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
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Status of Claims
Claims 1, 2 and 4-15 are currently pending. Claims 1, 2 and 4-15 have been amended by Applicants’ amendment filed 04-17-2026. Claims 3 and 16 have been canceled by Applicant’s amendment filed 04-17-2026. No claims have been added by Applicants’ amendment filed 04-17-2026.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Therefore, claims 1, 2 and 4-15 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.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed April 17, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below are herein withdrawn.
Specification Objection
The objection to the disclosure is withdrawn because it contains an embedded hyperlink and/or other form of Browser-executable code (e.g., as-filed Specification, paragraphs [0092], [0097]; and [0131]) due to Applicant’s amendment of the Specification, in the reply filed 04-17-2026.
Claim Rejections - 35 USC § 103
The rejection of claims 1-16 is withdrawn under 35 U.S.C. 103 as being unpatentable over Shim et al.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).
The combined references of Shim and Mason do not specifically exemplify Equation 1.
In view of the withdrawn rejection, Applicant’s arguments are rendered moot.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 2 and 4-15 are maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1 and 7 are indefinite for the recitation of the term “the individually designing the CDR sequences” such as recited in claim 1, line 6. There is insufficient antecedent basis for the term “the individually designing the complementarity determining region (CDR) sequences” in the claim because claim 1, line 2 recites the term “individually designing CDR sequences”.
Claims 1 and 4 are indefinite for the recitation of the term “optimizing” such as recited in claim 1, line 8 because it is completely unclear what is being “optimized” with regard to the CDR-H3. Moreover, the term “optimizing” is a relative term that renders the claim indefinite. The term “optimizing” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount of ‘optimization’ as compared to some other value that qualifies as an “optimizing” a CDR-H3, 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 terms “NGS reads”, “before and after panning”, “an antigen”, “number of reads”, “before panning”, and “after panning” such as recited in claim 1, lines 9-20 because claim 1 does not recite the presence of NGS reads, antigens, the production of reads, and/or the steps of NGS and/or panning and, thus, the metes and bounds of the claim cannot be determined.
Claim 2 is indefinite for the recitation of the term “scores are predicted”, “machine learning model”, “trained”, “input values”, and “results values” such as recited in claim 2, lines 1-5 because claim 2 depends from instant claim 1, wherein claim 1 does not recite predicting enrichment scores, the presence and/or use of a machine learning model, training a machine learning model, input values and/or results values. Moreover, claim 1 already recites that enrichment scores are calculated using Equation 1, such that it is unclear how why scores are predicted when they have been calculated and, thus, the metes and bounds of the claim cannot be determined.
Claim 5 is indefinite for the recitation of the term “excluding sequences derived from a VH1, VH4 or VH5 family” such as recited in claim 5, lines 1-3 because claim 5 depends from instant claim 1, wherein claim 1 does not recite “sequences derived from a VH1, VH4 or VH5 family” and/or any calculation where such sequences are produced and, thus, the metes and bounds of the claim cannot be determined.
Claims 7, 8 and 10 are indefinite for the recitation of the terms “each germline immunoglobulin gene” and/or “actual human-derived mature antibodies” such as recited in claim 7, line 6-7 and 10 because claim 7 depends from instant claim 1, wherein claim 1 does not recite the presence of germline immunoglobulin gene and/or actual human-derived mature antibodies. Moreover the meaning of the term “actual human-derived mature antibodies” is unclear, including whether the term is meant to refer to patient obtained antibodies, non-synthetic antibodies, and/or whether the term refers to something else and, thus, the metes and bounds of the claim cannot be determined.
Claim 8 is indefinite for the recitation of the term “the CDR-L3 to be designed” such as recited in claim 8, lines 18-19. There is insufficient antecedent basis for the term “the CDR-L3 to be designed” in the claim because claim 8, line 16 recites the term “CDR-L3 sequences being designed”, which refers to the present tense, wherein the term “to be designed” refers to designing that occurs at a future time.
