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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on August 5, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
Claims 1, 3 and 5-9 are currently pending in the instant application. Claims 1, 3, 6, 7 and 9 have been amended by Applicants’ amendment filed 08-05-2026. Claims 2, 4 and 10-14 have been canceled by Applicant’s amendment filed 08-05-2026. No claims have been added by Applicants’ amendment filed 08-05-2026.
Applicant's election with traverse of Group I, claims 1-9, directed to a method of screening an inhibitor; and Applicant’s election of Species as follows:
Species (A): selecting a substance is performed by using one or more x-ray crystallography, cryogenic electron microscopy and NMR spectroscopy (claim 3); and
Species (B): where the candidate substance is subjected to an in vivo antibiotic resistance assay, or a minimal inhibitory concentration (MIC assay) measurement (claim 9), in the reply filed November 25, 2025 was previously acknowledged.
Claims 10-14 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on October 22, 2025.
Claims 2 and 4 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement was deemed proper and was made FINAL.
The claims will be examined insofar as they read on the elected species.
Therefore, claims 1, 3 and 5-9 are under consideration to which the following grounds of rejection are applicable.
Declaration
The Examiner acknowledges receiving an executed Declaration under 37 C.F.R. § 1.130(b) signed by Hak Jin Lee on April 1, 2026 (“Lee Decl.”), and filed on April 9, 2026. The Lee decl. has been considered.
Priority
The present application filed July 15, 2022, claims the benefit of Republic of Korea Application KR10-2021-0093127, filed July 15, 2021.
Acknowledgment is made of Applicant's claim for foreign priority based on an Application filed in Republic of Korea (KR10-2021-0093127) on July 15, 2021.
Acknowledgment is made of the receipt of the certified English translation of the Republic of Korea patent application KR10-2021-0093127, filed April 9, 2026.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed August 5, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below are herein withdrawn.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 3 and 5-9 is withdrawn under 35 U.S.C. 103 as being unpatentable over Maravic et al. (hereinafter “Maravic”) (Nucleic Acids Research, 2003, 31(16), 4941-4949; of record) in view of Foik et. al. (hereinafter “Foik”) (European Journal of Medicinal Chemistry, 2018, 146, 60-67; and Supplementary Material, 2018, 1-11) as evidenced by Lee et al. (hereinafter “Lee”) (Antibiotics, 2021, 10(264), 1-17; of record).
The combined references are not the strongest references in light of the instant amendments to the claims.
In view of the withdrawn rejection, Applicant’s arguments are rendered moot.
Maintained Objections/Rejections
Claim Objections
The objection to claims 1 and 7 is maintained, and claim 8 is newly objected to, because of the following informalities: Claims 1, 7 and 8 recite the terms "Ser”, “Gln”, “Asn,” “Phe”, “ErmC’,” “ErmS,” where an abbreviation should be spelled out in the first encounter of the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 3 and 5-9 is maintained under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 is indefinite for the recitation of the term “substrate recognition” such as recited in claim 1, lines 10 and 15 because it is completely unclear what Erm protein substrate is being referred to that is interfered with by a conformational change in a region comprising the NTER and/or the shortest motif X (e.g., Domain V of bacterial 23S rRNA; CD44, proteins, etc.) and, thus, the metes and bounds of the claim cannot be determined.
Claims 1 and 6 are indefinite for the recitation of the term “an RNA substrate and/or a ligands” such as recited in claim 1, lines 11-12 because it is unclear whether the term is reciting: (i) an RNA substrate and/or a ligand; (ii) an RNA substrate and/or a ligand for an RNA substrate; or (iii) an RNA substrate and/or an Erm ligand. Moreover, it is unclear whether the term “RNA substrate” recited in line 12 refers to the “substrate” recognized by the Erm protein referred to in lines 10 and 15 and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “the spatial arrangement of residues” such as recited in claim 1, line 14. There is insufficient antecedent basis for the term “the spatial arrangement of residues” in the claim.
