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 .
DETAILED ACTION
The amended claims filed on March 2, 2026, have been acknowledged. Claims 14 and 18 were cancelled. Claims 1 and 10-11 were amended. Claims 1-13, 15-17, and 19-20 are pending and examined on the merits.
Rejections and/or objections not reiterated from the previous office action mailed August 28, 2025, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The applicant claims foreign priority from GB2013058.9 filed on August 21, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received 10/17/2022. Claims 1-16 find support in foreign application GB2013058.9 filed on August 21, 2020.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 1-5, 9-13, 15, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 7220577 (Zolotukhin; referenced in IDS), and further in view of Yuan et al. (Human Gene Therapy 22: 613-624. 2011), Urabe et al. (Journal of Virology 80: 1874–1885. 2006), United States Patent Application No. 2011/0104120 (Xiao), World Intellectual Property Organization Patent Application No. 2019/020992 (Cawood; Published January 31, 2019; referenced in IDS), and Emmerling et al. (Biotechnol. J. 11: 290-297. 2016). This is a new rejection made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been fully considered but is considered moot in response to the new rejection of record.
Regarding claims 1 and 10, Zolotukhin teaches a method of producing a combinatorial vector and virion libraries of replication competent adeno-associated viral vectors encoding modified chimeric Cap proteins comprising:
(a) introducing, into a population of first host cells, a DNA library comprising a plurality of DNA molecules, wherein each DNA molecule in the library comprises a recombinant AAV genome which comprises ITRs flanking a first AAV cap gene encoding first Cap polypeptides, and wherein DNA molecules in the library differ in the nucleotide sequences of their first AAV cap genes (the specification discloses that "recombinant AAV genome" refers to an AAV genome comprising AAV inverted terminal repeats (ITRs) flanking an intervening sequence (page 8, lines 9-13). Under this definition, Zolotukhin teaches that they introduced a library of mutated Cap genes comprising a nucleotide sequence encoding a portion of a Cap protein found in an AAV of a first serotype but not in an AAV of a second serotype differing from the first serotype into a vector comprising ITRs wherein the AAV2 Rep gene and mutated Cap gene are between the ITRs (this would fall under the Applicant’s definition of recombinant AAV genome) and transfected it into the Sf9 cells (Figure 1, Example 1, and column 2, line 6-column 4, line 10))
(b) culturing the population of first host cells under conditions
(Zolotukhin teaches that they cultured Sf9 insect cells for three days to produce a library of recombinant AAVs (Figure 1, Example 1, and column 2, line 6-column 4, line 10)):
(i) a second AAV cap gene encoding second Cap polypeptides is expressed in the first host cells, wherein the second Cap polypeptides are ones which confer a tropism on AAV particles encapsidated by such polypeptides towards second host cells (Zolotukhin teaches that Rep and Cap gene products having WT Rep and Cap function are provided to the SF9 cell wherein the Rep and Cap may be provided using any suitable means encoding WT AAV2 cap which confers a tropism to the second host cells of HEK293 cells (Figure 1, Example 1, column 2, line 6-column 4, line 10, and column 13, 26-53)),
(ii) an AAV rep gene and viral helper genes are expressed in the first host cells (Zolotukhin teaches that they introduced rep gene products having WT functional activity to the Sf9 cells encoding WT rep (Figure 1, Example 1, column 2, line 6-column 4, line 10, and column 13, 26-53). As there are more than one vector encoding Rep introduced into the Sf9 cells and the Rep protein is important for producing an AAV viral particle, the vector encoding Rep is also considered to encode viral helper genes), and
(iii) first AAV Cap polypeptides are not produced in the first host cells, by virtue of the expression of a repressor in the first host cells which represses or prevents expression of the first AAV Cap polypeptides (Zolotukhin teaches that the use of a heterologous system (insect cells) during the first step silences WT AAV genome promoters encoding the first chimeric capsid genes and aborts the expression of the modified capsid genes (column 6, line 58-column 7, line 26)),
wherein first recombinant AAV particles are produced which are encapsidated by the second Cap polypeptides (Zolotukhin teaches that the use of a heterologous system (insect cells) during the first step silences WT AAV genome promoters encoding the first chimeric capsid genes and aborts the expression of the modified capsid genes. As such, this results in all viral particles produced in Sf9 cells being encapsidated by WT AAV Cap (column 6, line 58-column 7, line 60);
