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 .
Priority
The present application, filed November 20, 2023, is a national stage application of
PCT/US2022/030251, filed May 20, 2022, and claims the benefit of U.S. provisional application 63/191040, filed May 20, 2021.
Status of the Application
Applicant’s preliminary amendment, received June 3, 2024, wherein claims 12-18, 34, and 35 are amended and claims 19-33, 36, and 37 are canceled, is acknowledged.
Claims 1-18, 34, and 35 are pending and examined on the merits herein.
Drawings
The drawings are objected to because Figure 15 shows nucleotide structures with overlapping labels that are difficult to interpret. Please provide a corrected Figure 15 where the chemical structures do not include overlapping labels.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
Claim 1 claims a compound comprising one or more of the formulae shown in the claims. These formulae include a wavy line to denote a connection to another part of the compound. This wavy line is interpreted herein as permitting the formulae as conjugated to any atom, molecule, or macromolecule.
In addition, claim 4 depends from claim 1 and requires a macromolecule covalently linked to one or more, independently, of the formula
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. Claim 4 is thus interpreted as requiring a macromolecule that includes a formulae recited in claim 1 and the formula of claim 4. The formulae of claim 1 and the formula of claim 4 may comprise, at least in part, the same chemical structure. Claims 5-11 are interpreted in the same way as claim 4.
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 13 and 16 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.
Claim 13 recites: “The compound of one of claim 4, wherein each x is 3 or 4, and each n is 2 or 3.”
Claim 16 recites: “The compound of claim 4, wherein each x is the same, and each ligand is the same.”
There is insufficient antecedent basis for variables x and n recited in these claims. Claim 4 does not recite x or n. In addition, claim 1, from which claim 4 depends, also does not recite x or n. Therefore, it is unclear what x or n are intending to limit in claims 13 and 16. For the purposes of expedited prosecution, claims 13 and 16 are interpreted as depending from claim 5, which includes variables x and n.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-6 and 12-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. Claim 1 is drawn to a compound comprising one or more of the formulae shown in the claim. Claims 2-6 and 12-17 further limit the structure of the compound of claim 1. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Subject matter that is not patent eligible is determined by evaluating a claim for patentability based on the eligibility test set forth below:
(1) Is the claim directed to one of the four statutory categories, i.e., a process, machine, manufacture, or composition of matter? The answer is “Yes”. Claims 1-6 and 12-17 are drawn to a composition of matter.
(2a) Prong 1: Does the claim recite or involve a judicial exception? The answer is “Yes”. Claims 1-6 and 12-17 recite a product of nature.
The formula of claim 1 shown below is satisfied by the amino acid sequence lysine-lysine, wherein each J1 is N(H) and each R12 is H.
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In addition, the formula of claim 4 is satisfied by the amino acid sequence glycine-lysine-lysine, wherein each J1 is N(H) each R11 and R12 are H, and y is 1.
Adney (Adney, E. M; et al. Genetics 2019, vol. 213, pp. 1401-1414; cited in PTO-892) teaches a mutational analysis of the human retrotransposon LINE-1 (p. 1401, Title). Adney teaches the structure of the mutants in their tri-alanine library of the LINE-1 ORF1, showing that mutant 2 in their library, which has residues 5-7 mutated to alanine, includes the sequence GKK as residues 2-4 (p. 1404, Figure 1A). Therefore, Adney teaches the wild type LINE-1 ORF1 includes the sequence GKK as residues 2-4.
Wingfield (Wingfield, P. T.; et al. Current Protocols in Protein Science 2017, 88, 6.14.1–6.14.3; cited in PTO-892) teaches protein synthesis is initiated by methionine in eukaryotes, and methionine is removed either by cleavage of N-terminal signal peptide used for secretion or by the enzyme methionine aminopeptidase (MAP) (p. 1, Background section, lines 1-9). Wingfield teaches the sequence of the protein substrate can be designated P1–P1′–P2′–P3′–etc., where P1 is
N-terminal methionine and processing occurs between P1 and P1′. Wingfield teaches the specificity of MAP is determined by the size of the side chain of P1′ (p. 1, Specificity section, lines 1-7). Wingfield teaches that when P1′ is glycine, cleavage by methionine aminopeptidase occurs (p. 2, Table 6.14.1). Therefore, after translation of the human LINE-1 ORF1, the N-terminal methionine would be removed by MAP to reveal an N-terminal glycine-lysine-lysine sequence.