Claims 1, 7 and 9 are indefinite for the recitation of the term “target adenine residue” such as recited in claim 1, line 17 because instant claim 1 does not recite any specific RNA substrate, such that it is unclear whether all RNA substrates will comprise an adenine residue that can be affected by an Erm protein including inhibiting or eliminating methylation in an antibiotic resistance assay, or that it will have an MIC (claim 9) and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “thereby selecting the candidate as the inhibitor of the Erm protein” such as recited in claim 1, line 18 because it is unclear how merely determining whether the conformational change is induced by the candidate substance “thereby selects the candidate as an inhibitor of the Erm protein”. The outcome of “determining” is either “yes” a conformational change leads to inhibition, or “no” a conformational change does not lead to inhibition, such that an inhibitor is selected regardless of the outcome of “determining” (e.g., even if there is no inhibition or elimination of methylation of a target residue) and, thus, the metes and bounds of the claim cannot be determined.
Claim 3 is indefinite for the recitation of the term “contacting in (b) comprises using one or more of X-ray crystallography…(NMR) spectroscopy” such as recited in claim 3, lines 1-3 because claim 3 depends from claim 1, wherein claim 1 already recites what (c) comprises (e.g., contacting the substance with an Erm protein…), such that claim 3 cannot recite that “contacting” comprises something entirely different. Moreover, it is unclear how a step of “contacting” comprises analytical techniques that appear to more properly align within steps (a) or (c) which recite designing and/or determining – which is consistent with the instant as-filed Specification at paragraphs [0036]-[0037] (e.g., selecting using one or more of x-ray crystallography, etc.) and paragraph [0040] (e.g., determining the structure from analysis by x-ray crystallography, etc.) and, thus, the metes and bounds of the claim cannot be determined.
Claim 7 is indefinite for the recitation of the term “a hydroxyl group of Ser in the shortest motif X ” such as recited in claim 7, line 4 because only a limited number of Erm proteins comprise a serine in the shortest motif X (please see the instant Specification, Figure 1). The term SQNF is only recited in the preamble of claim 1, thus, instant claim 1 encompasses all Erm proteins comprising an NTER and/or a motif X (e.g., all Erm proteins). However, only fourteen (14) out of forty-four (44) Erm proteins illustrated in Figure 1 comprise the SQNF motif, such that it is unclear whether inhibition of methylation of a target adenine can be determined for all Erm proteins encompassed in claim 1 that undergo a conformational change after contact with a substance including when there is no serine present and, therefore, no spatial distance change between Gln and Ser and, thus, the metes and bounds of the claim cannot be determined.
Claim 7 is indefinite for the recitation of the term “the exocyclic nitrogen atom at the 6-position” such as recited in claim 7, line 9. There is insufficient antecedent basis for the terms “the exocyclic nitrogen atom” and “the 6-position” in the claim. Moreover, claim 7 depends from claims 1 and 6, wherein claims 1 and 6 do not identify the specific RNA substrate that complexes with the Erm protein, such that it is unclear whether all RNA substrates will comprise a target adenine residue having an exocyclic nitrogen atom at the 6-position and, thus, the metes and bounds of the claim cannot be determined.
Claim 9 is indefinite for the recitation of the term “applying the candidate substance selected in (c) to lead to inhibition or elimination of methylation of a target adenine residue” in claim 9, lines 2-3 because the claim recites an outcome as opposed to reciting a step or component of a process and, thus, the metes and bounds of the claim cannot be determined. The Examiner suggests that Applicant amend the claim to recite, for example, “subjecting the candidate substance selected in (c) to an in vivo antibiotic resistance assay or to an MIC assay.”
Claims 5 and 8 are indefinite insofar as they ultimately depend from instant claim 1.
