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 1-16 are currently pending in the instant application, filed February 24, 2023.
Therefore, claims 1-16 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed February 24, 2023 is a CON of PCT/KR2021/011388, filed August 25, 2021, which claims the benefit of Republic of Korea Patent KR10-2020-0107932, filed August 26, 2020.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in the Republic of Korea on August 26, 2020.
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 statement (IDS) submitted on February 24, 2023 has been considered. An initialed copy of the IDS accompanies this Office Action.
Claim Objections/Rejections
Product-by-Process
Please Note: instant claim 16 is determined to be product-by-process claim. The structural elements of the product, comprising: a library of antibodies prepared by the method of claim 1 is not considered to limit the antibody library of claim 16, such that it is assumed that equivalent library of antibodies having CDR sequences are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. Moreover, even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
Claim Objection
Claim 3 objected to because of the following informalities: Claim 3 recites Equation 1 for the calculation of an enrichment score. However, Equation 1 and each of the components defined within claim 3 are blurry and very difficult to read (e.g., the equation including log, + or x, ni-pos, ni-pre, i, etc.).
Appropriate correction is required.
Specification Objection
This disclosure is objected to because it contains an embedded hyperlink and/or other form of
Browser-executable code (e.g., as-filed Specification, paragraphs [0092], [0097]; and [0131]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; it is noted that this can be achieved by amending the hyperlink(s) to remove the web-link and/or http:// recitations. See MPEP § 608.01.
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 1-16 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.
Claims 1 and 16 are indefinite as being incomplete for omitting essential steps, such omission amounting to a gap between the steps (See MPEP § 2172.01). The omitted steps for example, can be: (i) efficient simulation of natural diversity; (ii) library size of at least about 108; and/or (iii) NGS sequencing. The as-filed Specification teaches that library size is one of the most important factors that determines the quality of antibodies selected from the library; that efficient simulation of natural diversity is very important in the design and construction of a synthetic antibody library; and that the enrichment score is calculated from NGS data (see, e.g., paragraphs [0004]; [0006]; and [0162]), and as evidenced by Bai (Int. J. Mol. Sci., pg. 2659, first full paragraph, lines 13-15).
Claims 1 and 16 are indefinite for the recitation of the term “the designed CDR sequences” such as recited in claim 1, line 4. There is insufficient antecedent basis for the term “the designed CDR sequences” in the claim because claim 1, line 2 recites that term “individually designing CDR sequences of antibodies.” The Examiner suggests that Applicant amend the claim to recite, for example, “the individually designed CDR sequences.”
Claims 1 and 16 are indefinite for the recitation of the term “a library” such as recited in claim 1, line 4. There is insufficient antecedent basis for the term “a library” in the claim because claim 1, line 1 recites the term “an antibody library.”
Claims 1, 5, 7, 8, 10 and 16 are indefinite for the recitation of the term “the CDR sequences individually” such as recited in claim 11, line 4. There is insufficient antecedent basis for the term “the CDR sequences individually” in the claim because claim 1, line 2 recites that term “individually designing CDR sequences of antibodies.”
Claim 2 is indefinite for the recitation of the terms “predicted”, “the machine learning model is trained by”, “setting…as input values”, “setting as result values”, “calculated by measuring relative frequencies” and “before and after panning” such as recited in claim 2, lines 2-6 because claim 2 depends from instant claim 1, where claim 1 does not recite predicted enrichment scores, calculating enrichment scores, training a machine learning model, setting input values, setting result values, measuring, relative frequencies, and/or panning and, thus, the metes and bounds of the claim cannot be determined.
Claims 2 and 3 are indefinite due to the use of use parentheses to comments on or qualify part of the sentences including, for example, “(s)” in claim 2; and “[equation]” and “[Npre:…the npost]” in claim 3. It is unclear whether the limitations in parentheses are meant to be limitations in the claims, whether they are only suggestions, examples of a preferred embodiment, reference notes, or whether they refer to something else. Accordingly, the metes and bounds of the claim are not clear.
