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 1-26 are currently pending. Claims 1, 3-7, 10 and 11 have been amended by Applicants’ amendment filed 06-09-2026. Claims 17 and 28 have been canceled by Applicants’ amendment filed 06-09-2026. No claims have been added by Applicants’ amendment filed 06-09-2026.
Applicant's election without traverse of Group I, claims 1-11, directed to a method for identifying a group of complementarity determining region (CDR)3, 2 and/or 1 nanobody amino acid sequences; and Applicant’s election of Species without traverse as follows:
Species (A): wherein the required fragmentation coverage percentage is about 30 (claim 2); Species (B): the method of claim 1, further comprising a functional selection step comprising
selecting antigen-specific nanobodies (claim 7);
Species (B1): wherein the antigen-specific affinity chromatography is a resin conjugated to the
antigen (claim 8); and
Species (C) – (E): species directed to Groups III-V were not elected, in the reply filed
February 20, 2026 was previously acknowledged.
Claims 12-26 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 3-6 and 9-11 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
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, 7 and 8 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed November 1, 2022, claims the benefit of a 35 U.S.C. 371 national stage filing of International Application PCT/US2021/29869, filed April 29, 2021, which claims the benefit of US Provisional Patent Application 63/018559, filed May 1, 2020.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application 63018559, filed May 1, 2020, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claim 1 does not have support for; “a fragmentation coverage percentage equal to or more than a required fragmentation coverage percentage; wherein fragmentation coverage percentage is determined by a formula: f(x, chymotrypsin) = 0.0023x2 - 0.0497x + 0.7723, x[5,30]; f(x,trypsin) = 0.00006x2 - 0.00444x + 0.9194, x[5,30]”; and “wherein x is a length of the CDR3 region sequence, respectively”. Therefore, the priority date for the presently claimed invention is April 29, 2021, the filing date of PCT/US2021/29869.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claim 1 of the instant application.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 2, 7 and 8 is maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 is indefinite for the recitation of the term “the group” such as recited in claim 1, line 4. There is insufficient antecedent basis for the term “the group” in the claim because claim 1, lines 1-2 recites the term “a group of CDR3 nanobody amino acid sequences.” The Examiner suggests that Applicant amend the claim to recite, for example, “identified in the group of CDR3 nanobody amino acid sequences.”
Claim 1 is indefinite for the recitation of the term “each cDNA in the library” such as recited in claim 1, line 7. There is insufficient antecedent basis for the term “each cDNA in the library” in the claim because claim 1, line 6 recites the term “a nanobody cDNA library.”
Claim 1 is indefinite for the recitation of the term “those sequences” such as recited in claim 1, line 18. There is insufficient antecedent basis for the term “those sequence” in the claim because claim 1, line 15 recites the term “sequences of CDR3 regions.”
Claims 1 and 7 are indefinite for the recitation of the term “the CDR3 region sequence” such as recited in claim 1, lines 23-24. There is insufficient antecedent basis for the term “the CDR3 region sequence” in the claim because claim 1, line 15 recites the term “sequences of CDR3 regions.”
Claim 7 is indefinite for the recitation of the term “antigen-specific nanobodies” such as recited in claim 7, lines 2 and 3. There is insufficient antecedent basis for the term “antigen-specific nanobodies” in the claim because claim 1, lines 3 and 8 recite the terms “a nanobody” and “nanobodies.” Moreover, claim 7 depends from instant claim 1, wherein claim 1 does not recite the presence of antigen-specific nanobodies and, thus, the metes and bounds of the claim cannot be determined.
Claim 7 is indefinite for the recitation of the term “estimating” such as recited in claim 7, line 6 because the term “estimating” is a relative term that renders the claim indefinite. The term “estimating” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount of ‘estimation’ as compared to some other value that qualifies as “estimating” an affinity for each different CDR3 region sequence, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention and, thus, the metes and bounds of the claim cannot be determined.
Claim 7 is indefinite for the recitation of the term “each different i CDR3 region sequence” such as recited in claim 7, line 6. There is insufficient antecedent basis for the term “each different i CDR3 region sequence” in the claim because claim 7, line 4 recites the term “different nanobody fractions.”
Claims 2 and 8 are indefinite insofar as they ultimately depend from instant claim 1.