Claim 10 is indefinite for the recitation of the term “wherein the designing the CDR-H3 comprises…CDR-H3 to be designed” such as recited in claim 10, lines 2-15 because claim 10 depends from instant claim 1, wherein claim 1 already recites what “designing the CDR-H3 comprises” (e.g., by optimizing the CDR-H3 using an enrichment score), such that claim 10 cannot recite a different method of designing the CDR-H3 and, thus, the metes and bounds of the claim cannot be determined.
Claim 10 is indefinite for the recitation of the term “the calculated frequencies” such as recited in claim 10, line 10. There is insufficient antecedent basis for the term “the calculated frequencies” in the claim because claim 10, line 8 recites the term “analyzing and calculating frequencies”.
Claim 10 is indefinite for the recitation of the term “the CDR-H3 to be designed” such as recited in claim 10, lines 14-15. There is insufficient antecedent basis for the term “the CDR-H3 to be designed” in the claim because claim 1, line 7 recites the term “designing a CDR-H3”, which refers to the present tense, wherein the term “to be designed” refers to designing that occurs at a future time.
Claim 11 is indefinite for the recitation of the term “the possibility” such as recited in claim 10, line 4. There is insufficient antecedent basis for the term “the possibility” in the claim.
Claim 11 is indefinite for the recitation of the term “the possibility of N-glycosylation…cleavage and oxidation” such as recited in claim 11, lines 4-5 because the term “possibility” is a relative term that renders the claim indefinite. It is completely unclear how sequences comprising a “possibility of N-glycosylation…cleavage and oxidation” is determined and/or identified; and/or the Specification does not provide a standard for ascertaining the requisite amount of ‘possibility’ as compared to some other value that qualifies as a “possibility” that such reactions might occur, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention.
Claim 11 is indefinite for the recitation of the term “N-glycosylation…cleavage and oxidation” such as recited in claim 11, lines 4-5 because it is unclear from the term “and oxidation”, whether the exclusion of sequences applies only to sequences that may possibly undergo all five types of the recited reactions; or whether the term refers to sequences that may undergo any one of the recited reactions and, thus, the metes and bounds of the claim cannot be determined.
Claim 12 is indefinite for the recitation of the term “deimmunizing” such as recited in claim 12, lines 4-5 because claim 12 depends from instant claim 1, wherein claim 1 does not recite immunizing the designed CDR sequences and, thus, the metes and bounds of the claim cannot be determined.
Claims 6, 9 and 13-15 are indefinite insofar as they ultimately depend from instant claim 1.
Claim Rejections - 35 USC § 112(d)
The rejection of claims 2, 5, 6-8, 10 and 12 is maintained 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…using Equation 1” such as recited in claim 2, lines 2-6 because claim 2 depends from instant claim 1, where claim 1 does not recite predicted scores, a machine learning model, training a model, input values and/or results values. 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 5 recites (in part): “wherein the individually designing the CDR sequences of antibodies further includes designing…from a VH1, VH4 or VH5 family” in lines 1-3 because claim 5 depends from instant claim 1, wherein claim 1 does not recite “sequences derived from a VH1, VH4 or VH5 family” and/or any calculation where such sequences are produced. 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.
Claims 7 and 8 recite (in part): “wherein the individually designing the CDR sequences of antibodies further includes designing…of actual human-derived mature antibodies” in claim 7, lines 1-9 because claims 7 and 8 depend from instant claim 1, wherein claim 1 does not recite the presence of germline immunoglobulin gene and/or actual human-derived mature antibodies. Thus, claims 7 and 8 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 10 recites (in part): “wherein the designing of the CDR-H3 comprises designing each sequence…CDR-H3 to be designed” in lines 2-15 because claim 1 already recites what “designing the CDR-H3 comprises” (e.g., by optimizing the CDR-H3 using an enrichment score), such that claim 10 cannot recite a different method of designing the CDR-H3. Moreover, claim 1 does not recite the presence of a patient, a human, and/or actual human-derived mature antibodies. 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 12 recites (in part): “further comprising: after the individually designing complementarity determining region (CDR) sequences of antibodies, deimmunizing the individually designed CDR sequences” in lines 2-4 because claim 12 depends from instant claim 1, wherein claim 1 does not recite immunizing the designed CDR sequences. 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.
