim amendments filed 08/05/2026.
Regarding Claims 1 and 12-13, Vink et al. teaches a retroviral RNA vector comprising a transgene, a long terminal repeat, and an RNA packaging sequence, wherein the RNA packaging sequence is located 3' of the long terminal repeat and no long terminal repeat is located 3' of the RNA packaging sequence such that reverse transcription initiated at the primer binding site does not lead to reverse transcription of the RNA packaging sequence into vector DNA in a target cell (Abstract). Vink et al. teaches specific embodiments of the vector in which it would be arranged in a manner reading on claim one, for example: 5’ -> a promoter -> primer binding site (PBS) -> expressible transgene -> LTR -> PBS -> RNA packaging sequence -> 3’ and other relevant examples (Pg. 12, Line 15 through Pg. 13 Line 4). Vink et al. further teaches that lentiviral RNA genomes acquire a 5’ 7-methylguanylate (m7g) cap during transcription by RNA polymerase II and that ribosomes load onto the 5’ cap and scan in the 5 to 3 direction to initiation translation at the 5’ most ATG (Pg. 21, Section 2.2, Lines 1-10). The retroviral vector possesses within its genome the 5’ RNA cap and therefore it would inherently be present as evidenced by Chameettachal et al. in Figure 2. The retroviral vector can be an RNA vector in that HIV-1 retroviral vectors may be used (for instant claims 12-13) (Pg. 6, 2nd full paragraph).
Vink et. al teaches that one purpose of their invention is to produce a vector where “…reverse transcription initiated at the primer binding site does not lead to reverse transcription of the RNA packaging sequence into vector DNA in a target cell.” (Abstract). Therefore, Vink et al. does contemplate the production of a retroviral vector where reverse transcription of the RNA packaging sequence into vector DNA is prevented. However, Vink et al. does not specifically teach the removal of the primer binding site (PBS) in their vector as the mechanism to prevent reverse transcription.
Galla et al. teaches deletion of primer binding sites (PBS) in a retroviral vector, specifically vector dPBS, which lacks retroviral PBS (Pg. 309, 2nd Column, Design of Retroviral Vector mutants). Galla et al. teaches that mutating or removing the PBS from a retroviral vector allows for target gene expression mediated by Psuedotransduction and the avoidance of toxic side effects (Figure 2.) Galla et al. further teaches “When using mutants aPBS (PBS mutant) or dPBS (PBS removed), in which the initiation of RT is severely disabled, retroviral pseudotransduction must be dependent on “early translation” of the retroviral mRNA, and/or on passive transfer of proteins in retroviral particles (Supplemental Figure S4). However, retroviral particles are not expected to uptake major nonretroviral protein cargo except that specific domains are present which direct an interaction with gag proteins or proviral RNA.”(Discussion, 3rd Paragraph). Moreover Galla et al. teaches “the major advantage of the method is the potential to avoid DNA transfer while still introducing specific mRNA” (Discussion, Paragraph 6).
It would have been prima facie obvious to a person of ordinary skill in the art at the time of the instant application to modify the retroviral RNA vector as taught by Vink et al. by deleting the PBS as taught by Galla et al. One would have been motivated to combine these teachings to produce a vector with disabled initiation of reverse transcription to reduce or avoid formation of retroviral DNA and toxic side effects, while retaining packaging of the retroviral RNA and permitting the packaged RNA to serve as a cap-dependent translation template for transient expression of the transgene. Galla et al. specifically identifies avoidance of DNA transfer while introducing specific mRNA as an advantage of this approach. Galla et al. also demonstrates that mutating or removing the PBS in a retroviral vector produces a vector capable of successful transduction with avoidance of toxic side effects due to reduced production of viral products requiring reverse transcription.
There would be a reasonable expectation of success in combining these teachings as Galle et al. experimentally demonstrated that a PBS-deleted retroviral vector can be packaged into retroviral particles and can mediate transgene active without PBS, while Vink et al. demonstrated that RNA packaging elements retain function when positioned on the 3’ side of the transgene and 3’ LTR. Thus applying Galla et al.’s PBS deletion strategy to Vink et al.’s packaging architecture would expectedly have yielded a retroviral RNA vector comprising a 5' cap, a transgene, a 3' long terminal repeat (LTR) and an RNA packaging sequence, wherein translation of the transgene is initiated at the 5' end of the transgene in a cap-dependent manner, wherein the 3' LTR and the RNA packaging sequence are located 3' of the transgene, and wherein the vector does not comprise a primer binding site (PBS).