Furthermore, (Newton, J. C.; et al. bioRxiv 2020, doi: https://doi.org/10.1101/2020.10.29.360719; cited in PTO-892) teaches the sequence characteristics of the LINE-1 ORF1 N-terminal region (p. 10, second section under the discussion section). Newton cites Adney in teaching that deletion or mutation of the first three residues, GKK, reduces retrotransposition to 4.6% (emphasis added) (p. 10, second section under the discussion section, lines 6-9). Therefore, LINE-1 ORF1 includes the sequence element KK, which satisfies the limitations of claims 1-3 and 17. In addition, LINE-1 ORF1 includes, after removal of the N-terminal methionine, the sequence element GKK, satisfies the limitations of claim 4, wherein y is 1, J1 is N(H), and R11 is H. Finally, LINE-1 ORF satisfies claim 5, wherein y is 1, J1 is N(H), and R11 is H, x is 4, and n is 2, claim 6, wherein y is 1, J1 is N(H), R11 is H, x is 4, n is 2, and m is 0, and claims 12-16, which depend from claim 4 or claim 5.
Regarding claim 2, which further limits variable z and the ligand recited in claim 1, the present rejection applies to a formula of claim 1 that does not include variable z or a ligand. Accordingly, claim 2 further limits an alternative structure of claim 1, and thus is included in the present rejection. Similarly, claim 17 limits the variable z of claim 1, and thus is included in the present rejection.
Moreover, claim 15 further limits the ligand of claim 4. Because the present rejection applies to a formula of claim 4 that does not include a ligand, claim 15 further limits an alternative structure of claim 4, and thus is included in the present rejection.
(2a) Prong 2: Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is “No.” Claim 1 is drawn to a compound comprising one or more of the formulae as shown in the claim, and claims 2-6 and 12-17 further limit the structure of the compound of claim 1. However, none of claims 1-6 and 12-17 recite additional elements that integrate the judicial exception into a practical application.
(2b) Does the claim as a whole recite additional elements that amount to something significantly more than the judicial exception(s)? The answer is “No.”
Claim 1 is drawn to a compound comprising one or more of the formulae as shown in the claim, and claims 2-6 and 12-17 further limit the structure of the compound of claim 1. However, the structural elements of these claims do not amount to something significantly more than the judicial exception.
Therefore, in view of the foregoing, there is no indication that a compound of claims 1-3 and 17, satisfied by a protein sequence including a sequence element of lysine-lysine, or the compound of claims 4-6 and 12-16, satisfied by a protein sequence element of N-terminal glycine-lysine-lysine, possess markedly different characteristics than their naturally occurring counterparts existing in nature.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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 1-6 and 12-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Newton (Newton, J. C.; et al. bioRxiv 2020, doi: https://doi.org/10.1101/2020.10.29.360719; cited in PTO-892).
Newton teaches as described in the above rejection under 35 U.S.C. 101. Specifically, Newton teaches deletion or mutation of the first three residues of the LINE-1 ORF1, GKK, reduces retrotransposition to 4.6%. Therefore, the human LINE-1 ORF has an N-terminal sequence of GKK, which satisfies the requirements of claims 1-6 and 12-17, as described in the above rejection under 35 U.S.C. 101.
Thus Newton anticipates claims 1-6 and 12-17.
Claims 1-6 and 12-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Olah (Olah, Z.; et al. Plant Molecular Biology 1989, vol. 12, pp. 453-461; cited in PTO-892).
Olah teaches the bovine histone H 1 polypeptide contains several Phosphorylation sites for different protein kinases, and that the use of peptide substrates offers a powerful tool to investigate specificity determinants of various protein kinases. Olah teaches Phosphorylation
of the histone H2B-related peptide GKKRKRSRKA by the animal histone kinase II has been reported (p. 453, right column, first full paragraph, lines 1-9).
The peptide GKKRKRSRKA has an N-terminal GKK motif. As discussed in the above rejection under 35 U.S.C. 101, the N-terminal GKK sequence satisfies all requirements of claims 1-6 and 12-17.
