DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage entry 35 U.S.C. 371 of PCT/CN2022/128227 (filed on 10/28/2022), which claims benefit of foreign application CHINA 202111663496.7 (filed on 12/31/2021).
Claim Status
Claims 1-10 are pending and have been examined on the merits.
Claim Interpretation
For clarity of the record the following comments are made regarding claim interpretation under broadest reasonable interpretation:
None of the ‘optionally’ limitation are considered as required by the claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 10 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
The claim does not fall within at least one of the four categories of patent eligible subject matter because it is directed to a use of single polarity recombinant adeno-associated virus (spAAV) vector. The claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e. results in a claim which is not a proper process under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ678 (Bd.App.1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp.131, 149 USPQ 475 (D.D.C.1966).
Claim Rejections - 35 USC § 112
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 4 and 10 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 10 is directed to the use of spAAV vector. Claim 10 provides for the use of spAAV vector, but, since the claim does not set forth any steps involved in the method/process, it is unclear what method/process applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced.
Claim 4 is directed to an spAAV vector, wherein the spAAV genome packaged by the capsid protein is derived from the unpackaged spAAV genome of claim 1, this renders the claim indefinite, as it is unclear what the metes and bounds of the claim is. By definition, unpackaged spAAV vector genome is free DNA vector genome that is not enclosed within a viral protein. How one having ordinary skill in the art is to derive a packaged spAAV genome from unpackaged spAAV genome is unclear.
For compact prosecution, the claim is being interpreted as the spAAV genome vector of claim 4 is derived from the same plasmid used to obtain the unpackaged spAAV genome according to claim 1.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4-8 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou et al (Molecular therapy: the journal of the American Society of Gene Therapy, 2008), evidenced by Xiao et al (Journal of virology, 1997).
Zhou et al teaches a method to generate AAV vectors that contain vector DNA genome predominantly of a single polarity (See, p494 col 2 paragraph 1).
Regarding claims 1 and 6, Zhou et al generated single polarity AAV genome by creating deletion mutants of pDD-CMV-GFP by deleting various base pairs in the terminal repeat and D element (See, p495 col 1 paragraph 1).
Zhou et al teaches the use of pDDwt-CMV-GFP for the production of single stranded vector genomes through AAV replication that when mutated with a 3’ deletion of the D sequence in the ITR results in packaging deficiency of the vector genomes (See, Figure 1). This reads on, …specifically spAAV genome is single polarity, single stranded DNA.
pDD-2 plasmid was previously described in Xiao et al (See, p498 paragraph 3). Xiao et al teaches pDD-2 plasmid pDD-2 contains only one modified ITR sequence with D elements (See, p941, col 2 and Figure 1). Xiao et al also teaches in Figure 1, that pDD does not create a T-shaped hairpin palindrome (See, Figure 1). This reads on,… with one end lacking an ITR or portion thereof.
Zhou et al teaches various deletions of ITR and D element in pDDwt-CMV-GFP, including pDDΔ8-CMV-GFP, pDDΔ12-CMV-GFP, pDDΔ15-CMV-GFP, pDDΔ18-CMV-GFP, and pDDΔ29-CMV-GFP, which results in a truncated ITR. This reads on, …the other end having a truncated ITR (ITRt), wherein the ITRt does not form a T-shaped hairpin palindrome.
This also reads on, An spAAV transgenic plasmid for producing the unpackaged spAAV genome according to claim 1, of claim 6, as these plasmids have transgene GFP.
Zhou et al teaches plasmids that contain with the genome for the various AAV vectors with series deletions (See, p498 col 1 paragraph 2 Materials and Methods). Zhou et al teaches the AAV vectors (wt and deletions) were generated with a mixture of three plasmids consisting of an AAV vector plasmid, a helper plasmid XX2, and adenovirus helper plasmid XX6-80 transfected into 293 cells (See, p498 col 1-2).
Zhou et al teaches that the removal of packaging signal from one end of the double stranded AAV genome results in one polarity of the DNA will be packaged and the production of AAV preparation with only single polarity (See, p 494 col 2 paragraph 1). Combined with the teaching that deletion of D elements results in poor packaging or no packaging of strands and the teachings of the method of purifying the rAAV vector genomes through ultracentrifugation to remove unpackaged genomes, indicates the presence of unpackaged vector genomes. This reads on, an unpackaged single polarity recombinant AAV genome.
Regarding claim 4, following the discussion above, Zhou et al teaches in Figure 2 the polarities of the vector genomes generated by pDDwt-CMV-GFP and the various D deletion mutants of the method (See, p495 col 2 paragraph 1 and Figure 2). These show the packaged AAV vector genomes derived from the same plasmids as the spAAV vector genome of claim 1. Therefore, this reads on, an spAAV vector, comprising : a capsid protein, an spAAV genome packaged by the capsid protein; wherein the spAAV genome packaged by the capsid protein is derived from the unpackaged spAAV genome according to claim 1.
