DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 7/15/2026.
Claims 1-4, 7, 9-12, 15-19 and 22-27 are under examination.
This application claims priority as a 371 filing of PCT/GB2022/051437 filed 6/8/2022 which claims priority to GB 2108176.5 filed 6/8/2021 and GB 2207077.1 filed 5/14/2022.
Response to Amendments
Applicants amendment is sufficient to overcome the objections to the claims as well as the rejections under 35 USC 112, second previously set forth. For both, any new objection or rejection under 35 USC 112, second set forth below is necessitated by applicants amendment. The amendment is also sufficient to overcome the rejection under 35 USC 112, first. .
Claim Objections
Claim 3 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 3 recites components already required of claim 1 from which claim 3 depends. Claim 1 recites that the or5der of the claim naturally leads to the arrangement in claim 34 wherein the transgene is flanked by the 5’ and the 3’ LTRs. This is a new objection necessitated by applicants amendment.
Claim Rejections - 35 USC § 112, second paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12 and 27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This rejection is necessitated by applicants amendment
The term “improving” in claim 12 is a relative term which renders the claim indefinite. The term “improving” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicants have amended the claim to remove the comparative element wherein the claim previously indicated that the method improved the titre with the closed linear vector which indicates that this is over a non-closed linear vector. Hence, it is not clear to what the improvement is intended. This is also true of claim 27.
Claim Rejections - 35 USC § 112 ¶4 rejection
The following is a quotation of the fourth paragraph of 35 U.S.C. 112:
Subject to the [fifth paragraph of 35 U.S.C. 112 prohibiting improper multiple dependent claims], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 16 reciters that the production vectors .Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements, Claim 16 recites that the production vectors include one or more of GAG, POL, EVN and REV. However, claim 12 from which the claim ultimately depends requires all 4. Hence, the claim omits the full scope of claim 12. Hence, claim 16 does not require the full breadth of claim 12. This rejection is necessitated by applicants amendment
Claim Rejections - 35 USC § 112, first paragraph
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.
Claims 1-4, 7, 9-12, 15-19 and 22-27 are 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection is maintained in part but also in part new based upon applicants amendments.
Several components in the claims are recited in broad descriptive language wherein the specification provides a limited description that does not support the breadth. First, claim 1 recites “a hybrid 5’ long terminal repeat (LTR) sequence”. By amendment, the claim continues that the sequence is deleted of part of the U3 region and this hybrid is fused to a heterologous promoter to enable TAT-independent expression of the transgene. As to the former issue, there is no indication with what or how this hybrid element is constructed. As to the latter, the promoter is not TAT-independent, the 5’LTR is by the deletion. The disclosure provides a very broad definition,
(page 24 of the instant disclosure) Any suitable sequence for a hybrid 5′ LTR can be used in the present invention, and several are known in the art. A hybrid 5′ LTR is not a wild-type viral LTR.
But, the provided for function and hence structure is narrower.
(page 4 of the instant disclosure) In any aspect of the invention, the 5′ LTR is a hybrid LTR (may also be referred to as a modified 5′ LTR). A hybrid LTR indicates that a portion of the wild type LTR has been removed, and a heterologous sequence has been inserted. The hybrid 5′ LTR may permit Tat-independent transcription. In order to reduce or remove the dependence on Tat, all or part of the U3 region may be deleted. In order to maintain expression, the function of the U3 region may be replaced using a heterologous promoter. Such a promoter may be another viral promoter, for example the cytomegalovirus (CMV) promoter.
Second, claim 7 recites that the signal sequence includes “additional helper sequences”. There is a single disclosed “helper sequences” and that is an upstream sequence element (USE) see page 20 of the instant disclosure). These sequences are known to act as auxiliary poly(a) sequences and hence will be helpers to this function. However, the disclosure does not provide alternative sequences.
To this end, the MPEP provides such guidance (emphasis added). If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Compare Fonar, 107 F.3d at 1549, 41 USPQ2d at 1805 (disclosure of software function adequate in that art).
While the claims refer broadly to any hybrid LTR and any helper function for poly(a) sequences, the disclosure provides a more limited description. The hybrid LTR is one with TAT-independent transcription comprising a deleted U3 replaced with a heterologous sequence that functions as a promoter. The helper function is only disclosed as USE. Hence, 35 USC 112, first paragraph has not been met as there lacks sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Response to Arguments
As to claim 1 and use of the phrase “hybrid LTR”, the arguments are that the hybrid comprises a "a hybrid 5' long terminal repeat (LTR) sequence, wherein the hybrid 5' LTR sequence comprises a deletion of a portion of the U3 region compared to a wild type LTR and is fused to a heterologous promoter element to enable Tat-independent expression of the transgene". This is not the case; the claims recites simply that the hybrid LTR comprises a deletion wherein the hybrid LTR is fused to a heterologous promoter”. Hence, there is no descriptive element to make the sequence a hybrid as a deletion does not do so.