(c) infecting a population of second host cells with first recombinant AAV particles (Zolotukhin teaches infecting a second host cell with the first population of virions under conditions that allow production of a second population of virions (Figure 1, Example 1, and column 2, line 6-column 4, line 10));
(d) culturing the second population of host cells in a culture medium under conditions such that:
(i) first AAV Cap polypeptides are produced (Zolotukhin teaches that the second host cell comprises a nucleotide sequence encoding at least one AAV Cap protein, wherein the nucleotide sequence includes nucleic acid sequences from at least the first AAV serotype and the second AAV serotype (i.e. a second cap gene) (Figure 1, Example 1, and column 3, line 28-column 4, line 10). Zolotukhin teaches that the chimeric capsids are used to infect target cells or tissues to select for virions with particular tropisms (column 7, lines 52-60)), and
(ii) an AAV rep gene and viral helper genes are expressed in the second host cells ((Zolotukhin teaches that the second host cell comprises a first nucleotide sequence encoding at least one AAV Rep protein and that the second host cells (HEK293 cells) are co-infected with adenovirus5 comprising viral helper genes (Figure 1, Example 1, and column 2, line 6-column 4, line 10),
wherein an AAV particle library of second recombinant AAV particles is produced, wherein each second recombinant AAV particle in the library comprises an AAV genome which comprises ITRs flanking a first AAV cap gene encoding a first Cap polypeptide, wherein the particles in the library differ in the nucleotide sequences of their first AAV cap genes, and wherein each particle in the library is encapsidated by Cap polypeptides which are encoded by the first cap gene in its AAV genome (Zolotukhin teaches that each virion of the second population of virions includes: (i) a first nucleotide sequence encoding at least one AAV Rep protein; (ii) a second nucleotide sequence encoding at least one AAV Cap protein, wherein the nucleotide sequence includes nucleic acid sequences from at least the first AAV serotype and the second AAV serotype; and (iii) at least one AAV Cap protein encoded by the second nucleotide sequence. Zolotukhin teaches that they introduced a library of mutated Cap genes comprising a nucleotide sequence encoding a portion of a Cap protein found in an AAV of a first serotype but not in an AAV of a second serotype differing from the first serotype into a vector comprising ITRs wherein the AAV2 Rep gene and mutated Cap gene are between the ITRs and transfected it into the Sf9 cells (Figure 1, Example 1, and column 2, line 6-column 4, line 10))
Zolotukhin does not teach wherein the AAV rep gene and second cap gene are both present in the genome of a recombinant adenovirus which is present in the first host cells.
Although Zolotukhin teaches using Sf9 insect cells, and not mammalian cells as the first host cell, Zolotukhin does teach that to generate a seed library (in a first host cell), the vector library is introduced into a host cell. Rep and Cap gene products having WT Rep and Cap function are provided to the cell. Any host cell permissive to AAV growth might be used. However, host cells that silence AAV promoters and therefore prevent expression of the modified cap genes are preferred. For example, insect cells (e.g., Sf9 cells) might be used. Each virion of the seed library is composed of WT Cap proteins yet contains a unique non-naturally occurring nucleic acid encoding a modified (e.g., degenerate) Cap protein. The virions of the seed library can be incorporated within at least one host cell. A host cell is any cell permissive to infection by AAV, and
includes insect as well as mammalian cells (column 10, lines 11-44 and column 13, lines 25-32).
Yuan teaches that they generated plasmids encoding inducible Rep/Cap genes for generating AAV2, AAV8, and AAV9 viral vectors in HEK293 cells using the Gateway system. By utilizing the Gateway system, it was much easier to establish an inducible AAV plasmid containing different promoters, genes of interest, and alternative AAV serotypes. For example, only the vector shuttle plasmid needs modification for new promoter and new genes of interest. Similarly, only the packaging backbone plasmid needs to be modified to obtain the Cap gene of different AAV serotypes. Yuan teaches that they used adenoviruses encoding Cre recombinase to inducibly express the Rep and Cap genes (whole document).