Thus Olah anticipates claims 1-6 and 12-17.
Claims 1-6, 13, 16, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Valentijn (Valentijn, et. al. Tetrahedron 1997, vol. 53, pp. 759-770; cited in IDS received 01/09/2024).
Valentijn teaches di- and tri-antennary lysine-based galactose- and N-acetylgalactosamine-containing ligands for the hepatic asialoglycoprotein receptor (ASGP-R) (p. 759, Abstract, lines 1-3). As one example, Valentijn teaches compound 10 (p. 760, Figure 2; structure shown below), which has X as HN(CH2)3C(O)HN and R as NHAc.
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Compound 10 of Valentijn satisfies the requirements of a compound of claim 1 that includes the formula below.
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Compound 10 includes each J1 as N(H) and each R12 as -C(O)(CH2)z-(ligand), wherein z is 4 and the ligand is a carbohydrate. The ligand is an N-acetylated galactosamine moiety, as recited in claim 2, and includes z as 4, as required by claim 17.
In addition, Valentijn teaches compound 43 (p. 763, Figure 3; structure shown below). This compound is the same compound as claim 10, but conjugated to a solid support and with the hydroxyl groups of the GalNAc ligand modified with protecting groups. In this instance, the protected GalNAc groups are carbohydrates, as recited in claim 1, and thus satisfy the requirement of a ligand, and the macromolecule is a solid support, as required by claims 3-6, 13, and 16.
Therefore, compound 43 satisfies the requirements of claim 3, claim 4 wherein y is 3, J1 is NH, and R11 is -C(O)(CH2)z-(ligand) with z as 4, claim 5 wherein x is 4, J1 is NH, R11 is -C(O)(CH2)z-(ligand) with z as 4, and n is 2, and claim 6 wherein x is 4, J1 is NH, R11 is -C(O)(CH2)z-(ligand) with z as 4, n is 2, and m is 0. Moreover, compound 43 satisfies the limitations of claims 13 and 16.
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Thus Valentijn anticipates claims 1-6, 13, 16, and 17.
Claim Rejections - 35 USC § 103
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, 3-6, 12, 13, 15, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Valentijn (Valentijn, et. al. Tetrahedron 1997, vol. 53, pp. 759-770; cited in IDS received 01/09/2024) in view of Manoharan (Publication no. WO 2015006740 A2; cited in IDS received 01/09/2024).
Claims 1-6, 13, 16, and 17 are anticipated by Valentijn, as described in the above rejection under 35 U.S.C. § 102. In addition, claims 1, 3-6, 12, 13, 15, and 16 are obvious over Valentijn in view of Manoharan, as described below.
Valentijn teaches as described in the above rejection under 35 U.S.C. § 102. Specifically, Valentijn teaches compound 10, which satisfies the requirements of a compound of claim 1 and further includes
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, as required by claim 4. Compound 10 satisfies all requirements of claim 4 wherein y is 3, J1 is N(H), and R11 is -C(O)(CH2)z-(ligand), and z is 4, except for the requirement that the compound of claim 4 comprises a macromolecule. This compound similarly satisfies the limitations of claims 5 and 6, wherein y is 3, J1 is N(H), each R11 is -C(O)(CH2)z-(ligand) with z as 4, n is 2, and m is 0, except for the requirement that compound comprises a macromolecule
In addition, Valentijn teaches that recognition and uptake of β-D-galacto- or 2-acetamido-2-deoxy-β-D-galactopyranosyl-terminated glycoproteins by the hepatic asialoglycoprotein receptor (ASGP-R), uniquely localized on parenchymal liver cells, is a high-affinity and high-capacity process. Valentijn teaches these features were an incentive to use ligands for this receptor as a targeting device for the specific delivery of drugs or genes to parenchymal liver cells (p. 770, Introduction section, lines 1-4).
Valentijn does not teach compound 10 conjugated to a macromolecule, as required by the instant claims.
Manoharan teaches ligand-conjugates of oligonucleotides and methods for their preparation. Manoharan teaches the ligands are derived primarily from monosaccharides, and the conjugates are useful for the in vivo delivery of oligonucleotides (cover page, Abstract, lines 1-3).
