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
Claims 1-15 are currently pending in the instant application, filed November 28, 2023.
Therefore, claims 1-15 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed November 28, 2023 is a 35 U.S.C. 371 national stage filing of International Application PCT/KR2022/007577, filed May 27, 2022, which claims the benefit of the Republic of Korea Patent Application KR10-2021-0069538, filed May 28, 2021.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in the Republic of Korea on November 28, 2023. Applicant filed a certified copy of the Republic of Korea Patent Application No. KR10-2021-0069538 on November 28, 2023 as required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on November 29, 2023; January 15, 2025; and June 24, 2025 have been considered. Initialed copies of the IDSs accompany this Office Action.
Claim Objections/Rejections
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (See; paragraph [0099]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Objections
Claims 3 and 7 are objected to because of the following informalities: Claims 3 and 7 recite terms “bp,” “N”, “A”, “G”, “C”, “T”, “R”, “Y” and “H” 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 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 1-15 are rejected 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 “improved” such as recited in claim 1, lines 1 and 9 because the term “improved” is a relative term that renders the claim indefinite. The term “improved” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount of ‘improvement’ as compared to some other value that qualifies as ‘improved intracellular stability’ (e.g., wherein the mRNA sequence maintains its cellular structure and conformation as compared to the template sequence), such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “the basis” such as recited in claim 1, line 6. There is insufficient antecedent basis for the term “the basis” in the claim.
Claims 1, 5, 7 and 8 are indefinite for the recitation of the term “the designed template sequence” such as recited in claim 1, line 6. There is insufficient antecedent basis for the term “the designed template sequence” in the claim because claim 1, line 3 recites the term “a template sequence.”
Claim 1 is indefinite for the recitation of the term “various sequences” such as recited in claim 1, line 7. There is insufficient antecedent basis for the term “various sequences” in the claim because claim 1, lines 3-6, 8 and 9 recite terms including: template sequence, nucleotide sequence, sequences, and sequence, such that it is completely unclear to which sequences the term “various sequences” is referring.
Claim 1 is indefinite for the recitation of the term “by using sequences” such as recited in claim 1, line 8 because it is unclear how a library is constructed by using sequences of the produced primers and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “a sequence” such as recited in claim 1, line 9. There is insufficient antecedent basis for the term “a sequence” in the claim because claim 1, line 7 recites the term “various sequences.”
Claim 1 is indefinite for the recitation of the term “the constructed library” such as recited in claim 1, lines 9-10. There is insufficient antecedent basis for the term “the constructed library” in the claim because claim 1, line 7 recites that term “a library”.
Claims 2-5, 8 and 10-14 are indefinite for the recitation of the term “step” such as recited in claim 2, line 1 because claims 2-5, 8 and 10-14 ultimately depend from instant claim 1, wherein claim 1 does not recite any “steps” and, thus, the metes and bounds of the claim cannot be determined.
Claim 2 is indefinite for the recitation of the term “redundancy codon” and “a same amino acid” such as recited in claim 2, line 2 because claim 2 depends from instant claim 1, wherein claim 1 does not recite the presence of a redundancy codon or the same amino acids and, thus, the metes and bounds of the claim cannot be determined.
Claim 3 is indefinite due to the use of parentheticals such as, for example, the recitation of “(A, G, C, or T)”, “(A or G)”, “(C or T)” and “(A, C or T)” in claim 3, line 2. It is unclear whether the limitations in parentheses are meant to be limitations in the claims, whether the limitations are only suggestions, examples of a preferred embodiment, a synonym, or whether they refer to something else. Accordingly, the metes and bounds of the claim are not clear.
Claim 4 is indefinite for the recitation of the term “at least one selected from the group” such as recited in claim 4, line 2 because it is unclear as to the identity of the “at least one selected from the group” being referred to (e.g., at least one template sequence, at least one component selected from the group consisting of…, etc.) and, thus, the metes and bounds of the claim cannot be determined.