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.
The rejection of claims 1, 2 and 4-15 is maintained 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, 2 and 4-15 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 claims 1, 2 and 4-15 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., individually designing CDR sequences including designing CDR-H3; encompassing in silico design; optimizing CDR-H3 using enrichment scores; calculating enrichment scores using Equation 1, etc.). The claims broadly recite 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 lines 2-3; “and synthesizing antibodies including the individually designed CDR sequences to prepare the antibody library” in lines 4-5; “wherein, the individually designing the CDR sequences of antibodies includes designing heavy chain complementarity determining region 3 (CDR-H3) by optimizing the CDR-H3 using enrichment scores of candidate CDR-H3 sequences” in lines 7-8; “wherein the enrichment scores are calculated using following Equation 1 based on Next Generation Sequencing (NGS) reads before and after panning the antibody library against an
antigen: Equation 1
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” in lines 9-13;
“and, wherein in the Equation 1, Npre is a total number of NGS reads of the antibody library
including at least one of the candidate CDR-H3 sequences before panning Npost is a total
number of NGS reads of the antibody library after panning ni-pre is a number of reads of a
specific CDR-H3 sequence i in the antibody library before panning ni-post is a number of reads of
the specific CDR-H3 sequence i in the antibody library after panning npre is a set of read
numbers of the individually designed CDR sequences in the antibody library before panning.
npost is a set of read numbers of the individually designed CDR sequences in the antibody library
after panning, median(npre) is a median of the npre, and median(npost} is a median of the npost” in lines 15-22. 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, and 4-15 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, wherein the machine learning model is trained by setting at least one of the CDR-H3 sequences as input values, and setting, as result values, the enrichment scores calculated by measuring relative frequencies of the sequence before and after panning”; 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, claim 1 is 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 (e.g., algorithms, limitations, assumptions, specifications, etc.); 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, claim 1 DOES NOT qualify as eligible subject matter.
Dependent claims 2 and 4-15 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, 2 and 4-15 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).
Response to Arguments
Applicant’s arguments filed April 17, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) amended claim 1, as a whole, does not recite a mathematical concept because amended claim 1 recites a method of preparing an antibody library including designing CDR sequences, synthesizing antibodies, and performing antigen panning with Next Generation Sequencing analysis (Applicant Remarks, pg.17, first full paragraph); (b) a person cannot do the above emphasized features simply in their mind using observation, judgement and opinion, because the claimed features, designing CDR sequences and optimizing CDR-H3 regions using enrichment scores derived from Next Generation Sequencing data requires the millions of sequence reads, large-scale mass and complex biological data processing and analysis nature of claimed method does not fall into "mental process" as alleged by the Office Action (Applicant Remarks, pg. 17, second full paragraph); (c) the claimed feature is integrated into a practical application of the exception because claim 1 recites panning the antibody library, obtaining NGS reads, and calculating enrichment scores based on the reads, and
as the specification of the present application describes, the specific claimed Equation 1 statistically compensates for amplification bias and specifically preventing clones with low read counts from being overestimated (see paragraphs [0133] and [0139] (Applicant Remarks, pg. 20, entire page); (d) claim 1 recites significantly more than the judicial exception, such that when elements of amended claim 1 are combined, an inventive concept may be found in the non-conventional and non-generic arrangement of the additional elements (See, claim 1), where specific technological method that ties to experimentally derived sequencing data and applies the results to the design and synthesis of antibodies and an improvement in the manner in which experimentally derived NGS data are used to optimize CDR-H3 sequences prior to synthesis, including by optimizing the CDR-H3 using enrichment scores of candidate CDR-H3 sequences (Applicant Remarks, pg. 21, Step 2B through pg. 23, first full paragraph)
Regarding (a), Applicant’s assertion that claim 1 does not recite a mathematical concept, is not found persuasive. The claims as a whole are clearly directed to an abstract idea. For example, instant claim 1 recites that the claims are directed to a method of preparing an antibody library, comprising individually designing CDR sequences of antibodies using an enrichment score comprising Equation 1 below, which clearly demonstrates a mathematical relationship, formula or equations, and a calculation:
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(claim 1). Additionally, the claims recite predicting enrichment scores using a machine learning model (claim 2); further including individually designing a CDR-H2 (claim 5); further including designing CDR-H1, CDR-H2, CDR-L1, CDR-L2 by simulating a utilization frequences (claim 7), simulating a utilization frequency of each germline immunoglobulin gene…a frequency of each amino acid at each position is calculated by analyzing a combination thereof (claim 8), etc. Additionally, instant claim 1 does not actually recite steps of next generation sequencing and/or panning the antibody library against an antigen. The claims are clearly directed to an abstract idea including mathematical concepts such as mathematical relationships, formulas or equations, and/or calculations; and/or mental process such as observation, judgement and opinion without significantly more. Thus, the rejection is maintained.
