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 .
Application Status
This action is written in response to applicant’s correspondence received on July 1, 2026. Claims 1-39 are currently pending and examined herein.
Priority
The instant application claims priority based on a US Provisional Application No. 63/365,965 filed on June 07, 2022. The provisional application describes the instant SEQ ID NOs: 3 and 4 (Subsection 5.2. Sequences), and reduction to practice of this sequence pair (Figure 3). However, support for the recitation of “a methos of preventing, treating or delaying progression of cancer” and “SEQ ID NOs: 1, 2, 5, and 6” could not be found in this US Provisional Application. Further, it is stated in the instant Provisional Application “we are currently evaluating whether treatment with the S2E3Acc and S2E3Don vivo-morpholinos…to this end, we will initially use the A549 cell model…and subsequently we will use A549-derived tumors in nude mice…" (section "Future developments") which suggests that applicant do NOT have possession of a method of treating cancer because such experimentations have NOT been completed. Accordingly, the effective filling date of instant claims 32-35 drawn to a composition comprising at least 2 morpholinos comprising SEQ ID NO: 3 and 4 is June 07, 2022 while instant claims 1-31, and 36-39 is June 07, 2023.
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 deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located on pg. 12, SEQ ID NOs: 7-9.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
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) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Objections
Claims 1, 10, and 19, are objected to because of the following informalities: there is an extra space between the two words “wherein” and “a” in the wherein clause of “wherein a resulting decrease in SUMOylation activity…”. Appropriate correction is required.
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 1-27 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.
Claims 1, 10, and 19 recite “a resulting decrease in SUMOylation activity induced by the at least 2 morpholinos will, in turn, increase sensitivity of tumor cells to chemotherapeutics” (emphasis added). The terms “decrease” and “increase” in the claim is a relative term which renders the claim indefinite. These two terms are not defined by the claim, the specification does not provide a clear definition for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear which baseline, magnitude, or other objective standard against which the decrease in SUMOylation activity or increase in sensitivity to chemotherapeutics is to be determined. Accordingly, it is unclear what degree of change is sufficient to satisfy these limitations, and the scope of the claim cannot be ascertained with reasonable certainty.
Claims 2, 11, and 20 recite the limitation "administering the compound comprises administering at least 2 vivo-morpholinos", which renders the claim indefinite due to lack of clarity. The instant claims refer to “vivo-morpholinos”, but claims 1, 10, and 19 from which they depend on recites “administering…a compound comprising at least 2 morpholinos”. It is unclear if this recitation is further limiting “morpholinos” (e.g., administering at least 2 morpholinos, wherein the morpholinos are vivo-morpholinos comprising of SEQ ID NOs: 1 or 2). It is unclear whether claim 2 encompasses a compound comprising at least 2 morpholinos as required by claim 1 and, additionally at least 2 vivo-morpholinos. Thus, the metes and bound of the claim cannot be determined with reasonable certainty.
Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 112 – Written Description
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.
Claim 1-39 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Claims 1, 10, and 19 are drawn to a method of preventing, treating, or delaying progression of cancer, comprising administering a therapeutically effective amount of at least 2 morpholinos. The claims further recite comprising SEQ ID NO: 1, 3, 5, or 2, 4, 6, respectively. Claims 28, 32, and 36 are drawn to compositions comprising said morpholinos. The breadth of the claims is drawn to possession of at least 2 morpholinos with claimed function of therapeutically effective, wherein one of the morpholino is one of the listed sequences, and the remaining one or more could be any sequence targeting any transcript. Thus, the claims encompass a genus of morpholinos that (1) is therapeutically effective and (2) complementary to any transcript.