Regarding Claim 2, Vink et al. teaches embodiments of their vector that do not include an LTR positioned at the 5’ end, e.g., “5' - promoter - PBS - expressible trans gene - LTR - PBS - RNA packaging sequence - 3'.” (Pg. 12, Line 15 through Pg. 13 Line 4; claims 16-17).
Regarding Claims 3-4, Vink et al. teaches elements for the HIV vector to include RNA packaging signal and RRE (Pg. 8, Line 24 – Pg. 9, 1st Paragraph). Moreover, Vink et al. teaches “In HIV-1, a portion of the gag gene has found to be involved in RNA packaging” (Pg. 8, Line 34 – Pg. 9, 1st Paragraph)
Regarding Claim 5, Vink et al. teaches the vector of their invention may be ordered in such a way that the RNA packaging sequence is located 3' of the 3' LTR. For example, 5' - promoter - PBS - expressible transgene - LTR - PBS - RNA packaging sequence - 3'; or 5' - promoter - LTR - PBS - expressible transgene - LTR - RNA packaging sequence - 3' (claim 16 of Vink et al.).
Regarding Claim 7, Vink et al. teaches preparation of the vector may include the use of a strong heterologous intron to replace the HIV MSD and that “The use of the strong heterologous intron from pCI offers advantages over the inclusion of the MSD given that no flanking splice enhancers are required, and it also includes a splice acceptor which facilitates its removal from viral RNA in producer cells.” (Pg. 23, Line 17-24).
Regarding Claim 9, Vink et al. teaches the vector of their invention may comprise a PRE (Claim 11 of Vink et al.).
Regarding Claim 10, Vink et al. teaches the vector of their invention may contain the Rev Response Element (RRE) (Claim 7 of Vink et al.), which functions to promote RNA export from the nucleus (Pg. 2, Lines 1-12)
Regarding Claim 11, Vink et al. teaches the vector may contain LTR’s that are self-inactivating (Pg. 7, Line 24).
Regarding Claim 14, Vink et al. teaches the vector may contain a polyA at the 3’ end. (Pg. 11, final paragraph).
Regarding Claim 15, Vink et al. teaches nucleotide sequences encoding a vector genome because it expressly disclosers promoter- driven vector constructs have a defined 5’-3’ sequences ordering, including 5' - promoter - PBS - expressible transgene - LTR - PBS - RNA packaging sequence - 3'; or 5' - promoter - LTR - PBS - expressible transgene - LTR - RNA packaging sequence - 3' (claim 16). A list of construct sequences is also listed at Pg. 29.
Please note that the recited result “such that, following transcription and capping of the vector genome, translation is initiated at the 5' is merely an intended use or functional statement of the claimed product and does not further limit the structure of the claimed product. Therefore, the limitation does not distinguish over the prior art. See MPEP 2111.02 and 2114.
Regarding Claim 16, Vink et al. teaches the vector may contain a polyA at the 3’ end. (Pg. 11, final paragraph).
Regarding Claims 17-18, Vink et al. teaches the following with respect to their invention “…a host cell, a virion, a pharmaceutical composition, a method and uses including or involving the vector described above. Further, a cell or transgenic animal produced by using the vector is also described (Abstract).
Response to Applicants’ Arguments as they apply to the newly rejected Claims 1-5, 7, 9-18 under 35 U.S.C. 103
At pages 6-8 of the remarks filed on 08/05/2026, Applicants essentially argue the following, which pertains to the new 103 rejection: the teachings of Galla et al. in combination with Vink et al. would not lead a skilled person in the art to arrive at the claimed invention.
These arguments have been fully considered but have not been found persuasive.At pgs. 7-8, applicant provides the following, “The Examiner additionally cites Galla, asserting that this reference "teaches that mutating or removing the PBS from a retro viral vector allows for target gene expression mediated by Pseudotransduction and the avoidance of toxic side effects." The Examiner's reliance on pseudotransduction is misplaced. Although Galla identifies that transient transgene expression can arise through pseudotransduction, it does not disclose, recommend or suggest removal of the PBS as a generally applicable modification for retroviral vectors. The Examiner appears to extract the concept of pseudotransduction from Galla while disregarding the specific vector architecture that Galla teaches is required to achieve that effect.
Galla emphasizes that pseudotransduction depends on retroviral particle assembly and mRNA packaging, and all vector constructs disclosed in Galla position the packaging signal directly 5' of the trans gene (see Figure IA), while alternative arrangements are expressly reported to be ineffective (see page 312, left col.). Accordingly, even if the skilled person were to adopt the teaching of Galla, the skilled person would use a construct comprising a 5' LTR and packaging signal upstream of the transgene and thus would not arrive at the claimed invention.”
