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 .
Election/Restrictions
Applicant’s election of claims 13-20 with species election of a pair of SEQ ID NOs:1 and 3 in the reply filed on May 27, 2026 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)).
Status of Claims
Claims 1-20 are currently pending in the instant application. Claims 1-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Accordingly, claims 13-20 are under examination on the merits in the instant application.
Specification
The disclosure is objected to for containing sequence rule non-compliant subject matter. See page 30. Appropriate correction is required as instructed below.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specific deficiency – A nucleotide sequence appearing in the specification, see page 30, is not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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 13-20 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 claim(s) 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 instant claims are drawn to “a splice-switching oligonucleotide (SSO) targeted to a nucleic acid encoding a transposable-element (TE)-driven isoform of LIN28B”, wherein the SSO is at least 50% identical to one of SEQ ID NOs:1-4 or a “a corresponding reverse, complement, or reverse-complement sequence thereof.” As such, for a 50% identical sequence (the first 11-mer) to SEQ ID NO:1 is 5’-ATAAACTGACC; a corresponding reverse sequence is 5’-CCAGTCAAATA; a corresponding complement sequence is 5’-TATTTGACTGG; and a reverse-complement sequence is 5’-GGTCAGTTTAT.
The instant specification at best describes that “SSO1” is the entire 22-nt sequence of SEQ ID NO:1 that hybridizes to positions 7-28 of SEQ ID NO:3 and “SSO2” is the entire 25-nt sequence of SEQ ID NO:2 that hybridizes to positions 9-33 of SEQ ID NO:4. See page 8. The two species of “SSO1” (SEQ ID NO:1) and “SSO2” (SEQ ID NO:2) are not representative of the numerous structural variants within the claimed genus because there is no objective evidence that all of the structural variants as encompassed by the claims are indeed “targeted to” a TE-driven isoform of LIN28B as explicitly required by the claims, and furthermore, because the splice-switching activity provided by all of the structural variants cannot be extrapolated/predicted based on the two nucleotide sequences of SEQ ID NOs:1-2. That is, the SSO activity is strictly dependent on the nucleotide sequence and as such, other nucleotide sequence variants as broadly written cannot be have been adequately described for splice-switching activity.
Accordingly, it is concluded that the instant specification fails to adequately describe the entire genus of the claims in the manner to reasonably convey that the instant co-inventors had possession of the entire genus as of the filing date sought in the instant application.
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 13-16 and 19-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lundberg et al. (US 2019/0224340 A1).
Lundberg teaches making a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an RNA sequence of SEQ ID NO:10522. See paragraphs 0307 and 0421.
Lundberg’s SEQ ID NO:10522 is reproduced below from the sequence publication site as below by following the instructions provided at page 58.
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It is noted that Lundberg’s 20-mer SEQ ID NO:10522 is substantially complementary (3 mismatched bases) to a 20-mer fragment of SEQ ID NO:1 at positions 3-22, thereby having about 77% sequence complementarity with SEQ ID NO:1.
Lundberg teaches that the RNA can be chemically modified with “2’-methoxyethoxy” also known as “2’-O-(2-methoxyethyl)” and phosphorothioate linkages. See paragraphs 0162 and 0166.
Since all structural limitations set forth for the claimed composition are fully satisfied by Lundberg’s composition comprising SEQ ID NO:10522, it necessarily follows that Lundberg’s composition is deemed “a splice-switching oligonucleotide (SSO)” claimed in the instant case, absent objective evidence to the contrary.
Claims 13-17 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huang et al. (CN 108329387 A, English language translation attached following the last page of the CN reference).
Huang teaches making a pharmaceutical composition comprising an effective amount of an inhibitor of LIN28B-TST and a pharmaceutically acceptable carrier, wherein the inhibitor of LIN28B-TST is an RNA oligonucleotide having the sequence of SEQ ID NO:6 (5’-AGGUUCUUCAGAAGAGGAU) having “LIN28B-TST interfering” function. See paragraphs 0159 and 0194 of the English language translation.
It is noted that Huang’s 19-mer RNA sequence is fully complementary to nucleotide positions 5-23 of SEQ ID NO:2 claimed in the instant case, thereby having an overall nucleotide sequence complementarity level of 76% when compared to the entire length of SEQ ID NO:2.
It is also noted that Huang’s 19-mer RNA sequence is 100% homologous to nucleotide positions 11-29 of SEQ ID NO:4 claimed in the instant case.
Huang teaches that the RNA oligonucleotide can be modified such as by “using phosphothioester bonds” so as to “increase the stability of nucleic acid molecules”, which are thus suitable for introducing/injecting into cells/tissues in vivo. See paragraphs 0163-0164 of the English translation. Since all structural limitations set forth for the claimed composition are fully satisfied by Huang’s composition comprising SEQ ID NO:6, it necessarily follows that Huang’s composition is deemed “a splice-switching oligonucleotide (SSO)” claimed in the instant case, absent objective evidence to the contrary.
Accordingly, claims 13-17 and 19 are described by Huang 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.
Claims 13-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Jang et al. (Nature Genetics, 2019, 51:611-617, of record) in view of Vickers et al. (US 2006/0172962 A1).
Jang teaches that “the loss of AluJb-LIN28B was causal for the decreased oncogenic attributes in H1299 and H838 cells” and “re-expression of canonical LIN28B and AluJb-LIN28B in H1299 and H838 AluJb-P knockout cells reduced let-7 miRNA levels and modestly rescued proliferation”. See page 616.