The specification disclosed the structures of morpholinos and vivo-morpholinos (FIG. 4) and a total of 6 sequences, SEQ ID NOs: 1-6 (pg. 10), each pair targeting one SUMO gene, which are complete structures of only one species of the claimed genus of morpholinos. The specification also disclosed actual reduction to practice of only one pair SEQ ID NOs: 3 and 4 for the instant claim 10 (FIG. 5, pg. 13). The specification fails to disclose any structure of additional species, to what sequences are the morpholinos complementary to as at least 2 morpholinos are required in the instant claims. Without a recognized correlation between structure and function, one of ordinary skill in the art would not be able to identify without further testing which morpholinos complementary to undisclosed transcripts would also be therapeutic effective.
Moulton (J Drug Discov Develop and Deliv. 2016, 3(2): id1023) teaches the full potential of morpholinos “remain to be developed because there is no available system for systemic delivery that is both non-toxic and highly efficacious” (pg. 11, left-column, third paragraph). Further, considering the mechanism of action of morpholinos serving as translation-blocking agents, “morpholino itself does not cleave the mRNA, this range of possible effects on RNA stability means that the lifetime and concentration of mRNA can be increased, decreased, or unaffected by translation-blocking morpholino treatment” (pg. 6, right-column, third paragraph). Accordingly, morpholinos require empirical testing to determine whether a particular sequence is active and to establish an effective and non-toxic dosage for treatment of a disease, which indicates unpredictability in administering morpholinos as treatment.
Further, dependent claims of claims 1, 10, 19, 28, 32, and 36 are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of morpholinos, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of therapeutically effective morpholinos based on disclosure of SEQ ID NOs: 1-6. Further, Applicant was not in possession of compositions comprising the claimed genus of morpholinos.
Response to Arguments
Applicant argues design of two morpholinos to alter the normal splicing of each of the mRNA coding for SUMO1, SUMO2, and SUMO3 genes, and that the sequences targeted by each morpholino pair are indicated in the figures. Further, “evidence that the morpholinos targeting SUMO2 mRNA exert the expected effect when used as indicated in a cancer cell line” (pg. 11, para. 4).
Applicant’s arguments have been fully considered but are not persuasive. While an actual reduction to practice may establish possession of a particular species, the scope of the claims is not limited to the single demonstrated pair of morpholinos targeting SUMO2 mRNA or the 6 disclosed sequences. The claims require administering a compound comprising at least 2 morpholinos, but recite the sequence of only one of the two morpholinos (e.g., SEQ ID NO: 1 or 2 for claim 1, SEQ ID NO: 3 or 4 for claim 10, and SEQ ID NO: 5 or 6 for claim 19), while the sequence of the other required morpholino is not identified. In addition, the limitation “at least two” encompasses a genus of morpholinos, for which the specification does not disclose the maximum number of morpholinos that may be administered or representative species corresponding to the additional morpholinos encompassed by the claims. While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus”, it also acknowledges that “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” In view of the wide variant species encompassed by the genus, the one example described above is not enough and does not constitute a representative number of species to describe the whole genus. The specification also fail to disclose sufficient common structural characteristics or establish structure-function correlation that would demonstrate possession of the additional morpholinos encompassed by the claims.
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.
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 1-3, 7, 9, and 28-31 are rejected under 35 U.S.C. 103 as being unpatentable over Paschen et al (US 9169519 B2; Published Date: Oct 27, 2015) in view of Moulton (J Drug Discov Develop and Deliv. 2016, 3(2): id1023), Li et al (Bioconjugate Chem; 2008, 19:1464–1470), and NC_0000002.12 (Homo sapiens chromosome 2, GRCh38.p14 Primary Assembly, SUMO1 gene from base 202206171 to 202238597, NCBI reference sequence, constructed Apr 06, 2022, 15 pages).