Claims 5 and 7 are indefinite for the recitation of the term “setting the designed template sequence as two or more divided regions” such as recited in claim 5, lines 1-2 because it is completely unclear what the term “setting” means and/or refers to and, thus, the metes and bounds of the claim cannot be determined.
Claims 5, 6, 7 and 8 are indefinite for the recitation of the terms “the divided regions” and “divided regions” such as recited in claim 5, line 3. There is insufficient antecedent basis for the term “the divided regions” in the claim because claim 5, line 2 recites the term “two or more divided regions”. The Examiner suggests that Applicant amend the claim to recite, for example, “ends of the two or more divided regions overlap each other.”
Claim 6 is indefinite for the recitation of the term “the overlapping portions” such as recited in claim 6, line 1. There is insufficient antecedent basis for the term “the overlapping portions” in the claim. Moreover, claim 6 depends from instant claims 1 and 5, wherein claims 1 and 5 do not recite overlapping portions and, thus, the metes and bounds of the claim cannot be determined.
Claim 7 is indefinite for the recitation of the term “having a size” such as recited in claim 7, line 3 because claim 7 depends from instant claims 1 and 5, wherein claim 1 and 5 do not recite the template sequences having any particular size and, thus, the metes and bounds of the claim cannot be determined.
Claim 7 is indefinite for the recitation of the terms “10 bp to 1,000 bp” and “1b to 100 bp” in claim 7, lines 3-4 due to reciting a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim), since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, for example, claim 7 recites the broad range or limitation of 10 bp to 1,000 bp, while the claim also recites the narrower statement of the range or limitation of 1 bp to 100 bp. Accordingly, the metes and bounds of the claim are not clear.
Claim 8 is indefinite for the recitation of the terms “synthesizing sequences of divided regions” and “sequences complementary thereto” such as recited in claim 8, lines 1-2 because step (B) is directed to producing primers, and claim 8 depends from instant claim 1, wherein claim 1 does not recite the presence of divided regions and/or sequences complementary to any designed template sequences and, thus, the metes and bounds of the claim cannot be determined.
Claim 8 is indefinite for the recitation of the term “the designed template sequence” such as recited in claim 8, line 2. There is insufficient antecedent basis for the term “the designed template sequence” in the claim.
Claim 9 is indefinite for the recitation of the terms “remaining regions” and “a first region” such as recited in claim 9, lines 2-3 because claim 9 depends from instant claims 1 and 8, wherein claims 1 and 8 do not recite the presence of “remaining regions” and/or “a first region” at the 5’ end and, thus, the metes and bounds of the claim cannot be determined.
Claim 10 is indefinite for the recitation of the term “sequential PCR” such as recited in claim 10, line 2 because it is unclear whether the term refers to a type of PCR (e.g., nested PCR), or whether the term refers to performing PCR sequentially or repeatedly (as suggested in the as-filed Specification (paragraph [0035]) and, thus, the metes and bounds of the claim cannot be determined.
Claim 10 is indefinite for the recitation of the term “PCR products” such as recited in claim 10, line 2 because claim 10 depends from instant claim 1, wherein claim 1 does not recite the presence of PCR products. Moreover, the claim recites that primer sequences and PCR products are used to perform sequential PCR, such that claim 10 is unclear and, thus, the metes and bounds of the claim cannot be determined.
Claim 11 is indefinite for the recitation of the terms “cells”; “a DNA sequence”; “an RNA sequence”; “constructing a library”; “transfecting cells”; “DNA encoding a target protein”; and “obtained RNA sequence” such as recited in claim 11, lines 2-7 because claim 11 depends from instant claim 1, wherein claim 1 does not recite the presence of cells; a DNA sequence encoding the target protein; an RNA sequence; constructing a library; transfecting cells; DNA encoding a target protein; RNA; and/or an obtained RNA sequence. It is noted that mRNA is recited in the preamble of instant claim 1, but not in the body of the claim, such that the term “mRNA” is not given patentable weight. Moreover, claim 1, step D recites ‘selecting a sequence with improved intracellular stability’, such that step (D) cannot comprise something different from already comprising “selecting”. Clearly, steps D1 to D3 do not result in selecting anything such that claim 11 is not reciting what step (D) ‘comprises’ and, thus, the metes and bounds of the claim cannot be determined.