Claim Rejections - 35 USC § 112(d)
The rejection of claims 3 and 9 is maintained, and claim 7 is newly rejected, under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3 recites (in part): “wherein the contacting in (b) comprises using one or more of X-ray crystallography, cryogenic electron microscopy…(NMR) spectroscopy” in lines 1-3 because claim 3 depends from instant claim 1, wherein the step of “contacting in (b)” does not comprise using the various instrumentation and/or analysis techniques as recited in claim 3. Moreover, the as-filed specification does not support the use of these techniques for “contacting” the substance with an Erm protein. Thus, claim 3 is an improper dependent claim for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 7 and 9 recite (in part): “a target adenine” in claim 7, line 9 because claim 7 depends from claims 1 and 6; and claim 9 depends from instant claim 1, wherein claims 1 and 6 do not recite any specific RNA substrate, such that not all RNA substrates will comprise a target adenine including an exocyclic nitrogen atom at the 6-position (claim 7); or that every substance is a candidate substance, and is therefore selected in (c) (e.g., because every substance undergoes the determining step, and are thereby selected), such that they will all lead to inhibition or elimination of methylation in an antibiotic resistance assay, or an MIC measurement (claim 9). Thus, claims 7 and 9 are improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
New Objections/Rejections
Notice of Non-Compliant Amendment (37 CFR 1.121)
The amendment to the claims filed on August 5, 2026 does not comply with the requirements of 37 CFR 1.121(c) because the status identifiers of claim 48 has been submitted with improper markings to indicate that changes have been made relative to the immediate prior version of claims filed on April 9, 2026.
Amendments to the claims filed on or after July 30, 2003 comply with 37 CFR 1.121(c), which states:
(c)(2) Claims - When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.”
Specifically, instant claim 3 in the claims filed August 5, 2026 does not include strike-throughs, underlining, double brackets, etc. that indicate that amendments have been made to instant claim 3. For example, claim 3, lines 1-3 recites the term “wherein the contacting in (b) comprises using one or more of X-ray…spectroscopy”; while claim 3, lines 1-3 (of the claims filed 04-09-2026) recites the term “wherein the selecting a candidate substance is performed by using one or more of x-ray…spectroscopy.” There are no markings indicating amendments to the instant claims as compared to the claims filed 04-09-2026.
To be fully responsive, Applicant is required to comply with the Notice of Non-Compliant Amendment (37 CFR 1.121). In the interests of compact prosecution, an action on the merits has been prepared. However, future amendments must comply with 37 CFR 1.121(c) in order to avoid a notice of non-compliant amendment.
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, 3 and 5-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. An analysis with respect to the claims as a whole reveals that they do not include additional elements that are sufficient to amount to significantly more than the judicial exception. See Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 110 U.S.P.Q.2d 1976 (2014); Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116, 106 U.S.P.Q.2d 1972 (2013); Mayo Collaborative Svcs. v. Prometheus Laboratories, Inc., 132 S. Ct. 1289, 101 U.S.P.Q.2d 1961 (2012). See also 2014 Interim Guidance on Patent Subject Matter Eligibility, available at http://www.gpo.gov/fdsys /pkg/ FR-2014- 12-16/pdf/2014-29414.pdf (“2014 Interim Guidance”), and the Office’s examples to be considered in conjunction with the 2014 Interim Guidance in examination of nature-based products, available online at http://www.uspto.gov/patents/law/exam/mdc_examples_nature-based_products.pdf (“Nature-Based Products Examples”). This rejection is proper.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of three issues: (1) whether the claim is directed to one of the four categories recited in §101; (2) whether the claim recites or involves a judicial exception (i.e., a law of nature, natural phenomenon, or natural product); and (3) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. In the instant case, the claims are directed to a natural product; as well as, being directed to an abstract idea. Therefore, they must each be considered to determine whether, given their broadest reasonable interpretation, they amount to significantly more than the judicial exception.
The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claims 1, 3 and 5-9 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below.