Regarding claims 1-3, Paschen teaches a method for treating cancer in a subject comprising an effective amount of an agent that decreases the levels of SUMO conjugated proteins (Col. 1, lines 54-57; Col. 4, line 40). Paschen further teaches the agent comprises inhibitory RNA complementary to a sequence encoding members of the SUMO conjugation pathway, including SUMO1, SUMO2, or SUMO3, or any combinations thereof , “selected from any of GenBank Accession Nos. NM_001005781.1, NM 001005782.1, NM_03352.4 (SUMO1); NM 001005849.1, NM_006937.3 (SUM02); NM_006936.2 (SUM03)…” (Col. 5, lines 10-43), which are known transcripts of SUMO gene splice variants. Paschen further teaches exemplary miRNA inhibitors targeting SUMO1, SUMO2, and SUMO3 genes (Col. 8, lines 1-6). Thus, Paschen teaches administering at least two inhibitors to decrease levels of SUMO conjugated proteins, and established that the SUMO genes, including their transcript structure, are known targets for RNA interference. Paschen also teaches that administering these inhibitors in cancer cell decreases levels of expression or conjugation, or both, of at least one member of the SUMO conjugation pathway, and thereby sensitizes the cancer cell to a therapeutic regimen, including chemotherapy (col. 11, lines 55-65). Pasche further discloses the combination of an inhibitor of at least one member of the SUMO conjugation pathway and chemotherapeutic is synergistically effective and greater than the sum of the cellular effects of the inhibitor or chemotherapy alone (col. 11, lines 28-34).
However, Paschen does not teach wherein the inhibitory RNA are morpholinos.
Moulton teaches “morpholinos can be designed to alter splicing of pre-mRNA…targeting either the upstream (5’) end of an intron (the splice donor site) or the downstream (3’) end of an intro (the splice acceptor site)…typically at least 15 bases of intronic sequences are targeted, with the oligo target either abutting or overlapping the exonic sequence…targeting the internal splice sites is most likely to result in splicing out the exon abutting the splice junction, thus excluding that exon from the mature mRNA…for example…exon 2 is directly ligated to exon 4, with exon 3 missing. This exclusion of an exon from a mature mRNA is sometimes called “exon skipping” (pg. 4, left-column). Further, Moulton teaches morpholinos offer several advantages over other antisense oligos which include not requiring catalytic systems (e.g., RICS, RNAse-H) for their activity, having far less off-target interactions, are water-soluble and stable long-term (pg. 11, section “Therapeutic potential”).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Paschen’s inhibitory RNAs to morpholinos as taught by Moulton because it would have merely amounted to a simple substitution of one known element for another to obtain predictable results, as both inhibitory RNAs and morpholinos are both gene-silencing strategies that operate via sequence complementarity. It would have also been obvious because it would have merely amounted to using a known technique (morpholinos targeting splice junctions) to improve similar device (identified SUMO splice variants) in the same way. One would have been motivated to have done so for the advantages and mechanism of action of morpholinos taught by Moulton. One would have had a reasonable expectation of success in doing so because Paschen already teaches a method of targeting SUMO genes and splice variants using inhibitory RNAs, and designing morpholinos complementary to known splice junctions would have been a routine and predictable design.
Further, Moulton teaches “vivo-morpholinos are widely-used and commercially available delivery moiety consisting of an eight-branched dendrimer carrying a guanidinium moiety at each brand tip” (pg. 9, third paragraph). Li also teaches a method of synthesizing vivo-morpholinos by conjugating a morpholino with “a transporter containing a triazine” and successfully delivering vivo-morpholinos that inhibited translation in tissues (pg. 1465, left-column, second paragraph; Fig. 1)
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Paschen’s inhibitory RNAs to vivo-morpholinos as taught by Moulton and Li because it would have merely amounted to applying a known technique to a known device (method or product) ready for improvement to yield predictable results. One would have been motivated to have done so for the advantage of improving morpholinos in vivo delivery into cells and subjects. One would have had a reasonable expectation of success in doing so because Li teaches a method of synthesizing vivo-morpholinos and their delivery in vivo.