Jang does not teach targeting AluJb-LIN28B by a splice-switching oligonucleotide.
Vickers teaches that a 2’MOE- and phosphorothioate-modified, 20-mer splice switching oligonucleotide targeting the splice site or splice junction (the junction between an exon and an intron (donor site or 5’ splice site) or the junction between an intron and exon (acceptor site or 3’ splice site)) of a target pre-mRNA, wherein the oligonucleotide results in the reduction of the targeted transcript isoform by inducing exon skipping, thereby altering the ratio of transcript isoforms, wherein the oligonucleotide can be formulated as a pharmaceutical composition with a pharmaceutically acceptable carrier. See Tables 5-6; paragraphs 0029-0030, 0168, and 0213-0219.
It would have been obvious to one of ordinary skill in the art before the effective filing date to make a 20-mer chemically modified antisense oligonucleotide targeting/complementary to the splice junction of Jang’s AluJb-LIN28B. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to make a pharmaceutical composition that targets and inhibits the oncogenic expression of AluJb-LIN28B for potential application in cancer treatment, because AluJb-LIN28B was known to induce cancer cell proliferation when overexpressed while reducing oncogenic properties when knocked out as evidenced by Jang, and because making a pharmaceutical composition comprising a chemically modified 20-mer splice switching oligonucleotide targeting the exon/intron junction or intron/exon junction was an art-recognized methodology for inducing exon skipping, thereby inhibiting the expression of the desired target as evidenced by Vickers. Since the nucleotide sequence information of AluJb-LIN28B including all exon/intron junctions and intron/exon junctions was available before the effective filing date as evidenced by Jang, one of ordinary skill in the art would have pursued the finite number of known exon/intron or intron/exon junctions of AluJb-LIN28B and therefore would have had a reasonable expectation of success in making a splice switching oligonucleotide that is at least 50% identical to SEQ ID NO:1 targeting exon 1/intron 1 junction of AluJb-LIN28B.
Accordingly, claims 13-17 and 19-20 taken as a whole would have been prima facie obvious before the effective filing date.
Claims 13-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (Cell Reports, 2018, 22:2016-2025, applicant’s citation) in view of Vickers et al. (US 2006/0172962 A1).
Guo teaches that LIN28B-TST is a LIN28B transcript variant that is a “tumor-specific transcript” and “is produced from a de novo alternative transcription initiation site” and encodes “a long protein isoform with additional N-terminal amino acids and is critical for cancer cell proliferation and tumorigenesis.” See page 2016.
Guo discloses the nucleotide sequence encoding the “additional N-terminal amino acids” that are “critical for cancer cell proliferation and tumorigenesis.” See Supplemental Figure S1(E) disclosing the following portion of LIN28B-TST encoding the tumor-associated N-terminal amino acids.
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It is noted that the sequence of 5’-ATGAGCCACCGCCGCCAGGT (see boxed) is identical to the 20-mer sequence at positions 1-20 of SEQ ID NO:3 claimed in the instant case.
Guo does not teach making an oligonucleotide targeting the 20-mer boxed sequence for making a pharmaceutical composition that inhibits the tumor-specific transcript.
Vickers teaches that a 2’MOE- and phosphorothioate-modified, 20-mer antisense oligonucleotide targeting the start codon of a target sequence inhibits target expression, wherein the oligonucleotide can be formulated as a pharmaceutical composition with a pharmaceutically acceptable carrier. See Table 2; paragraph 0168.
It would have been obvious to one of ordinary skill in the art before the effective filing date to make a 20-mer chemically modified antisense oligonucleotide targeting/complementary to 5’-ATGAGCCACCGCCGCCAGGT, thereby obtaining the oligonucleotide sequence of 5’-ACCTGGCGGCGGTGGCTCAT, which comprises a 14-mer sequence (see underlined) that is identical to positions 9-22 of SEQ ID NO:1 claimed in the instant case, thereby amounting to at least 50% identity to SEQ ID NO:1 and at least 50% reverse complementary to SEQ ID NO:3. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to make a pharmaceutical composition that targets and inhibits the “tumor-specific transcript” of LIN28B-TST for potential application in cancer treatment, because the target 20-mer sequence in LIN28B-TST was known to encode the “additional N-terminal amino acids” that are “critical for cancer cell proliferation and tumorigenesis” thus the oncogenic activity of LIN28B-TST was known to be associated with the nucleotide sequence including the target 20-mer sequence, and because making a pharmaceutical composition comprising a chemically modified 20-mer antisense oligonucleotide targeting a start codon of a desired target sequence was an art-recognized methodology for inhibiting the expression of the desired target as evidenced by Vickers.
Since all structural limitations set forth in the claims are fully satisfied by the antisense oligonucleotide rendered obvious in the instant rejection, it necessarily follows that the antisense oligonucleotide rendered obvious in the instant rejection must inherently possess the splice-switching oligonucleotide function, absent objective evidence to the contrary.
Note that the Office does not have the facilities and resources to provide the factual evidence needed in order to determine and/or compare the specific activities of the instantly claimed oligonucleotide that is at least 50% identical to SEQ ID NO:1 versus the antisense oligonucleotide rendered obvious in the instant rejection. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the claimed oligonucleotide is different from the oligonucleotide rendered obvious in the instant rejection, thereby establishing the patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ2d 1922(PTO Bd.Pat. App. & Int. 1989).
Accordingly, claims 13-17 and 19-20 taken as a whole would have been prima facie obvious before the effective filing date.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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