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 February 26, 2026, have been acknowledged. Claim 12 was cancelled. Claims 1-11 and 13-16 were amended. Claims 1-11 and 13-16 are pending and examined on the merits.
Priority
The applicant claims foreign priority from GB2013057.1 filed on August 21, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received 10/17/2022. Claims 1-11 and 13-16 find support in foreign application GB2013057.1 filed on August 21, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) filed on February 26, 2026, and April 17, 2026, have been considered. It is noted that although the February 26, 2026, IDS identifies 20070051238 as a relevant US Patent Application, it should actually be 20070015238, as cited in the Japanese Office Action.
Withdrawn Claim Rejections - 35 USC § 101
The prior rejection of claim 12 under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more is withdrawn in light of Applicant’s cancellation of claim 12.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 1-4, 7-8, 10, and 12-15 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent No. 7220577 (Zolotukhin) is withdrawn in light of Applicant’s amendments to claim 1 to require the first host cell is a mammalian cell.
The prior rejection of claims 1-6, 9-10, 12-13, and 15-16 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 2011/0104120 (Xiao) is withdrawn in light of Applicant’s amendments to claim 1 to require the first recombinant AAV to be purified.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1 and 11 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2011/0104120 (Xiao) as applied to claim 1 above, and further in view of World Intellectual Property Organization Patent Application No. 2019/020992 (Cawood; Published January 31, 2019; referenced in IDS) is withdrawn in light of Applicant’s amendments to claim 1 to require the first recombinant AAV to be purified.
New 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, 7-10, and 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 7220577 (Zolotukhin), and further in view of Yuan et al. (Human Gene Therapy 22: 613-624. 2011) and Urabe et al. (Journal of Virology 80: 1874–1885. 2006). 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 claim 1, Zolotukhin teaches a method of producing replication competent adeno-associated viral vectors encoding modified chimeric Cap proteins comprising:
(a) culturing a population of first host cells (Zolotukhin teaches that they cultured Sf9 insect cells for three days to produce recombinant AAVs (Figure 1, Example 1, and column 3, line 28-column 4, line 10), wherein each first host cell comprises:
(i) a nucleic acid molecule encoding a recombinant AAV genome ((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 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 Sf9 cells (Figure 1, Example 1, and column 3, line 28-column 4, line 10);
(ii) a nucleic acid molecule encoding a first AAV cap gene which encodes first AAV capsid polypeptides, wherein the first AAV capsid polypeptides confer a tropism on AAV particles which comprise such polypeptides towards second host cells (Zolotukhin teaches that they introduced cap gene products having WT functional activity to the Sf9 cells using baculoviruses encoding WT AAV2 cap which confers a tropism to the second host cells of HEK293 cells (Figure 1, Example 1, and column 3, line 28-column 4, line 10));
(iii) a nucleic acid molecule encoding an AAV rep gene (Zolotukhin teaches that they introduced rep gene products having WT functional activity to the Sf9 cells using baculoviruses encoding WT rep (Figure 1, Example 1, and column 3, line 28-column 4, line 10));
(iv) nucleic acid molecules encoding viral helper genes (Zolotukhin teaches that they introduced rep gene products having WT functional activity to the Sf9 cells using baculoviruses encoding WT rep (Figure 1, Example 1, and column 3, line 28-column 4, line 10). As there are more than one RepBac introduced to the Sf9 cells and the Rep protein is important for producing an AAV viral particle, the RepBac encoding Rep is also considered to encode viral helper genes);
such that the expression of each of (i)-(iv) in the first host cells is sufficient to produce first recombinant AAV particles comprising the AAV genome in the first host cells, wherein the first AAV particles are encapsidated by first AAV capsid polypeptides (Zolotukhin teaches culturing the first host cell under conditions that allow production of a first population of virions containing the vectors, wherein the virions include at least one WT AAV Cap protein (i.e. first AAV capsid polypeptides) and harvesting the first population of virions from the first host cell (Figure 1, Example 1, and column 3, line 28-column 4, line 10));
(b) infecting a population of second host cells with the first recombinant AAV particles which are produced from Step (a) (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 3, line 28-column 4, line 10));
(c) expressing in the population of second host cells:
(i) a nucleic acid molecule encoding a second AAV cap gene which encodes second AAV capsid polypeptides, wherein the second AAV capsid polypeptides confer a tropism on AAV particles which comprise such polypeptides towards third host cells (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 (i.e. a third host cell (column 7, lines 52-60));
(ii) a nucleic acid molecule encoding an AAV rep gene (Zolotukhin teaches that the second host cell comprises a first nucleotide sequence encoding at least one AAV Rep protein (Figure 1, Example 1, and column 3, line 28-column 4, line 10));
(iii) nucleic acid molecules encoding viral helper genes (Zolotukhin teaches that the second host cells (HEK293 cells) are co-infected with adenovirus5 comprising viral helper genes (Figure 1, Example 1, and column 3, line 28-column 4, line 10));
wherein all of (i)-(iii) are independently either present in the second host cells or are subsequently introduced into the second host cells, such that the expression of each of (i)-(iii) in the second cells is sufficient to produce second recombinant AAV particles comprising the recombinant AAV genome in the second host cells, wherein the second recombinant AAV particles are encapsidated by the second AAV capsid polypeptides (Zolotukhin teaches that they harvested the second population of virions from the second host cell. Zolotukhin teaches that these viral particles are encapsidated by their chimeric capsids (Figure 1, Example 1, and column 3, line 28-column 4, line 10));
(d) culturing the second host cells in a culture medium under conditions such that second recombinant AAV particles comprising the recombinant AAV genome are produced, the second recombinant AAV particles each being encapsidated by a capsid comprising the second capsid polypeptides (Zolotukhin teaches that they harvested the second population of virions from the second host cell. Zolotukhin teaches that these viral particles are encapsidated by their chimeric capsids (Figure 1, Example 1, and column 3, line 28-column 4, line 10))
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 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 until Cre recombinase 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.