Claim 11 is indefinite for the recitation of the term “the obtained RNA sequence” such as recited in claim 11, line 7. There is insufficient antecedent basis for the term “the obtained RNA sequence” in the claim.
Claim 12 is indefinite for the recitation of the term “repeatedly preformed one or more times” such as recited in claim 12, line 2 because claim 12 depends from instant claims 1 and 11, wherein claims 1 and 11 do not recite repeating any of steps D1 to D3 and, thus, the metes and bounds of the claim cannot be determined.
Claim 13 is indefinite for the recitation of the term “a vector” such as recited in claim 13, line 3 because claim 13 depends from instant claims 1 and 11, wherein claims 1 and 11 do not recite the presence of a vector and, thus, the metes and bounds of the claim cannot be determined.
Claim 14 is indefinite for the recitation of the term “the obtained RNA and DNA synthesized therefrom” such as recited in claim 14, line 2. There is insufficient antecedent basis for the term “the obtained RNA and DNA synthesized therefrom” in the claim. Moreover, claim 14 depends from claims 1, 11 and 13, wherein claims 1, 11 and 13 do not recite the presence of DNA or RNA, and/or synthesizing DNA or RNA and, thus, the metes and bounds of the claim cannot be determined.
Claim 15 is indefinite for the recitation of the terms “the target protein or mRNA encoding the target protein”; and “a cancer immunotherapeutic agent…therapeutic agent” such as recited in claim 15, lines 1-4 because claim 15 depends from instant claim 1, wherein claim 1 does not recite the presence of any disease, a target protein, mRNA, administering a therapeutic agent; any cancer immunotherapeutic agent…and/or an immune disease therapeutic agent and, thus, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-15 are 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 2-5, 8 and 10-14 recites (in part): “wherein…step” in claim 2, line 1 because claims 2-5, 8 and 10-14 depend from claim 1, wherein claim 1 does not recite any ‘steps.’ Thus, claims 2-5, 8 and 10-14 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.
Claim 6 recites (in part): “wherein the overlapping portions of each of the divided regions have no introduced variations” in lines 1-2 because claim 6 depends from instant claims 1 and 5, wherein claims 1 and 5 do not recite the presence of overlapping portions. Thus, claim 6 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.
Claim 7 recites (in part): “wherein the setting of the designed template sequence as two or more divided regions…the divided regions overlap each other” in lines 1-4 because claim 7 depends from claims 1 and 5, wherein claims 1 and 5 do not recite regions having a size, or that the divided regions have ends. Thus, claim 7 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.
Claim 8 recites (in part): “synthesizing sequences of divided regions of the designed template…thereto as primers” in lines 1-3 because claim 8 depends from claim 1, wherein claim 1 does not recite the presence of divided regions and/or the presence of sequence complementary to the designed template sequence. Thus, claim 8 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.
Claim 9 recites (in part): “wherein the synthesizing of the primers…from the 5’ end” in lines 1-3 because claim 9 depends from claims 1 and 8, wherein claims 1 and 8 do not recite the presence of remaining regions, or excluding a first region located at the 5’ end. Thus, claim 9 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.
Claim 10 recites (in part): “wherein step (C) comprises…and PCR products” in lines 1-2 because claim 10 depends from claim 1, wherein claim 1 does not recite the presence of PCR products. Thus, claim 10 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.
Claim 11 recites (in part): “wherein step (D) comprises:…from the obtained RNA sequence” in lines 1-7 because claim 11 depends from instant claim 1, wherein claim 1 does not recite the presence of cells; a DNA sequence; an RNA sequence; constructing a library; transfecting cells; DNA encoding a target protein; and obtained RNA sequence. Moreover, claim 1-D recites ‘selecting a sequence with improved intracellular stability’, while claim 11, steps D1 to D3 do not result in selecting anything. Thus, claim 11 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.