Regarding (b), Applicant’s assertion that claim 1 does not include mental processes, is not found persuasive. It is noted that the instant claims do not recite next generation sequencing data, millions of sequencing reads, and/or large-scale mass and complex biological data processing and analysis. Assuming arguendo that the claims require this type of data analysis, this clearly indicates that the claims are directed to an abstract idea in the form of mathematical relationships, formulas or equations, and/or calculations. Due to the broadness of the instant claims, the Examiner contends that mental processes can clearly be part of the instant method. For example, in individually designing CDR sequences, by inputting data parameters such as length distribution, selecting the machine learning model, the number of rounds of panning, the type of NGS, determining read length, etc. Thus, the rejection is maintained.
Regarding (c), Applicant’s assertion that the claims integrate the judicial exception into a practical application, is not found persuasive. Once again, it is noted that the claims do not recite steps of NGS sequencing and/or panning. Moreover, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). Additionally, what is taught in the Specification is not recited in the instant claims. There is absolutely no indication that Equation 1 statistically compensates for amplification bias and specifically preventing clones with low read counts from being overestimated as asserted by Applicant. Moreover, the claims are very broadly recited, such that no particular antibodies, design parameters, what is being optimized with regard to the CDR-H3, computer programs, algorithms, the computer simulation models used, the type and/or method of optimizing the CDR sequences, carrying out a specific NGS and panning technique, the number and size of the reads obtained, the antigen, the number of rounds of panning, the enrichment scores obtained, how the enrichment scores are applied to designing the CDR sequences, how the enrichment scores predicted by the machine learning model are used to optimize the antibodies, etc. are recited in the instant claims. Thus, the claims clearly do not integrate the judicial exception into a practical application. The claims remain rejected.
Regarding (d), Applicant’s assertion that claim 1 recites significantly more than the judicial exception, is not found persuasive. Please see the discussion supra regarding the Examiner’s response to Applicant’s arguments including what is recited in claim 1 (as well as, what is not recited in claim 1). It is completely unclear how the CDR sequences are designed, what in the CDR sequences is optimized; how the CDR sequences are optimized; the structure of the candidate CDR-H3 sequences; how the results of Equation 1 are used to design the CDR sequences, the identity of the antibodies, the identity of the proposed antigen, what data is analyzed; how the data is analyzed, the specific machine learning model, etc. Nothing in the very broadly recited claims appears to recite ‘significantly more’ than the judicial exception. As noted in the rejection of record, the steps of the method are well-known, purely conventional, or routine in the art as evidenced by Bai, Bai and Shim, Shim, and Shim ‘306. Thus, the claims remain rejected.
New Objections/Rejections
Claim Objection
Claim 1 objected to because of the following informalities: Claim 1 recites components individual components of Equation 1 in the body of claim 1, which are very difficult to read (e.g., the equation including ni-pos, ni-pre, i, etc.).
Appropriate correction is required.
Claim 7 objected to because of the following informalities: Claim 7 recites “(CDR-L2” in line 6, wherein the term “(CDR-L2)” might be more appropriate.
Appropriate correction is required.
Notice of Non-Compliant Amendment (37 CFR 1.121)
The amendment to the claims filed on October 12, 2025 does not comply with the requirements of 37 CFR 1.121(c) because the text of claim 15 has been submitted with markings to indicate that changes have been made relative to the immediate prior version of claims filed on February 24, 2023.
