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 .
Claims 1-19, 22 and 23 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.
Information Disclosure Statement
An IDS filed 12/6/2023 has been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action. Initials indicate that the document has been considered even if the reference is lined through.
Claim Objections
Claims 1, 12, 16, 18 and 22 are objected to because of the following informalities: claim 1 recites simply a 3’ self-inactivating (SIN) sequence. For completeness and consistency in the claims reference should be to --a self-inactivating 3’ LTR--. This is the more common means of referencing it and provides consistency with later claims.
Articles to independent limitations allow the claim to distinguish the separate limitations from compound ones. Claim 3 recites “the 5’ and 3’ LTR sequences” wherein the 3’ LTRR requires an article. The recitation should be –the 5’ and the 3’ LTR--. Claim 12 requires an article prior to “producer cell” in line 4. In claim 18, “POL” requires its own article. It is an independent limitations and not a compound. Although rejected below, the term “derivative in claim 19 also requires an article for the same reason. In claim 22, each of the vectors also require either an “a” or “an” or a “the”. Articles are also required in part (a) of claim 23 prior to “packaging” and “producer”.
The abbreviations in claim 16 have been previously established and do not need to be spelled out a second time.
Appropriate correction is required.
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 1-19, 22 and 23 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.
Claim 1 recites a closed linear DNA vector “suitable for use” as a lentiviral transfer vector. It is unclear if the linear DNA is a transfer vector or can simply be used as one. This confusion is imparted by the language in claim 12 which recites “a method for improving the infectious titre of lentiviral particle “when the transfer vector is a closed linear DNA vector” wherein this vector is that of claim 1. This suggests that it can be a transfer vector but must not necessarily be one and the metes and bounds of the claim are unclear.
Claim 4 recites preferably wherein it is unclear if the indicated limitation , a 5’ spacer sequence” is required or not.
The term “strong” in claim 8 is a relative term which renders the claim indefinite. The term “strong” 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.
Claim 9 recites the limitation "said sequences" in claim 1. There is insufficient antecedent basis for this limitation in the claim. There are multiple sequences mentioned- some in claim 9 and some in claim 1 and claim 9 does not clarify if it is all or only one and if one which one. This is complicated by the recitation that the signal (sequence) has 90% homology to said sequences meaning all of them. This recitation as a whole is included in the 112 first rejection.
Claim 11 recites that the 3’ SIN LTR is deleted at a site of the wild-type LTR “compared to” “nucleotides -149 to -9 with respect to transcription start site”. It is not clear to what transcription start site the claim refers and to what the nucleotides are meant to reflect.
Claim 14 is unclear for reference to parts (e), (f), (g), (h). This appears to provide a continuation from claim 1 but these parts are labeled (a) through (e) and hence this connection is unclear. In claim 16, these elements are recited again using (i) through (iv) and ultimately depend from claim 14. The difference in notations suggests that these are distinct requirements rather than modifications in claim 16 of those recited in claim 14. However, they are duplicate elements. Hence, the claims are unclear as to how many options exist in claim 16.
Claim 16 recites the limitation "said closed linear DNA vector" in claim 15. There is insufficient antecedent basis for this limitation in the claim. There are multiple references to closed linear DNA vectors both in claim 15 and claim 1 and it is not clear to which the claim references. It is noted that claim 22 refers to the closed linear transfer vector which distinguishes it from those recited in claim 15. However, referring generally to closed linear DNA as in claim 16 does not automatically limit the claim to the production vectors especially since there are one or more of these closed linear vectors.
Claim 19 is vague and indefinite in that the metes and bounds of the term “derivative thereof” are unclear. It is unclear the nature and number of steps required to obtained a “derivative” of HEK293. The term implies a number of different steps that may or may not result in a change in the functional characteristics of the cell from the source that it is “derived from”.
Claim 22 recites the limitation "GAG-POL encoding production vector" in claim 15. There is insufficient antecedent basis for this limitation in the claim. GAG and POL are expressed in tandem in claim 18 but not in claim 15. Hence, this limitation lacks antecedent basis.
