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 .
1. Claims 3, 5-7, 9, 10, 18, 19, 21, 22, 25-33, 35-38, and 41-66 have been cancelled. Claims 4, 8, 11-16, 20, 23, 24, 34, 39, 40, and 67 have been amended.
Claims 1, 2, 4, 8, 1-17, 20, 23, 24, 34, 39, 40, and 67 are pending and under examination.
Claim Objections
1. Claim 4 is objected to because of the recitation that the VLDLR protein comprises “a nucleotide sequence encoding a polypeptide of at least 95% identical to SEQ ID NO: 4”. A polypeptide cannot comprise a nucleotide sequence. Furthermore, the polypeptide cannot have sequence identity to SEQ ID NO: 4 because SEQ ID NO: 4 is a nucleotide, not an amino acid sequence. Appropriate correction is required.
2. Claim 8 is objected to because of the recitation that the LDLR protein comprises “a nucleotide sequence encoding a polypeptide of at least 95% identical to SEQ ID NO: 1”. A polypeptide cannot comprise a nucleotide sequence. Furthermore, the polypeptide cannot have sequence identity to SEQ ID NO: 1 because SEQ ID NO: 1 is a nucleotide, not an amino acid sequence. Appropriate correction is required.
3. Claim 11 is objected to because it contains a limitation which refers to Table 1. MPEP 2173.05(s) states in part:
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim.
In this case, table 1 is referred to for the purpose of claiming a promoter, which can be easily incorporated into the claims. Appropriate correction is required.
4. Claim 12 is objected to because of the recitation “a nucleic acid sequence of SEQ ID NO: 15, or a variant thereof having at least identity thereto”. Appropriate correction to “the nucleic acid sequence set forth by SEQ ID NO: 15, or a variant thereof” is required.
5. Claim 34 is objected to because of the recitation “a composition of claim 1”. Appropriate correction to “the composition of claim 1” is required.
6. Claims 39 and 40 are objected to because of the recitation “or a functional fragment”, in line 3. Appropriate correction to “or the functional fragment” is required.
7. Claim 67 is objected to because of the recitation “human VLDR that comprises a nucleotide sequence of SEQ ID NO: 4”, in line 4. Appropriate correction to “human VLDR having the nucleotide sequence set forth by SEQ ID NO: 4” is required.
Claim Rejections - 35 USC § 102
8. 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.
9. Claims 1, 2, 14, and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Turunen et al. (Mol. Ther., 2016, 24: 620-635; cited on the IDS filed on 10/28/2022).
Turunen et al. teach a method for lowering the cholesterol levels in an LDLR-deficient mice, the method comprising administering to the LDLR-deficient mice a composition comprising (1) a DNA plasmid Sleeping Beauty (SB) transposon vector encoding mouse VLDLR or LDLR from a liver specific promoter (LSP) together with a DNA plasmid encoding the SB100x transposase; or (2) an all-in-one DNA plasmid comprising the SB transposon encoding mouse VLDLR or LDLR from LSP and an expression cassette encoding the SB100x transposase. The VLDLR/LDLR genes are flanked by transposon end sequences comprising transposase recognition sites (claims 1, 2, 14, and 24) (see Abstract; p. 621, column 1, p. 622, Fig. 1; p. 625, Fig. 3a; p. 631, column 1 first paragraph; p. 632, column 1, first paragraph; paragraph bridging p. 632 and 633; paragraph bridging p. 625 and 626; see the attached Fig. S1). Thus, Turunen et al. teach all claim limitations and anticipate the claimed invention.
Claim Rejections - 35 USC § 103
10. 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.
11. Claims 1, 2, 4, 14, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Turunen et al., in view of Wilson et al. (U.S. Patent No. 5,652,224).