Claims 2 and 7 are indefinite for the recitation of the term “the sequences” such as recited in claim 2, line 6. There is insufficient antecedent basis for the term “the sequences” in the claim because claim 1, line 2 recites that term “individually designing CDR sequences of antibodies.”
Claim 3 is indefinite for the recitation of the terms “enrichment scores are calculated”, “total number of NGS reads”, “panning”, “specific CR-H3 sequences”, and/or “set of read numbers”, such as recited in claim 3, lines 2-10 because claim 3 depends from instant claim 1, where claim 1 does not recite calculating enrichment scores, NGS reads, numbers of reads, and/or panning and, thus, the metes and bounds of the claim cannot be determined.
Claim 3 is indefinite for the recitation of the term “a library” such as recited in claim 1, line 5 because claim 3 depends from claim 1, where claim 1 recites the term “an antibody library” such that it is unclear whether the NGS reads of a library as recited in claim 3 refer to the antibody library of claim 1 and, thus, the metes and bounds of the claim cannot be determined.
Claim 3 is indefinite for the recitation of the term “individual CDR-H3 sequences” such as recited in claim 3, lines 8-10. There is insufficient antecedent basis for the term “individual CDR-H3 sequences” in the claim because claim 1, line 2 recites that term “individually designing CDR sequences of antibodies.”
Claim 4 is indefinite for the recitation of the terms “designing optimized sequences” and “predicted to be above 0” such as recited in claim 4, lines 2 and 4. There is insufficient antecedent basis for the term “optimized sequences” in the claim. Moreover, claim 4 depends from instant claim 1, wherein claim 1 does not recite designing optimized sequences and/or provide any value range for the enrichment score and, thus, the metes and bounds of the claim cannot be determined.
Claim 5 is indefinite for the recitation of the terms “sequences derived from the VH1, VH4 or VH5 family are excluded” such as recited in claim 5, lines 2-3. There is insufficient antecedent basis for the term “the VH1, VH4 or VH5 family” in the claim. Moreover, claim 5 depends from instant claim 1, wherein claim 1 does not recite sequences derived from VH families, and/or excluding any sequences from designing and, thus, the metes and bounds of the claim cannot be determined.
Claim 6 is indefinite for the recitation of the terms “polymorphism” such as recited in claim 6, line 7 because claim 6 depends from instant claim 1, wherein claim 1 does not recite the presence of polymorphisms in the antibodies of the library and, thus, the metes and bounds of the claim cannot be determined.
Claim 6 is indefinite for the recitation of the term “the complementarity determining regions” such as recited in claim 6, line 6. There is insufficient antecedent basis for the term “the complementarity determining regions” in the claim because claim 1, line 2 recites the term “complementarity determining region (CDR) sequences of antibodies.”
Claim 7 is indefinite for the recitation of the terms “utilization frequency”, “germline immunoglobulin gene”, ”a frequency of mutation”, “somatic hypermutations at each amino acid position”, “calculated by analyzing” and “actual human-derived mature antibodies” such as recited in claim 7, lines 2-8 because claim 7 depends from instant claim 1, wherein claim 1 does not recite a utilization frequency, germline immunoglobulin gene, mutations, a frequency of mutation, somatic hypermutations at each amino acid position, calculated by analyzing and actual human-derived mature antibodies and, thus, the metes and bounds of the claim cannot be determined.
Claims 7 and 10 are indefinite for the recitation of the term “therefor” such as recited in claim 7, line 4 because the term “therefor” is almost always used in legal context and means “for this” or “for that” as evidenced by Collins (pg. 1), such that the use and meaning of the term within the claims is unclear and, thus, the metes and bounds of the claim cannot be determined.
Claim 8 is indefinite for the recitation of the terms “a utilization frequency”, ”a frequency of mutation”, “somatic hypermutations at each amino acid position”, “calculated by analyzing” and “actual human-derived mature antibodies”, “analysis results”, “human-derived mature antibodies”, and “to be designed” such as recited in claim 8, lines 2-14 because claim 8 depends from instant claim 1, wherein claim 1 does not recite utilization frequency, mutations, a frequency of mutation, somatic hypermutations at each amino acid position, calculated by analyzing, actual human-derived mature antibodies, analysis results, human-derived mature antibodies, and/or designing that takes place at a future time and, thus, the metes and bounds of the claim cannot be determined.