Urabe teaches that they compared to efficacy of generating recombinant AAV vectors in insect and mammalian cells and found that genomes packaged into capsids differ in size from rAAV5 produced in HEK293 cells. The majority of the vector genome of rAAV5 produced in HEK293 cells in the present study is in single-stranded monomeric form, irrespective of the size of the vector genome. When the size of vector DNA is shorter than the size of the wild-type AAV genome, insect cells tend to package longer, 4.7-kb DNA into type 5 capsids. The 4.7-kb longer virion DNA in Sf9-produced rAAV5 appears to be a cleavage product of multimers of replicated vector genomes. If the size of a multimer is within the packaging limit, it is efficiently introduced into AAV capsids. If a multimer is larger than 4.8 kb in size, a partially truncated multimer is packaged into AAV capsids in insect cells. Sequencing of 4.7-kb DNA packaged into virions will be a key to disclosing the difference between packaging of vector DNA into capsids in HEK293 cells and insect cells.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the AAV library production method of Zolotukhin by producing the first recombinant AAV particles in mammalian HEK293 cells using inducible Rep/Cap genes, as identified by Yuan, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because although Zolotukhin exemplifies using Sf9 insect cells as the first host cells, they also identify that any suitable host cells, including mammalian cells, that silence AAV promoters and therefore prevent expression of the modified cap genes are preferred for generating the seed library. As the inducible Rep/Cap genes of Yuan would only express the modified cap after Cre expression, the modified Cap gene would be completely suppressed (i.e. the loxP cites act as a repressor) until Cre recombinase (the inducer) is added. Furthermore, Urabe teaches that producing AAV vectors in insect cells leads to packaging additional DNA into the vector genome, cleavage product of multimers of replicated vector genomes, when the size of vector DNA is shorter than the size of the wild-type AAV genome whereas the majority of the vector genome of rAAV5 produced in HEK293 cells in the present study is in single-stranded monomeric form, irrespective of the size of the vector genome. Therefore, it would have been obvious to prefer performing the production of the first recombinant AAV virion in a mammalian cell to avoid packaging replicated vector genomes that may impact vector production down the line and increase the variability between different rounds of production and different modified capsids. Furthermore, Yuan specifically identifies that with their method, it was much easier to establish an inducible AAV plasmid containing different promoters, genes of interest, and alternative AAV serotypes as only the vector shuttle plasmid needs modification for new promoter and new genes of interest. Similarly, only the packaging backbone plasmid needs to be modified to obtain the Cap gene of different AAV serotypes. Therefore, it would have been simple to consistently iterate with different combinations of promoters, modified capsids, genes of interest, and promoters using the system of Yuan. Therefore, it would have been obvious to use the inducible Rep/Cap plasmids of Yuan in mammalian cells as this would allow for complete silencing of the modified Cap/Rep genes, allowing the WT Rep and Cap genes to produce virions, as required by Zolotukhin in the first host cells, while avoiding some of the drawbacks associated with using insect cells for AAV production. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Zolotukhin, Yuan, and Urabe do not teach using adenoviruses to express the AAV rep gene and the second cap gene.
However, Xiao teaches a method of producing a recombinant virus particle comprising an AAV capsid ( e.g., AAV particle), the method comprising:
providing a cell (a first host cell) in vitro with a nucleic acid encoding a capsid protein, an AAV rep coding sequence, a recombinant vector genome (e.g., a rAAV genome) comprising a heterologous nucleic acid, and helper functions for generating a productive infection which can be provided by an adenovirus (i.e. viral helper genes); and allowing assembly of the recombinant virus particle comprising the AAV capsid and encapsidating the recombinant vector genome (paragraphs 0009-0103 and 223). Xiao teaches that the viral vector genome can comprise a cap coding sequence encoding a shuffled capsid coding sequence of two or more different AAV and an AAV rep coding sequence (paragraphs 0093-103).
Xiao teaches that the viral vector genome can comprise a cap coding sequence encoding a shuffled capsid coding sequence of two or more different AAV and an AAV rep coding sequence which has a tropism for a target cell type (paragraphs 0093-103);
Xiao teaches that the resulting viral vector is encapsidated by the AAV capsid protein and is isolated and administered to a mammalian subject to assess its tropism (paragraphs 0093-103).