Claim Rejections - 35 USC § 112(d)
The rejection of claim 7 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 7 recites (in part): “selecting antigen-specific nanobodies using an antigen-specific affinity chromatography…and performing steps e. through I” in lines 2-6 because claim 7 depends from instant claim 1, wherein claim 1 does not recite the presence of antigen-specific nanobodies. 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.
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, 7 and 8 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., abstract idea, a law of nature, natural phenomenon, or natural product); and (3) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. In this case, the claims as a whole are directed to an abstract idea. Therefore, they must each be considered to determine whether, given their broadest reasonable interpretation, they amount to significantly more than the judicial exception.
The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claim(s) 1, 2, 7 and 8 do not recite something significantly different than the judicial exception. The rationale for this determination is explained below:
In the instant case, the claims broadly directed to a method of identifying a group of complementarity determining region (CDR)3 nanobody amino acid sequences and obtaining a nanobody comprising a CDR3 nanobody amino acid sequence identified in the group, the method comprising: (a) obtaining a blood sample from a camelid immunized with an antigen; (b) using the blood sample to obtain a nanobody cDNA library; (c) identifying a sequence of each cDNA in the library; (d) isolating nanobodies from the blood sample from the camelid immunized with the antigen; (e) digesting the nano bodies of (d) with trypsin or chymotrypsin to create a group of digestion products; (f) performing a mass spectrometry analysis of the group of digestion products to obtain mass spectrometry data; (g) selecting sequences identified in that correlate with the mass spectrometry data; (h) identifying sequences of CDR3, regions in the sequences from (g); and (i) selecting from the sequences of CDR3 regions of (h) those sequences having a fragmentation coverage percentage equal to or more than a required fragmentation coverage percentage; wherein the fragmentation coverage percentage is determined by a formula f(x,chymotrypsin) = 0.0023x2-0.0497x+0.7723,x[5,30] when chymotrypsin is used in (e) or a formula f(x,trypsin)=0.00006x2- 0.00444x+0.9194, x[5,30] when trypsin is used in (e), and wherein x is a length of the CDR3 region sequence, respectively; and (j) obtaining the nanobody comprising a sequence of CDR3 regions selected in (i).
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 revised Step IIA – Prong One of the analysis, which asks if the claimed invention is directed to a judicial exception, such that claims 1, 2, 7 and 8 are directed to an abstract idea including: (a) mathematical concepts such as mathematical relationships, formulas or equations, and/or calculations in the form of complete in silico implementation of all steps as recited in the instant claims (as taught in the Specification); and in the form of identifying the sequence of each cDNA in a library; digesting the nanobodies; performing mass spectrometry; selecting from the CDR3 region sequences; identifying sequences of CDR3 regions; selecting from the CDR3 region sequences having a fragmentation coverage percentage equal to or greater than a required fragmentation coverage percentage according the a formula f(x,chymotrypsin) = 0.0023x2-0.0497x+0.7723,x[5,30] when chymotrypsin is used in step (e), or a formula f(x,trypsin)=0.00006x2-0.00444x+0.9194, x[5,30] when trypsin; and obtaining a nanobody comprising a sequence of CDR3 regions selected in (i); as well as, (b) mental processes such as concepts performed in the human mind, such as observation, evaluation, judgement and opinion in the form of selecting, identifying, calculating, etc. The claims recite the judicial exception of an abstract idea that falls within the groupings of abstract ideas enumerated in the 2019 PEG including encompassing mathematical concepts, mental processes that can be carried out in the human mind, and/or by using a generic computer that performs routine and conventional functions including concepts including executing mathematical concepts, such as mathematical relationships, formula, equations, calculations. Thus, under the revised Step IIA analysis, the claims are directed to an abstract idea. Step IIA – Prong One [YES].