Claim 12 recites (in part): “wherein step (D)…are repeatedly performed one or more times” in lines 1-2 because claim 12 depends from claims 1 and 11, wherein claims 1 and 11 do not recite repeating any steps. Thus, claim 12 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.
Claim 13 recites (in part): “wherein step (D) further comprises…from the transfected cell” in lines 1-5 because claim 13 depends from instant claims 1 and 11, wherein claims 1 and 11 do not recite the presence of a vector. Thus, claim 13 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.
Claim 14 recites (in part): “wherein step (D) further comprises…DNA synthesized therefrom” in lines 1-2 because claim 14 depends from instant claims 1, 11 and 13, wherein claims 1, 11 and 13 do not recite synthesizing RNA and/or DNA. Thus, claim 14 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.
Claim 15 recites (in part): “wherein the target protein or mRNA encoding…disease therapeutic agent” in lines 1-4 because claim 15 depends from claim 1, wherein claim 1 does not recite the presence of any disease, a target protein, mRNA, a cancer immunotherapeutic agent, a cancer therapeutic vaccine, an infectious disease vaccine, a protein replacement therapeutic agent, an allergy therapeutic agent, and/or an immune disease therapeutic agent. Thus, claim 15 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.
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.
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 1-15 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 phenomenon and 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 1-15 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below.
In the instant case, claims 1-15 are broadly directed to a method of screening for an mRNA sequence with improved intracellular stability, the method comprising: (A) designing a template sequence comprising a sequence in which a variation has been introduced into a nucleotide sequence encoding a target protein such that there is no change in an amino acid sequence of the target protein; (B) producing primers on the basis of the designed template sequence; (C) constructing a library comprising various sequences into which variations have been introduced, by using sequences of the produced primers; and (D) selecting a sequence with improved intracellular stability from the constructed library, wherein the target protein or mRNA encoding the target protein is used as a cancer immunotherapeutic agent, a cancer therapeutic vaccine, an infectious disease vaccine, a protein replacement therapeutic agent, an allergy therapeutic agent, or an immune disease therapeutic agent.
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 1-15 are drawn to natural phenomenon in the form of a natural correlation between a protein and/or a sequence encoding a protein that has improved intracellular stability and that it is a treatment for a disease or condition including that it is a cancer immunotherapeutic agent, a cancer therapeutic vaccine, an infectious disease vaccine, a protein replacement therapeutic agent, an allergy therapeutic agent, or an immune disease therapeutic agent; and an abstract idea including: (1) mathematical concepts such as mathematical relationships, formulas and/or calculations (e.g., designing a template sequence, producing primers, constructing a library, selecting a sequence, etc.). The claims are broadly directed to screening for an mRNA sequence with improved intracellular stability. 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 a template sequence comprising a sequence in which a variation has been introduced into a nucleotide sequence encoding a target protein such that there is no change in an amino acid sequence of the target protein” in lines 3-5; “producing primers on the basis of the designed template sequence” in line 6; “constructing a library comprising various sequences into which variations have been introduced, by using sequences of the produced primers” in lines 7-8; and “selecting a sequence with improved intracellular stability from the constructed library” in lines 9-10, which resemble “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 2-15 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 5 provides: “setting the designed template sequence as two or more divided regions, wherein ends of each of the divided regions overlap each other” 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].
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 screening for an mRNA sequence with improved intracellular stability are covered.
For instance, the claims are recited without any specificity as to the methods of screening for an mRNA sequence; the mRNA sequences; the improved intracellular stability; the specific cells; the type of stability; the method of designing a template sequence; the template sequence; the variations introduced; the methods of assessing the variations; the sequence encoding a target protein; the amino acid sequences; the target protein; the method of producing primers; the basis upon which the template sequences are designed; the method of construction a library; the various sequences; the variations introduced; the sequences of the produced primers that are used; the method of selecting a sequence with improved intracellular stability; the identity of the sequences in the constructed library; how improved the intracellular stability is; a specific reference stability, etc., wherein the steps of the method are well known, purely conventional or routine in the art. Step IIB: [NO].