Xiao teaches that the AAV rep and cap genes can be introduced to cells using plasmids or adenoviral vectors, including as part of the adenoviral helper vector. Xiao teaches that the nucleic acid encoding the AAV vector genome can be incorporated into a delivery vector such as a hybrid adenovirus particle (i.e. recombinant adenovirus) or plasmid (paragraphs 0210-0230).
However, Cawood teaches that their invention has the advantage of providing a simple, cost-effective, way to manufacture AAV particles where the Rep and Cap proteins of AAV can be encoded within the Adenovirus to provide the high expression levels and increased yields of recombinant proteins which are required to make the AAV particles by maintaining the replication of the Adenoviral genome, but also preventing the production Adenovirus particles in the final AAV preparation.
MLP maintains its full expression activity level in cells where a repressor is not bound, providing high level virus replication with minimal disturbance to the virus life cycle. The virus of the invention described herein is therefore fully active when not repressed but is capable of being repressed, depending on the presence or absence of a repressor. A repressor binding site has not previously successfully been inserted into the MLP in situ for the regulation of its expression in an adenovirus genome. The current inventors have further improved this system to place the repressor protein coding sequence under the control of the Major Late Promoter itself. In this approach, the Major Late Promoter self-represses itself because when the Major Late Promoter tries to transcribe the structural proteins of the virus, it will also transcribe a repressor capable of repressing its own activity, thereby allowing for a negative feedback loop that prevents MLP activity and providing tight regulation of MLP expression (page 2, paragraph 3-page 4, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of introducing the WT rep and cap genes to the first host cells of the combined method of Zolotuhkin, Yuan, and Urabe by using adenoviruses comprising nucleic acids encoding the rep and cap genes with a MLP promoter with a repressor gene downstream, as identified by Cawood, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Xiao teaches that AAV rep and cap genes can be introduced to cells using adenoviral vectors and Cawood teaches that the MLP promoter can maintain a high level of expression of the rep and cap genes to improve the yield of these recombinant proteins and improve viral production of the AAV vector while allowing repression to provide tight regulation of MLP expression and limit the development of unwanted adenoviral particles in the AAV production method. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Zolotuhkin, Yuan, Urabe, Xiao, and Cawood do not teach wherein the nucleic acid encoding the rep gene is introduced into the second host cell in the genome of a second adenovirus.
However, Emmerling teaches that they aimed: (i) to increase rAAV production by improving plasmids used for transfection. A plasmid system termed rep/cap split-packaging was optimized with superior results. They developed a new rep and cap packaging plasmids termed rep/cap split-packaging. In this split-packaging approach, the rep and cap encoding sequences were placed onto two plasmids to reduce the likelihood of generation of replication competent (rc) AAV during vector production and to reduce toxicity by ablation of Rep78 expression. Further modifications resulted in the development of optimized rep/cap split-packaging plasmids with rep plasmid pUC repopt Δrep78/Δcap and cap plasmid pUC capopt p5p19p40cap (Fig. 1B). On these plasmids, they inactivated dispensable promoters by mutating their TATAA box motif and we deleted potential start codons in any of the cap open reading frames to avoid the expression of nonfunctional and truncated viral gene products. Importantly, optimization of the split packaging constructs resulted not only in significantly increased Cap expression levels, but also altered the ratio of the expressed proteins. Vector titers were analyzed by qPCR-based quantification of encapsidated vector genomes. Using the optimized rep/cap split-packaging system, the titer was more than two-fold increased compared to the conventional packaging system and about 1.5-fold enhanced compared to the non-optimized split-packaging system (whole document).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the AAV production method of Zolotukhin by using a split rep/cap system in the second host cells, as identified by Emmerling, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Emmerling teaches that splitting the rep and cap genes resulted not only in significantly increased Cap expression levels, but also altered the ratio of the expressed proteins and increased vector titer. Therefore, it would have been obvious that the inducible Rep/Cap plasmid could be modified to only express the modified cap gene such that the modified cap gene could be expressed as part of the AAV genome of the first recombinant AAV virion while the Rep gene is expressed through the optimized split system using an adenoviral vector as Xiao and Cawood already identify that adenoviral vectors can be used to express rep genes in host cells and Emmerling has shown that this the split cap/rep system leads to increased Cap expression and increased viral titers. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 2, Zolotukhin teaches that they introduced a mutated Cap gene comprising a nucleotide sequence encoding a portion of a Cap protein found in an AAV of a first serotype but not in an AAV of a second serotype differing from the first serotype into a vector comprising ITRs wherein the AAV2 Rep gene and mutated Cap gene are between the ITRs (this would fall under the Applicant’s definition of recombinant AAV genome) and transfected it into the first host cells (Figure 1, Example 1, and column 3, line 28-column 4, line 10).