Manoharan teaches that efficient delivery to cells in vivo requires specific targeting and substantial protection from the extracellular environment, and one method of achieving specific targeting is to conjugate a targeting moiety to the iRNA agent (p. 1, Background of the invention section, lines 1-3). Manoharan teaches the asialoglycoprotein receptor (ASGP-R) is a high capacity receptor, highly abundant on hepatocytes, and shows a 50-fold higher affinity for N-Acetyl-D-Galactosylamine (GalNAc) than D-Gal. Manoharan teaches that certain carbohydrate conjugates have been shown to be a valuable delivery alternatively to liposomes for siRNA delivery (p. 1, Background, line 12 to p. 2, line 4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to conjugate compound 10 to a macromolecule, such as an siRNA agent, for the purposes of delivering siRNA to hepatocytes. One of ordinary skill in the art would have been motivated to conjugate compound 10 to a macromolecule, such as an siRNA agent, for the purposes of delivering siRNA to hepatocytes because Valentijn teaches their ligands as having affinity for the ASPG-R receptor and suggests they may be conjugated to drugs or genes, and because Manoharan suggests conjugates of ligands for the ASPG-R receptor that consist of oligonucleotides. Accordingly, one of ordinary skill in the art would have recognized compound 10 as a ligand to target ASPG-R on hepatocytes, and thus would have contemplated a conjugate comprising compound 10 and an oligonucleotide macromolecule, such as an siRNA agent.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Valentijn teaches compound 10 as a ligand for ASPG-R, and Manoharan suggests conjugates of ligands for the ASPG-R receptor that include oligonucleotides like GalNAc, one of ordinary skill in the art would have reasonably considered substituting a ligand in an oligonucleotide conjugate of Manoharan targeting ASPG-R for compound 10 of Valentijn, because such a substitution would be expected to also target the oligonucleotide to ASPG-R-expressing hepatocytes.
Therefore the invention taken as a whole is prima facie obvious.
Claims 7-9, 18, and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Valentijn (Valentijn, et. al. Tetrahedron 1997, vol. 53, pp. 759-770; cited in IDS received 01/09/2024) in view of Manoharan (Publication no. WO 2015006740 A2; cited in IDS received 01/09/2024) as applied to claim 1 above, and further in view of Khvorova (Publication no. WO 2018031933 A2; cited in PTO-892).
Valentijn teaches as described in the above rejections under 35 U.S.C. 102 and 35 U.S.C. 103. Specifically, Valentijn teaches compound 43 (p. 763, Figure 3; structure shown below). This compound is the same compound as compound 10, but conjugated to a solid support and with the hydroxyl groups of the GalNAc ligand modified with protecting groups. Valentijn further teaches deprotection and release from the solid support of the fully protected and immobilized galactoside compound 43 was achieved by treating of sodium hydroxide resulting in crude compound 10 (p. 763, second paragraph, lines 1-4).
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In addition, Valentijn teaches the importance of the linker length affecting the affinity of their compounds for ASPG-R. Valentijn teaches that the derivative of compound 10 with X as NH (named as compound 8 by Valentijn) has a Ki value for parenchymal liver cells of 4 nM, and compound 10 has a Ki value of 3 nM (p. 763, Table 1). Valentijn teaches compound 9, which has X as glycine, has lower affinity for parenchymal liver cells with a Ki of 10 nM. Valentijn teaches this observation may be ascribed to a restricted conformational flexibility of the glycyl-lysine moiety in compound 9 compared with compound 8, and as expected, the presence of the conformationally less restricted γ-aminobutyric acid unit in compound 10 had only little effect on the affinity (p. 764, first paragraph, lines 7-11).
Valentijn does not teach a compound that satisfies all limitations of present claims 7-9 and 18.
Manoharan teaches as described in the above rejection under 35 U.S.C. 103. In addition, Manoharan teaches linker structures that may be used for the conjugation of oligonucleotides to a ligand. Specifically, Manoharan teaches that when the linker group is incorporated into an intermediate compound useful for preparing a conjugate of the present invention, X can be a
reactive phosphoramidite compatible with solid phase oligonucleotide synthesis and deprotection, or attached to a solid support (e.g.,
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) that enables solid phase oligonucleotide synthesis (p. 5, Linker Groups section, lines 1-8).