Regarding claim 5, following the discussion above, Figure 2 of Zhou et al shows that pDDΔ15-CMV-GFP, pDDΔ18-CMV-GFP, and pDDΔ29-CMV-GFP have packaged genomes of single polarity and are single stranded by the design of the AAV vector method (See, p495 col 2 paragraph 1 and Figure 2). This reads on, wherein the spAAV genome packaged by the capsid protein is single polarity, single stranded DNA.
Regarding claims 7 and 8, following the discussion above, Zhou et al teaches the transduction of rat brain with single polarity rAAV vectors by injecting AAV- DDΔ18-CMV-GFP(+), AAV- DDΔ18-CMV-GFP(-), and 1:1 mix of the two AAV vectors into the striatum of rats (See, p496 col 2 paragraph 1). Figure 4 of Zhou et al teaches that transgene expression is positive in neurons 2 weeks post injection (See, Figure 4).
This reads on, a method of delivering an exogenous nucleic acid to a cell, comprising contacting the cell with one or more spAAV vectors according to claim 4, wherein the genome of the one or more spAAV vectors comprising a gene expression cassette of the exogenous nucleic acid, of claim 7.
This also reads on, wherein the one or more spAAV vectors comprise an spAAV vector containing only the sense strand single stranded DNA sequence of the exogenous nucleic acid, of claim 8, as the AAV- DDΔ18-CMV-GFP(+), AAV- DDΔ18-CMV-GFP(-), are sense strands of similar plasmids.
Regarding claim 10, following the discussion above, Zhou et al teaches transducing the AAV vectors in mice and rats for transgene expression in various cell populations (See, Figures 3-5). This reads on, use of the spAAV vector according to claim 4 int eh preparation of a product for gene expression.
Therefore, claims 1 and 4-10 are anticipated by Zhou et al and evidenced by Xiao et al.
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.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al (Molecular therapy: the journal of the American Society of Gene Therapy, 2008).
The teachings of Zhou et al are set forth above.
Regarding claim 9, following the discussion of claim 4 above, Zhou et al transduces the AAV vectors into mouse muscle, rat brains, and mouse liver, Figures 3, 4 and 5 depict the expression of the AAV vectors in the cell populations within via GFP visualization.
Zhou et al does not teach isolating individual cells containing the AAV vector; however, isolation of any single transfected cell would have been prima facie obvious for the purpose of confirmation of transduction, measurement of transduction efficiency, and further study. Therefore there was motivation to isolate individual cells. There was a reasonable expectation of successfully isolating cells because cell isolation from tissue was well within the purview of the artisan of ordinary skill. Thus, an isolated host cell comprising the spAAV vector according to claim 4 is considered to have been obvious over Zhou et al.
Claims 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al (Molecular therapy: the journal of the American Society of Gene Therapy, 2008) as applied to claims 1 and 4-10 above, and further in view of Zhou et al (Scientific Reports, 2017; as cited in the IDS filed on 08/29/2024)(Referred to as Zhou2).
The teachings of Zhou et al are set forth above.
Regarding claim 2, following the discussion above, Zhou et al teaches the unpackaged spAAV genome has a 3’ end that lacks an ITR or a portion thereof but does not teach that hit also has a 5’ end comprising the ITRt.
Zhou2 teaches the design of a rAAV vector plasmid with two mutant inverted terminal repeats (ITRs) that lack B-B’ and C-C’ regions (p 2 paragraph 1).
Zhou2 teaches an rAAV vector ITRΔBC that has deletion of B’, C, and C’ elements in both ITRs, therefore the 3’ ITR lacks a portion and 5’ comprises a truncated ITR or both 3’ and 5’ are truncated ITRs (See, p2 paragraph 2 and Figure 1). This reads on, wherein the 3’ end of the unpackaged spAAV genome lacks an ITR or a portion thereof, and the 5’ end comprises the ITRt of claim 2.
Zhou2 teaches that rAAV with two ITRΔBC is a capable of efficient transgene expression in vitro and has higher GFP expression when compared to wild type rAAV (See, p 4-5 and figure 4). Zhou2 teaches that the Rep binding element (RBE) is located in the A-A’ region, that has not been modified in the methods. Zhou2 also teaches that the rAAVΔBCs ability to be packaged, indicates that the RBE was not affected in the ITRΔBC deletion. The terminal resolution site is adjacent to the D element and unaffected in Zhou2. This reads on, wherein the ITRt comprises a RBE and terminal resolution site (trs) of claim 3.
It would have been prima facie obvious to a person having ordinary skill in the art to have further modified the plasmid used for the generation of the rAAV vectors of Zhou et al to further comprise of truncated ITRs as taught by Zhou2. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to make this modification to the AAV vectors to improve transgene expression when compared to wild type AAV in vitro, as taught by Zhou2. One would have had a reasonable expectation of success evidenced by Zhou et al and Zhou2 in vitro assays of transgene expression.
Conclusion
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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