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 1-19, 22 and 23 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.
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”. There is no indication with what or how this hybrid element is constructed. 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.
As to self-inactivating sequences, this is to function in the claims as a 3’ LTR. The sequence while broadly claimed also includes a claim that requires that one or more deletions are present and in claim 122 that this deletion is 133 of the U3 region. As to SIN in the disclosure is limited to this 133 nucleotide deletion to remove the U3 region.
(page 25 of the instant disclosure) In a preferred embodiment, the sequence encoding the 3' LTR is a sequence for a 3' self-inactivating (SIN) LTR. Alternatively put, the vector includes a 3' SIN LTR sequence A 3' SIN LTR has one or more deletions compared to a wild-type lentiviral 3' LTR, and may be referred to a modified 3' LTR. The one or more deletions are transferred into the 5 'LTR after one round of reverse transcription. This deletion abolishes transcription of the full-length virus after it has incorporated into a host cell. The one or more deletions may include partial or complete deletion of promoter or enhancer elements including the TATA box and binding sites for transcription factors Sp1 and NF-KB. 3' SIN LTRs are well known in the art, and a skilled person will be able to identify appropriate constructs. In a preferred embodiment the 3' SIN LTR comprises a 133 nucleotide deletion in the U3 region of the 3' LTR, at nucleotide position -149 to -9 with respect to the transcription start site of a wild-type lentiviral 3' LTR. A SIN 3' LTR is not a wild-type viral LTR.
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. Third, claim 9 recites that the poly(a) signal has “at least 90% homology to said sequences”. The claim lacks for clarity above as reference is made to 90% identity to all of the sequences. However, the description only cites to use of a single poly(a) sequence. As to poly(a) sequences, the disclosure teaches a limited number of single sequences that are not multiple sequences as recited (page 20 of the instant disclosure).
In a preferred embodiment, the sequence encoding a strong poly(A) signal is selected from the SV40 Late polyA sequence, or a sequence having at least 90% homology thereto, rabbit 3-globin (rbGlob) poly(A) sequence, or a sequence having at least 90% homology thereto, or bovine growth hormone poly(A) (bGHpA), or a sequence having at least 90% homology thereto. Such may be described as "strong" poly(A) signals.
Fourth, claim 19 recites a HEK293 cell or a variant or a derivative thereof. HEK293 is a human embryonic kidney cell line that is used to produce virus. The derivative cells or variant cells provided are simply HEK293F, a suspension culture and HEK293T an adherent culture which comprises SV40 larger T antigen. But claiming any variant and any derivative encompasses known and unknown HEK variants and derivatives. These include according to the disclosure those that could be derivatized (bridging ¶, page 29-30 of the disclosure)
Finally claim 23 recites that the producer or packaging cells are “adapted for” the production of a lentiviral particle. This appears to be simply introducing helper components into the cell. There is no other adaptation that is provided for in the disclosure. This is provided for on (page 31)
In the method of the present invention, packaging cells, such as HEK293F cells growing in suspension under serum-free conditions, are transfected with one or more vector(s) adapted for the production of a lentiviral particle. Preferably, the transfection is a transient transfection.
The different functions necessary for the production of a lentiviral particle can be provided to the packaging cells by any number of vectors. In particular, these functions may be provided by at least one, two, three or four vectors. In a particular embodiment of the invention, the different functions necessary for production of a lentiviral particle are provided to the packaging cell by the transfection, in particular transient transfection, of four vectors adapted for producing lentiviral particles, wherein one vector encodes envelope proteins (Env vector), one vector encodes lentiviral Gag and Pol proteins (Gag-Pol vector), one vector encodes a lentiviral Rev protein (Rev vector) and one vector is the closed linear transfer vector of the present invention comprising a transgene expression cassette between sequences encoding the lentiviral 5' hybrid LTR and 3' SIN LTR.