For example, the modification of codons in individual polynucleotide sequences encoding a heterologous protein of interest, without altering the amino acid sequence of the polypeptide to enhance the amount of functional expression in a host organism of interest, wherein this approach exploits redundancy in the genetic code by providing a universal set of codons which can be used at certain positions in the polynucleotide sequence in order to achieve improved heterologous protein production in a range of host cells was known in the art, such that optimization of the translation efficiency of messenger RNAs on the basis of their secondary structure characteristics, and the provided set of criteria can be used to increase protein expression in particular hosts to provide a library of polynucleotides each of which vary at a minimum of a single codon position; analyzing the secondary structure of each mRNA corresponding to a polynucleotide sequence of the library in silico as evidenced by Westerhof (WO2016086988; Abstract; and pg. 8, lines 14); and it was known that the development of mRNA drugs has broad interest, including exploring delivery into various cell types and applications as diverse as cancer vaccination, cell reprogramming, and protein replacement therapies; such that for cellular reprogramming, all genes are codon optimized and assembled by gene synthesis, inserted into pST1-plasmids containing 2hBg, mtRNR1-AES, or AES-mtRNR1 3’ UTR, in vivo transcribed using PCR products, the synthetic mRNA was co-transcriptionally capped with beta-S-ARCA (D1); and a final mRNA library was produced; and that during the selection process, first strand cDNA synthesis was done from total RNA isolations using SuperScript II Kit and oligo(d)T-primers as evidenced by Von Niessen (Molecular Therapy, pg. 824, col 1, first full paragraph; pg. 832, col 2; pg. 833, col 1, first full paragraph). Moreover, methods such as computer-implemented or computer-assisted methods for optimizing a nucleic acid sequence for expression of a protein in a host, where related to these methods are methods for removing adverse motifs and features from the nucleic acid sequence (e.g., after the iterations of the NSGAIII algorithms are completed) before gene synthesis and protein expression; as well as, methods for quantifying and calculating the multiple objectives in the optimization algorithms, as well as methods for identifying adverse motifs and features to reduce or remove; and that Figure 1, block 106 shows an electronic device receives an initial population set, wherein the initial population set comprises a plurality of initial candidate nucleic acid sequences capable of expressing the protein, wherein the initial population set is randomly generated, and the initial population set is of a predetermined size (e.g., determined by a user); and basic characteristics of the highly expressed genes are identified; mRNA-seq experiments and data analysis are performed following Illumina's recommended mRNA-Seq workflow for standard samples, wherein TruSeq Stranded mRNA Library Prep Kit can be used for library preparation was known in the art as evidenced by Fan (US20210366574; paragraphs [0065]]; [0067]; and [0108]); and methods that exploit redundancy of the genetic code to generate large, semi-targeted libraries that balance low cost, simple production with library output sizes suitable for protein screening were known in the art, wherein a degenerate codon (DC) is a mixture of nucleotide triplets capable of collectively encoding more than one amino acid, such that DC libraries combine mixtures of nucleotides at specific positions during DNA synthesis to include only specific subsets of the codon table and ultimately allow expression of protein mixtures from a single pooled DNA synthesis reaction; as well as, degenerate codon design (DeCoDe), which is an algorithm for total-library DC optimization based on ILP as evidenced by Shimko (Bioinformatics; pg. 3358, col 1, first full paragraph; and col 2, last full paragraph). Thus, the steps of the method for screening an mRNA sequence including designing a template, producing primers, constructing a library, and selecting a sequence are 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) 2-15 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 2 encompasses the method of claim 1, wherein the introduction of the variation in step (A) comprises introducing a redundancy codon encoding a same amino acid into all or part of the nucleotides sequence encoding the target 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 1-15 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 § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and
103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for
the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Westerhof et al. (hereinafter “Westerhof”) (International Patent WO2016086988, published June 9, 2016) in view of Chiocchini et. al. (hereinafter “Chiocchini”) (US Patent Application Publication 20180291413, published October 11, 2018).