In the instant case, claims 1, 3 and 5-9 are broadly directed to a method of screening an inhibitor of an erythromycin ribosome methylation (Erm) protein that induces resistance to macrolide-licosamide-streptogramin B (MLSB) antibiotics by targeting a region of the Erm protein comprising an N-terminal end region (NTER) and/or a shortest motif X immediately following the NTER, wherein the shortest motif X consists of an amino acid sequence Ser-Gln-Asn-Phe (SONF), the method comprising: (a) designing substance that targets the region of the Erm protein comprising the NTER and/or the shortest motif X and induces a conformational change so as to interfere with substrate recognition by the Erm protein; (b) contacting the substance with the Erm protein or a complex of the Erm protein and an RNA substrate and/or a ligand to select a candidate substance that induces a conformational change in the region of the Erm protein comprising the NTER and/or the shortest motif X, wherein the conformational change alters the spatial arrangement of residues within the NTER and/or the shortest motif X and interferes with substrate recognition by the Erm protein; and (c) determining whether the conformational change induced by the candidate substance leads to inhibition or elimination of methylation of a target adenine residue in the RNA substrate by the Erm protein, thereby selecting the candidate substance as the inhibitor of the Erm protein.
Beginning with Step I of the analysis, which asks whether the claimed invention falls within a statutory category, such that the instant claims are directed to a process comprising a natural phenomenon and an abstract idea, thus, the instant claims are directed to a statutory category. Step I: [YES].
Proceeding to Step IIA – Prong One: of the analysis, which asks if the claimed invention is directed to a judicial exception. Instant claims 1, 3 and 5-9 are drawn to natural phenomenon in the form of a natural correlation between contacting a substance with an Erm protein or a complex of the Erm protein and an RNA substrate and/or a ligand; wherein the substance induces a conformational change in the region of the Erm protein comprising the NTER and/or the shortest motif X; and does or does not lead to inhibition or elimination of methylation of a target adenine residue in the RNA substrate by the Erm protein; and an abstract idea including: (1) mathematical concepts such as mathematical relationships, formulas and/or calculations (e.g., designing a substance that targets the region of the Erm including the NTER and/or the shortest motif X such as by using x-ray crystallography, cryo-EM, NMR, etc.; measuring changes in the spatial distance between amino acid residues; determining whether the conformational change induced by the candidate substance leads to inhibition or elimination of methylation of a target adenine residue in the RNA substrate by the Erm protein such as by an in vivo antibiotic resistance assay, MIC measurement, etc.). The claims are broadly directed to assessing the ability of a candidate molecule to produce a metabolic product. Step IIA – Prong One [YES].
Proceeding to revised Step IIA – Step IIA - Prong Two of the analysis asks whether the claim recites additional elements that integrate the exception into a practical application of the exception. In the instant case, the dependent claims are directed to a judicial exception in the form of a natural phenomenon and an abstract idea. Claims 1 recites: “designing substance that targets the region of the Erm protein comprising the NTER and/or the shortest motif X and induces a conformational change so as to interfere with substrate recognition by the Erm protein” in line 7-10; “contacting the substance with the Erm protein or a complex of the Erm protein and an RNA substrate and/or a ligand to select a candidate substance that induces a conformational change in the region of the Erm protein comprising the NTER and/or the shortest motif X, wherein the conformational change alters the spatial arrangement of residues within the NTER and/or the shortest motif X and interferes with substrate recognition by the Erm protein” in lines 11-15; and “determining whether the conformational change induced by the candidate substance leads to inhibition or elimination of methylation of a target adenine residue in the RNA substrate by the Erm protein, thereby selecting the candidate substance as the inhibitor of the Erm protein” in lines 16-18, which resembles “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)), and are analogous to “organizing information through mathematical correlations” (i.e. Digitech Image Techs., LLC v Electronics for Imaging, Inc., 758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)); and are examples of “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)); and resembles “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Additionally, the dependent limitations of claims 3 and 5-9 also suffer from the same issue. In other words, the dependent limitations do not rectify the rejection of the independent claim. By way of example, the limitations of claim 3 provides: “wherein the contacting in (b) comprises using one or more of X-ray crystallography, cryogenic electron microscopy (cryo-EM), and nuclear magnetic resonance (NMR) spectroscopy”; while claim 9 recites, “further comprising applying the candidate substance selected in (c) to lead to inhibition or elimination of methylation of a target adenine residue in the RNA substrate to an in vivo antibiotic resistance assay or to a minimal inhibitory concentration (MIC) measurement” in lines 1-4, which is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)); and “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Thus, the claims do not integrate the judicial exceptions into a practical application of the exceptions. Step IIA – Prong Two [NO].