As exemplary linker structures, teaches
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and
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(pp. 5-6). Each of these are related to the linker of claim 9, except the first structure is missing the carbon denoted by W, and the second structure is missing the methylene group adjacent to O-X. Manoharan teaches the DMTr group may be removed under acidic conditions (p. 81, caption, Scheme 9 caption, lines 4-5), and thus is considered as an acid-labile group.
Moreover, Manoharan teaches each of the above linkers conjugated to an oligonucleotide. Manoharan specifically teaches the linker structures
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and
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(pp. 8-9).
Manoharan further teaches triantennary GalNAc ligands that may be used for solid-phase oligonucleotide synthesis. As one example, Manoharan teaches a cytidine analog derivatized with a triantennary GalNAc ligand at the C-5 position of the cytidine nucleobase (p. 106, Scheme 23; structure shown below). These GalNAc ligands are protected with acetyl groups. Manoharan further teaches such an analog may be converted to a phosphoramidite or conjugated to a solid support, indicating its suitability for solid-phase oligonucleotide synthesis.
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Manoharan further teaches their invention includes ligand conjugates of oligonucleotides which have advantageous properties, such as improved delivery of the oligonucleotide or other biologically active agents (p. 2, Summary of the Invention section, first paragraph, lines 1-3). Manoharan teaches their conjugates can be formulated for administration to a subject, and that it is understood these formulations, compositions and methods can be practiced with conjugates of other oligonucleotides (p. 62, Formulations section, lines 1-5) (emphasis added).
Finally, Manoharan teaches an oligonucleotide of their invention may be an siRNA or iRNA agent (p. 47, first paragraph, lines 1-4), and that the term "iRNA agent" refers to an RNA agent (or can be cleaved into an RNA agent) which can down regulate the expression of a target gene (e.g., a siRNA) (p. 47, third paragraph, lines 1-2). Manoharan teaches the sequence of the iRNA agent, or a cleavage product thereof, is able to direct sequence specific silencing (p. 47, fourth paragraph, lines 5-7). This is interpreted herein as equivalent to an activation of gene silencing.
Khvorova teaches oligonucleotide conjugates characterized by efficient and specific tissue distribution (cover page, Abstract). Khvorova teaches that the linker L in their conjugates, which connects an oligonucleotide to a hydrophobic moiety (pp. 32-33, [0192]) may be the divalent linker (L2) (p. 33, [0195]; structure shown below).
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify compound 10 of Valentijn with a linker that satisfies the present claims 7-8. One of ordinary skill in the art would have been motivated to modify compound 10 with a linker that satisfies present claims 7-8 because Valentijn suggests compound 10 conjugated to, for example, a gene, to promote delivery to liver cells, because Manoharan also teaches triantennary GalNAc ligands conjugated to oligonucleotides for targeting liver cells, further suggesting suitable linkers for such a conjugation, and because Khvorova teaches a specific linker that satisfies the requirements of claims 7-8 for conjugation of a peptide to a nucleic acid.
In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because Valentijn teaches triantennary GalNAc ligands that may be used for gene delivery, Manoharan teaches linkers that may be used to conjugate triantennary GalNAc ligands to, for example, oligonucleotides, and Khvorova teaches additional linkers that are structurally similar to those of Manoharan for conjugation of ligands to oligonucleotides, including a linker required by claims 7 and 8, one of ordinary skill in the art would have considered the full scope of linkers taught by Manoharan and Khvorova for conjugation of compound 10 to an oligonucleotide macromolecule, including the specific linker taught by Khvorova.
Regarding the additional succinic acid linker required by the structure of claim 9, because Manoharan teaches conjugation of the linker to a succinic acid group and solid support for solid-phase oligonucleotide synthesis, one of ordinary skill in the art would have considered modifying compound 43 of Valentijn by conjugation to a solid support by a linker known in the art, including the linker of Khvorova. Moreover, one of ordinary skill in the art would have contemplated modifying the linker of Khvorov with a succinic acid linker to a solid support and additional DMTr protection, as taught by Manoharan, because such modifications would permit this derivative of compound 43 to be used for solid-phase oligonucleotide synthesis. In addition, because Valentijn teaches the deprotection and release of compound 43 achieved under basic conditions using sodium hydroxide, one of ordinary skill in the art would have recognized compound 43 as compatible with the conditions required by solid-phase oligonucleotide synthesis.