Regarding claim 1, Westerhof teaches the modification of codons in individual polynucleotide sequences encoding a heterologous protein of interest, without altering the amino acid sequence of the polypeptide to enhance the amount of functional expression in a host organism of interest, wherein this approach exploits redundancy in the genetic code by providing a universal set of codons which can be used at certain positions in the polynucleotide sequence in order to achieve improved heterologous protein production in a range of host cells, such that optimization of the translation efficiency of messenger RNAs on the basis of their secondary structure characteristics, and the provided set of criteria can be used to increase protein expression in particular hosts (interpreted as designing a template sequence comprising introducing codon variations with no change in amino acid sequence of the target protein; mRNA; and improved intracellular stability, claim 1A) (Abstract). Westerhof teaches that total RNA was isolated, cDNA was synthesized using an oligo-dT primer, and samples were analyzed by quantitative PCR, wherein the oligonucleotides used for amplification of both native and optimized IL-10, OVA and GFP and TIP-41 were SEQ ID NO: 2, 4, 5, 7, 8 and 9 (interpreted as producing primers, claim 1B) (pg. 65, lines 1-14). Westerhof teaches a method of providing a DNA comprising a coding sequence for functional expression of a heterologous protein in a host cell comprising the steps of; (a) providing a library of polynucleotides each of which vary at a minimum of a single codon position; (b) analyzing the secondary structure of each mRNA corresponding to a polynucleotide sequence of the library in silico under the temperature and salt concentrations relevant for the preferred host; and (c) selecting a polynucleotide having at least 110 and fewer than 250 stem loop transitions per kilobase pair (kbp); and (d) synthesizing said polynucleotide (interpreted as designing a template sequence; constructing a library; and selecting a sequence, claim 1C-D) (pg. 104, claim 1).
Regarding claim 2, Westerhof teaches that the present invention provides a series of synonymous codons which are believed to have wide application for the expression of heterologous genes in commonly used host cells, for example prokaryotic cells, fungal cells, plant cells and animal cells and which have been surprisingly found to correspond with increased functional protein expression therein, wherein codon optimization is centered on increasing gene expression in specific cellular or environmental contexts; and selecting mRNAs from the library of synonymous variants that have the most even distribution of stems and loops (interpreted as introducing redundancy codons encoding the same amino acid; and improved intracellular stability, claims 1 and 2) (pg. 4, lines 19-26; and pg. 29, lines 30-31)
Regarding claim 3, Westerhof teaches one codon per amino acid that was most often identified as an expression codon across these 11 plant species was selected, wherein most of these codons were C-ending, except for the amino acids Arg (CGT) and Gly (GGT), such that the codons of the amino acids Gln, Glu and Lys, that can only be encoded by A or G-ending codons, were G-ending; and N triplets include AAAT and AAC; R triplets include CGT, CGC, CGA, CGG, AGA and AGG; Y triplets include TAT and TAC; and H triplets include CAT and CAC (interpreted as introducing N (A, G, C, or T, R (A or G), Y (C or T) or H (A, C, or T) into third nucleotides of codons, claim 3) (pg. 52, lines 7-11; and pgs. 89-98, Tables 6A-E and relative synonymous codon use frequency).
Regarding claim 4, Westerhof teaches that elements can include, for example, strong and/or constitutive promoters, 5' and 3' UTR's, transcriptional and/or translational enhancers, transcription factor or protein binding sequences, start sites and termination sequences, ribosome binding sites, recombination sites, polyadenylation sequences, sense or antisense sequences, sequences ensuring correct initiation of transcription and optionally polyA signals ensuring termination of transcription and transcript stabilization in the host cell (interpreted as one or more of a promoter, UTR, and polyA sequence, claim 4) (pg. 38, lines 33-34; and pg. 39, lines 1-5).