Essentially, applicant argues that Galla does not disclose or recommend PBS removal as a generally applicable modification of retroviral vectors. This argument is not persuasive.
Galla expressly designed and experimentally validated the vector named as dPBS, which lacks retroviral PBS for the stated purpose of disabling reverse transcription (Pg. 309, 2nd column, Design of Retroviral Vector Mutants; Pg. 10, Fig. 1A and legend). Galla demonstrates that the PBS of this vector was precisely deleted, and the deletion is confirmed by sequencing (Pg. 314, Retroviral Vectors and Plasmids). Galla therefore provides teachings, rather than merely suggesting that deletion of PBS may be used to inhibit retroviral transcription while retaining RNA-mediated transgene delivery.
Applicants’ argument that Galla positions the RNA packaging signal 5’ of the transgene and that a POSA therefore would not arrive at the arrangement required by claim 1 is not found persuasive.
This argument characterizes the teachings of Galla et al. in isolation rather than considering the combined teachings of Galla et al. and Vink et al. Galla is not relied upon for the location of the RNA packaging sequence; Vink expressly provides the claimed downstream packaging architecture. Moreover, Galla et al.’s results do not establish that an RNA packaging sequence must necessarily precede the transgene. Galla et al. teaches that efficient RNA-mediated pseudotransduction depends on the accessibility of the translation unit to cap-dependent ribosomal scanning and reports that expression from an internal promoter positioned downstream of ψ was inefficient in that specific context (Pg. 312, 2nd column, final full paragraph transitioning to Pg. 313, 1st full paragraph). Vink et al.’s solution is compatible with this requirement in that Vink et al. teaches positioning the transgene upstream of the RNA packaging sequence while retaining functional packaging of the RNA genome.
A person seeking to adapt Vink et al.’s packageable, cap-dependent, RNA architecture for transient RNA-mediated transgene delivery while avoiding reverse-transcription of DNA would have been motivated by Galla et al. to delete PBS.
Applicants’ arguments concerning the teachings of Mock et al. are not persuasive with respect to the present rejection as the present rejection does not rely upon Mock et al.
Maintained and modified rejections in response to Applicants’ arguments or amendments
Claim 8 remains rejected under 35 U.S.C. 103 as being unpatentable over Vink et al. (WO 2015/056014 Al, IDS filed 06/01/2023) as evidenced by Chameettachal et al. (Chameettachal A et al., J Mol Biol. 2023, of record) in view of Galla et al. (Galla M et al., Mol Cell. 2004, of record) as applied to claim 1 above and in view of Hernández et al. (Hernández G et al., Trends Biochem Sci., 2019, of record)
This rejection has been modified in response to the claim amendments filed 08/05/2026.
Regarding claim 1, the combined teachings of Vink et al. and Galla et al. render obvious the claimed vector, as iterated above in the 103 rejection, the content of which is incorporated herein, in its entirety.
Regarding Claim 8, Vink et al. and Galla et al. do not expressly teach the inclusion of a Kozak sequence in their viral vectors.
However, Kozak sequences were well known in the art prior to the instant application. Hernández et al. describes the Kozak sequence (Kozak motif) as follows: “Selection of the translation initiation site (TIS) is a crucial step during translation. In the 1980s Marylin Kozak performed key studies on vertebrate mRNAs to characterize the optimal TIS consensus sequence, the Kozak motif.” (Abstract) and further teaches “Ever since its characterization the Kozak motif has been regarded as the optimal sequence to initiate translation in all eukaryotes.”
Hernández et al. further teaches optimal, strong, moderate, and weak Kozak sequences have also been well documented (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the instant application to have incorporated a Kozak sequence within the vector of Vink et al. and Galla et al. Vink and Galla together teach production of a vector such that RNA packaging sequence into vector DNA in a target cell does not occur as the reverse transcription of the retroviral vector is prevented. This would allow for a vector to produce an expressible transgene with minimal effects from viral products. To further enhance the production of the expressible (single stranded) transgene of interest (and therefore the vector), one of ordinary skill in the art would consider adding a Kozak sequence to optimize the initiation of translation of the expressible transgene, resulting in a superior vector.
There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the prior art to give predictable results.
Response to Applicants’ Arguments as they apply to the modified rejection of claim 8 under 35 U.S.C. 103
At pages 8 of the remarks, Applicants essentially argue that the amended claim 1 is not anticipated by Vink et al. and therefore the combined teachings of Vink and Hernandez do not render obvious claim 8.
The combined teachings of Vink, Galla, and Hernández render obvious claim 8 as discussed in the 103 rejection above.
Conclusion
Claims 1-5 and 7-18 remain rejected.
Applicants’ 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G. Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KODYE LEE ABBOTT/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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