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
The instant application is a national stage entry under 35 U.S.C. § 371 of PCT/US2022/013476 (filed 01/24/2022). Acknowledgement is made of Applicants’ claim for benefit of U.S. Provisional Application No. 63/141,110 (filed 01/25/2021).
Election/Restrictions
Applicant’s elections in the reply filed on 01/16/2026 in response to an Election of Species requirement is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The species elections are as follows:
SEQ ID NO: 2 as a species for (a), directed to one or more antisense oligonucleotides (ASOs) of the method of claim 1; i.e., the ASO of claim 13.
SEQ ID NO: 10 as a species for (b), directed to one or more ASOs of the method of claim 23; i.e., the ASO of claim 35.
SEQ ID NO: 52 as a species for (c), directed to one or more ASOs of the method of claim 74; i.e., the ASO of claim 84.
SEQ ID NO: 2 as a species for (d), the isolated nucleic acid of claim 116.
Claims 1-9, 13, 17-18, 22-23, 35, 74, 84, 116 read on the elected invention and are examined on the merits herein.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of the first paragraph of pre-AIA 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 1-9, 17-18, and 22-23 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 claims 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims under rejection are directed to method of modulating expression of a transgene in a cell, wherein the method comprises use of antisense oligonucleotides (ASOs). Claim 1 is directed to a method which uses ASOs which specifically bind to an AAV ITR; claims 2-9, 17-18, and 22 depend directly from claim 1. Claim 23 is directed to a method which uses ASOs which specifically bind to a transcriptional control region sequence of a transgene or a protein coding region of an mRNA transcribed from the transgene.
The scope of claim 1 as currently written encompasses use of ASOs which specifically bind to any AAV ITR; i.e., a first genus of molecules. Likewise, the scope of claim 23 encompasses use of ASOs which specifically bind to any transcriptional control or protein coding region of an mRNA transcribed from any transgene; i.e., a second genus of molecules. The issue at hand is whether or not there is sufficient written description for the full first and second genera of ASOs.
To satisfy the written description aspect of 35 U.S.C. 112(a) for a claimed genus of molecules, it must be clear that: (1) the identifying characteristics of the claimed molecules have been disclosed, e.g., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed cor-relation between function and structure, or by a com-bination of such identifying characteristics; or (2) a representative number of species within the genus must be disclosed. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding the first genus of molecules:
Regarding (1), Applicants have not identified any particular core chemical structure of either the ASO or the targeting region of AAV ITR that correlates to altered expression of the transgene in the cell, and as such, one of ordinary skill in the art would not immediately envisage the design of an ASO effective to achieve said altered expression. Therefore, Applicants have not disclosed the identifying characteristics of the claimed molecules.
Regarding (2), Applicants have failed to provide disclosure of species which are representative of the full scope of the claimed invention. The instant disclosure is limited to ASOs having the sequences of SEQ ID NOs: 2-8; these sequences all bind to an AAV2 ITR encoded by SEQ ID NO: 1. As evidenced by Srivastava, there are at least 13 AAV serotypes (pg. 554; par. 1); thus, Applicants’ disclosure is limited to ASOs which specifically bind to AAV2 ITR, which only represent a narrower genus of ASOs which bind to a distinct AAV serotype. This limited disclosure is not considered to be representative of the full breadth of the genus, as claimed.
Regarding the second genus of molecules:
Regarding (1), Applicants have not identified any particular core chemical structure of either the ASO or the transcriptional control or protein coding region of transgene that correlates to altered expression of the transgene in the cell, and as such, one of ordinary skill in the art would not immediately envisage the design of an ASO effective to achieve said altered expression. Therefore, Applicants have not disclosed the identifying characteristics of the claimed molecules.