Regarding claims 5 and 6, Westerhof teaches that it can be desirable to limit application of the method to specific regions of the polynucleotide sequence or to omit certain regions from application of the method, for instance to avoid disruption of secondary structural motifs or regulatory elements in the polynucleotide sequence (interpreted as two or more divided regions, wherein omitted regions do not have introduced variations; and encompassing where divided regions overlap, claims 5 and 6) (pg. 38, lines 4-7).
Regarding claim 7, Westerhof teaches that the polynucleotide will have a maximum stem size of less than 19 bp; or optionally in the range 10bp to 19bp, 11 bp to 18bp, 12bp to 17bp, 13bp to 16bp or 14bp to 15bp. More preferably, the polynucleotide will have a maximum loop size of less than 20 bp, optionally in the range 10bp to 20bp (interpreted as a portion of about 1 bp to 100 bp, claim 7) (pg. 31, lines 14-18).
Regarding claims 8 and 9, Westerhof teaches that it can be desirable to limit application of the method to specific regions of the polynucleotide sequence or to omit certain regions from application of the method, for instance to avoid disruption of secondary structural motifs or regulatory elements in the polynucleotide sequence (interpreted as two or more divided regions; and omitting a first region, claim 9) (pg. 38, lines 4-7). Westerhof teaches that after modification of the codon composition of the polynucleotide sequence encoding the protein of interest, subsequent expression of the polynucleotide sequence in the chosen host cell can be carried out, wherein regulatory elements include, for example, strong and/or constitutive promoters, 5' and 3' UTR's, transcriptional and/or translational enhancers, transcription factor or protein binding sequences, start sites and termination sequences, ribosome binding sites, recombination sites, polyadenylation sequences, sense or antisense sequences, etc. (interpreted as synthesizing designed sequences or complementary sequences as primers, claim 8) (pg. 38, lines 21-23 and 33-34; and pg. 39, lines 1-5). Westerhof teaches that total RNA was isolated, cDNA was synthesized using an oligo-dT primer, and samples were analyzed by quantitative PCR, wherein the oligonucleotides used for amplification of both native and optimized IL-10, OVA and GFP and TIP-41 were SEQ ID NO: 2, 4, 5, 7, 8 and 9 (interpreted as synthesizing designed sequences or complementary sequences as primers, claim 8) (pg. 65, lines 1-14).
Regarding claim 10, Westerhof teaches that samples were analyzed by quantitative PCR in triplo, wherein the oligonucleotides used for amplification of both native and optimized IL-10, OVA and GFP and PIP-41 were SEQ ID NOS: 2-5 and 7-9 (interpreted as performing sequential PCR, claim 10) (pg. 65, lines 3-4).
Regarding claims 11 and 13, Westerhof teaches modifying the polynucleotide sequence using replacement codons, inserting the polynucleotide sequence into an expression vector; introducing said expression vector into a host cell; and culturing the host cell to produce the heterologous protein; such that the selection of mRNA structures with the most even distribution of stems and loops is positively correlated with higher levels of expression in commonly used host cells, for example prokaryotic cells, fungal cells, plant cells and animal cells to provide a DNA comprising a coding sequence for functional expression of a heterologous protein in a host cell (interpreted as transfecting the cells with a DNA sequence; obtain an RNA sequence encoding the target protein; and constructing a library, claim 11) (pg. 5, lines 22-23; pg. 6, lines 2-5; and pg. 7, lines 17-22). Westerhof teaches that polynucleotide sequences encoding the protein of interest can be prepared by any suitable method known to those of ordinary skill in the art, including but not limited to, for example, direct chemical synthesis or cloning (interpreted as further comprising cloning, claim 13) (pg. 37, lines 14-17).