Proceeding to revised Step IIA – Prong Two of the analysis, which asks if the claims recite additional elements that integrate the judicial exception into a practical application of the exception. In the instant case, the claims are directed to a judicial exception in the form of an abstract idea. Claim 1 recites: “(a) obtaining a blood sample from a camelid immunized with an antigen; (b) using the blood sample to obtain a nanobody cDNA library; (c) identifying a sequence of each cDNA in the library” in lines 5-7 (encompassing a generic computer that carries out general computer functions); “(d) isolating nanobodies from the blood sample from the camelid immunized with the antigen; (e) digesting the nano bodies of (d) with trypsin or chymotrypsin to create a group of digestion products; (f) performing a mass spectrometry analysis of the group of digestion products to obtain mass spectrometry data” in lines 8-12; “(g) selecting sequences identified in that correlate with the mass spectrometry data; (h) identifying sequences of CDR3, regions in the sequences from (g)” in lines 13-16; and (i) selecting from the sequences of CDR3 regions of (h) those sequences having a fragmentation coverage percentage equal to or more than a required fragmentation coverage percentage; wherein the fragmentation coverage percentage is determined by a formula f(x,chymotrypsin) = 0.0023x2-0.0497x+0.7723,x[5,30] when chymotrypsin is used in (e) or a formula f(x,trypsin)=0.00006x2- 0.00444x+0.9194, x[5,30] when trypsin is used in (e), and wherein x is a length of the CDR3 region sequence, respectively; and (j) obtaining the nanobody comprising a sequence of CDR3 regions selected in (i)” in lines 17-26, which resembles “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)), and are analogous to “organizing information through mathematical correlations” (i.e. Digitech Image Techs., LLC v Electronics for Imaging, Inc., 758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)); and are examples of “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)); and resembles “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Additionally, the dependent limitations of claims 2, 7 and 8 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 7 provides, “wherein (d) further comprises a functional selection comprising selecting antigen-specific nanobodies using an antigen-specific affinity chromatography and eluting the antigen-specific nanobodies under varying degrees of stringency thereby creating different nanobody fractions, and performing (e) through (i) on the different nanobody fractions individually and estimating an affinity of each different (i) CDR3 region sequence for the antigen based on a relative abundance of the CDR3 region sequence in each of the different antibody fractions” in lines 1-8, which is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)); and “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Thus, the claims do not integrate the judicial exceptions into a practical application of the exceptions. Step IIA – Prong Two [NO].
Proceeding to Step IIB of the analysis: the question then becomes what element or what combination of elements is sufficient to amount to significantly more than the abstract idea? The instant independent claim is recited at a high level of generality, such that substantially all practical applications of the judicial exception related to the method of identifying a group of CDR3 region nanobody amino acid sequences, are covered. For instance, the claims are recited without any specificity as to the particular nanobodies; the nanobody sequences; the reduced number of sequences; what they are false positives with regard to; the specific control; the method of comparing; the method of obtaining; the camelid (e.g., a camel, llama, alpaca, guanaco, etc.); the antigen used for immunization; the method of using the blood sample; the process of creating a cDNA library; the number and length of the sequences in the cDNA library; the digestion products; the method of performing MS; the specific MS analysis conducted (e.g., ESI, IP-MS, MALDI, MALDI-TOF, etc.); the method of selecting sequences; the properties of the selected sequences; the method of correlating the MS data; the method of identifying CDR regions in the sequences; the method of selecting CDR3 region sequences; the required fragmentation coverage percentage; how the formulas were derived; the lengths of the CDR3 region sequences; the sequences of the nanobody CDR3 regions obtained, etc. Step IIB: [NO].
For example, using camelid heavy-chain-only (hcAbs) and their antigen binding fragments for the preparation and amplification of variable domains of HcAb (VHH/Nb) cDNA libraries from B lymphocytes of two lama glamas, recovering 13.6 million unique Nb sequences in the databases by next-generation genomic sequences was known in the art; and it was hypothesized that the estimated false discovery rate (FDR) of CDR3 identifications could be inflated due to the large database size and the unusual Nb sequence structure, such that to test this, antigen-specific HcAbs was proteolyzed with trypsin or chymotrypsin, while employing a state-of-the-art search engine Proteome Discovery (Sequest HT) for identification using two different databases: a specific “target” database derived from the immunized llama, and a “decoy” database of similar size from an irrelevant llama with literally no identical sequences (Fig S1D)Thus, any CDR3 peptides identified from the decoy database search were considered as false positives (Elias and Gygi, 2007), wherein a surprisingly large number of false-positive CDR3 peptides were nonspecifically identified from the decoy database search, wherein these spurious peptide-spectrum-matches generally contained poor MS/MS fragmentations on the CDR3 fingerprint sequences (Fig S1E-F); and the vast majority (95%) of these erroneous matches could be removed by implementing a simple fragmentation filter, requiring a minimum coverage of 50% (by trypsin, Fig 1G) and 40% (by chymotrypsin, Fig 1H) of the CDR3 high-resolution diagnostic ions in the MS2 