Amendments to the claims filed on or after July 30, 2003 comply with 37 CFR 1.121(c), which states:
(c)(2) Claims - When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.”
Specifically, the amendments to the claims filed April 17, 2026 include the identifier for claim 15 “(Currently Amended).” However, there are no markings indicating that claim 15 has been amended, and a comparison with the claims filed February 24, 2023 indicate that instant claim 15 has not been amended.
To be fully responsible, Applicant is required to comply with the Notice of Non-Compliant Amendment (37 CFR 1.121). In the interests of compact prosecution, an action on the merits has been prepared. However, future amendments must comply with 37 CFR 1.121(c) in order to avoid a notice of non-compliant amendment.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2 and 4-15 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Xuelian Bai (hereinafter “Bai”) (Dissertation, EWHA Womans University, Department of Life Sciences, July 2020, 1-102) as evidenced by Villa et al. (hereinafter “Villa”) (US Patent No. 8735331, issued May 27, 2014). This is a new rejection necessitated by amendment of the claims in the response filed 04-17-2026.
Regarding claim 1, Bai teaches that a synthetic scFv antibody library with >8,000 individually designed sequences for each complementarity-determining region (CDR) was sequenced using the Illumina Miseq platform with ~350 bp paired-end reads after three rounds of panning against protein A (antigen), wherein the 1.5~2.3 million sequences obtained by NGS for each variable domain (VH, VL, and VK) were divided into FASTA files containing ~105 sequences each for easier analysis; and the CDR sequences were extracted from the FASTA files using a Python script developed in-house in the comma-separated values (.csv) format, wherein the germline origin of the individual CDR-H1, -H2, -L1, -L2, and -L3 sequences was determined using a VBA program, such that for CDR-H3, the extracted sequences were grouped according to their lengths (9 to 20 amino acids) (interpreted as designing an antibody library; designing CDR sequences including CDR-H3; NGS; panning against an antigen protein A; obtaining reads; extracting sequences; and synthesizing an antibody library, claim 1) (pg. 15, Section IIA, first full paragraph). Bai teaches that for CDRs other than CDR-H3, sequences were designed as described previously in Bai et al. (PLoS One, 2015, 10, 1-18), wherein the designed sequences were then evaluated for their potential binding to human MHC class 2 molecules using netMHCIIpan-3.1 software (interpreted as designing all other sequences) (pg. 15, Section IIB, first full paragraph, lines 1-3). Bai teaches that for CDR-H3, the relative frequency of each individual CDR sequence (a total of 7,526 unique sequences) before and after three rounds of panning against protein A was compared, and the enrichment score was calculated using the formula:
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56
626
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where Npre and Npost are the total number of NGS reads before and after the panning, respectively, and npre and npost are the number of NGS reads for each specific CDR-H3 sequence before and after the panning, respectively (interpreted as Equation 1, calculating an enrichment score, claim 1) (pg. 16, first full paragraph).
Regarding claim 2, Bai teaches that the CDR-H3 sequences and their ESs were used as inputs to train machine learning models for the prediction of efficiently enriched sequences, wherein seventy percent of the sequence-ES data was used as the training set, and the remaining 30% was used as the evaluation set for Amazon Machine Learning (https://console.aws.amazon.com/machine-learning /home, accessed on Nov. 2017). A .csv (comma-separated values) file containing the CDR sequences, their ESs, and the amino acid residue at each position of each sequence was created (Supplemental materials) for each CDR-H3 length to train a machine learning model; and the following parameters were used: maximum machine learning model size,100 MB; maximum number of data passes, 100; L2 regularization, mild (10-6), wherein the models were validated using the evaluation data set (interpreted as using a machine learning model; training the machine learning model; setting CDR-H3 input values; setting results values; and predicting enrichment scores, claim 2) (pg. 16, second full paragraph).