Regarding (2), Applicants have failed to provide disclosure of species which are representative of the full scope of the claimed invention. As is well known in the art, transcriptional control regions of a gene may include promoter, enhancers, silencers, and insulators. Additionally, the use of heterologous promoters in conjunction with transgenes is very common. This is compounded by the extraordinarily large number of possible transgenes encompassed by the instant claims. Applicants’ disclosure is limited to SEQ ID NOs: 10-24 (ASOs which bind to the CMV enhancer as set forth in SEQ ID NO: 9); SEQ ID NOs: 26-39 (ASOs which bind to the CBA promoter as set forth in SEQ ID NO: 25); and SEQ ID NOs: 41-50, 91-95, and 106-110 (ASOs which bind to the codon-optimized ß-glucocerebrosidase, or GBA, nucleic acid sequence set forth in SEQ ID NO: 40). This limited disclosure is not considered to be representative of the full breadth of the genus, as claimed.
These may be contrasted with the method of claim 74, wherein the ASO(s) bind specifically to a WPRE or polyadenylation (polyA) element of a transgene; Applicants’ disclosure of SEQ ID NOs: 52-79 and 111-120 (ASOs which bind to WPRE), as well as SEQ ID NOs: 81-90 and 96-104 (ASOs which bind to polyA) is sufficient written description of the genus of ASO molecules which specifically bind to WPRE or polyA.
Thus, in regards to the instant claims under rejection, one of ordinary skill in the art, in looking to the instant specification, would not be able to determine that Applicants were in possession of the invention, as claimed, at the time the invention was made.
Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112(a).
The Examiner notes Applicants do have sufficient written description for ASOs which bind to an ITR of an AAV2, a CMV enhancer, a CBA promoter, and a GBA gene. Thus, the instant rejections may be overcome by amending the relevant claims to reflect these genera for which Applicants’ have sufficient description.
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 1-9, 13, 17-18, 22-23, 35, 74, and 84 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.
Regarding claim 1: The formatting of the instant claims confers a degree of ambiguity to the scope thereof. The limitation in claim 1 reciting “…a cell containing a recombinant adeno-associated virus (AAV) (rAAV) vector comprising a transgene flanked by AAV inverted terminal repeats (ITRs) with one or more antisense oligonucleotides (ASOs)…” when read by a person having ordinary skill in the art could be interpreted as the rAAV comprising both the transgene flanked by ITRs as well as one or more ASO(s); an rAAV comprising a closed-ended DNA (ceDNA) vector wherein the closed-loop structure is formed by an ASO binding to an ITR sequence would be encompassed by the scope of claim 1 in this interpretation. Therefore, the instant claims as currently written do not clearly and precisely define the metes and bounds of the invention, rendering the claims indefinite.
The following serves as claim interpretation for purposes of examination (supported by Working Example 6); additionally, amending claim 1 to the following would overcome the indefiniteness rejection:
1. A method for modulating expression of a transgene in a cell, comprising contacting the cell with one or more antisense oligonucleotides (ASOs),
wherein the cell contains a recombinant adeno-associated virus (rAAV) vector comprising the transgene flanked by AAV inverted terminal repeats (ITRs),
wherein the one or more ASOs specifically bind to at least one of the AAV ITRs, and
wherein binding of the one or more ASOs to the AAV ITR results in altered expression of the transgene in the cell relative to expression of the transgene in a cell that does not contain the one or more ASOs.
Regarding claims 23, 74: Following the above discussion, the instant claims likewise suffer from the same deficiencies as set forth above. For examination purposes, the methods of these claims are also interpreted as contacting (e.g., incubating) a cell already containing an rAAV with one or more ASOs.
Regarding claims 2-9, 13, 17-18, 22, 35, 84: These claims depend from claims 1, 23, or 74, inherit their deficiencies, and are likewise rejected for indefiniteness.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 23 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Adams, et al. (US 2010/0310576).
Adams, et al. teaches aspartyl-tRNA synthetase polypeptides and polynucleotides having non-canonical biological activities (Abstract).