As discussed above, Paschen teaches known transcripts of SUMO gene splice variants (Col. 5, lines 10-43) and Moulton teaches the design of morpholinos targeting splice isoforms. However, neither Paschen or Moulton teach SEQ ID NOs: 1 or 2.
SEQ ID NOs: 1 and 2 aligns with the publicly available SUMO1 gene in human chromosome 2 (NCBI Accession Number: NC_0000002.12), specifically at the internal splice site overlapping the exon 2 sequence of transcript NM 001005782.2, a newer version of NM 001005782.1, one of SUMO1 gene splice variants taught by Paschen.
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The obviousness to modify Paschen’s inhibitory RNAs to morpholinos applied above equally applies here. Further, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have further modified Paschen’s inhibitory oligos to the instantly recited sequences because it would have merely amounted to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success (“obvious to try”). One would have been motivated to have done so because the target gene sequence (SUMO1) and its exon-intron structure were known, and designing morpholinos complementary to those splice junctions would have been routine and predictable design. For instance, SUMO1 splice variant of transcript NM_001005781.1 taught by Paschen is absent of exon 2, and designing morpholinos targeting exon 2 splice sites would arrive at the instantly recited SEQ ID NOs: 1 and 2. One would have had a reasonable expectation of success in doing so because morpholino design is constrained to a finite number of predictable target regions within a known transcript given that morpholino design is not open-ended due to these considerations: at least 15 bases of intronic sequences and the other end of the oligo complementary to either abutting or overlapping the exon sequence, GC content constraints, avoidance of secondary structure, and uniqueness within transcriptome. Therefore, only a finite number of morpholinos can be designed, and the instantly recited sequences represent one of a limited number of predictable morpholino candidates that would have been obtained through routine optimization.
Regarding claims 7, the obviousness to modify Paschen’s inhibitory oligos to morpholinos comprising SEQ ID NOs: 1 or 2 are discussed above as applied to claim 1. Paschen provides one exemplary sequence targeting each SUMO1, SUMO2, and SUMO3 gene (Col. 8, lines 1-6).
Paschen does not teach administering at least two morpholinos targeting the same gene.
Moulton teaches “when two translation-blocking morpholinos target the same mRNA, their combination has greater-than-additive efficacy” (pg. 8, left column, fourth paragraph).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Paschen’s method to further comprise additional morpholinos targeting the same gene because it would have merely amounted to combining prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of maximizing translation-blocking efficiency. One would have had a reasonable expectation of success in doing so because Paschen already teaches a method comprising an inhibitory RNA targeting the same gene.
Regarding claims 9, the obviousness to modify Paschen’s inhibitory oligos to morpholinos comprising SEQ ID NOs: 1 or 2 are discussed above as applied to claim 1. Paschen further teaches “a method of sensitizing a cancer cell to a therapeutic regimen” comprising administering inhibitory RNAs in an amount effective to decrease the levels of SUMO conjugated proteins in the cancer cell (Col. 11, lines 55-58). Sensitizing cancer cells to therapy would have been reasonably understood to prevent or delay the development of resistance to chemotherapy. Accordingly, Paschen’s teachings render obvious the limitation of “inhibiting establishment of chemo resistance”.
Regarding claims 28-31, the obviousness to modify Paschen’s inhibitory oligos to morpholinos comprising SEQ ID NOs: 1 or 2 are discussed above as applied to claim 1. The obviousness to modify Paschen’s method to include additional morpholinos are discussed above as applied to claims 7. Further, Paschen teaches the inhibitory RNAs are “administered in a pharmaceutically acceptable composition” (Col. 12, lines 18-20), which positively meets the claim limitations recited in the instant claims.
Claims 4-6, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Paschen et al in view of Moulton et al, and NC_0000002.12 (cited supra) as applied to claims 1 above, and further in view of NC_000017.11 (Homo sapiens chromosome 17, GRCh38.p14 Primary Assembly, SUMO2 gene from base 75165586 to 75182959, NCBI reference sequence, constructed Apr 06, 2022, 7 pages).