Thus, the claims do not integrate the judicial exceptions into a practical application of the exceptions. Step IIA – Prong Two [NO].
Proceeding to Step IIB of the analysis: the question then becomes what element or what combination of elements is sufficient to amount to significantly more than the abstract idea? The instant independent claims are recited at a high level of generality, such that substantially all practical applications of the judicial exception related to the method of assessing a candidate molecule are covered. For instance, the claims are recited without any specificity as to the identity of the Erm protein; the identity of the substrate; the identity of the RNA substrate; the structure of the NTER region; the structure of the shortest motif X; the method of designing; the substance; the conformational change induced; the method of interfering; the substrate recognized by the Erm protein; the method of contacting; the complex; the identity of the ligands; the method of determining; how candidate substances are selected even if there is no conformational change and/or no inhibition or elimination of methylation; the method of selecting; the alteration in the conformational change; the target adenine residue; the identity of the candidate substances; the amount of inhibition of methylation, etc., wherein the steps of the method are well known, purely conventional or routine in the art. Step IIB: [NO].
For example, it was known that macrolide–lincosamide–streptogramin B antibiotic resistance occurs through the action of erythromycin ribosome methylation (Erm) family proteins, causing problems due to their prevalence and high minimal inhibitory concentration, and feasibilities have been sought to develop inhibitors. Erms exhibit high conservation next to the N-terminal end region (NTER) as in ErmS, 64SQNF67. Side chains of homologous S, Q and F in ErmC’ are surface-exposed, located closely together and exhibit intrinsic flexibility; these residues form a motif X. In S64 mutations, S64G, S64A and S64C exhibited 71%, 21% and 20% activity compared to the wild-type, respectively, conferring cell resistance. However, mutants harboring larger side chains did not confer resistance and retain the methylation activity in vitro. All mutants of Q65, Q65N, Q65E, Q65R, and Q65H lost their methyl group transferring activity in vivo and in vitro. At position F67, a size reduction of side-chain (F67A) or a positive charge (F67H) greatly reduced the activity to about 4% whereas F67L with a small size reduction caused a moderate loss, more than half of the activity. The increased size by F67Y and F67W reduced the activity by about 75%. In addition to stabilization of the cofactor, these amino acids could interact with substrate RNA near the methylatable adenine presumably to be catalytically well oriented with the SAM (S-adenosyl-L-methionine). These amino acids together with the NTER beside them could serve as unique potential inhibitor development sites as evidenced by Lee (Antibiotics; Abstract). Additionally, contacting peptides with ErmSF protein or a complex of the ErmSF protein and a 23S rRNA substrate to produce a conformational change in ErmSF including in the NTER and motif X, wherein the conformational change produces inhibition in methylation, followed by an in vivo antibiotic resistance assay was known in the art as evidenced by Jin (The Korean Journal of Microbiology; Abstract; pg. 8, Briefs; and Figures 3 & 5). Moreover, molecular docking approach followed by biochemical screening was applied to search for inhibitors targeting both cofactor and substrate binding pockets of ErmC’ methyl-transferase, such that based on the results of the molecular docking-based virtual screening of the clean-leads subset of the ZINC database, 29 compounds were chosen for experimental verification including inhibitor 28 (ZINC code 32747906), with an IC50 of 100 mM, decreased the minimal inhibitory concentration of erythromycin in the Escherichia coli strain overexpressing ErmC' (interpreted as assaying for MIC), wherein docking analysis of inhibitor 28 to the ErmC’ structure and the competitive ligand binding assay revealed a non-competitive model of inhibition, such that inhibitor 28 served as a template for similarity-based virtual screening, which resulted in the identification of two derivatives 3s (ZINC code 62022572) and 4s (ZINC code 49032257) with an IC50 of 116 mM and 110 mM, respectively; and that based on ligand docking into the target site, the probable chemical bonds between the inhibitors 28, 3s and 4s and the amino acid residues of ErmC’ were determined (Figure S1), wherein all three inhibitors interact with the same nine amino acids, e.g., Gln10, Asn 11, Phe12, Gly38, Gly40, Asn101, Ile102, Pro103, Tyr104; and the last four amino acids are included in the 100-GNIPY sequence found in motif IV; and that that potential lead compounds should selectively bind to the ErmC' to block its rRNA methylation activity, wherein the potency of the chosen compounds in the inhibition of ErmC' was determined at a concentration range of 125-500 mM, such that 23 compounds inhibited the in vitro activity of ErmC' (Table 1) was known in the art as evidenced by Foik (European Journal of Medicinal Chemistry; Abstract; of record; pg. 62, col 2, second full paragraph; pg. 65, col 1, last partial paragraph; and Figure S1). Thus, the steps of the method for screening for substances that target the NTER and/or shortest motif X of an Erm protein (including in silico screening), to produce a conformational change is induced, and determine whether the conformational change produces inhibition in methylation, followed by an in vivo antibiotic resistance assay was well known, purely conventional, or routine in the art including the detection and analysis of proteins associated with preeclampsia. Step IIA [YES].