Furthermore, because Manoharan teaches triantennary GalNAc ligands protected with acetyl groups and used for solid-phase oligonucleotide synthesis, one of ordinary skill in the art would have contemplated the derivative of compound 43 obvious over Valentijn in view of Manoharan and Khvorova with acetyl groups in place of the benzyl protecting groups, because each would be expected to be effective protecting groups to enable solid-phase synthesis of oligonucleotides derivatized with triantennary GalNAc ligands.
Regarding claim 18, compound 10 of Valentijn satisfies all requirements of the compound of claim 18 shown below, except for the specific linker to the macromolecule and the middle linker derived from 5-aminopentanoic acid linker. Compound 10 of Valentijn teaches this linker derived from 4-aminobutyric acid.
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify compound 10 of Valentijn and prepare the above compound of claim 18. One of ordinary skill in the art would have been motivated to modify compound 10 of Valentijn and prepare the above compound of claim 18 because Valentijn suggests compound 10 conjugated to, for example, a gene, to promote delivery to liver cells, because Manoharan also teaches triantennary GalNAc ligands conjugated to oligonucleotides for targeting liver cells, further suggesting suitable linkers for such a conjugation, and because Khvorova teaches the specific linker shown in claim 18 for conjugation of a ligand to an oligonucleotide.
In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because Valentijn teaches triantennary GalNAc ligands that may be used for gene delivery, Manoharan teaches linkers that may be used to conjugate triantennary GalNAc ligands to, for example, oligonucleotides, and Khvorova teaches additional linkers for conjugation of ligands to oligonucleotides, including the linker of claim 18, one of ordinary skill in the art would have considered the full scope of linkers taught by Manoharan and Khvorova for conjugation of compound 10 to an oligonucleotide macromolecule, including the specific linker taught by Khvorova.
Regarding the linker derived from 5-aminopentanoic acid required in the compound of claim 18, because compound 10 of Valentijn includes a linker derived from 4-aminobutyric acid, and because Valentijn teaches that the length of this linker has an effect on the affinity of these compounds for ASPG-R, one of ordinary skill in the art would have contemplated derivatives of compound 10 with longer linkers, including a linker longer by 1 carbon, because a longer linker in this position may have even higher affinity for ASPG-R than compound 10.
Regarding claims 34-35, because Manoharan suggests compositions comprising ligand-oligonucleotide conjugates and a method of activating gene silencing in a cell using ligand-oligonucleotide conjugates, such as conjugates comprising ligand and iRNA agent, one of ordinary skill in the art would have contemplated compositions comprising a compound of claim 18, and the method of activating gene silencing in a cell by contacting the cell with a compound of claim 18, each obvious over Valentijn in view of Manoharan and Khvorova.
Therefore the invention taken as a whole is prima facie obvious.
Allowable Subject Matter
Claims 10-11 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 10-11 require the structures as shown in the claims, each of which include the amino acid substituted with variable group R3 between the peptide and linker. Claims 10-11 require variable group R3 includes a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group.
The closest prior art to the structure of claims 10-11 is considered the combination of Valentijn, Manoharan, and Khvorov, each as described in the above rejections under 35 U.S.C. 102 and 103. However, none of Valentijn, Manoharan, and Khvorov, nor any other prior art identified by the Office, teach or suggest inclusion of an amino acid substituted with variable group R3 between the linker to the solid support and a ligand. Manoharan generally teaches the use of peptide scaffolds for displaying carbohydrate-containing ligands (e.g., see structures on pp. 16-18). However, Manoharan does not teach a specific compound that satisfies the requirements of claims 10 or 11, and Manoharan does not provide guidance that would motivate one of ordinary skill in the art to modify another carbohydrate-containing ligand, such as a compound of Valentijn, to include the amino acid substituted with variable group R3 as required by claims 10 and 11.
Conclusion
Claims 1-9, 12-18, 34, and 35 are rejected.
Claims 10-11 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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/B.M.B./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693
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