Regarding claims 4-6, Paschen teaches inhibiting members of the SUMO conjugation pathway, including SUMO2, by using inhibitory RNAs complementary to a portion of an RNA sequence encoding SUMO (col. 5, lines 10-14). The obviousness to modify Paschen’s inhibitory oligos to morpholinos are discussed above as applied to claim 1.
Paschen does not explicitly teach reducing SUMO2 gene splice variant 1 or increasing SUMO2 gene splice variant 2.
The instantly recited SEQ ID NOs: 3 and 4 aligns with the publicly available SUMO2 gene in human chromosome 17 (NCBI Accession Number: NC_000017.11), specifically at the internal splice site overlapping the exon 3 sequence of transcript NM_006937.4, a newer version of NM_006937.3, one of SUMO2 gene splice variants taught by Paschen. The instantly recited SEQ ID NOs: 8 and 9 also aligns with SUMO2 of transcripts NM_006937.4 and NM_001005849.2, starting nucleotides 345 and 273, respectively, that correspond to exon-exon junctions (sequence alignment shown below). Both SUMO2 transcripts are taught by Paschen (col. 5, lines 25-27).
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Paschen’s inhibitory oligos to morpholinos comprising SEQ ID NO: 3 or 4 because it would have merely amounted to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success (“obvious to try”) as morpholino design is constrained to a finite number of predictable target regions within a known transcript as discussed above and applied to claim 1 for SEQ ID NOs: 1 and 2. Following this modification, Paschen’s method targeting splice junction at exon 3 of SUMO2 gene, in addition to targeting SUMO1 gene, would have resulted in increased translation of SUMO2 gene splice variant 2 lacking exon 3, and reduced translation of SUMO2 gene splice variant 1 containing exon 3. Because SEQ ID NO: 8 and 9 are sequences within the SUMO2 splice variant 1 and splice variant 2, respectively, reduction of expression levels of SUMO splice variant 1 necessarily results in a corresponding reduction in the amount of SEQ ID NO: 8, while increase in expression levels of SUMO splice variant 2 results in a corresponding increase in the amount of SEQ ID NO: 9.
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Regarding claims 8, the obviousness to modify Paschen’s inhibitory oligos to morpholinos comprising SEQ ID NOs: 1 and 2 discussed above as applied to claim 7 combined with the obviousness to modify Paschen’s inhibitory oligos to morpholinos comprising SEQ ID NOs: 3 or 4 discussed above as applied to claim 4, the instant claim limitations are met.
Claims 10-18, and 32-35 are rejected under 35 U.S.C. 103 as being unpatentable over Paschen et al in view of Moulton, Li et al, as applied to claims 1-3 above, and further in view of NC_000017.11 (cited supra).
Regarding claims 10-15, the obviousness to modify Paschen’s inhibitory oligos to vivo-morpholinos, particularly comprising SEQ ID NOs: 3 or 4 are discussed above as applied to claims 1-3, and 4-6, respectively.
Regarding claims 16-17, the obviousness to modify Paschen’s inhibitory oligos to morpholinos comprising SEQ ID NOs: 3 or 4 equally applies here as to claims 4-6. The obviousness to further modify Paschen’s method to target SUMO genes using additional morpholinos, SEQ ID NOs: 3 and 4 is discussed above as applied to claims 7 and 8.
Regarding claim 18, the teachings of Paschen on inhibiting establishment of chemo resistance is discussed above as applied to claim 9.
Regarding claims 32-35, the obviousness discussed above as applied to claims 10-17 equally applies here. Paschen further teaches the inhibitory RNAs are “administered in a pharmaceutically acceptable composition” (Col. 12, lines 18-20), which meets the instantly recited claim limitations.