spectra (Fig 1K-L), such that the filter was further optimized based on the CDR3 length (Fig 1I-J) before integrating into an open-source software Augur Llama (Fig S2A-C) that we developed for reliable Nb proteomic analysis as evidenced by Xiang (bioRxiv, Aug 2020, 1-44; of record; pg, 2, entire page; and pg. 3, first partial paragraph); and the formation of cDNA libraries from a llama blood sample was known in the art, wherein llamas were immunized 7 times by subcutaneously administration of U373 cells stably expressing EGFRvIII (U373-vIII) (~108 cells), wherein sera was collected before and after immunization and evaluated for the binding to purified EGFRvIII ectodomain in enzyme-linked immunosorbent assays (ELISA). Four days after he last immunization, peripheral blood lymphocytes (PBLs) were collected from blood and purified by density gradient centrifugation on Ficoll-Paque PLUS gradients, wherein the total RNA extracted from these cells was transcribed into cDNA (RT-PCR) and used for the generation of immune libraries as previously described was known in the art as evidenced by van Vught (Thesis; pg.123, Section 2.3; of record). Additionally, computational methods for modifying nanobodies to improve antigen binding affinity and specificity including using an algorithm that uses the 3D structures of protein-nanobody complexes as the initial structures and by successive mutations in the CDR domains to find optimum binding amino acids for hypervariable residues of CDRs to increase the binding affinity and nanobody selectivity was known in the art as evidenced by Hacisuleyman (BioRxiv, 2019, 1-20; Abstract); and the steps of the method recited in claim 1 was known in the art including
a highly optimized pipeline that allows the rapid production of large repertoires of high-affinity nanobodies against selected proteins based on high-throughput DNA sequencing of a marrow lymphocyte VHH cDNA library from an immunized llama combined with mass spectrometric (MS) identification of high-affinity VHH regions derived from serum of the same animal; and MS identification of affinity-purified heavy-chain antibodies isolated from an individual llama using a DNA sequence database generated from the same animal, wherein cDNA was generated from total lymphocyte RNA and performed nested PCR to specifically amplify sequences encoding the VHH variable regions; sequencing of this PCR product using a high-throughput Roche 454 (GFP) or Illumina MiSeq (mCherry) platform resulted in ~800,000 or ~3,000,000 unique reads, respectively, such that these reads were translated, filtered and trypsin digested in silico to create a searchable peptide database for MS analysis; and an automatic ranking pipeline, coupled with careful manual inspection, overcame these issues and provided 44 high-probability hits for nanobodies against GFP, such that the llama antibody against GFP (LaG) 1–44 and subjected them to further screening as evidenced by Fridy (Nature Methods, 2014, 1-12; Abstract; pg. 1, col 2; pg. 2, col 2; and pg. 3, Figure 2). Moreover, compositions and methods for producing large repertoires of recombinant nanobodies with high affinities and specificities against any antigen are known in the art, wherein DNA sequences of the PCR amplicons from the cDNA library are then determined using any suitable technique; and the amplified cDNAs are sequenced by high-throughput 454 sequencing or MiSeq sequencing. In embodiments, the high-throughput sequencing results in 80,000 to 5,000,000 unique reads, such that determining the sequences in this manner provides a catalog of sequences encoding the VHH variable regions of the Ag-specific and non-specific HCAbs, wherein the amino acid sequences of these VHH variable regions are deduced (translated in silico), thus providing a catalog of VHH variable regions, some of which are specific for one or more epitopes present the antigen administered to the camelid, and many of which are not specific for the antigen, such that the translated reads can be subjected to computational analysis, which can include but is not necessarily limited to in silico protease digestion, the results of which can be stored in a text file or indexed in a searchable peptide database stored on a computer or other digitized media text file or searchable database can be configured to account for a variety of parameters, such as the distinct sequences of in silico digested peptides, the number of cDNA sequencing reads that relate to each of those peptides sequences, and the sequences of the complementarity determining regions (CDR1, CDR2 and CDR3), the framework regions if desired; such that the reads were translated, filtered, and trypsin-digested in silico to create a searchable peptide database for MS analysis as evidenced by Rout (US20170212130, published July 27, 2017; Abstract; and paragraphs [0039]; and [0053]); and, intensity pattern modeling including the use of a web application llama.med.harvard.- edu/software has been demonstrated to improve peptide and protein identification from MS/MS spectra, wherein fragment ion intensities were modeled using a machine-learning approach that estimates the likelihood of observed intensities given peptide and fragment attributes, such that from 1 million spectra,, 27,000 spectra were chosen with high-quality, non-redundant matches as training data; and using the same 27,000 spectra, intensity was modeled with mismatched peptides, then two probabilistic models were used to compute the relative likelihood of an observed spectrum given that a candidate peptide is matched or mismatched, wherein using a ‘decoy’ proteome approach to estimate incorrect match frequency demonstrated that an intensity-based method reduced peptide identification error by 50-96% without any loss in sensitivity as evidenced by Elias (Nature Biotechnology, 2004, 22(2), 214-219; of record; Abstract; and pg. 217, Fig 2). 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 an abstract idea requiring no more than a generic computer to perform generic computer functions that 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)).