Claim 8 is indefinite for the recitation of the term “the analysis” such as recited in claim 8, line 11. There is insufficient antecedent basis for the term “the analysis” in the claim because claim 8, lines 8-9 recite the term “analyzing and calculating a frequency”.
Claim 9 is indefinite for the recitation of the term “the light chain” such as recited in claim 9, lines 2-3. There is insufficient antecedent basis for the term “the light chain” in the claim because claim 9, line 2 recites the term “light chain complementarity determining region sequences.”
Claim 10 is indefinite for the recitation of the terms “actual human-derived mature antibodies”, “analysis of frequencies”, “analysis results”, “human-derived mature antibodies” and “analysis result” such as recited in claim 8, lines 4-5, 7-8 and 11-12 because claim 10 depends from instant claim 1, where claim 1 does not recite actual human-derived mature antibodies, analysis of frequencies, human-derived mature antibodies, analysis result and/or future designing and, thus, the metes and bounds of the claim cannot be determined.
Claims 11-13 are indefinite for the recitation of the term “after the designing of the CDR amino acid sequences” such as recited in claim 11, line 1. There is insufficient antecedent basis for the term “the designing of the CDR amino acid sequences” in the claim. Moreover, claims 11-13 depend from instant claim 1, where claim 1 does not recite ‘designing of the CDR amino acid sequences’ and, thus, the metes and bounds of the claim cannot be determined.
Claims 11-13 are indefinite for the recitation of the term “the designed sequences” such as recited in claim 11, line 4. There is insufficient antecedent basis for the term “the designed sequences” in the claim because claim 1, line 2 recites that term “individually designing CDR sequences of antibodies.”
Claim 14 is indefinite due to the use of use parentheses to comments on or qualify part of the sentences including, for example, “(VH3-23, Genebank accession No. Z12347)” in claim 14, lines 3-4. It is unclear whether the limitations in parentheses are meant to be limitations in the claims, whether they are only suggestions, examples of a preferred embodiment, reference notes, or whether they refer to something else. Accordingly, the metes and bounds of the claim are not clear. The Examiner requests that Applicant provide SEQ ID NOs for the sequences.
Claim 15 is indefinite insofar as they ultimately depend from instant claim 1.
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 2-8 and 10-13 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 recites (in part): “wherein the enrichment scores are predicted by a machine learning model, and the machine learning model is trained by…after panning” such as recited in claim 2, lines 2-6 because claim 2 depends from instant claim 1, where claim 1 does not recite predicted enrichment scores, calculating enrichment scores, training a machine learning model, setting input values, setting result values, measuring, relative frequencies, and/or panning. Thus, claim 2 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 3 recites (in part): “wherein the enrichment scores are calculated using following Equation 1…Median of npost]” such as recited such as recited in claim 3, lines 2-10 because claim 3 depends from instant claim 1, where claim 1 does not recite calculating enrichment scores, NGS reads, numbers of reads, and/or panning. 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.