Regarding claim 4, Bai teaches that preliminary CDR-H3 sequence repertoires of different lengths were designed as previously reported in Bai et al. (supra), wherein the designed sequences were evaluated by the machine learning models for the predicted enrichment by phage display, and the sequences with the predicted ES > 0 (i.e. their relative numbers increased by panning) were selected for library construction, and the selected sequences were further analyzed for HLA-DRB binding as described above to identify and remove potentially immunogenic sequences, such that the designed CDR sequences, with the adjoining framework sequences and the adaptor sequences for PCR amplification, were reverse translated to DNA sequences and synthesized as oligo pools (interpreted as selecting candidate sequences, claim 4) (pg. 16, last partial paragraph; and pg. 17, first partial paragraph).
Regarding claim 5, Bai teaches that the CDRs of OPALT were designed for all variable gene families, except for CDR-H2 for which sequences derived from VH1, VH4 or VH5 families were avoided because these CDRs were strongly disfavored in VH3-23 scaffold during panning (interpreted as designing CDR-H2; and excluding VH1, VH4 or VH5 family, claim 5) (pg. 60, first full paragraph, lines 5-8).
Regarding claim 6, Bai teaches that a phage antibody library (OPAL, Optimized Phage Antibody Library) with CDRs designed and synthesized by random mononucleotide combination method was also produced, wherein this method only creates the amino acid sets at rectangular positions in the codon table, and it is impossible to prepare arbitrary sets of amino acids using the degenerate codons; and because of the random combination, many non-natural CDR sequences are synthesized and integrated into the library (interpreted as CDRs comprising a polymorphism, claim 6) (pg. 7, first full paragraph, lines 14-19). Bai teaches that the CDR diversity of synthetic antibody libraries is most frequently generated by the concatenation of random mono- or trinucleotide units (interpreted as CDRs comprising a polymorphism, claim 6) (pg. 56, second full paragraph, lines 1-2).
Regarding claim 7, Bai teaches that the CDRs were designed with non-combinatorial diversity to have sequence diversity similar to that of human antibody CDRs, by analyzing and simulating the characteristics of CDR sequences of known human antibodies, wherein the human immunoglobulin sequences were downloaded from the IMGT database (http://imgt.org) and the CDR sequences were extracted, then the CDR sequences of the human antibody germline immunoglobulin genes in the V-base (http://www2.mrc.-lmb.cam.ac.uk/vbase/alignments2.php) were compared with the mature CDR sequences extracted from the IMGT database, to find (i) the germline CDR sequence closest to each mature CDR sequence, and to identify the location, type, and frequency of mutations that occurred in the mature CDR, and (ii) the frequency of each germline CDR used in mature human antibody repertoire (interpreted as simulating a frequency of each germline immunoglobulin gene; a frequency of mutation into each 20 amino acids by somatic hypermutations at each amino acid; and actual human-derived mature antibodies, claims 7 and 8) (pg. 11, second full paragraph). Bai teaches that the CDR sequences for the new library were designed as described previously, i.e., by simulating the amino acid frequency of natural human antibodies for CDR-H3 and by simulating the germline gene usage and somatic hypermutations of natural human antibodies for the other CDR (interpreted as simulating a frequency of each germline immunoglobulin gene; a frequency of mutation into each 20 amino acids by somatic hypermutations at each amino acid; and actual human-derived mature antibodies, claims 7 and 8) (pg. 55, first full paragraph, lines 1-4).
Regarding claim 8, Bai teaches that Ylanthia diversified CDR-L3 and CDR-H3 using TRIM and Slonomic technologies, respectively, wherein six to seventeen amino acids representing the lengths of most naturally occurring CDR-H3 sequences were implemented in Ylanthia CDR-H3, and also potential post-translational modification (PTM) sites were avoided or reduced (interpreted as encompassing 7 to 8 amino acid sequences from the N-terminus of the CDR designed by simulating; and actual human-derived mature antibodies, claim 8) (pg. 9, second full paragraph, lines 6-10). Bai teaches that for the CDR-H3 and CDR-L3, the identification of germline sequences is often difficult due to mechanisms such as V(D)J recombination as well as junctional flexibility, P-addition, and N-addition, such that the 2 or 3 amino acids at the end of CDR-L3 were designed by simulating the sequence frequency of the corresponding positions in CDR-L3 of the mature human antibody (interpreted as 2-3 amino acid sequences from a C-terminus; and actual human-derived mature antibodies, claim 8) (pg. 11, last partial paragraph, lines 1-5).