Regarding claim 15, Westerhof teaches methods of the present invention will be useful in the production of a large number of different proteins in the agricultural, chemical, industrial and pharmaceutical fields, particularly for example antibodies, vaccines, hormones and other protein therapeutics (interpreted as therapeutic agents including vaccines, claim 15) (pg. 40, lines 15-18). Westerhof teaches that the protein of interest can be used as a therapeutic agent (interpreted as protein therapeutic agents including vaccines, claim 15) (pg. 44, line 13).
Westerhof does not specifically exemplify repeating steps D1 to D3 (claim 12); and determining sequences of RNA and DNA (claim 14).
Regarding claims 12 and 14, Chiocchini teaches methods for designing and producing nucleic acid molecules and the production of encoded proteins using these nucleic acid molecules including the automation for the in vitro generation of coding DNA molecules, the in vitro transcription of these DNA molecules to generate protein coding RNA molecules, and the in vitro translation of these protein coding RNA molecules to produce proteins (interpreted as encompassing transfection of DNA; obtaining RNA; and synthesizing protein, claims 11-14) (Abstract). Chiocchini teaches that steps of the method can be repeated one or several times to further increase the efficiency of error reduction (interpreted as repeatedly performing, claim 12) (paragraph [0169], last 3 lines). Chiocchini teaches the in vivo assembly methods, a mixture of all of the fragments to be assembled is often used to transfect the host recombination and assembly cell using standard transfection techniques, wherein the ratio of the number of molecules of fragments in the mixture to the number of cells in the culture to be transfected should be high enough to permit at least some of the cells to take up more molecules of fragments than there are different fragments in the mixture (interpreted as transfection, claim 11) (paragraph [0190], lines 1-8). Chiocchini teaches nucleic acid molecules produced by method of the invention and/or using compositions for the invention can vary substantially in size and form, such that nucleic acid molecules assembled by methods of the invention will typically encode polypeptides of between ninety amino acids and two thousand amino acids (paragraph [0195], lines 1-7). Chiocchini teaches that when nucleic acid
molecule are used in IVTT (and/or IVTr or IVTl) reactions, it is generally seen that more protein is generated from coding regions that contain codons preferred for Saccharomyces cerevisiae or more generally, having a lower GC content than codons preferred for mammalian systems, even when the IVTr (and/or IVTr or IVTl) "machinery" is derived from mammalian cells (e.g., HeLa cells) (paragraph [0198]). Chiocchini teaches a list of vectors including: BACULODIREcr Linear DIMA; BAcULoDIREcr Linear, DNA Cloning Fragment DNA; BAcULoDIREcr N-term Linear DNA_verA; BAcULoDIREcr C-Term Baculovirus Linear DNA…and pZEO-2 (paragraph [0200]). Chiocchini teaches that the T7 promoter is an RNA polymerase II promoter are used by cells to generate mRNA molecules, wherein tRNA molecules are typically transcribed from DNA using RNA polymerase III promoters (paragraph [0206]). Chiocchini teaches sequencing of individual nucleic acid molecules to achieve error correction (interpreted as determining sequences, claim 14) (paragraph [0142], lines 1-2; and [0159])
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of automating the design and production of nucleic acid molecules as exemplified by Chiocchini, it would have been prima facie obvious for one of ordinary skill in the art at the time the invention was made to modify the method of optimizing coding sequences for functional protein expression as disclosed by Westerhof to include the methods of synthesizing proteins including by generating coding DNA molecules, in vitro transcription of the DNA molecules, generating protein coding RNA molecules, and in vitro translating the protein coding RNA molecules to produce the proteins of interest as taught by Chiocchini with a reasonable expectation of success in identifying codons optimized to produce mRNA sequences that show a significant increase in stability and translatability; in modifying regulatory sequences capable of influencing transcription or translation of a gene or gene product; and/or in increasing protein expression efficiency and production levels even when the codons are not the optimal codons of cells from which the IVTT machinery is derived from.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103(a) as obvious over the art.
Conclusion
Claims 1-15 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
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/AMY M BUNKER/Primary Examiner, Art Unit 1684
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