In sum, when the relevant factors are analyzed, the claims as a whole do NOT recite additional elements that amount to significantly more than the judicial exception itself. Accordingly, claim 1 DOES NOT qualify as eligible subject matter.
Dependent claim(s) 3 and 5-9 when analyzed as a whole are held to be patent ineligible under 35 U.S.C. 101 because they do not add anything that makes the abstract idea recited in claim 1 significantly different. For example, claim 5 encompasses the method of claim 1, wherein the candidate substance is a compound, a nucleic acid, a peptide, or a protein, but it does not add anything that makes the natural phenomenon in claim 1 significantly different.
Thus, the claims as a whole do NOT recite additional elements that amount to significantly more than the judicial exception itself.
In light of the above consideration and the new guidance, claims 1, 3 and 5-9 are non-statutory. This rejection is newly recited as necessitated by the new Guidance set forth in the Memorandum of July 30, 2015 updating the June 25, 2014 guidance (see June 25, 2014 memorandum from Deputy Commissioner for Patent Examination Policy Andrew Hirshfeld titled Preliminary Examination Instructions in view of the Supreme Court Decision in Alice Corporation Pty. Ltd. v. CLS Bank International, et al. (Alice Corp. Preliminary Examination Instructions) and the Revised Patent Subject Matter Eligibility Guidance (See, Federal Register, vol. 84, No. 4, January 7, 2019).
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 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, 3, 5 and 6 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Stsiapanava et al. (hereinafter “Stsiapanava”) (Scientific Reports, 2019, 9(14607), 1-9) as evidenced by Jin et al. (hereinafter “Jin”) (US Patent Application No. 20230130352, published April 27, 2023).
Regarding claims 1 and 5, Stsiapanava teaches that ErmE is a methyltransferase (MTase) from Saccharopolyspora erythraea that di-methylates A2058 in 23S rRNA using S-adenosyl methionine (SAM) as methyl donor protecting the ribosomes from macrolide binding (interpreting ErmE as an Erm protein comprising a modification in motif X that changes the conformation; and interpreting A2058 23S rRNA as an RNA substrate, claim 1) (Abstracts, line 2-4). Stsiapanava teaches that ErmE consists of an N-terminal Rossmann-like a/b catalytic domain and a C-terminal helical domain, wherein a comparison with ErmC’ indicates that despite only 24% sequence identity, ErmE has the same function, and reveals highly similar catalytic domains (interpreted as designing a substance that targets an RNA substrate; contacting the substance with the Erm protein; and induced a conformational change, claim 1) (Abstract, lines 5-7). Stsiapanava teaches in Figure 2 that ErmE comprises GQNF in motif X (interpreted as contacting by mutation; causing a conformational change in motif X; and the candidate substance is an amino acid, claim 1a, 1b and 5) (pg. 2, Figure 2). Stsiapanava teaches that ErmE contains a longer loop harboring an additional 3 helix that interacts with the catalytic domain to stabilize the tertiary structure, such that ErmE also differs from ErmC’ by having long disordered extensions at its N- and C-termini (interpreted as designing a substance that targets an RNA substrate; and induces a conformational change in the N-terminal end region and in motif X, where S is G, altering the spatial arrangement, claim 1) (Abstract, lines 10-12). Stsiapanava teaches that ErmE (EC 2.1.1.184) is a dimethyltransferase from the actinomycete Saccharopolyspora erythraea, from which the first macrolide antibiotic erythromycin was originally extracted, wherein ErmE provides resistance to macrolide, lincosamide, and streptogramin B (MLS) antibiotics to S. erythraea (interpreted as determining that the conformational change induced by the mutation does not lead to inhibition or elimination of methylation of a target adenine residue in an RNA substrate, thereby selecting the candidate substance, claim 1c) (pg. 1, first full paragraph, lines 10-12).