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, 7 and 8 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 of claim 2, significantly different. For example, claim 2 encompasses the methods of claim 1, wherein the required fragmentation coverage is about 30%, but they do not add anything that makes the natural phenomenon in claim 1 significantly different.
Thus, the claims as a whole do NOT recite additional elements that amount to significantly more than the judicial exception itself.
In light of the above consideration and the new guidance, claims 1, 2, 7 and 8 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 June 18, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) although in silico digestion is mentioned in Example 1, the Example merely describes an initial data analysis with no actual “digestion” occurring; while Example 2 describes nanobodies isolated from sera, or blood, are digested by this method, where one of skill in the art understands that “digestion” means cleavage of antibodies into smaller fragment using proteolytic enzymes (Applicant Remarks, pg. 8, last partial paragraph; and pg. 9, first partial paragraph, lines 1-3); (b) the present invention is a significant improvement in the field of nanobody discovery and creation of high affinity nanobodies because prior art methods which are described in Example 1 as a "decoy database" provide a high rate of false positive CDR3 identifications (see specification, page 27, line 35 to page 28, line 11), while the present invention resolved or removed 95% of those false positive identifications. The amended claims also are methods used in conjunction with a particular manufacture - a nanobody, such that these considerations alone result in the present claims being limited to a practical application of the judicial exception; and the combination of many different required elements in the claims requiring 9 different steps also limits the claims to a practical application of the judicial exception (Applicant Remarks, pg. 9, last full paragraph, last partial paragraph; and pg. 10, first partial paragraph); and (c) the claims amount to significantly more under Step 2B. Applicant has amended the claims herein so that the present claims have the priority date of May 1, 2020, and thus the Xiang et al. reference is not a prior art reference and not evidence of what was well-understood or routine in the industry (Applicant Remarks, pg.10, first full paragraph)
Regarding (a), 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). As an initial matter, it is noted that instant claim 1 does not recite: (i) isolating nanobodies from sera or blood; and (ii) how a blood sample is used to obtain a cDNA library. Contrary to Applicant’s argument, one of ordinary skill in the art would understand that in silico protease digestion can be (and is) carried out. The Examiner contends that the steps of the method are well-known, purely conventional, or routine in the art, wherein all steps (a)-(j) recited in claim 1 can be carried out computationally and/or be computationally simulated.
For example, in silico immune simulations are known in the art as evidenced by Singh (pg. 2, first full paragraph); as well as, computer simulations of blood function is known in the art as evidenced by Diamond (pg. 1349, col 1, first full paragraph). Additionally, complete populations of virtual patients for in silico clinical trials is known in the art as evidenced by Sinisi (Abstract); including in silico clinical trials comprising the use of AI-guided models as evidenced by Calabrese (Abstract). As previously noted, in silico iterative trypsin digestion with high sequence coverage, which provides a correlation between residue abundance and average peptide length is known in the art as evidenced by Meyer (Title, Abstract; pg. 2, col 1, first full paragraph; pg. 3, Figure 2; and pg. 4, Figure 3); and in silico protease digestion of camelid nanobodies, which results in distinct sequences that can be stored text file or indexed in a searchable peptide database is known in the art as evidenced by Rout (paragraph [0039]). Clearly, the steps as described in Example 1 of the instant Application can be carried out in silico, where in silico digestion actually occurs. Thus, the steps of the method are well-known, purely conventional or routine in the art.