Overall, the packaging cell or producer cell to which the closed linear transfer vector is introduced should have all of the packaging functions necessary to produce a functional lentiviral particle, and these packaging functions may be introduced to the cell through transient transfection, stably integrated into the cellular genome, or a combination of the two.
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 as well as any variant or derivative of HEK293, the disclosure provides a more limited description. The hybrid LTR is one with TAT-independent transcription comprising a deleted U3 replaced with a heterologous sequences that functions as a promoter. The helper function is only disclosed as USE and HEK variants and derivatives are the known HEK293F and HEK293T. Furthermore, the claims refer to a poly(a) sequences that is 90% homologous to what as written is all of SV40, rbGlob, bGHpA. This creates a large array of sequences that would have to be tested to identify functional combinations. Finally, the claims refer to cells adapted for lentiviral production wherein the only adaptation that is taught is generation of producer or packaging cell lines that comprise all of GAG, POL, REV and ENV. 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.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 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.
Claims 12-19 and 23 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method for improving infectious titers of a lentivirus, the method comprising introducing a closed linear DNA vector comprising in order 1 5’LTR, a promoter operably linked to a transgene, a 3’ SIN sequence, a poly(a) sequence and a spacer sequence into a packaging or a producer cell wherein the packaging or the producer cells comprises GAG, POL, ENV and REV wherein total DNA transfected is less than 1 μg/ml, the construct molar ratio is preferably (written as transfer:GAG/POL:REV:ENV DNA constructs) 4:1:2:1, 3:1:3:2, 3:1:3:1.5, or 3:1:2:1, does not reasonably provide enablement for any other embodiment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to a method of producing lentivirus wherein the closed linear DNA vector is meant to improve the infectious particle titre.
2) Scope of the invention. The scope of the invention is broad in that the method entails only in the broadest claim introducing the closed linear DNA vector into any packaging or producer cell. Dependent claims recite that the packaging cell can comprise one or more production vectors and these can include any of GAG, POL, ENV and REV.
3) Number of working examples and guidance. The specification teaches that HEK293 cells were transfected with 4 lentiviral production vectors aa transfer vector, GagPol, Rev and VSV-G (see pages 34-35 of the instant disclosure). The experimental system used closed linear transfer vectors as well as production vectors and furthermore tested a 5’ spacer sequence as well as polyA sequences. The disclosure also teaches that the following modifications are necessary to increase yield or “for improving infectious titer”.
0085] Further, the method of producing the lentiviral particle or the method of improving the infectious lentiviral titre using the closed linear DNA transfer vector may be optimized by altering the total amount of DNA used for the transfection of the cell, notably by reducing the total amount of DNA used for transfection of the cell. This reduction is achieved when compared to other DNA vector types such as plasmids. Preferably, the total DNA transfected is less than 1 μg/ml, less than 0.9 μg/ml, less than 0.8 μg/ml or less than 0.75 μg/ml. Optimally, the total amount of DNA transfected is 0.7 μg/ml or less, such as 06 μg/ml or 0.5 μg/ml.
[0086] Additionally or alternatively, the method of producing the lentiviral particle or the method of improving the infectious lentiviral titre using the closed linear DNA transfer vector may be optimised by altering the ratios between the various DNA constructs. Thus, the construct ratios may be altered such that an enhanced production of infectious lentiviral particles is achieved.
[0087] When a packaging cell is transfected with 4 DNA constructs (the closed linear transfer vector, GAG/POL vector, REV vector and ENV (or VSVg) vector), any appropriate construct molar ratio may be used. However, to gain an optimised infectious titres, the construct molar ratio is preferably (written as transfer:GAG/POL:REV:ENV DNA constructs) 4:1:2:1, 3:1:3:2, 3:1:3:1.5, or 3:1:2:1. The construct ratio may be any suitable ratio that falls between these ratios, such as 3:1:2.5:1 and the like. Preferably, the construct ratio is 4:1:2:1.