Regarding claim 23: Adams, et al. teaches a host cell comprising an expression vector, wherein the expression vector comprises a polynucleotide encoding an AspRS polypeptide (par. 0017), disclosing an embodiment wherein the expression vector is an AAV vector (pars. 0152, 0162); this reads on the cell containing a recombinant adeno-associated virus (AAV) (rAAV) vector comprising a transgene limitation recited in claim 23. Additionally disclosed are antisense oligonucleotides that specifically hybridize to the AspRS polynucleotide, wherein the antisense oligonucleotide is designed to block or inhibit translation of mRNA (pars. 0017, 0184); this reads on the wherein the one or more ASOs specifically bind to a protein coding region of a messenger ribonucleic acid (mRNA) transcribed from the transgene limitation recited in claim 23. Adams, et al. also teaches a screening method wherein the host cell and antisense oligonucleotides are used in a cell-based assay to identify antisense oligonucleotides for effectiveness in altering expression of the AspRS polynucleotide (par. 0303); this reads on the method for modulating expression of a transgene in a cell limitation as well as the wherein binding of the one or more ASOs to the transcriptional control region sequence or the protein coding region results in altered expression of the transgene in the cell relative to expression of the transgene in a cell that does not contain the one or more ASOs limitation recited in the instant claim.
Claim 116 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Leake, et al. (US 2004/0334405).
Leake, et al. teaches methods and compositions for performing gene silencing (Abstract).
Regarding claim 116: Leake, et al. teaches a 27mer siRNA directed against a CMV promoter (par. 0209), comprising the sequence set forth in SEQ ID NO: 30 (Table 6; pg. 21). SEQ ID NO: 30 shares 100% sequence identity to instant SEQ ID NO: 2; please see end of Office action for all sequence alignments. This reads on the isolated nucleic acid comprising the sequence set forth in SEQ ID NO: 2 limitation recited in claim 116.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 23 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Adams, et al. (US 2010/0310576), in view of Xia, et al. (Protein Expr Purif. 2006) and Leake, et al. (US 2004/0334405).
The teachings of Adams, et al. and Leake, et al. are set forth above; Adams, et al. anticipates claim 23.
Xia, et al. teaches protein expression levels driven by CMV promoters (Abstract).
Regarding claim 35: Following the above discussion, Adams, et al. does not teach the antisense oligonucleotide (ASO) as comprising a sequence at least 90% identical to the sequence set forth in SEQ ID NO: 10, as required by the instant claim.
However, Adams, et al. teaches the vector may further comprise a promoter (par. 0146). Xia, et al. teaches the CMV promoter is active in a broad range of cell types, the most commonly used promoter in mammalian expression plasmids, and increases the levels of recombinant protein expression in various cell types (pg. 116; col. 1, par. 1). Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the vector of Adams, et al. by using the CMV promoter, as taught by Xia, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would have been motivated to use the CMV promoter for the activity in a broad range of cell types and increased level of protein expression as taught by Xia, et al. Further, as Adams, et al. teaches the expression vector may comprise a promoter, and as Xia, et al. evidences CMV is the most common promoter used in expression constructs, a skilled artisan would have more than a reasonable expectation of success.
Following on from the above modification, neither Adams, et al. nor Xia, et al. teaches the remaining limitation of the instant claim.
However, Leake, et al. teaches an antisense strand of a 27mer siRNA directed against a CMV promoter (pars. 0195, 0209), comprising the sequence set forth in SEQ ID NO: 30 (Table 6; pg. 21). SEQ ID NO: 30 shares 100% sequence identity to instant SEQ ID NO: 2; please see end of Office action for all sequence alignments. This reads on the wherein the one or more ASO comprises a nucleic acid sequence that is at least 90% identical to the sequence set forth in SEQ ID NO: 10 limitation recited in claim 35.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the screening method of Adams, et al. by substituting the ASO with the 27mer siRNA of Leake, et al. This conclusion of obviousness is based on the ‘substitution rationale’. The use of the 27mer siRNA in place of the ASO is a predictable use of prior art elements according to their established functions of silencing gene expression, leading to the predictable result of inhibition of the AspRS polynucleotide. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results; see MPEP 2143(I)(B).
Claims 23 and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Adams, et al. (US 2010/0310576) in view of Dumonceaux, et al. (US 2018/0237775).
The teachings of Adams, et al. is set forth above; Adams, et al. anticipates claim 23.
Dumonceaux, et al. teaches antisense oligonucleotides and uses thereof (Title).