Claim 4 recites (in part): “wherein, designing optimized sequences using the enrichment scores… or predicted to be above 0” such as recited such as recited in claim 4, lines 2 and 4 because claim 4 depends from instant claim 1, wherein claim 1 does not recite designing optimized sequences and/or provide any value range for the enrichment score. Thus, claim 4 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 5 recites (in part): “wherein, when designing CDR sequences individually… or VH5 family are excluded” such as recited such as recited in claim 5, lines 2-3 because claim 5 depends from instant claim 1, wherein claim 1 does not recite sequences derived from VH1, VH4 or VH5 family and/or excluding any sequences from designing. Thus, claim 5 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 6 recites (in part): “wherein heavy chain complementarity determining region 1 (CDR-H1), heaving chain…have polymorphism” such as recited such as recited in claim 6, lines 2-7 because claim 6 depends from instant claim 1, wherein claim 1 does not recite sequences the CDR sequences have a polymorphism. 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, when designing the CDR sequences individually…of actual human-derived mature antibodies” in claim 7, lines 2-8 because claim 7 depends from instant claim 1, wherein claim 1 does not recite a utilization frequency, germline immunoglobulin gene, mutations, a frequency of mutation, somatic hypermutations at each amino acid position, calculated by analyzing and actual human-derived mature antibodies. 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): “wherein, when designing the CDR sequences individually…same amino acid lengths as CDR-L3 to be designed” in claim 8, lines 2-14 because claim 8 depends from instant claim 1, wherein claim 1 does not recite utilization frequency, mutations, a frequency of mutation, somatic hypermutations at each amino acid position, calculated by analyzing, actual human-derived mature antibodies, analysis results, human-derived mature antibodies, and/or designing that takes place at a future time. 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 10 recites (in part): “wherein, when designing the CDR sequences individually…same amino acid lengths as CDR-H3 to be designed” in claim 8, lines 2-12 because claim 10 depends from instant claim 1, where claim 1 does not recite actual human-derived mature antibodies, analysis of frequencies, human-derived mature antibodies, analysis result and/or future designing. 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.
Claims 11-13 recite (in part): “after the designing the CDR amino acid sequences” such as recited in claim 11, line 2 because claims 11-13 depend from instant claim 1, where claim 1 does not recite designing CDR amino acid sequences. Thus, claims 11-13 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.
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 1-16 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. The claims as a whole are directed to a method of preparing an antibody library, comprising individually designing CDR sequences or antibodies; and synthesizing antibodies including the designed CDR sequences, wherein designing the CDR sequences individually CDR-H3 is optimized using enrichment scores of candidate CDR-H3 sequences; and an antibody library prepared by the method of claim 1. In the instant case, the claims are directed to a natural product, 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 claims as a whole, claims 1-16 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
In the instant case, claim 1 is broadly directed to a method of preparing an antibody library, comprising individually designing CDR sequences or antibodies; and synthesizing antibodies including the designed CDR sequences, wherein designing the CDR sequences individually CDR-H3 is optimized using enrichment scores of candidate CDR-H3 sequences; while claim 16 is directed to an antibody library prepared by the method of claim 1.
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, 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 claim 16 is drawn to natural products in the form of a naturally occurring antibodies and/or non-naturally occurring antibodies that do not possess markedly different characteristics such as different biological or pharmacological functions or activities, chemical or physical properties and or structure/function and form as compared to naturally occurring antibodies as recited in claim 16; and claims 1-16 are directed to an abstract idea in the form of mathematical concepts such as mathematical relationships, formulas or equations, and/or calculations; and/or mental process such as observation, judgement and opinion (e.g., designing CDR sequences individually including in silico design; CDR-H3 optimization using enrichment scores, etc.). The claims broadly recite preparing an antibody library, and an antibody library produced by the method of claim 1. Step IIA – Prong One [YES].