4) State of the art. The art teaches that for producing lentivirus vectors, 4 components are necessary and often these are found in a packaging or producer cell. These components are GAG, POL, ENV (i.e. VSV-G) and REV (Milone and O’Doherty, 2018, bridging ¶ page 1529-1530).
The basic genes required for retroviral and lentiviral survival and function are the gag, pol, and env genes; gag encodes structural proteins, pol encodes enzymes required for reverse transcription and integration into the host cell genome, and env encodes the viral envelope glycoprotein [3]
5) Unpredictability of the art. The disclosure states that a packaging cells or producer cells are cells used for production of lentiviral particles. The difference between the two cell (Tridgett et al, 2024, Molecular Therapy).
Stable packaging cell lines have all LVV genetic sequences, except the LVV transfer plasmid stably integrated into the cell genome, thus requiring preparation, testing, and transfection of only one plasmid to produce LVV, as opposed to four for fully transient production. Stable producer cell lines, however, have all LVV-producing elements integrated, thus requiring no plasmid transfection to produce LVV.
But considering different definitions that still require production of lentivirus, they all require helper functions too make the lentivirus
(disclosure, ¶0204) In the method of the present invention, packaging cells, such as HEK293F cells growing in suspension under serum-free conditions, are transfected with one or more vector(s) adapted for the production of a lentiviral particle. Preferably, the transfection is a transient transfection. The different functions necessary for the production of a lentiviral particle can be provided to the packaging cells by any number of vectors. In particular, these functions may be provided by at least one, two, three or four vectors. In a particular embodiment of the invention, the different functions necessary for production of a lentiviral particle are provided to the packaging cell by the transfection, in particular transient transfection, of four vectors adapted for producing lentiviral particles, wherein one vector encodes envelope proteins (Env vector), one vector encodes lentiviral Gag and Pol proteins (Gag-Pol vector), one vector encodes a lentiviral Rev protein (Rev vector) and one vector is the closed linear transfer vector of the present invention comprising a transgene expression cassette between sequences encoding the lentiviral 5' hybrid LTR and 3' SIN LTR.
As well, the claims require that the method lead to improved infectious titer and work to optimize the output. However, the method uses neither the full complement of helper functions nor the optimized conditions.
6) Undue experimentation. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention. The invention recites use of a broad group of sequence. Given the unpredictability of the art, the poorly developed state of the art with regard to predicting the structural/ functional characteristics of antagonists, the lack of adequate working examples and the lack of guidance provided by applicants, the skilled artisan would have to have conducted undue, unpredictable experimentation to practice the claimed invention.” In this case, the methods as claimed are incomplete by only requiring one or more of GAG, POL, ENV and REV wherein the art teaches the requirement of all 4. Secondly, the specification is dedicated to producing lentivirus titers and recognizes that the titer is low. To obviate this, the inventors test conditions to optimize and claim a method for improving the titer. However, these optimizations are not found in the claims.
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, 8-10, 12-14,17-19 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Machado et al (US 20220168332) in view of LeBouch (U.S. 20020168346).
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 and hybrid LTR. This is designed to improve the vector by reducing lentiviral sequences to avoid recombination (see ¶0040).
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 claims 8 and 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 (see e.g. abstract, ¶ 0027, 0035). The gag and pol genes can be expressed together (see claim 12). The limitations of claims 13, 14 and 18 are met. As recited in claims 17, 19 and 23, HEK293 cells comprising these genes are cultured wherein the ENV protein can be VSV-G and particles harvested (see ¶0043 and 0099).
Claims 6, 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 6, 7 and 11 and allow improved vectors for therapeutic use.
Conclusion
Claims 2, 4 and 5 appear to be free of the art as the art identified does not teach spacer sequences of greater than 250 nucleotides which are greater than 250 nucleotides. Nor is one found 5’ to the 5’ LTR. Claims 15, 16 and 22 are free of the art as the art does not teach closed linear DNA for the lentivirus accessory genes.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634