Regarding claims 3 and 7, Stsiapanava teaches that the crystal structure of ErmE was determined to 1.75 Å resolution (interpreted as contacting; X-ray crystallography; and a change in the distance between Gln and carbon 4 of the phenyl group, claims 3 and 7) (pg. 7, fourth full paragraph, line 1).
Regarding claim 6, Stsiapanava teaches in Figure 2 that ErmE comprises GQNF in motif X (interpreted as a conformational change in motif X from S to G; and a change in the spatial distance between amino acids, claim 1a, 1b, 5 and 6) (pg. 2, Figure 2). Stsiapanava teaches that ErmE contains a longer loop harboring an additional 3 helix that interacts with the catalytic domain to stabilize the tertiary structure, such that ErmE also differs from ErmC’ by having long disordered extensions at its N- and C-termini (interpreted as a change in length of the NTER, and altering the spatial arrangement, claim 1) (Abstract, lines 10-12).
Stsiapanava does not specifically exemplify where the Erm protein is ErmC’ or ErmS (claim 8); or an in vivo assay or inhibitory concentration measurement (claim 9).
Stsiapanava meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Claims 1 and 5-9 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Jin et al. (hereinafter “Jin”) (The Korean Journal of Microbiology, 2011, 47(3), 200-208; and English Machine Translation, 2011, 47(3), 1-9).
Regarding claims 1 and 5-8, Jin teaches that ErmSF harbors idiosyncratic long N-terminal end region (NTER) 25% of which is comprised of arginine well known to interact with RNA, such that NTER was found to be important because when it was truncated, most of the enzyme activity was lost; and based on these facts, capability of NTER peptide to inhibit the enzymatic activity of ErmSF was sought (interpreted as a substance that targets an Erm protein; an Erm protein; causing a conformational change in NTER; and interacts with an RNA substrate; motif X; interpreting truncation as amino acids; and a peptide as the substance, claim 1a and 1b) (Abstract, lines 6-10). Jin teaches in Figure 1, an amino acid sequence alignment of the N-terminal end region of several Erm proteins, wherein unlike the other homologous proteins, ErmSF harbors a uniquely long N-terminal end region and it contains 18 arginine residues which account for around 25% of NTER amino acids (interpreted as SQNF, amino acid changes in the NTER region; and contacting the Erm protein with the substance, claim 1b) (pg. 4, Figure 1; and pg. 6, col 2, last partial paragraph, lines 1-2). Jin teaches that it was investigated whether the NTER could inhibit the activity of ErmSF in vivo by simultaneously expressing ErmSF and an NTER-containing peptide containing an amino acid that plays an important role in activity within a cell (interpreting the substance to be a peptide; and the assay to be a in vivo antibiotic assay, claims 5 and 9) (pg. 2, first partial paragraph). Jin teaches that an erythromycin stock solution (25 mg/ml) was dropped on a paper discs to reach the final amounts of 100 mg erythromycin; on the agar plate, E. coli cells were spread with cotton swabs and then paper discs containing erythromycin were placed in the center and incubated overnight at 37°C; cells containing ErmSF grew in the presence of erythromycin, whereas control cells harboring empty pACYC184 did not: (A) Expression of ErmSF; Lanes: M, molecular size marker; I, cells harboring pACYC184, empty vector; 2, cells harboring pAHJ101 which was not induced with JPTG; 3, cells harboring pAHJ101 which was induced with JPTG. (B) Antibiotic susceptibility assay. E coli cells expressing ErmSF (containing pAHJ101, right part of agar plate) and without ErmSF in it (harboring empty pACYC184, left pan of agar plate) (interpreted contacting the substance with an Erm protein; and the substance is a peptide, claims 1b and 5) (pg. 5, Figure 3). Jin teaches that the antibiotic resistance of E. coli