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
Claims 1-20 are pending.
Applicant’s election of species of claim 15 formula and guanidine group in the reply filed on 05/12/2026 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)).
Claim is 17 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/12/2026.
Claims 1-16 and 18-20 are examined here, along with elected species of claim 15 formula and ionizable group, a guanidine group of cl. 16.
Priority
The claim to benefit of 63/373,968, filed on 08/30/2022, is recognized. All examined claims enjoy the filing date of ‘968.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/30/2024, 07/23/2024, 06/09/2025, and 06/12/2026 were filed before the mailing date of the instant first Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
See, e.g., par. 6, 9, 32, 53, which have sequences greater than 9 nt. that lack SEQ ID NOs.
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 Objections
Claims 2 and 11 are objected to because of the following informalities: claim 2 should have a definite article before the “acid,” since acid has been recited in cl. 1 to avoid confusion; cl. 11, the “L” needs to be distinguished in the structure; either needs to be separated or distinguished with a bigger font. 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.
Claim 19 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 recites the limitation "m is 2". There is insufficient antecedent basis for this limitation in the claim. Claim 14 structure does not have a “m”.
In the interest of compact prosecution, since claim 15 has a “m,” claim 19 will be interpreted to depend on claim 15.
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.
Claims 1, 2, 4, 6, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Hudziak et al. (1996, Antisense and Nucleic Acid Drug Development, 6, 267-272, “Hudziak”) and Isola et al. (1999, Anal. Chem., 71, 13, 2266–2269, “Isola”).
Hudziak discloses morpholino monomers linked together by a phosphorodiamidate linkages, thus termed either morpholino phosphorodiamidate (MO-PDA) or, as in instant specification, phosphorodiamidate morpholino (PMO). Hudziak concludes that PMO “back-bone is sufficiently stable for use in a biological milieu” (pg. 272) as an antisense oligomer therapeutic following exposing PMOs of 25-mers to phosphoric acid and various enzymes (see reagents on pg. 267, and results of Table 1 on pg. 268, relevant to instant cl. 1b, 1f, 2, 6). Fig. 1 illustrates the PMO, see excerpt below (relevant to instant 10):
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Hudziak discloses that “oligomer stored for 2 months under neutral conditions in PBS at ambient temperature remains unchanged, treatment with strong acid will fragment MO-PDA backbone” (pg. 270). Following treatment with phosphoric acid, the digested product was sequenced using Maldi-time-of-flight (TOF) mass spectrometer (pg. 267).
Hudziak does not disclose all the elements of claim 1 (1a, 1c-1e).
Isola discloses a method of chemical cleavage Maxam-Gilbert sequencing of biotin-conjugated DNA sequence that is captured by streptavidin-coated magnetic beads, with the captured fragments separated from other fragment by use of hot ammonia treatment, followed by sequencing of the digested DNA with MALDI-TOF mass spectrometer (abstract). Isola purchased synthetic oligonucleotides that are conjugated to a biotin at the 5’-end (pg. 2267, relevant to instant cl. 1a). Isola conducted the cleavage reaction based on the methodology of Maxam and Gilbert to derive biotinylated DNAs G, C, G+A, C+T. The dried cleaved product was mixed with streptavidin-coupled magnetic beads and washed in binding buffer and ethanol (pg. 2267, relevant to instant cl. 1c, 1d). Following the biotin capture with streptavidin-magnetic bead, the captured DNA bead was resuspended in ammonium hydroxide and incubated at 650C for 10 min to release the captured DNA (relevant to instant cl. 1e, 4) and then analyzed by MALDI-TOF mass spectrometer (pg. 2267-2268, relevant to instant cl. 1f). The advantages of mass-spectrometer sequencing, includes no requirement of radioactive material or dye tagging and is rapid, since time-consuming gel-electrophoresis is not required (pg. 2266). Further, by biotinylating the DNA, it can be separated from other DNA fragments, since mass spectrometer would analyze all products/fragments added (pg. 2268).