Step IIA - Prong Two asks whether the claim recites additional elements that integrate the exception into a practical application of the exception. In the instant case, the claims are directed to a judicial exception in the form of a natural product and an abstract idea. Claim 1 recites: a method of preparing an antibody library, comprising: “individually designing complementarity determining region (CDR) sequences of antibodies” in line 2; “and synthesizing antibodies including the designed CDR sequences to prepare a library” in line 4; “wherein, when designing the CDR sequences individually, heavy chain complementarity determining region 3 (CDR-H3) is optimized using enrichment scores of candidate CDR-H3 sequences” in lines 5-6. Claim 16 recites “an antibody library prepared by the method of claim 1”. These limitations simply describe a process of collecting and analyzing information, 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)); as well as, “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)). Moreover, many of Applicant’s process steps can be practiced as a mental process performed in the human mind, by pen and paper, or through the use of a generic computer, for example, “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)). Hence, these limitations are akin to an “abstract idea itself” which was at issue in Alice Corp. and has been identified among non-limiting examples to be an abstract idea. 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 2 recite “wherein the enrichment scores are predicted by a machine learning model, and the machine learning model is trained by a) setting at least one CDR-H3 sequences as input values, and b) setting, as result values, the enrichment scores calculated by measuring relative frequencies of the sequence before and after panning”; while claim 3 recites, “wherein the enrichment scores are calculated using following Equation 1,
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”; which clearly resembles “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 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)). The claims do not provide other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment, e.g., an immunization step that integrates an abstract idea of data comparison into a specific process of immunizing that lowers the risk that immunized patients will later develop chronic immune-mediated diseases, as discussed in Classen Immunotherapies Inc. v. Biogen IDEC, 659 F.3d 1057, 1066-68, 100 USPQ2d 1492, 1499-1502 (Fed. Cir. 2011) (see MPEP § 2106.05(e)). 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 claim is recited at a high level of generality, such that substantially all practical applications of the judicial exception are covered. For instance, claims 1 and 16 are recited without any specificity as to identity of the antibodies in the library; the structure of the antibodies; the number of antibodies in the library; the method of individually designing CDR sequences; the structures of the CDR sequences; the method of synthesizing; the structure of the CDR-H3; how optimization occurs; what is meant by optimizing; what is optimized; the number, structure, and reactivity of the candidate CDR-H3 sequences; how enrichment scores are used and/or calculated; the enrichment scores of the candidate CDR-H3 sequences; how they are used without any NGS data, etc., wherein the steps of the method are well-known in the art.
For example, it was known that a novel synthetic single chain variable fragment (scFv) library with complementarity-determining region (CDR) diversities aimed at improved amplification efficiency was designed and constructed. A previously reported synthetic scFv library with low, non-combinatorial CDR diversities was panned against protein A superantigen, and the library repertoires before and after the panning were analyzed by next generation sequencing, wherein the enrichment or depletion patterns of CDR sequences after panning served as the basis for the design of the new library, especially for CDR-H3 with a higher and more random diversity, a machine learning method was applied to predict potential fast-amplified sequences among a simulated sequence repertoire; as well as optimization of CDR-H3 sequences by machine learning, including post-panning enrichment scores (Ess) of individual CDR-H3 sequences were calculated from the NGS data, and 70% of the sequence and their Ess were used as a training set as evidenced by Bai (International Journal of Molecular Sciences; Abstract; and pg. 5, Section 2.3); and it was known that many large synthetic antibody libraries have been designed, constructed, and successfully generated high-quality antibodies suitable for various demanding applications, such that while synthetic antibody libraries have many advantages such as optimized framework sequences and a broader sequence landscape than natural antibodies, their sequence diversities typically are generated by random combinatorial synthetic processes which cause the incorporation of many undesired CDR sequences, wherein the construction of a synthetic scFv library is described using oligonucleotide mixtures that contain predefined, non-combinatorially synthesized CDR sequences, such that each CDR is first inserted to a master scFv framework sequence and the resulting single-CDR libraries are subjected to a round of proofread panning, where the proofread CDR sequences are assembled to produce the final scFv library with six diversified CDRs as evidenced by Bai and Shim (Methods in Molecular Biology, 2017, Chapter 2, Abstract). It is also known that the ability of monoclonal antibodies to specifically bind a target antigen and neutralize or stimulate its activity is the basis for the rapid growth and development of the therapeutic antibody field, such that in recent years, traditional immunoglobulin antibodies have been further engineered for better efficacy and safety, and technological developments in the field enabled the design and production of engineered antibodies capable of mediating therapeutic functions hitherto unattainable by conventional antibody formats; and representative of this newer generation of therapeutic antibody formats are bispecific antibodies and antibody–drug conjugates, each with several approved drugs and dozens more in the clinical development phase as evidenced by Shim (Biomolecules, 2020, Abstract); and a method for constructing an antibody library, wherein in the individual designing of the complementarity determining region sequences, for CDR-H1, CDR-H2, CDR-L1, or CDR-L2, the sequences therefor are designed by simulating i) an utilization frequency of each germline immunoglobulin gene, ii) a frequency of mutation into any amino acid types by somatic hypermutations at each amino acid position, iii) a length distribution frequency of sequences comprising each complementarity determining region, or iv) a frequency of each amino acid at each position calculated by analyzing a combination thereof, of the complementarity determining regions of actual human-derived mature antibodies was known in the art as evidenced by Shim (US2017362306, paragraph [0029]).