Regarding claims 3-4, Zolotukhin teaches that the second host cell is HEK293 cells (Figure 1 and Example 1).
Regarding claim 5, Zolotukhin teaches that the AAV vector genome can include reporter genes (17, lines 32-67).
Regarding claim 8, as shown in Figure 1 of Yuan, the Loxp sites are found within the rep gene. The P40 promoter is found within the 3’ region of the rep gene and this promoter drives expression of the cap gene. Therefore, the first AAV cap gene is operably-associated with the repressible P40 promoter, wherein the loxp sites (the repressor), is present in the first cells but not in the second host cells once Cre recombinase is added and the Loxp sites are removed and the modified cap is expressed.
Regarding claim 9, Zolotuhkin teaches that the first AAV particles are of serotype 2 (Figure 1 and column 6, lines 6-12). Zolotukhin does not teach that the second AAV particles of serotype 9 but does teach that poly morphisms from AAV serotypes 1-8 can be incorporated into a WT AAV2 cap sequence to generate a pool of degenerate AAV capsid genes containing sequences from AAV serotypes 1-8.
Xiao teaches that the capsid can be a scrambled capsid sequence that includes sequences from two or more capsids including AAV9 (i.e. a mutated derivative of serotype 9) (paragraph 0312).
As such, Xiao successfully reduces to practice that AAV9 can be included in a scrambled capsid sequence comprising at least two different AAV serotype gene sequences (similar to the degenerate AAV capsid genes of Zolotukhin) and Zolotukhin considers any of AAVs 1-8 as possible sequences to be combined in the degenerate AAV pool. It would have obvious to extend this to AAV9 as well. Therefore, it would have been obvious that AAV9 could also be used as one of the serotypes incorporated into the WT AAV2 cap sequence to generate a pool of degenerate AAV capsid genes containing sequences from multiple AAV serotypes.
Regarding claim 11, Zolotukhin teaches that HEK293 cells are infected with a low multiplicity of infection (e.g. 0.1). The low MOI ensures that most of the cells are infected with a single AAV vector-containing virion. (column 7, lines 35-51).
Regarding claim 12, as the AAV2 WT cap genes are not provided to the second host cells (HEK293 cells), they will not be produced in the second host cells (Figure 1 and Example 1).
Regarding claims 13 and 19-20, Zolotukhin teaches that the third host cell can be adipocytes (i.e. fat cells) or embryonic stem cells (Example 10).
Regarding claim 15, Zolotukhin teaches that they harvested the second population of virions from the second host cell (Figure 1, Example 1, and column 3, line 28-column 4, line 10).
Claims 1, 6-7, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 7220577 (Zolotukhin; referenced in IDS), and further in view of Yuan et al. (Human Gene Therapy 22: 613-624. 2011), Urabe et al. (Journal of Virology 80: 1874–1885. 2006), United States Patent Application No. 2011/0104120 (Xiao), World Intellectual Property Organization Patent Application No. 2019/020992 (Cawood; Published January 31, 2019; referenced in IDS), and Emmerling et al. (Biotechnol. J. 11: 290-297. 2016) as applied to claim 1 above and further in view of United States Patent Application 20180327722 (Vink). This is a new rejection made in response to Applicant’s amendments to claim 1.
The teachings of Zolotuhkin, Yuan, Urabe, Xiao, Cawood, and Emmerling are as discussed above.