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 claim 3, Zolotukhin teaches that the second host cell is HEK293 cells (Figure 1 and Example 1).
Regarding claim 4, Zolotukhin teaches that the recombinant AAV genome comprising the AAV2 Rep gene and the chimeric capsid gene between ITRs is in a plasmid (pTR-AAV2) (Figure 1 and Example 1) and Yuan teaches that they used a plasmid to express the inducible Rep and Cap genes (whole document).
Regarding claim 5, although Zolotukhin teaches using baculoviruses to produce WT Rep and Cap, Zolotukhin teaches that Rep and Cap gene products may be provided using any suitable means (column 13, lines 25-52). Urabe teaches that plasmids are routinely used to carry AAV and adenovirus genes for producing recombinant AAVs in HEK293 cells. Therefore, it would have been well understood that plasmids could be used to transfect HEK293 cells with the WT Rep and Cap genes.
Regarding claims 7-8 and 14, Zolotukhin teaches that the first capsid is AAV2 and the second capsid can be a chimeric of two different AAV capsids selected from AAV capsid genes from serotypes 1-8 (Figure 1, Example 1, and column 2, line 6-column 4, line 10). Zolotukhin teaches that AAV2 is 66% and 62% different from the capsid genes of AAV4 and AAV5, respectively (Table 2). Therefore, a chimeric capsid of AAV4 and AAV 5 would have less than 99% amino acid sequence identity to an AAV2 capsid.
Regarding claim 9, Zolotukhin teaches that a particularly preferred vector of the invention is an AAV2 vector pseudotyped with a chimeric capsid derived from degenerate capsid genes of both AAV serotype 2 and at least one AAV serotype other than 2, e.g., AAV1, AAV3, AAV4, AAV5, AAV6, AAV7, and AAV8 capsids (column 17, lines 34-67).
Although Zolotukhin does not identify AAV9 as one of the other serotypes, Yuan teaches that they generated inducible AAV9 capsid gene vectors. Therefore, it would have been well understood that AAV9 would have been another possible AAV serotype for generating modified capsids.
Regarding claims 10 and 15, Zolotukhin teaches that the third host cell can be adipocytes (i.e. fat cells) or embryonic stem cells (Example 10).
Regarding claim 13, 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).
Regarding claim 16, Zolotukhin teaches that as an example, to select for rAAV virions with a modified tropism, cells (i.e. third host cells) normally non-permissive to AAV infection are infected with the rAAV virions. Only those modifiedr AAV virions exhibiting a tropism to the non-permissive cell type will result in a productive infection. Similarly, rAAV virions that exhibit an increased or decreased ability to infect a particular cell or tissue type can be selected. Selected virions that can specifically target diseased cells or tissues over non-diseased cell or tissues are useful for treating various diseases (column 7, line 52-column 8, line 34).
Although Zolotukhin does not specifically identify cancer cells as the specifically targeted diseased cells, it is well known within the field that gene therapy for cancers, including leukemia and melanoma, benefit from specifically targeting cancerous cells with AAV viruses to preferentially deliver the gene of interest, such as a suicide gene, while limiting targeting of non-cancerous cells. This is known to help improve the efficacy of killing cancerous cells by increasing the number of vectors that transfect the cancer cells while also reducing the risk of problematic side effects associated with killing non-cancerous cells. Therefore, it would have been obvious that the third host cell could be a cancer cell, such as a cancerous leukemia or melanoma cell.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 7220577 (Zolotukhin), Yuan et al. (Human Gene Therapy 22: 613-624. 2011) and Urabe et al. (Journal of Virology 80: 1874–1885. 2006), as applied to claim 1 above, and further in view of Emmerling et al. (Biotechnol. J. 11: 290-297. 2016). This is a new rejection made in response to Applicant’s amendments to claim 1.