The “cleaner” mass-spec results of biotin/streptavidin process of Isola is illustrated when compared to Table 2 of Hudziak, where some reads have a “d” designation, which represents “Obscured by peaks of doubly charged ions from the undegraded sample,” additional artifacts are also noted in the Table and discussed on pg. 269-270.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the method of sequencing a PMO using strong acid as taught by Hudziak in view of Isola and arrive at the claimed invention with a reasonable expectation of success. Based on the successful sequencing of DNA by Isola of utilizing biotinylated-DNA then capturing the biotinylated-DNA with magnetic streptavidin beads to isolate biotinylated-DNA from crude products for a “cleaner” mass-spectrometer reading and successful sequencing of a 25-mer by Hudziak, a skilled artisan would reasonably expect success by combining Isola’s method of conjugating a biotin for DNA oligomer sequencing to Hudziak’s method of sequencing PMO by substituting PMO of Hudziak for Isola’s DNA and then capturing the PMO-biotin conjugate using streptavidin to sequence a biotin-PMO. Thus, cl. 1, 2, 4, 6, and 10 are obvious.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Hudziak et al. (1996, Antisense and Nucleic Acid Drug Development, 6, 267-272, “Hudziak”) and Isola et al. (1999, Anal. Chem., 71, 13, 2266–2269, “Isola”) as applied to claims 1, 2, 4, 6, and 10, above, and further in view of Summerton (2003, Letters in Peptide Science, 10, 215-236, in IDS of 5/30/2024)
Disclosure regarding rejection 1, 2, 4, 6 and 10 is noted above.
Summerton discloses that morpholino backbone is cleaved by strong acids, such as trifluoroacetic acid (pg. 217).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted the phosphoric acid used to degrade PMOs of Hudziak in view of Summerton and arrive at the claimed invention with a reasonable expectation of success. A skilled artisan would reasonably expect success by substituting phosphoric acid, which was successful in degrading PMO of Hudziak, with trifluoroacetic acid, a strong acid, of Summerton, followed by sequencing process of Isola. Thus, claim 3 is obvious.
Claims 5, 7, 8, 9, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Hudziak et al. (1996, Antisense and Nucleic Acid Drug Development, 6, 267-272, “Hudziak”) and Isola et al. (1999, Anal. Chem., 71, 13, 2266–2269, “Isola”) as applied to claims 1, 2, 4, 6, and 10, above, and further in view of Moulton and Yan (2008, Curr. Protoc. Mol. Biol., 83, Unit 26.8, 1-29).
Disclosure regarding rejection 1, 2, 4, 6 and 10 is noted above.
Hudziak and Isola do not disclose peptide-PMO (cl. 5), biotin conjugated to 3’-end of the PMO (cl. 7) and has a linker (cl. 8), a PMO-L-biotin formula (cl. 9), with the PMO-L-biotin structure of cl. 11, with a linker comprising a divalent PEG group (cl. 12).
Moulton’s review paper discloses use of morpholino oligomers and indicates that a morpholino oligomer linked to a 3’-biotin affinity tag via a linker are commercially available and notes biotin-tag for binding to streptavidin (pg. 26.8.23, see structure below of Fig. 26.8.4, relevant to instant cl. 7, 8, 9, 11).
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Moulton discloses spacers, such as a polyethylene glycol, for flexibility (pg. 26.8.22). Further, Moulton discloses that a PMO conjugated to a cell-penetrating peptide (CPP) is required for target affinity of the PMO (pg. 26.8.17, relevant to instant cl. 5).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the biotinylated-PMO of Hudziak and Isola in view of Moulton and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art could have substituted the biotinylated-PMO of Hudziak/Isola with 3’-biotin bound to morpholino via linker/spacer of Moulton and would reasonably expect success since it is known that biotin-tag has an affinity for streptavidin. Thus, cl. 5, 7-9, 11 are obvious.
Regarding instant cl. 12, Moulton indicates biotin is attached to morpholinos through flexible polyethylene-glycol spacers (pg. 26.8.22), and since the spacer links biotin to a morpholino oligo, it would be considered a divalent PEG.
Claims 14, 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Hudziak et al. (1996, Antisense and Nucleic Acid Drug Development, 6, 267-272, “Hudziak”) and Isola et al. (1999, Anal. Chem., 71, 13, 2266–2269, “Isola”) and Moulton and Yan (Using Morpholinos to Control Gene Expression, 2008, Curr. Protoc. Mol. Biol., 83, Unit 26.8, 1-29, “Moulton”) as applied to claims 1, 2, 4-12 above, and further in view of Cankarova et al. (2011, Tetrahedron Letters, 52, 5782-5788).
Disclosure regarding rejection of claims 1, 2, 4-12 is noted above.
Hudziak, Isola and Moulton do not disclose a linker with linker formula of cl. 14 and 18 nor n is 2 (cl. 20).
Cankarova discloses that biotinylation of organic compounds is a “very frequent approach for detailed studies of biochemical properties of biologically active substances,” including nucleic acids (pg. 5782). Cankarova discloses a solid-phase synthesis of attaching a poly ethylene glycol (PEG) moiety spacers to a biotin molecule (abstract). Advantages of addition of PEG moiety is that it is inert and avoids decreasing the biotinylated system’s solubility in water (pg. 5782). Scheme 6 describes a few end products that can be used with additional reactions (see figure below, pg. 5784).
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The end products disclose biotin conjugated to modifiable linker/spacers comprising PEG (see above, each have greater than or equal to 1 PEG moiety, relevant to instant cl. 14, 18). Scheme 1 illustrates addition of 2 ethyleneoxy units (pg. 5783, relevant to instant cl. 20) and discloses additional PEGs can be added (as seen in the results of Scheme 6 above, pg. 5784).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted PMO conjugated to a biotin via a linker/spacer of Hudziak/Isola/Moulton in view of Cankarova and arrive at the claimed invention with a reasonable expectation of success. A skilled artisan would reasonably expect success of substituting one type of linker with PEG of Hudziak, Isola and Moulton and with another of PEG-unit linkers to improve off-target effects by PEG moiety’s inertness when conjugating biotin to PMO. Thus, cl. 14, 18 and 20 are obvious.
Claims 13, 15-16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Hudziak et al. (1996, Antisense and Nucleic Acid Drug Development, 6, 267-272, “Hudziak”) and Isola et al. (1999, Anal. Chem., 71, 13, 2266–2269, “Isola”) and Moulton and Yan (2008, Curr. Protoc. Mol. Biol., 83, Unit 26.8, 1-29, “Moulton”) and Cankarova et al. (2011, Tetrahedron Letters, 52, 5782-5788, “Cankarova”) as applied to claims 1, 2, 4-12, 14, 18, 20 above, and further in view of Moulton (WO2009005793, pub. 1/8/2009, “’793”, in IDS, cite 2 of 5/30/24) and Schissel et al. (2/2022, ACS Bio Med Chem Au, 2, 150-160, “Schissel”).
Disclosure regarding rejection of cl. 1, 2, 4, 6-14, 18, 20 is noted above. It should be added that Moulton discloses cell-penetrating peptides (CPP), which use arginine-rich peptides to alter targeting specificity (pg. 26.8.17). Further, Moulton also discloses end modifications that can be made at 3’ end and indicates that biotin can be attached to morpholinos through flexible PEG spacers (pg. 26.8.22). Moulton discloses that reactive morpholinos end modifications, including a primary amine that can be conjugated at 5’ or 3’ end.
Hudziak, Isola and Moulton do not disclose a linker with linker formula of cl. 15, 16, nor where m is 2 (cl. 19).
‘793 discloses a tissue specific peptide or cell penetrating peptide (CPP) conjugate to a PMO antisense oligomer (see Fig. 1B below, pg. 1-3), which comprises a peptide with two arginine with guanidine group terminals (relevant to instant cl. 13, 15, 16, 19).
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The instant cl. 15 formula is different than peptide group of ‘793. However, similar to instant formula of cl. 15, the guanidine side chain is flanked by amide groups and the CPP would function similar to the linker of instant formula 15 and are not patentably distinct. Moulton and Cankarova teach adding PEG moiety to a nucleic acid. ‘793 teaches conjugating a “marker compound,” i.e. “a detectable compound attached to transport peptide for evaluation of transport,” which include fluorescent moiety.
Hudziak, Isola, Moulton, Cankarova, and ‘793 do not teach conjugating biotin to CPP or transport peptide.
Conjugating a biotin moiety to a PMO via a CPP-linker is known in the art.
Schissel discloses a PMO conjugated to cell-penetrating peptides and a trypsin-cleavable linker and biotin moiety (see which comprise arginine and glycine/lysine amino acids (both L- and D- isoforms), and a trypsin-cleavable linker and biotin moiety (see, e.g., DPV7, Tat, Tatp, etc. . . as arginine containing PMOs on pg. 151). Thus illustrating that biotin and CPP can be conjugated together and that both can be conjugated to a PMO, thus the CPP is effectively a linker (relevant to instant cl. 8). Arginine comprises a guanidine group (relevant to instant cl. 13, 16). Although Schissel, Hudziak, Isola, and Moulton do not disclose the exact formula of cl. 15, the CPP conjugated to biotin and bound to PMO is not patentably distinct from the formula of cl. 15, and serves as a linker and linkers are interchangeable to link two products of interest, here, a PMO and biotin.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified a PMO-biotin via a PEG linker of Hudziak/Isola/Cankarova in view of ‘793 and Schissel and arrive at the claimed invention with a reasonable expectation of success. A skilled artisan would reasonably expect success of conjugating a biotin and PMO of Hudziak and Isola via any type of noted linkers, including one comprising a CPP of ‘793 and a PEG moiety of Cankarova. A skilled artisan would reasonably expect success in sequencing a PMO-linker-biotin of Hudziak, Cankarova, Moulton, and ‘793 as taught by the process of Isola of the biotin conjugate binding to the streptavidin magnetic beads. Thus, cl. 15, 16 and 19 are obvious.
Allowable Subject Matter
No claim allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST).
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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