The teachings of Turunen et al. are applied as above for claims 1, 2, 14, and 24. Turunen et al. do not teach the human VLDLR having an amino acid sequence at least 95% identical to SEQ ID NO: 6 (claim 4). Wilson et al. teach the VLDLR set forth by SEQ ID NO: 2, which is 99.7% identical to SEQ ID NO: 6 and administering the nucleic acid encoding it to LDL-deficient mice to lower the cholesterol levels in these mice (see column 4, line 61 through column 5, line 3; Examples 1 and 4-6; see the attached Sequence Alignment). One of skill in the art would have found obvious to modify the method of Turunen et al. by replacing the mouse VLDLR with the human VLDLR taught by Wilson et al. to achieve the predictable result of lowering the cholesterol levels in the LDL-deficient mice.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
12. Claims 1, 2, 8, 13, 14, 16, 20, 23, 24, 39, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Turunen et al., in view of all Hoge et al. (U.S. Patent No. 8,980,864), Bire et al. (PLOS One, 2013, 8: 1-10), and Yusa (Microbiology Spectrum, 2015, p. 1-16).
The teachings of Turunen et al. are applied as above for claims 1, 2, 14, and 24. Turunen et al. do not teach the human LDLR having an amino acid sequence at least 95% identical to SEQ ID NO: 3 (claim 8). Hoge et al. teach the mutant LDLRs (including the one set forth by SEQ ID NO: 33, which is 99.9% identical to SEQ ID NO: 4) and administering the encoding nucleic acids to LDL-deficient mice (see Example 11, Table 4; Example 12, Table 5; Examples 16, 22, 28, 35, and 39; see the attached Sequence Alignment). Hoge et al. teach several mutants which, similar to the one set forth by SEQ ID NO: 33 contain one point mutation as compared to the wild type LDLR. Thus, these mutants must necessarily exhibit the same percent identity to SEQ ID NO 3, i.e., 99.9%. One of skill in the art would have reasonably concluded that any of the disclosed LDLR mutants could be used to lower the level of cholesterol in the LDL-deficient mice. One of skill in the art would have found obvious to modify the method of Turunen et al. by using a nucleic acid encoding the human LDLR encoding one of the mutants disclosed by Hoge et al. to achieve the predictable result of lowering the cholesterol levels in the LDL-deficient mice.
Turunen et al. and Hoge et al. do not teach insulators nor do they teach delivering an mRNA encoding SB100x (claims 13 and 16). Bire et al. teach using the combination of insulated transposons (to isolate the transgene from the neighboring regulatory elements and stabilize the transgene) and transposase delivery via an mRNA (to avoid consistent transposase expression, which could lead to destabilizing effects with respect to the integrated transgene) to improve the quality of the integration process and sustain the expression of the transposon vectors (see Abstract; p. 2, column 1; p. 6, column 2). Thus, one of skill in the art would have found obvious to modify Turunen et al. and Hoge et al. by using insulators and mRNA to deliver SB100x with the reasonable expectation that doing so would result in enhanced expression and therapeutic effect.
With respect to claim 17, Yusa teaches the Myotis lucifugus piggyBac-like transposase (see p. 3, column 1, first paragraph; paragraph bridging p. 6 and 7; p. 7, column 1, first full paragraph). Using the Myotis lucifugus piggyBac-like transposase would have been obvious to one of skill in the art to achieve the predictable result of delivering the VLDLR or LDLR genes to the LDL-deficient mice.
With respect to claim 20, Hoge et al. teach that the nucleic acids could be delivered to the mice by using LNPs (see Examples 27, 28, and 39). Using LNPs to for the delivery of the SB transposon and transposase would have been obvious to one of skill in the art to achieve the predictable result of delivering the VLDLR or LDLR genes to the LDL-deficient mice.
With respect to claim 23, Turunen et al. teaches in vitro transfer to HepG2 cells to optimize the method for liver-directed gene transfer (see p. 621, column 2 through p. 623; p. 632, paragraph bridging columns 1 and 2). Thus, performing in vitro experiments would have been obvious to one of skill in the art with the reasonable expectation that doing so would identify conditions suitable for liver-directed gene transfer.
With respect to claim 34, Bire et al. teach that, similar to SB, the piggyBac transposon (PB) could be used for transgene delivery. Bire et al. teach that PB has the highest transposition rates and cargo capacity in mammalian cells and exhibits less lower risk for insertional mutagenesis as compared to SB (see paragraph bridging p. 1 and 2). Based on these teachings, one of skill in the art would have found obvious to replace SB with PB with the reasonable expectation that doing so would lead to efficient and safer therapy. As evidenced by Yusa, PB transposon is derived from Trichoplusia ni (Abstract).