As to claim 7 and the requirement that there be an additional helper sequence, this is a broad non-descript term. It is unclear what help must be provided and furthermore what structure is required. Applicants indicate that the specification teaches as examples USE and DSE sequences. The Court indicated that while applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a precise definition of a representative number of members of the genus, such as by reciting the structure. Structural features that could distinguish the compounds of the claimed genus from others not encompassed by the genus are missing from the disclosure. In this case, the sequence must be a helper sequence but to what end or with what structure the claims lack description.
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 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.
Claims 1, 3, 4, 9, 10, 12, 17-19, 23, 24, 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Machado et al (US 20220168332) in view of LeBouch (U.S. 20020168346). This rejection is maintained but extended to newly added claims 24, 26 and 27.
Machado et al teach a vector that comprises a 5’LTR, a promoter directing expression of a transgene and a 3’ SIN LTR. Furthermore, a linker (spacer) is provided for in the vector (see ¶ 0064). The vector can be a closed linear DNA (see ¶0074).
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Missing from the vector is specifically a hybrid 5’ LTR and a polyA sequence. However, construction of SIN lentivirus vectors with hybrid LTR comprising promoter sequences and polyadenylation sequences. Lebouch et al teach in figure 3 and ¶0021 a lentivirus with a polyA tail replacing part of the 3’ LTR. This is designed to improve the vector by reducing lentiviral sequences to avoid recombination (see ¶0040). Following this is vector sequence which given the lack of characterization of the spacer can be a spacer sequence.
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to incorporate the hybrid LTR and the polyA sequence. Such a modification would have resulted in a vector encompassed by claim 1. As noted above: 1) Machado et al teach construction of lentiviral vectors can be made using closed linear vectors 2) LeBouch teaches components normally associated with modified vectors that provide improved function by reducing recombination. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the lentivirus would have improved stability.
As recited in claim 3, both Machado (figure 1) and Lebouch (figure 3) teach that the transgene is flanked by the LTR.
As recited in claim 9 a strong polyA sequence is taught such as rabbit b globin polyA (see ¶0021 of Lebouch). As recited in claim 10, the 3’ SIN has a deletion (se ¶0021).
Lebouch teaches production of lentivirus using packaging cells comprising GAG, POL, ENV and REV as recit4ed in claims 12 and 27 (see e.g. abstract, ¶ 0027, 0035). As recited in claim 18, the gag and pol genes can be expressed together (see claim 12). As recited in claims 17, 19, 23 and 26, HEK293 cells comprising these genes are cultured wherein the ENV protein can be VSV-G and particles harvested (see ¶0043 and 0099).
Claims 7 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Machado et al (US 20220168332) in view of LeBouch (U.S. 20020168346) as applied to claims 1, 3, 8-10, 12-14,17-19 and 23 above, and further in view of Moreira et al (The EMBO J, 1995, pages 3809-3819) and Miyoshi et al (JVI, 1998, pages 8150-8157).
As to the missing elements from the teachings of Machado and LeBouch, several are well known in the art. For example, Miyoshi et al teach 3’LTR SIN are made by deleting 133 from the U3 region and the U3 region of the 5’LTR is replaced with CMV promoter (see page 8151, col 2).
(page 8155, col 1)This is consistent with our result that replacement of the U3 region of the 59 LTR with the CMV promoter resulted in Tat-independent transcription (Table 2). In the absence of Tat, this hybrid CMV-LTR promoter can drive high levels of expression comparable to those of the wild-type LTR in the presence of Tat. This allows production of HIV vectors in a system devoid of Tat.
Moreira et al teach that association of USE with polyA sequences efficiency providing motivation to add this sequence to enhance the polyA activity of the vector of Machado in view of LeBouch.
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to the specific modifications above as Miyoshi et al teach that the modifications lead to a safer higher expressing vector that can express in the absence of TAT and Moreira provides an enhanced polyA sequence by incorporation of USE. Such a modification would have resulted in a vector of claims 7 and 11 and allow improved vectors for therapeutic use.
Response to Arguments
Applicants argue that Machado does not teach a spacer after the SIN and after the polyA signal. However, these components are taught by LeBouch et al which teaches as set forth above and depicted below, a right LTR that comprises a polyA sequence and as shown has a linker sequence. The claims do not specify the nature of a spacer and hence the vector sequences would naturally comply with this feature. A spacer in the art traditionally means a sequence that separates features. The diagram depicts this. This is as recited in new claim 24 at the 5’ end also. It is not clear how long the sequence is and hence the claims drawn to 250 nucleotides are not explicitly taught.
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Conclusion
Claims 2, and 255 appear to be free of the art as the art identified does not appear to teach spacer sequences of greater than 250 nucleotides which are greater than 250 nucleotides. Claims 15, 16 and 22 are free of the art as the art does not teach closed linear DNA for the lentivirus accessory genes.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached 8 am - 5 pm.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634