Regarding claim 9, Bai teaches OPALT, consisting of sub-libraries with different CDR-H3 amino acid lengths, was constructed, such that six non-combinatorial diversified CDRs were assembled by PCR to construct OPALT-λ (DPL3 lambda light chain) and OPALT-κ (DPK22 kappa light chain) libraries with 1.1x1010 and 3.4x109 individual clones, respectively; and panning of the libraries successfully generated target-specific antibodies with nanomolar affinities to various antigens (interpreted as kappa light chain and lambda light chain, claim 9) (pg. 91, first full paragraph, lines 1-5).
Regarding claim 10, Bai teaches that the CDR-H3 of OPALT was designed to have lengths ranging from 9 to 16 amino acids, and unlike OPALS, the synthesized oligonucleotide pool for OPALT’s CDR-H3 was separated by lengths prior to library construction, wherein the frequencies of the appearance of the CDR-H3 with different lengths in the sequences obtained from panning were analyzed (Figure 15) (interpreted as excluding 3 amino acids from a C-terminus of the CDR-H3; and containing 9 to 16 amino acids, claim 10) (pg.82, first full paragraph, lines 1-4; and pg. 83, Figure 15).
Regarding claim 11, Bai teaches that after simulating the CDR sequences based on the amino acid frequencies, those sequences with sites for N-glycosylation, aspartate isomerization, asparagine deamidation, nonenzymatic cleavage, or oxidation were minimized or excluded from the designed sequences (interpreted as excluding sequences with a possibility of N-glycosylation, isomerization, deamidation, cleavage, and oxidation, claim 11) (pg. 11, last partial paragraph, lines 7-9; and pg. 12, first partial paragraph).
Regarding claim 12, Bai teaches that the designed CDR sequences were deimmunized in silico using netMHCIIpan-3.1 program (interpreted as deimmunizing CDE sequences, claim 12) (pg. 55, first full paragraph, line 8).
Regarding claim 13, Bai teaches that the designed CDR sequences, with adjoining framework sequences and the adaptor sequences for PCR amplification, were reverse translated to DNA sequences and synthesized as oligo pools (interpreted as reverse translating the designed CDR sequences; and into polynucleotide sequences; and comprising framework region sequences, claim 13) (pg. 16, last partial paragraph, line 6; and pg. 17, first partial paragraph, lines 1-2).
Regarding claim 14, Bai teaches that the synthetic library can be constructed using germline framework sequences that have superior stability, solubility, and expression level, thus avoiding or reducing problems of the natural antibody library, although at the same time the framework diversity is sacrificed, wherein such human germline immunoglobulin variable segments as DP47 and DPK22 are the preferred frameworks for the construction of synthetic antibody libraries based on their favorable properties such as high stability and expression levels in various hosts, and compatibility with each other (interpreted as comprising SEQ ID NO: 70 and 71, or fragments thereof, claim 14) (pg. 6, first full paragraph, lines 9-15), where it is known that framework sequences DP47 and DPK22 comprise SEQ IN NOS: 70 and 71 or a fragment thereof as evidenced by Villa (col 11, lines 15-20; col 12, lines 40-45 Figure 1, SEQ ID NOS: 22 and 26).
Regarding claim 15, Bai teaches that Human germline immunoglobulin variable segments DP47, DPL3 and DPK22 were synthesized and cloned into a pUC57 vector and used as the frameworks for library construction, wherein the framework genes were also cloned to pFcF (a pcDNA3.1-based vector with human IgG1 Fc and a pair of asymmetric SfiI sites) so that PCR amplification can be performed using different sets of primers (Table 4) in order to prevent cross-amplification (interpreted as IgG, claim 15) (pg. 19, first full paragraph, lines 1-6).
Bai meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Conclusion
Claims 1, 2 and 4-15 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684
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