Thus, the claims as a whole simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality to the judicial exception, wherein the steps are well-understood, routine and conventional activities previously known to the industry, as discussed in Alice Corp., 134 S. Ct. at 2359-60, 110 USPQ2d at 1984 (see MPEP § 2106.05(d)). 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, claims 1 and 16 DO NOT qualify as eligible subject matter.
Dependent claims 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 enrichment scores are predicted by a machine learning model, but it does not add anything that makes the abstract idea in claim 1 significantly different.
In light of the above consideration and the new guidance, claims 1-16 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 may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Shim et al. (hereinafter “Shim”) (US Patent Application Publication No. 20170362306, published December 17, 2017) in view of Mason et. al. (hereinafter “Mason”) (US Patent Application Publication 20220157403, published May 19, 2022; WO20208555, filed April 8, 2020; effective filing date April 9, 2019).
Regarding claims 1 and 16, Shim teaches a method for constructing an antibody library, the method including: individually designing complementarity determining region (CDR) sequences of an antibody; and synthesizing antibodies that include the designed complementarity determining region sequences to construct a library (interpreted as preparing an antibody library; individually designing CDR sequences; synthesizing an antibody library; and an antibody library, claims 1 and 16) (paragraph [0011]). Shim teaches that in the individual designing of the complementarity determining region sequences for CDR-H3: (a) each sequence therefor excluding three amino acids from a C-terminus for the CDR is designed by using a frequency of each amino acid at each position in the CDR of actual human-derived mature antibodies, and (b) a 3 amino acid sequence from the C-terminus of the complementarity determining region is designed by analyzing and calculating frequencies of the corresponding 3 amino acid sequences in the complementarity determining region of actual human-derived mature antibodies, then simulating sequences that reflect the calculated frequencies (interpreted as optimizing CDR-H3; and interpreting simulating sequences as using an enrichment score, claims 1 and 16) (paragraphs [0094]-[0096]).
Regarding claim 2 (in part), Shim teaches in Table 14 mutations in CDRs and framework regions (FRs) before and after the panning selection (interpreted as before and after panning, claim 2) (paragraph [0210]; and Table 14).
Regarding claim 3 (in part), Shim teaches in Table 14 mutations in CDRs and framework regions (FRs) before and after the panning selection (interpreted as before and after panning, claim 2) (paragraph [0210]; and Table 14).
Regarding claim 4, Shim teaches that since the contribution of CDR-H3 is larger than that of other CDRs in the antigen-antibody interaction, the larger number of CDR-H3 sequences compared to other CDRs were designed, such that two pools of 3,918 oligonucleotide sequences, one of which encoding CDR-H3 sequences of an even-number amino acid lengths and the other encoding CDR-H3 sequences of odd number amino acid lengths, were designed, wherein Table 3 shows that total unique CDR sequences (interpreting designed CDR-H3 as candidate sequences; and calculating the actual unique sequences as enrichment scores above zero, claim 4) (paragraphs [0172]-[0173]; and Table 3).
Regarding claim 5, Shim teaches that in the method for constructing antibody library, the antibodies can include amino acid sequences encoded by VH3-23 (interpreted as excluding VH1, VH4 or VH5, claim 5) (paragraph [0125]).
Regarding claim 6, Shim teaches that the purpose of constructing a single CDR library is to remove CDR sequences that cause inaccuracy and premature translational termination due to insertion/deletion/substitution of nucleotides present in the synthesized CDR oligonucleotide; and since the efficiency of chemical synthesis of oligonucleotides is not perfect, there are many sequences having insertion/deletion/substitution causing premature translational termination in the synthesized CDR oligonucleotides, and phage clones containing the sequences may not have HA-tag, and thus be removed by panning (interpreted as having a polymorphism, claim 6) (paragraph [0190], lines 1-5 and 16-21).