The teachings of Zolotuhkin, Yuan, and Urabe are as discussed above.
The combined teachings of Zolotuhkin, Yuan, and Urabe do not teach wherein the nucleic acid encoding the rep gene is introduced into the second host cell in the form of a plasmid.
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 a plasmid as Emmerling has shown that this 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.
Claims 1 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 7220577 (Zolotukhin), Yuan et al. (Human Gene Therapy 22: 613-624. 2011) and Urabe et al. (Journal of Virology 80: 1874–1885. 2006), as applied to claim 1 above, and further in view of United States Patent Application No. 2011/0104120 (Xiao) as applied to claim 1 above, and further in view of World Intellectual Property Organization Patent Application No. 2019/020992 (Cawood; Published January 31, 2019; referenced in IDS). 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.
The teachings of Zolotuhkin, Yuan, and Urabe are as discussed above.
The combined teachings of Zolotuhkin, Yuan, and Urabe do not teach wherein the cap and rep gene are encoded in a recombinant adenovirus that comprises a repressible Major Late Promoter (MLP).
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)
Xiao does not teach wherein the recombinant adenovirus comprises a repressible Major Late Promoter (MLP).
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 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 8-11, 13, and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/021,691 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. This rejection is repeated with regards to the rejection in the Non-final Office action mailed on August 26, 2026. Applicant’s traversal is addressed below.
Although ‘691 focuses on producing a library of recombinant AAV particles, it will still produce AAV particles as required by the instant application.
Regarding claim 1, ‘691 also claims culturing a first population of cells with each of components (i)-(iv) to produce a recombinant AAV particle with encoding a first capsid while encapsidated by a second capsid. Then, introducing these particles into a second host cell with the (i)-(iii) components and wherein the resulting capsid is encapsidated by the first capsid to target a third host cell (claim 1).
Regarding claim 2, ‘691 claims that the AAV genome is introduced into the first host cells (claim 1).
Regarding claim 3, ‘691 claims that the first or second host cell can be HEK293 cells (claim 4).
Regarding claims 4-5, ‘691 claims the AAV genome encoding the rep and cap genes can be in a plasmid (claim 2).
Regarding claims 5-6 and 11, ‘691 claims that the rep gene can be present in the first and the second population of host cells using a recombinant adenovirus and wherein the recombinant adenovirus has a repressible major late promoter as described in instant claim 11 (claims 1 and 10).
Regarding claims 8-9, ‘691 claims that the first AAV particle can have an AAV2 serotype and the second recombinant particle can have an AAV9 serotype (claim 9).
Regarding claims 10 and 15-16, ‘691 claims that the third host cells can be cancer cells (such as melanoma cells) or embryonic stem cells (claims 13 and 19-20).
Regarding claim 13, ‘691 claims that the second AAV particle can be isolated (claim 15).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants respectfully request that the Examiner hold this rejection in abeyance pending notification of allowable subject matter. Applicant’s argument(s) has been fully considered, but is not persuasive. The rejection cannot be held in abeyance, and it is maintained for the reasons of record until the aforementioned issues are resolved.
Claims 1, 7, and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/021,691 in view of United States Patent No. 7220577 (Zolotukhin). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on August 26, 2026. Applicant’s traversal has been addressed above.
The teachings of ‘691 are as discussed above. ‘691 specifically claims that the DNA library of different cap genes differ in their nucleotide sequences. As stated supra, ‘691 claims that the first cap sequence can be AAV2 (claims 1 and 9).
‘691 is silent as to the amount of difference in the cap sequences of the first and second cap sequences.
Zolotukhin also teaches developing AAV capsid libraries wherein the first capsid is AAV2 and the second capsid can be a chimeric of two different AAV capsids selected from AAV capsid genes from serotypes 1-8 (Figure 1, Example 1, and column 2, line 6-column 4, line 10). Zolotukhin teaches that AAV2 is 66% and 62% different from the capsid genes of AAV4 and AAV5, respectively (Table 2). Therefore, a chimeric capsid of AAV4 and AAV 5 would have less than 99% amino acid sequence identity to an AAV2 capsid.
Therefore, it would have been obvious that one could develop a library of second capsids that have less than 99% sequence identity between the first capsid (AAV2) and the mutated capsid library, as shown by Zolotukhin.
This is a provisional nonstatutory double patenting rejection.
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.
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/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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