The combined teachings of Zolotuhkin, Yuan, Urabe, Xiao, Cawood, and Emmerling do not teach wherein the repressor is an antisense RNA.
However, Vink teaches that they designed an shRNA sequence that targets the AAV2 and AAV5 cap gene using criteria for designing an effective shRNA:
A or T at position 1
40-80% A/T content
>50% A/T content in positions 1-14
(A/T % positions 1-14)/(A/T % positions 15-21) =>1
No A at position 20
An A or T at position 13 OR a T at position 14
No 'AAAAAA', 'TTTTT', 'CCCC' or 'GGGG'
Vink teaches that a region of homology between AAV2 cap gene and AAV 5 cap gene (nucleotides 3086-3106 of AAV2 GenBank sequence AF043303) was found to match these criteria. The 3086-3106 region is in the coding region of the Cap gene and not the 5’ or 3’ UTR region. Vink teaches that this shRNA sequence could be used to knock down both Rep and Cap expression in AAV2 and AAV5 (paragraphs 0227-0236)
Vink teaches that the nucleic acid vector comprises nucleic acid sequences encoding shRNA, which targets the rep and cap transcripts (rep and cap mRNA molecule). In this way, it is possible to control the expression of Rep and Cap proteins.
The advantage of controlling expression of Rep proteins at a transcript level is that it is possible to maintain all of the native promoters of the rep and cap genes (P5, P19 and P40) in order to maintain the correct stoichiometry of the various rep and cap transcripts required for efficient AAV vector production. It also means that the integrity of the rep and cap genes are not affected as they are not required to be modified (paragraphs 0124-0132).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted loxp and Cre recombinase based repression system of the AAV production method of Zolotuhkin, Yuan, Urabe, Xiao, Cawood, and Emmerling with the shRNA based repression system of Vink to repress Cap expression to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Vink teaches that there is a distinct advantage of controlling expression of Rep proteins at a transcript level as it is possible to maintain all of the native promoters of the rep and cap genes (P5, P19 and P40) in order to maintain the correct stoichiometry of the various rep and cap transcripts required for efficient AAV vector production while also maintaining the integrity of the rep and cap genes as they are not required to be modified. On the contrary, the loxp and Cre recombinase based repression system requires modification of the rep gene to insert the loxp sites in the gene. Furthermore, Loxp systems are known to leave a leftover loxp site after excision that can interfere with efficient expression of the unrepressed gene. Therefore, using the shRNA of Vink would simplify the process by not requiring genetic modification of the Rep gene and maintain the integrity of the rep and cap genes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 7 and 17, the combined teachings of Zolotuhkin, Yuan, Urabe, Xiao, Cawood, Emmerling, and Vink do not teach wherein the antisense RNA (shRNA in the case of Vink) targets the 3’ or 5’ UTR regions.
However, Vink does successfully reduces to practice that antisense RNA molecules, such as shRNA, can be used to target the capsid mRNA for degradation. Although Vink does not target the 5’ UTR or 3’ UTR regions, it is well understood in the art that antisense RNA that targets the 3’ or 5’ UTR can be used to degrade mRNA. Furthermore, it is routine within the field to use known sequences to develop their antisense RNA for targeting the refion of interest, such as the 5’ or 3’ UTR regions. As identified above, Vink used specific criteria for identifying their shRNA that targets the Cap gene. However, there are many other known methods for identifying a region of interest for different antisense RNA molecules so that they target the region of interest. Furthermore, Vink identifies that the sequences of various capsid serotypes are known within the art (paragraph 0098). Therefore, it would have been obvious to one of ordinary skill in the art that they could target the 3’ or 5’ UTR regions of the capsid gene for degradation as these sequences are well known within the art and one of ordinary skill could use the sequence information to design an antisense molecule to target the 3’ or 5’ UTR and Vink already successfully reduces to practice that antisense RNA molecules, such as shRNA, can be used to target the capsid mRNA for degradation.
Furthermore, as taught by MPEP 2144.05 (II)(A), generally, "[W]here 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 Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). In the instant case, targeting a different region of the capsid gene represents the substitution of equivalents doing the same thing as the original invention, by substantially the same means (degrading mRNA), is not such an invention as will sustain a patent. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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 KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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