Regarding claim 74: Following the above discussion, Adams, et al. teaches the vector may further comprise a polyadenylation signal (par. 0146), but does not teach an ASO which binds thereto.
However, Dumonceaux, et al. teaches an ASO that hybridizes with a polyadenylation signal of a target pre-mRNA (par. 0007), which is useful for silencing expression of a target protein (par. 0011); this reads on the wherein the one or more ASOs specifically bind to a polyadenylation element of an mRNA transcribed from the transgene limitation recited in the instant claim.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the screening method of Adams, et al. by substituting the ASO of the same disclosure with the ASO of Dumonceaux, et al. This conclusion of obviousness is based on the ‘substitution rationale’. The use of the ASO which hybridizes with a polyadenylation signal in place of the ASO which hybridizes with the AspRS polynucleotide is a predictable use of prior art elements according to their established functions of nucleic acids designed to bind to RNA sequences, leading to the predictable result of inhibiting expression of the AspRS polynucleotide. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results; see MPEP 2143(I)(B).
Claims 23, 74, and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Adams, et al. (US 2010/0310576), in view of Mich, et al. (US 2021/0015898) and Chan, et al. (Clin Exp Pharmacol Physiol. 2006), as evidenced by Lim and Brown (RNA Biol. 2016).
The teachings of Adams, et al. is set forth above; Adams, et al. anticipates claim 23.
Mich, et al. teaches expression constructs that result in high levels of protein expression (par. 0012).
Chan, et al. teaches rational design of antisense oligonucleotides (Abstract).
Regarding claims 74, 84: Following the above discussion, Adams, et al. does not teach the limitations of the instant claims. However, Mich, et al. teaches inclusion of a WPRE3 element in AAV vectors increases transgene expression level (par. 0041). Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the vector of Adams, et al. by including a WPRE3 element, as taught by Mich, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would be motivated to do so for the increased transgene expression, as taught by Mich, et al. Additionally, as Mich, et al. teaches the use of a WPRE3 element in an AAV vector (par. 0015; Fig. 2), a skilled artisan would have more than a reasonable expectation of success.
The WPRE3 element taught by Mich, et al. is encoded by SEQ ID NO: 19 (par. 0015). This sequence is disclosed in DNA format, and therefore comprises thymine nucleotides. However, the mRNA of the transcribed WPRE3 shares 100% sequence identity with SEQ ID NO: 52; please see end of Office action for all sequence alignments.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the screening method of Adams, et al. by including an ASO which binds to the WPRE3 element. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would have been motivated to do so because, as taught by Chan, et al., effective ASOs should be designed to target regions where mRNA is accessible for hybridization, such as structures comprising loops (pg. 534; par. 2); and, as evidenced by Lim and Brown, WPRE comprises two RNA stem-loop structures (Abstract). Therefore, it would have been obvious to one skilled in the art to include ASOs targeting WPRE in a screening method for evaluating ASO efficacy, in order to screen a comprehensive selection of ASOs for the best chance of success. Further, as evidenced by the Chan, et al. disclosure, the design of ASOs is a technique well known in the art, and so a skilled artisan would have a reasonable expectation of success.
Thus, the modifications as set forth above render obvious the wherein the one or more ASOs specifically bind to a woodchuck post-translational regulatory element (WPRE) of an mRNA transcribed from the transgene, wherein binding of the one or more ASOs to the WPRE results in altered expression of the transgene in the cell relative to expression of the transgene in a cell that does not contain the one or more ASOs limitation recited in claim 74, as well as the wherein the one or more ASO comprises a nucleic acid sequence that is at least 90% identical to the complement of the sequence set forth in SEQ ID NO: 52 limitation recited in claim 84.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at (571)272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
SEQUENCE ALIGNMENTS
Query, ‘Qy’ (SEQ ID NO: 10) vs. Database, ‘Db’ (US 2004/0224405; SEQ ID NO: 30)
PNG
media_image1.png
179
691
media_image1.png
Greyscale
Query, ‘Qy’ (SEQ ID NO: 52) vs. Database, ‘Db’ (US 2021/0015898; SEQ ID NO: 19)
PNG
media_image2.png
193
685
media_image2.png
Greyscale