EHJP1-71+AHJ101, which simultaneously possessed pHJP1-71 and PAHJ101 plasmids expressing NTER-containing peptides and ErmSF respectively, was compared with that of E. coli simultaneously possessing empty carriers pET23b and pACYC184, such that in the case of E. coli containing the two types of empty plasmids, growth was inhibited around disks containing 10, 50, and 100 mg of antibiotics, and an inhibition zone was clearly observed, while on the other hand, E. coli EHJP1-71+AHJ101 which simultaneously expresses NTER peptide and ErmSF, was not inhibit at all (Fig. 5) (interpreted as determining whether conformational change leads to inhibition, thereby selecting the candidate substance/peptide, claim 1c) (pg. 6, col 2, first full paragraph; and pg. 7, Figure 5). Jin teaches that since the attachment sites of the NTER and ErmSF protein bodies are different, it is possible that the highly expressed NTER-containing peptide attached to the NTER attachment site of ErmSF, while ErmSF attached to the protein body attachment site, successfully inducing demethylation in A2058 and thereby exhibiting resistance (pg. 7, col 2, first full paragraph, lines 10-15). Jin teaches that the amino acid attached following the NTER is a very important amino acid that causes loss of activity when removed (pg. 8, col 1, Briefs, lines 11-13). Jin teaches that the peptide was expressed much more than ErmSF within the cell even without induction by IPTG; however, inhibition of activity could not be confirmed in vivo, such that it was considered that the activity of ErmSF is not achieved by the simple attachment of the NTER peptide, but rather through dynamic interactions such as conformational changes, such that it is believed that if the structure of the complex between ErmSF and 23S rRNA and the specific biochemical elucidation of the attachment mode between NTER and ErmSF protein body are established, this approach could contribute to the creation of inhibitors for this protein (interpreted as the conformational change induced by the peptide leads to inhibition or elimination of methylation of a target adenine in the RNA substrate by the Erm protein; ErmS; 23S rRNA; change in spatial distance between residues in NTER, and amino acids in the shortest motif X, claims 1c and 5-8) (pg. 8, col 1, Briefs, lines 21-31).
Regarding claim 9, Jin teaches that it was investigated whether the NTER could inhibit the activity of ErmSF in vivo by simultaneously expressing ErmSF and an NTER-containing peptide containing an amino acid that plays an important role in activity within a cell (interpreting the substance to be a peptide; and the assay to be a in vivo antibiotic assay, claims 5 and 9) (pg. 2, first partial paragraph). Jin teaches that an erythromycin stock solution (25 mg/ml) was dropped on a paper discs to reach the final amounts of 100 mg erythromycin; on the agar plate, E. coli cells were spread with cotton swabs and then paper discs containing erythromycin were placed in the center and incubated overnight at 37°C; cells containing ErmSF grew in the presence of erythromycin, whereas control cells harboring empty pACYC184 did not: (A) Expression of ErmSF; Lanes: M, molecular size marker; I, cells harboring pACYC184, empty vector; 2, cells harboring pAHJ101 which was not induced with JPTG; 3, cells harboring pAHJ101 which was induced with JPTG. (B) Antibiotic susceptibility assay. E coli cells expressing ErmSF (containing pAHJ101, right part of agar plate) and without ErmSF in it (harboring empty pACYC184, left pan of agar plate) (interpreted as an antibody susceptibility assay, claim 9) (pg. 5, Figure 3).
Jin does not specifically exemplify x-ray crystallography, NMR or cryo-EM (claim 3).
Stsiapanava meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Conclusion
Claims 1, 3 and 5-9 are rejected.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684
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