With respect to claims 39 and 40, Turunen et al. teach the need for determining the optimal transposase/transposon ratio for achieving optimal in vivo therapeutic effect (see p. 631, column 2, last paragraph). One of skill in the art would have found obvious to use routine experimentation and vary the ratio with the reasonable expectation that doing so would identify the optima ratio for therapy. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed sequences was other than routine or that the results should be considered unexpected in any way as compared to the closest prior art (see MPEP 2144.05 II).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
13. Claims 1, 2, 11, 12, 14, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Turunen et al., in view of Nathwani et al. (Blood, 2006, 107: 2653-2661; cited on the IDS filed on 1/18/2023).
The teachings of Turunen et al. are applied as above for claims 1, 2, 14, and 24. Turunen et al. do not teach the LP1 promoter (claims 11 and 12). Nathwani et al. teach the LP1 promoter (comprising the human apolipoprotein HCR, the hAAT promoter, and the SV40 intron (see p. 2654, column 2 and Fig. 1). Modifying Turunen et al. by using the LP1 promoter taught by Nathwani et al. would have been obvious to one of skill in the art to achieve the predictable results of expressing VLDLR or LDLR in the liver of the LDL-deficient mice. The specification discloses that the claimed LP1 promoter is the one disclosed by Nathwani et al. (see p. 3, lines 14-21; p. 23, lines 11-30).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
14. Claims 1, 2, 14, 24, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Turunen et al., in view of both Tsoika et al. (Current Pharmaceutical Design, 2018, 24: 3623-3633) and Naeli et al. (Fronters in Genetics, 2017, 8: 1-7).
The teachings of Turunen et al. are applied as above for claims 1, 2, 14, and 24. Turunen et al. do not teach an anti-PCSK9 miR (claims 15 and 34). Tsoika et al. teach that PCSK9 binding to LDLR leads to LDLR degradation, and thus, inhibiting PCSK9 is important for reducing LDL-cholesterol levels; Tsoika et al. teach that inhibition could occur by silencing agents such as siRNAs and antisense oligonucleotides (see Abstract; p. 3624, Fig. 1; p. 3627, column 2). While Tsoika et al. do not teach miRs, Naeli et al. that anti-PCSK9 miRs could be used as inhibitors (see Abstract). Thus, further including an anti-PCSK9 miR in the transposon vector would have been obvious to one of skill in the art with the reasonable expectation that doing so would result in enhanced therapeutic effect.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
15. Claims 1, 2, 4, 14, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Turunen et al. taken with Wilson et al., in further view of both Barrett et al. (U.S. Patent No. 11,446,398) and Nathwani et al.
The teachings of Turunen et al. and Wilson et al. are applied as above for claims 1, 4, 2, 14, and 24. Turunen et al. and Wilson et al. do not specifically teach that the human VLDLR is encoded by a nucleic acid at least 90% identical to SEQ ID NO: 4 (claim 67). However, it is noted that there is no evidence that specifically using SEQ ID NO: 4 leads to unexpected results. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, Barrett et al. teach a VLDR-encoding nucleic acid having 99.5% homology to SEQ ID NO: 4 encoding the human VLDLR (see the attached Sequence Alignment). Using this sequence would have been obvious to one of skill in the art to achieve the predictable result of lowering the cholesterol levels in an LDLR-deficient mice.
With respect to the LP1 promoter recited in claim 67, Nathwani et al. teach the LP1 promoter (comprising the human apolipoprotein HCR, the hAAT promoter, and the SC40 intron (see p. 2654, column 2 and Fig. 1). Using the LP1 promoter taught by Nathwani et al. would have been obvious to one of skill in the art to achieve the predictable results of expressing VLDLR or LDLR in the liver of the LDL-deficient mice. The specification discloses that the claimed LP1 promoter is the one disclosed by Nathwani et al. The specification also teaches that LP1 promoter is set forth by SEQ ID NO: 15 (see p. 3, lines 14-21; p. 23, lines 11-30). And even assuming that the sequence of the LP1 promoter taught by Nathwani et al. would not be set SEQ ID NO: 15, there is no evidence of record that SEQ ID NO: 15 is associated with unexpected properties. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
16. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633