Claims 19-21, 25, 27, 36-39 are rejected under 35 U.S.C. 103 as being unpatentable over Paschen et al in view of Moulton, Li et al, as applied to claims 1-3 above, and further in view of NC_000021.9 (Homo sapiens chromosome 21, GRCh38.p14 Primary Assembly, SUMO3 gene from base 44805617 to 44818062, NCBI reference sequence, constructed Apr 06, 2022, 6 pages) and NM_001286416.2 (Homo sapiens small ubiquitin like modifier 3 (SUMO3), transcript variant 2, mRNA, NCBI reference sequence, priority to Apr 21, 2022).
Regarding claims 19-21, the obviousness to modify Paschen’s inhibitory oligos to vivo-morpholinos are discussed above as applied to claims 1-3.
However, Paschen does not teach the instantly recited SEQ ID NOs: 5 or 6.
SEQ ID NOs: 5 and 6 aligns with SUMO3 gene in human chromosome 21 (NCBI Accession Number: NC_000021.9), specifically at the internal splice site overlapping the exon 3 sequence of transcript NM_006936.3, a newer version of NM_006936.2 recited by Paschen. Another SUMO3 gene transcript NM_001286416.2 also demonstrates an additional SUMO3 gene splice variant, lacking exon 3, was known in the art. Accordingly, designing morpholinos to skip exon 3 of SUMO3 gene would arrive to the instantly recited SEQ ID NOs: 5 and 6, which therefore represents predictable antisense candidates derived from a known transcript sequence, and its selection would have been the result of routine morpholino design and optimization. Thus, the obviousness rationale and reasonable expectation of success discussed above in claim 1 apply equally to claims 19-21.
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Regarding claim 25, the obviousness to further modify Paschen’s method to target SUMO genes using additional morpholinos, SEQ ID NOs: 5 and 6 is discussed above as applied to claim 7.
Regarding claim 27, the teachings of Paschen on inhibiting establishment of chemo resistance is discussed above as applied to claim 9.
Regarding claims 36-39, the obviousness discussed above as applied to claims 19-21 and 25 equally applies here. Paschen further teaches the inhibitory RNAs are “administered in a pharmaceutically acceptable composition” (Col. 12, lines 18-20), which meets the instantly recited claim limitations.
Claims 22-24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Paschen et al in view of Moulton, Li et al, NC_000021.9 and NM_001286416.2 as applied to claims 19-21, and 25 above, and further in view of NC_000017.11 (cited supra).
Regarding claims 22-24, and 26, the obviousness to modify Paschen’s inhibitory to morpholinos, particularly SEQ ID NOs: 5 and 6 is discussed above as applied to claims 19-21 and 25. The obviousness to modify Paschen’s method to target SUMO genes with additional morpholinos, particularly SEQ ID NOs: 3 and 4 is discussed above as applied to claims 4-6. Further, following this modification, Paschen’s method targeting splice junction at exon 3 of SUMO2 gene, in addition to targeting SUMO3 gene, would have resulted in increased translation of SUMO2 gene splice variant 2 lacking exon 3, and reduced translation of SUMO2 gene splice variant 1 containing exon 3.
Response to Arguments
Applicant argues “the use of the specific morpholinos presented in this application to increase chemosensitivity in tumor cells is not knowledge included in any of the documents referenced” (pg. 15, para. 3).
Applicant’s arguments have been fully considered but are not persuasive because as stated in previous Office Action mailed 03/03/2025 (regarding claims 9, 18, and 27) that Paschen teaches “a method of sensitizing a cancer cell to a therapeutic regimen” comprising administering inhibitory RNAs in an amount effective to decrease levels of SUMO conjugated proteins in the cancer cell (col. 11, lines 55-58). Further, as explained in the instant Office Action, Paschen teaches contacting cancer cells with inhibitors that decrease level of expression or conjugation, or both, of at least one member of the SUMO conjugation pathway, thereby sensitizing cancer cells to a therapeutic regimen including chemotherapy (col. 11, lines 55-65). Further, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Conclusion
No claims are allowable.
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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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights