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
Applicant’s reply filed February 27, 2026, including remarks, sequence listing, and amendments to the drawings and specification, is acknowledged. Claims 1-26 are pending.
Restriction/Election
Applicant elected Group I (claims 1-17), with traverse, in the reply filed February 27, 2026. The traversal is on the grounds that the non-naturally occurring nucleic acid ligand of Ishiguro does not meet the limitations of the claims because, allegedly, Ishiguro’s ligand “merely… exhibit[s] cross species reactivity,” and was “simply selected by a conventional SELEX process.” Applicant asserts that the instant invention is directed to ligands specific for “two or more heterologous targets that are structurally and/or functionally different,” and are “not selected or obtained by conventional SELEX method.”
This is not found persuasive. Ishiguro’s ligand meets the scope of the claims for the reasons described in the prior action and below. The instant claims are directed to ligands specific for “two or more different targets.” Ishiguro’s ligand has specific binding affinity to both human IL-17A and mouse IL-17A. These proteins are not structurally the same, and therefore, are “different targets.” Indeed, as noted in the prior action, and as Applicant concedes, human IL-17A and mouse IL-17A are structurally dissimilar (“sequence homology of 63%”). Neither the process through which exemplary ligands encompassed by the claims were made, nor the targets to which the exemplary ligands were found to have specificity, are relevant to the analysis of the instant claim scope; the exemplary ligands are not required of the claims, no such process is recited in the claims, and no specific targets are required of the claims. Even should a specific process through which the ligands were prepared be claimed, MPEP 2113(I) states that “if the product in [a] product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” Furthermore, the instant claims also lack unity of invention over the teachings of King and Bates, and Ding as described below.
The requirement is still deemed proper and is therefore made FINAL. Accordingly, claims 18-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 1-17 are under examination hereinafter.
Priority
Applicant’s priority claims to Application Nos. KR10-2020-0054192 and PCT/KR2021/005773 are acknowledged. The certified copy of Application No. KR10-2020-0054192 has been received. The priority date of the claims under examination is May 7, 2020.
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 - The incorporation by reference paragraph required by 37 CFR 1.821(c)(1) is defective. Specifically, USPTO records indicate that the size of the sequence listing filed February 27, 2026 is “152,163 bytes,” rather than “148,600 bytes” as indicated in the incorporation by reference paragraph. Appropriate correction is required.
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 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.
Claim Rejections - 35 USC § 112(b)
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 1-17 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 1-4 recite the term “specific binding affinities,” which is a relative term which is not defined by the claim. The specification provides that this term “may mean that the nucleic acid ligand binds to its targets with generally much higher affinity than binding to other non-target components or ingredients present in a mixture or sample” ([0143]). This does not provide a standard for ascertaining the requisite degree of “specific binding affinities,” however, because other standards may apply (“may mean”), and the specification’s only recited standard is, itself, relative (“generally much higher affinity”), and lacks a clear standard to understand its scope. The skilled artisan would not be apprised of the scope of ligands with “specific binding affinities” to two or more different targets, which renders the claims indefinite.
Claims 5-17 are rejected for depending from claims 1-4 and failing to remedy the indefiniteness.
Claims 5 and 14 recite the term “about,” which is a relative term which is not defined by the claim. The specification, while providing various standards which the term “about” “may mean” ([0136]), does not provide any standard for ascertaining which of the various standards for “about” applies to the percent binding site ranges recited in claim 5, or the ligand length range recited in claim 14. Accordingly, the skilled artisan would not be reasonably apprised of the scope of the inventions of claims 5 and 14.
Claim 15 is rejected for depending from claim 14 and failing to remedy the indefiniteness.
Claim 16 recites that the non-natural nucleic acid ligand “consists of one nucleic acid sequence selected from the group consisting of SEQ ID NO: 6 to SEQ ID NO: 183,” which requires that the ligand is one of the recited sequences set forth in the sequence listing, i.e., a specific nucleobase sequence and any modifications applied thereto as set forth in the listing. The sequence listing, however, provides two separate definitions for the “n” nucleotides in each SEQ ID NO: “n is 5-(N-(1-naphthylmethyl)carboxamide)-2'-deoxyuridine(Nap-dU),” and “n is a, c, g, or t.” It is not clear which of the disparate definitions should be applied to each of the one or more “n” nucleotides in each SEQ ID NO, and therefore, the scope of sequences which the nucleic acid ligand must consist of is unclear.
Because the Examiner cannot infer the intended scope of claim 16 without considerable speculation (i.e., as to which definition applies to each of the one or more “n” nucleotides in each SEQ ID NO), this claim will not be examined with respect to the prior art. See MPEP 2173.06(II).
Claim Rejections - 35 USC § 112(a) – 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.
Claims 1-17 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 for the reasons that follow.
MPEP 2163.II.A3.(a).(i) states the following:
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.”
“Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For 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. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Species Encompassed – Claims 1-13
The claims depend from one or more of claims 1-4, wherein claims 1-4 encompass related species of non-natural nucleic acid ligand. Each of claims 1-4 recite “a non-natural nucleic acid ligand having specific binding affinities for two or more different targets, wherein each of the targets has a three-dimensional structure.” In view of the indefiniteness described above, this phrase is interpreted hereinafter as encompassing any nucleic acid molecule (i.e., a molecule comprising any two or more linked nucleotides), which “specifically” binds (i.e., interacts or associates with a target in a sample) to two or more targets with three-dimensional structure. The invention also encompasses non-natural nucleic acid ligands which are conjugates between nucleic acid sequences and various substances, e.g., biotin, or fluorescent substances ([0165]-[0166]).
Claim 1 requires that “the non-natural nucleic acid ligand is not a coupled body of a plurality of aptamers.” “[A] coupled body of a plurality of aptamers” is interpreted as two or more separate aptamers which are coupled, fused, linked, or conjugated, wherein each aptamer is an oligonucleotide that has specific binding affinity for only one target ([0002]; [0135]; [0150]). This phrase is interpreted as excluding nucleic acid ligands prepared from two or more separate sequences, wherein each of the sequences have affinity to a single target. Claim 1, therefore, encompasses ligands wherein the binding sites to the two or more different targets are two or more overlapping nucleic acid sequences. Claim 1 also encompasses ligands comprising a nucleic acid sequence which binds a target, conjugated to a substance, which binds a different target, because the phrase “not a coupled body of… aptamers” only excludes aptamer fusions/conjugates, i.e., fusions/conjugates of oligonucleotides with affinity to one target ([0002]; [0135]).
Claim 2 requires that “all or part of a nucleic acid sequence forming a binding site to one target forms all or part of a nucleic acid sequence forming a binding site to another target.” This phrase is interpreted as encompassing ligands wherein the binding sites to the two or more different targets are two or more overlapping nucleic acid sequences.
Claim 3 requires that “in the nucleic acid ligand, binding sites to two or more targets are not present separately from each other.” This phrase is interpreted as excluding ligands prepared from two or more separate aptamer sequences ([0153]). Claim 3, therefore, is interpreted as encompassing ligands wherein the binding sites to the two or more different targets are two or more overlapping nucleic acid sequences. This claim is also interpreted as excluding ligands comprising a nucleic acid sequence which binds a target, conjugated to a substance, which binds a different target, as these would be considered “separate” binding sites.
Claim 4 requires that the “binding sites to two or more targets are formed in one single nucleic acid ligand.” This phrase is not interpreted as imposing any additional structural limitations on the claim, because the claim is already directed to “a... nucleic acid ligand having specific binding affinities for two or more different targets.” This phrase also does not exclude ligands which are prepared from two or more separate sequences wherein each of the sequences have specific binding affinity to a single target. Accordingly, claim 4 is interpreted as encompassing non-natural nucleic acid ligands with affinity to two or more different targets, including aptamer fusions/conjugates.
The targets encompassed by the claims are virtually unlimited. The claims encompass targets which are cells, viruses, proteins, carbohydrates, nucleic acids, “plasma proteins,” which are interpreted as any protein found in blood plasma, “therapeutic targets,” which are interpreted as virtually any substance with three-dimensional structure, as well as targets characterized by various functions/characteristics, e.g., “membrane proteins,” “oxidases,” “receptors,” “tumor proteins,” various proteins, e.g., “albumin,” “transthyretin,” CD28,” “ICOS,” and variants of proteins, e.g., “KRAS G12D” ([0138]-[0146]; [0245]). The claims also do not exclude nucleic acid molecules which bind to nucleic acid targets via hybridization ([0144]). Even where the targets are more limited (e.g., claims 9 or 12), the targets, still, represent an enormous and incredibly diverse set of targets with three-dimensional structure. For example, claims 9 and 12 encompass structurally diverse proteins (e.g., “albumin,” “PDGF”) from any species, with any number of variant residues. Claims 9 and 12 also encompass large classes of structurally diverse targets (e.g., “lipoproteins,” “acetylcholine receptors”) which in some cases, are not even limited to proteins (e.g., any three-dimensional target of “respiratory syncytial virus”).
Taken together, the genus of non-natural nucleic acid ligands encompassed by claims 1-13 is defined exclusively by function, i.e., binding to two or more targets encompassed by the claims, in the manner described by the claims. None of claims 1-13 define the nucleobase sequence, chemical composition, binding sites, etc., of the non-natural nucleic acid ligand. The specification has not adequately described the genus of ligands which achieve the functions of binding two or more targets encompassed by the claims, in the manner described by the claims.
Species Disclosed in the Specification
The specification describes non-natural nucleic acid ligands consisting of the nucleic acid sequences set forth in Tables 1-3 ([0324]). The ligands correspond to SEQ ID NOs: 6-183, wherein “each part designated as 6 indicates 5-(N-(l-naphthylmethyl)carboxamide)-2'-deoxyuridine (Nap-dU)” ([0323]).
The specification describes that the ligands were prepared using a sequential SELEX method, with a first selection for a specific plasma proteins selected from “human serum albumin (HSA; Abeam, UK product name: Recombinant human serum albumin Protein (His tag), catalog number: ab217817), immunoglobulin G (IgG; Abeam, UK, product name: Recombinant Human IgG 1 protein (His tag), catalog number: ab219660), or transferrin (TF; Abeam, UK, product name: Recombinant human Transferrin protein (Active), catalog number: abl55698),” and a second selection for a protein selected from “Wild-type KRAS protein: Abeam, product name: Recombinant Human KRAS protein (His tag), Catalog number: ab96817,” “KRAS G12D protein: Signal Chem, product name: KRAS (G12D) Protein(R06-32BH), Catalog number: R06-32BH,” “KRAS G12C protein: Signal Chem, product name: KRAS (G12C) Protein (R06-32DH), Catalog number: R06-32DH,” “KRASG12V protein: Signal Chem, product name: KRAS (G12V) Protein (R06-32CH), Catalog number: R06-32CH,” PD-L1 protein: R&D SYSTEMS, product name: Recombinant Human PD-L1/B7-H1 His-tag Protein, Catalog number: 9049-B7-100,” “BCL-2 protein: R&D SYSTEMS, product name: Recombinant Human Bcl-2 (minus C-Terminus) Protein, CF, Catalog number: S27-BC-050,” 4-1BB protein: R&D SYSTEMS, product name: Recombinant Human 4-1BB/TNFRSF9 Fc Chimera Protein, CF, Catalog number: S3S-4B-100,” “CD3d/e protein: Prosci, product name: CD3 delta/epsilon Heterodimer Recombinant, Protein (Fc Chimera), Catalog number: 96-164” ([0275]-[0324]).
Thus, the specification describes non-natural nucleic acid ligands, consisting of the specific sequences set forth in Tables 1-3, wherein each ligand specifically binds to two specific protein targets, wherein the protein targets are highly specific, commercially available proteins, many of which are “recombinant,” or have a “His tag,” or which are missing the “C-terminus,” or which are an “Fc Chimera.” The specification does not provide any information as to the structure(s) of the non-natural nucleic acid ligands and the structure(s) of the specifically described protein targets which are necessary for the specific binding described in the specification.
The specification does not describe any non-natural nucleic acid ligands which specifically bind more than two targets (“two or more”), bind to non-protein targets (“cells, viruses”), bind to naturally-occurring protein targets, or bind to the overwhelming majority of targets recited in claims 1-13 (e.g., “gamma globulin,” “fibrinogen,” “amylin,” “CD20,” ICOS,” “KRAS G12S,” “KRAS G12R,” etc.). The specification provides no information for the skilled artisan to ascertain the structure(s) of ligands encompassed by the claims which would specifically bind to two or more of the overwhelmingly diverse targets encompassed by the claims. For example, the specification does not identify core structural features of ligands which are responsible for their binding functions, identify core structural features which would generalize across the many targets/combinations of targets encompassed by the claims, or provide any prediction models which would allow the skilled artisan to determine which ligand structures encompassed by the claims would bind to the many combinations of two or more targets encompassed by the claims.
Guidance in the Art
The prior art teaches species within the claimed genus of claims 1-4. See the teachings of Ishiguro (Ishiguro et al., February 2011, Arthritis & Rheumatism, Vol. 63, No. 2, pg. 455-466; of record), and King (King et al., WO 03/002592 A1, published 9 January 2003) as evidenced by Bates (Bates et al., WO 2005/035579 A1, published 21 April 2005), and Ding (Ding et al., 10 February 2020, Analytical Chemistry, 92, pg. 4108-4114 and Supplementary Information), described below. However, these references provide no information for the skilled artisan to ascertain the structure of ligands encompassed by the claims which specifically bind to two or more of the overwhelmingly diverse targets encompassed by the claims. Indeed, Ishiguro’s results would suggest to the skilled artisan, that in order to arrive at a ligand of the instant claims, the skilled artisan would essentially need to perform a separate screening experiment for each possible combination of two or more of the three-dimensional targets encompassed by the claims. This would involve screening incalculable numbers of nucleic acid sequences based on Ishiguro (“Selection-amplification of hIL-17A aptamers and construction of a doped library. The preparation of a pool of 5 x 1014 different RNA molecules randomized over 30 nucleotides (30N RNA pool),” pg. 456, right col.). Furthermore, Ishiguro’s identified aptamers, both of which specifically bind to human IL-17A and mouse IL-17A, do not appear to share any core structural features which confer their binding functions (see disparate nucleobase sequences and secondary structures in Fig. 1A).
Based on a thorough search of the prior art, Ishiguro’s results are indicative of the state of the art as a whole; there is no means to ascertain the structure(s) of ligands encompassed by the claims which would specifically bind to two or more of the overwhelmingly diverse targets encompassed by the instant claims, nor could the skilled artisan identify core structural features which would generalize across the many targets/target combinations encompassed by the claims.
Conclusion
The specification describes the non-natural nucleic acid ligands set forth in Tables 1-3, which fulfill the claimed functions. However, considering the large variation in the genus of ligands, the extremely small percentage of species described in the specification and prior art, and the lack of a reasonable structure-function relationship provided by the specification or prior art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
Dependent Claims 14-17
Claims 14-17 do not further limit the genus of non-natural nucleic acid ligands so as to resolve the lack of structure-function correlation described above.
Claim 14 further limits the non-natural nucleic acid ligand to consist of about 100 or less nucleotides. The genus is still unlimited in terms of nucleobase sequence, chemical composition, target(s), etc. The specification and prior art do not provide a reasonable structure-function relationship for ligands consisting of about 100 or less nucleotides which would achieve the recited functions.
Claim 15 is also insufficiently described, because it also encompasses virtually any ligand consisting of about 100 or less nucleotides, i.e., DNA-based ligands, RNA-based ligands, ligands consisting of combinations of natural and modified nucleotides, ligands consisting of modified nucleotides. The genus is still virtually unlimited in terms of nucleobase sequence, chemical composition, target(s), etc.
Claim 16 recites that the ligand consists of one nucleic acid sequence selected from SEQ ID NO: 6 to SEQ ID NO: 183. The specification describes ligands consisting of the non-natural nucleic acid ligands set forth in Tables 1-3, which the specification states correspond to the SEQ ID NOs. However, as described in paragraph 8 above, the sequence listing sets forth two disparate definitions of the “n” nucleotides in each SEQ ID NO. Under the interpretation that any of the one or more “n” nucleotides may be “a, c, g, or t,” the specification still has not sufficiently described this genus of ligands.
Claim 17 still encompasses virtually any ligand structure; the genus is still unlimited in terms of nucleobase sequence, chemical composition, target(s), etc. The specification and prior art do not provide a reasonable structure-function relationship for single- and double-stranded DNA and RNA ligands which would achieve the recited functions.
Claim Rejections - 35 USC § 102 – Ishiguro
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 1-8, 10-11, 14-15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ishiguro (Ishiguro et al., February 2011, Arthritis & Rheumatism, Vol. 63, No. 2, pg. 455-466; of record).
Regarding claims 1-4, Ishiguro teaches a non-natural nucleic acid ligand (“Apt21-2”) which has specific binding affinity for two different targets, each of which have three-dimensional structure, i.e., human IL-17A and mouse IL-17A (“SPR analysis indicated that… Apt21-2 bound stably to not only hIL-17A, but also mIL-7A… Mouse IL-17A is a 147-amino acid, 21-kd glycoprotein with 63% amino acid homology to hIL-17A (155 amino acids),” pg. 457, right col.; Fig. 1). Ishiguro’s ligand is a 33-nt RNA-based nucleic acid sequence (pg. 457, right col.; Fig. 1A) in which “all or part of a nucleic acid sequence forming a binding site to one target forms all or part of a nucleic acid sequence forming a binding site to another target,” “the binding sites to [the] two [] targets are not present separately from each other,” and are “formed in one single nucleic acid ligand.” Therefore, Ishiguro’s ligand is also “not a coupled body of a plurality of aptamers,” as interpreted herein. Accordingly, Ishiguro’s ligand meets each of the limitations of claims 1-4.
Regarding claim 5, this claim encompasses ligands wherein the portion of the nucleic acid sequence forming the binding sites to the targets is “about 1% to about 99%” of the entire sequence of the ligand. The meaning of “about” is unclear, and is interpreted hereinafter as +/- 20%. Ishiguro’s ligand is 33-nts in length (“Apt21-2 (33-nt long),” pg. 457, right col.), such that, when applied to Ishiguro’s ligand length, claim 5 would require one to all of the nucleotides of Ishiguro’s ligand to form the binding sites to the targets. Ishiguro is silent as to the portions of the ligand which form the target binding sites. However, Ishiguro’s ligand must, inherently, comprise binding sites to the two different targets, wherein the binding sites represent one to all of the nucleotides of the ligand.
Regarding claim 6, as stated above, Ishiguro’s ligand (“Apt21-2”) has specific binding affinity for two different targets, i.e., human IL-17A and mouse IL-17A (“Mouse IL-17A is a 147-amino acid, 21-kd glycoprotein with 63% amino acid homology to hIL-17A (155 amino acids),” pg. 457, right col.; Fig. 1).
Regarding claim 7, Ishiguro’s ligand targets proteins.
Regarding claim 8, the term “plasma protein” is interpreted as a protein which can be found in blood plasma, and the term “therapeutic target,” is interpreted as encompassing any “target” with three-dimensional structure, e.g., cell, virus, protein, etc., because the term “therapeutic” recites an intended use/purpose for the target. Human IL-17A could be considered a therapeutic target (“IL-17A… is involved in host defense, inflammation, and autoimmune disorders,” pg. 455, left col.). Ishiguro teaches that IL-17A is comprised by lymphocytes (“The proinflammatory cytokine interleukin-17A (IL-17A) is produced primarily by the CD4+ T cell subset called Th17 cells,” pg. 455, left col.), which are a component of blood plasma. Thus, mouse IL-17A could be considered a plasma protein. Ishiguro’s ligand meets the limitations of claim 8.
Regarding claim 10, Human IL-17A is a protein present in a cell (“The proinflammatory cytokine interleukin-17A (IL-17A) is produced primarily by the CD4+ T cell subset called Th17 cells,” pg. 455, left col.).
Regarding claim 11, Human IL-17A is a cytokine (“The proinflammatory cytokine interleukin-17A (IL-17A) is produced primarily by the CD4+ T cell subset called Th17 cells,” pg. 455, left col.).
Regarding claim 14, Ishiguro’s ligand consists of 33 nucleotides (“Apt21-2 (33-nt long),” pg. 457, right col.).
Regarding claim 15, Ishiguro’s ligand consists of RNA nucleotides and modified nucleotides thereof (pg. 456, right col.; pg. 457, right col.; Fig.1A and description).
Regarding claim 17, Ishiguro’s ligand consists of single-stranded RNA (pg. 456, right col.; pg. 457, right col.; Fig.1A and description).
Claim Rejections - 35 USC § 102 – King as evidenced by Bates
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-8, 10-11, 14-15, and 17 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by King (King et al., WO 03/002592 A1, published 9 January 2003) as evidenced by Bates (Bates et al., WO 2005/035579 A1, published 21 April 2005).
King teaches a non-natural nucleic acid ligand (“GS-522”) which has specific binding affinity to the plasma protein, thrombin, which is a protein with three-dimensional structure (“The 15-mer d(GGTTGGTGTGGTTGG), (<400>2), also known as GS-522 has been the subject of a number of structural and functional studies. These known thrombin-binding aptamers are characterised by a central core of two guanine quartets (Guschlbauer et al, 1990) formed from eight conserved guanine residues,” pg. 3). King is silent as to whether the ligand has specific binding affinity to a different target with three-dimensional structure. However, Bates teaches that King’s ligand also has specific binding affinity to nucleolin, which is a protein with three-dimensional structure (“GRO D,” “ggttggtgtggttgg,” Table 2, pgs. 33-34; “GROs and other polypeptide-binding oligonucleotides,” pg. 9).
Thus, as evidenced by Bates, King’s ligand is a 15-nt DNA-based nucleic acid sequence in which “all or part of a nucleic acid sequence forming a binding site to one target forms all or part of a nucleic acid sequence forming a binding site to another target,” “the binding sites to [the] two [] targets are not present separately from each other,” and are “formed in one single nucleic acid ligand.” Therefore, King’s ligand is also “not a coupled body of a plurality of aptamers,” as interpreted herein. Accordingly, King’s ligand meets each of the limitations of claims 1-4.
Regarding claim 5, this claim encompasses ligands wherein the portion of the nucleic acid sequence forming the binding sites to the targets is “about 1% to about 99%” of the entire sequence of the ligand. The meaning of “about” is unclear, and is interpreted hereinafter as +/- 20%. King’s ligand is 15-nts in length, such that, when applied to King’s ligand length, claim 5 would require one to all of the nucleotides of King’s ligand to form the binding sites to the targets. King and Bates are silent as to the portions of the ligand which form the target binding sites. However, King’s ligand must, inherently, comprise binding sites to the two different targets, wherein the binding sites represent one to all of the nucleotides of the ligand.
Regarding claim 6, as stated above, as evidenced by Bates, King’s ligand has specific binding affinity for two different targets, i.e., thrombin and nucleolin.
Regarding claim 7, King’s ligand targets proteins.
Regarding claim 8, the term “plasma protein” is interpreted as a protein which can be found in blood plasma, and the term “therapeutic target,” is interpreted as encompassing any “target” with three-dimensional structure, e.g., cell, virus, protein, etc., because the term “therapeutic” recites an intended use/purpose for the target. Nucleolin could be considered a therapeutic target (“plasma membrane nucleolin is indicative of not only malignant cells, but also of pre-malignant cells,” Bates, pg. 7). Thrombin is a known component of blood plasma (King, pg. 21). Thus, thrombin could be considered a plasma protein. King’s ligand meets the limitations of claim 8.
Regarding claims 10-11, nucleolin is a protein present in a cellular membrane, and therefore, could be considered a “membrane protein” (“plasma membrane nucleolin is indicative of not only malignant cells, but also of pre-malignant cells,” Bates, pg. 7.).
Regarding claim 14, King’s ligand consists of 15 nucleotides.
Regarding claim 15, King’s ligand consists of DNA nucleotides (“d(GGTTGGTGTGGTTGG),” pg. 3).
Regarding claim 17, Ishiguro’s ligand consists of single-stranded DNA (“d(GGTTGGTGTGGTTGG),” pg. 3).
Claim Rejections - 35 USC § 102 – Ding
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 1, 4, 6-11, 14-15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ding (Ding et al., 10 February 2020, Analytical Chemistry, 92, pg. 4108-4114 and Supplementary Information).
Regarding claims 1 and 4, as stated above, the claims are interpreted as encompassing nucleic acid ligands comprising a nucleic acid sequence which binds a target, conjugated to a substance, which binds a different target. Ding teaches such a non-natural nucleic acid ligand (“EB-Sgc8”), which has specific binding affinity for two different targets, each of which have three-dimensional structure, i.e., PTK7 receptor protein, and albumin (“PTK7 receptor-specific aptamer Sgc8 with the small molecule Evans Blue (EB)… The EB molecule could insert into the hydrophobic region of serum albumin,” Abstract).
Regarding claim 6, as stated above, Ding’s ligand has specific binding affinity for two different targets, i.e., PTK7 receptor protein, and albumin (“PTK7 receptor-specific aptamer Sgc8 with the small molecule Evans Blue (EB)… The EB molecule could insert into the hydrophobic region of serum albumin,” Abstract).
Regarding claim 7, the targets of Ding’s ligand are proteins.
Regarding claim 8, the term “plasma protein” is interpreted as a protein which can be found in blood plasma, and the term “therapeutic target,” is interpreted as encompassing any “target” with three-dimensional structure, e.g., cell, virus, protein, etc., because the term “therapeutic” recites an intended use/purpose for the target. PTK7 could be considered a therapeutic target (“this EB-Sgc8/HAS complex demonstrated prolonged blood half-life and increased tumor accumulation,” pg. 4019, left col.). Albumin is a known plasma protein (“human serum albumin (HSA)… plasma protein,” pg. 4109, left col.).
Regarding claim 9, the plasma protein target of Ding’s ligand is albumin.
Regarding claims 10 and 11, PTK7 is a receptor protein present in a cell or a protein present in a cellular membrane (“PTK7 receptor,” Abstract; “In Vivo Measurements of EB-Sgc8 Aptamers Targeting Ability,” pg. 4111-4112).
Regarding claims 14-15, Ding’s ligand consists of 47 DNA nucleotides (Supplementary Information, pg. 2).
Regarding claim 17, Ding’s ligand consists of single-stranded DNA (Supplementary Information, pg. 2).
Notice to Joint Inventors
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.
Claim Rejections - 35 USC § 103 – Tanaka in view of Ding
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 1, 4, 6-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka (Tanaka et al., 2007, Oligonucleotides, 17:12-21) in view of Ding (Ding et al., 10 February 2020, Analytical Chemistry, 92, pg. 4108-4114 and Supplementary Information).
Regarding claims 1, 4, 6-9, 12-13, Tanaka teaches non-natural nucleic acid sequences, which have specific binding affinity for a three-dimensional protein target, i.e., KRAS G12V (“RNA aptamers were selected against mutant KRAS (G12V) proteins,” Abstract; “Aptamer selection procedures,” pg. 14, left col.; Table 1, pgs. 17-18). Tanaka suggests the sequences could be used as a therapy for diseases associated with KRAS mutations, e.g., cancers (“Mutations in the KRAS gene are the most frequent among the RAS family, accounting for 85% of the total RAS mutations found in all tumors… DNA/RNA aptamers that have the ability to bind to their targets with high affinity are candidates for a new type of nucleic acid therapeutics,” pg. 13, left col.; pg. 20, right col.). Thus, the target of Tanaka’s sequences could be considered a therapeutic target.
Tanaka does not teach a non-natural nucleic acid ligand which has specific binding affinity to two different protein targets, wherein the second protein target is the plasma protein albumin.
As described above, Ding teaches a non-natural nucleic acid ligand (“EB-Sgc8”) which has specific binding affinity to a therapeutic target protein associated with cancer (PTK7 receptor), and the plasma protein albumin (Abstract; Fig. 1). Ding teaches that their nucleic acid ligand employs a well-known strategy called an “HSA [human serum albumin] “hitchhike”,” owing to the presence of the HSA binding molecule, Evans blue (pg. 4109, left col.). Ding suggests that this hitchhike strategy can facilitate higher tumor accumulation of aptamers, because longer blood retention time will allow for more interaction time between tumor tissues and aptamers (pg. 4109, left col.). Indeed, Ding demonstrates that their non-natural nucleic acid ligand exhibits “prolonged blood half-life and increased tumor accumulation” (pg. 4109, left col.).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have combined a non-natural nucleic acid sequence of Tanaka with the HSA binding molecule Evans blue in view of Ding, to arrive at the invention of claims 1, 4, 6-9, 12-13. It would have amounted to combining a known nucleic acid sequence with binding affinity to a therapeutic target protein, with a known molecule which binds HSA and which is suitable for conjugation to a nucleic acid sequence, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in preparing the combination because the sequences of Tanaka’s nucleic acids were known, and because means to prepare a nucleic acid sequence conjugated to Evans blue was known as evidenced by Ding. The skilled artisan would have been motivated to combine a non-natural nucleic acid sequence of Tanaka with the HSA binding molecule Evans blue in an effort to leverage the “HSA [human serum albumin] “hitchhike”” strategy taught by Ding, for the potential therapeutic uses taught by Tanaka.
Regarding claims 10-11, KRAS G12V is a protein present in a cell, which would be considered a “tumor protein” (“Mutations in the KRAS gene are the most frequent among the RAS family, accounting for 85% of the total RAS mutations found in all tumors…” pg. 13, left col.).
Regarding claims 14-15, Tanaka teaches non-natural nucleic acid sequences within the recited length range, which consist of RNA nucleotides (Table 1).
Regarding claim 17, Tanaka’s non-natural nucleic acid sequences consist of single-stranded RNA (Table 1).
Conclusion
No claims are allowed.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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