Regarding claim 7, Shim teaches that the method for constructing an antibody library, wherein in the individual designing of the complementarity determining region sequences, for CDR-H1, CDR-H2, CDR-L1, or CDR-L2, the sequences therefor are designed by simulating (i) an utilization frequency of each germline immunoglobulin gene, (ii) a frequency of mutation into any 20 amino acid types by somatic hypermutations at each amino acid position, (iii) a length distribution frequency of sequences comprising each complementarity determining region, or (iv) a frequency of each amino acid at each position calculated by analyzing a combination thereof, of the complementarity determining regions of actual human-derived mature antibodies (interpreted as simulating as recited in claim 7, claim 7) (paragraph [0029).
Regarding claim 8, Shim teaches (a) 7 or 8 amino acid sequences from a N-terminus of the complementarity determining region are designed by simulating i) an utilization frequency of each germline imm1moglobulin gene, ii) a frequency of mutation into each of 20 amino acids by somatic hypermutations at each amino acid position, iii) a length distribution frequency of sequences comprising CDR-L3, or iv) a frequency of each amino acid at each position calculated by analyzing a combination thereof, of the complementarity determining region of actual human-derived mature antibodies, and (b) 2 or 3 amino acid sequences from a C-terminus of the complementarity determining region are designed by analyzing and calculating a frequency of each amino acid at each position in the complementarity determining region of actual human-derived mature antibodies, then simulating sequences that reflect the calculated frequencies; and wherein the CDR-L3 contains 9 to 11 amino acids and the analysis of the frequencies is conducted according to each length, the CDR-L3 sequences being designed based on an analysis result of complementarity determining region CDR-L3 of human-derived mature antibodies, which have the same amino acid lengths as CDR-L3 to be designed (interpreted to encompass 7 to 8 amino acid sequences; and 2 to 3 amino acid sequences for CDR-L3 of claim 8, claim 8) (paragraphs [0031]-[0033]).
Regarding claim 9, Shim teaches that when a light chain complementarity determining region sequence is designed, a corresponding light chain can be a kappa light chain or lambda light chain (interpreted as a light chain is a kappa or lambda light chain, claim 9) (paragraph [0028]).
Regarding claim 10, Shim teaches that in the individual designing of the complementarity determining region sequences for CDR-H3: (a) each sequence therefor excluding three amino acids from a C-terminus for the CDR is designed by using a frequency of each amino acid at each position in the CDR of actual human-derived mature antibodies, and (b) a 3 amino acid sequence from the C-terminus of the complementarity determining region is designed by analyzing and calculating frequencies of the corresponding 3 amino acid sequences in the complementarity determining region of actual human-derived mature antibodies, then simulating sequences that reflect the calculated frequencies; and wherein the CDR-H3 contains 9 to 20 amino acids and the analysis of the frequencies is conducted according to each length, the CDR-H3 sequences being designed based on an analysis result of complementarity determining region CDR-H3 of human-derived mature antibodies, which have the same amino acid length as CDR-H3 to be designed (interpreted as encompassing designing CDR-H3 as recited in claim 10, claim 10) (paragraphs [0094]-[0097]).
Regarding claim 11, Shim teaches that after the designing of the complementarity determining region amino acid sequences, excluding sequences having N-glycosylation, isomerization, deamidation, cleavage, and oxidation motifs from the designed sequences (interpreted as excluding the sequences recited in claim 11, claim 11) (paragraph [0039]).
Regarding claim 12, Shim teaches that in the designing of CDR sequences, sequences including the following post-translational modification sequences were excluded, wherein the post-translational modifications of proteins can affect the functions and physicochemical properties of the proteins, and thus it is advantageous to exclude such sequences as much as possible in the design of the antibody library (interpreted as encompassing excluding immunogenic sequences or deimmunizing the designed sequences, claim 12) (paragraph [0122]).
Regarding claim 13, Shim teaches that after the designing of the complementarity determining region amino acid sequences, reverse-translating the designed sequences into a polynucleotide sequences and then designing an oligonucleotide sequence, in which framework region sequences of variable regions of a human antibody germline gene flanking the complementarity determining region are linked to the 5' and 3' ends of the reverse-translated polynucleotide (interpreted as reverse translating the designed sequences, claim 13) (paragraph [0040]).
Regarding claim 14, Shim teaches a method for constructing an antibody library, wherein the antibodies include amino acid sequences encoded by VH3-23 (Genebank accession No. Z12347), VK3-A27 (Genebank accession No. X93639), VL1g (GenBank accession No. Z73663), or fragments thereof (interpreted as sequences as encoded in claim 14, claim 14) (paragraph [0041]).
Regarding claim 15, Shim teaches constructing an antibody library, wherein the antibodies are selected from the group consisting of IgA, IgD, IgE, IgM, IgG, Fc fragments, Fab, Fab', F(ab')2, scFv, single variable domain antibody, and Fv (interpreted as the antibodies of claim 15, claim 15) (paragraph [0044]).
Shim does not specifically exemplify a enrichment using a machine learning model (claim 2, in part); and an enrichment score calculated using equation 1 (claim 3, in part).
Regarding claim 2 (in part), Mason teaches methods to make predictions classifying one or more properties of a binding protein such as an antibody, for example, antibody affinity or specificity for an antigen, wherein the system can include one or more machine learning models that can extrapolate complex relationships between amino acid sequence and function, such that the system can be trained on high-quality training data generated through a two-step single-site and combinatorial deep mutational scanning approach, wherein the trained models can then make predictions on novel variant sequences generated in silico; and the present disclosure describes amino acid sequences generated by the systems and methods provided, and uses of the generated sequences to produce proteins for therapeutic and diagnostic use (interpreted as encompassing machine learning models that are trained, claim 2) (Abstract). Mason teaches that the input amino acid sequence can be a portion of a complementarity determining region (CDR) of the antibody, CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, a region within the framework domains of the antibody (e.g., FR1, FR2, FR3, FR4), or a region within the constant domains of the antibody (e.g., CHI, CH2, CH3), or any combination thereof (interpreting a CDR-H3 input value, claim 2) (paragraph [0008], lines 1-8).
Regarding claim 3 (in part), Mason teaches that flow process 400 can include deep mutational scanning to determine enrichment scores for each amino acid position assayed to determine which positions are more or less amenable to accepting mutations, where the enrichment scores can be the ratio of clonal frequencies of variants enriched for antigen specificity by FACS,fi,Ag+, to the clonal frequencies of the variants present in the original library, fi,Ab+, where the enrichment ratio (ER) has the equation:
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(interpreted as an enrichment score; and encompassing equation 1 of claim 3, claim 3) (paragraph [0088]). Mason teaches that a clone was defined based on the specific amino acid sequence of the CDRH3, wherein heatmaps and their corresponding sequence logo plots can then be generated based on the enrichment scores from the first step of the screening process (interpreted as encompassing equation 1 for CDR-H3, claim 3) (paragraph [0089]).
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 producing antigen-specific antibody libraries as exemplified by Mason, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of constructing an antibody library including by individually designing the CDR sequences of an antibody, followed by synthesizing the designed antibodies that include the designed CDR regions as disclosed by Shim to include the methods of the lead candidate optimization including the use of machine learning models for multiple antibody locations including CDRH3, binding affinity scores, deep mutational scanning, and/or the generation of enrichment scores as taught by Mason with a reasonable expectation of success in improving the therapeutic antibody development process; in generating antigen specific libraries in mammalian cells at multiple locations along the antibody; and/or in improving the ability to identify amino acid sequences that improves one or more properties of the binding protein including physiochemical properties to a plurality of antigens; as well as, having a high functional diversity.
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 1-16 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