Regarding (b), As an initial matter, it is unclear to the Examiner what Applicant means by “the claims are limited to a practical application.” Applicant’s assertion that the claims are limited to a practical application of the judicial exception because (i) the invention is a significant improvement in the field of nanobody discover and the creation of high affinity nanobodies; and (ii) because the claims recite a multitude of steps, is not found persuasive. Additionally, MPEP 2145 indicates:
Rebuttal evidence may also include evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art. Rebuttal evidence may consist of a showing that the claimed compound possesses unexpected properties. Dillon, 919 F.2d at 692-93, 16 USPQ2d at 1901. A showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (underline and italics added).
Additionally, the evidence must be reasonably commensurate in scope with the claimed invention. See, e.g., In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990); In re Grasselli, 713 F.2d 731, 743, 218 USPQ 769, 777 (Fed. Cir. 1983) (underline and italics added).
in order for evidence of secondary considerations to be accorded substantial weight, there must be a nexus, i.e., a legally and factually sufficient connection or correspondence between the submitted evidence and the claimed invention. Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366, 1373, 2019 USPQ2d 483355 (Fed. Cir. 2019), cert. denied, 141 S.Ct. 373 (2020). See MPEP § 716.01(b) (underline and italics added).
Moreover, MPEP 716.02(b) states:
the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (See also; In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977).
MPEP 716.02(c) indicates that:
unexpected results must be weighed against evidence supporting a prima facie obviousness. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978); and where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977). “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
The Examiner contends that the instant claims do not recite a practical application of the judicial exception. The claims do not recite what Applicant argues. The instant claims do not recite the creation of high affinity nanobodies; a decrease in false positive CDR3 identifications; resolving or removing 95% of false positive identifications generated by “decoy databases,” etc. The result of the steps as recited in instant claim 1 is obtaining a nanobody comprising a sequence of CDR3 regions (e.g., encompassing all nanobodies). The instant claims do not recite a practical application of the judicial exception that results in a significant improvement in the field of nanobody discovery as asserted by Applicant. It is noted that -
No evidence supporting the unexpected results has been provided by Applicant.
Applicant’s has not provided any evidence of improved properties that are reasonably commensurate in scope with the claimed invention.
There is no nexus or co-extensiveness between Applicant’s asserted improvements and the steps as recited in claim 1.
Applicant has not pointed to where these advantages or surprising results were recognized in the as-filed Specification.
Evidence has not been provided that the “superior results” asserted by Applicant were unknown in the prior art.
Thus, the claims remain rejected.
Regarding that instant claim 1 recites a combination of many different required elements within the nine (9) steps recited in claim 1, the Examiner notes that the number of recited steps in a claim does render the claim significantly more than the judicial exception. All of the steps as recited in claim 1 are well-known, purely conventional, or routine in the art and, thus, they are all equally obvious (please see the teachings of Xiang, van Vught, Hacisuleyman, Fridy, Rout, and Elias supra). Additionally, the claims are directed to an abstract idea; and virtually every step recited in instant claim 1 can be carried out in silico with the aid of a generic computer, computer programs, algorithms, databases, etc. Thus, the claims remain rejected.
Regarding (c), Applicant’s assertion that Xiang et al. reference is not a prior art reference over the amended claims and, thus, is not evidence of what was well-understood or routine in the industry, is not found persuasive. The Examiner notes that the claims and Specification of US Provisional Patent Application 63018559 (and, WO2021222546, filed April 29, 2021) do not teach the limitations as recited in instant claim 1, including:
a fragmentation coverage percentage equal to or more than a required fragmentation coverage percentage; wherein fragmentation coverage percentage is determined by a formula:
f(x, chymotrypsin) = 0.0023x2 - 0.0497x + 0.7723, x[5,30]
f(x,trypsin) = 0.00006x2 - 0.00444x + 0.9194, x[5,30]
x is a length of the CDR3 region sequence
Instead, US Provisional Patent Application 63018559 (Specification) teaches:
“Peptides…with sufficient coverage (≥ 30%) were used for Nb mapping” (pg. 2, lines 9-10).
“those sequences having less than a calculated fragmentation coverage percentage; wherein the non-excluded sequences comprise a group having the reduced number of false positive CDR3 sequences” (pg. 10, lines 26-28).
“The term "required fragmentation coverage percentage" refers to a percentage obtained using the following formula:
f(x,Enzyme) is the function to calculate fragmentation coverage (%) of peptides digested by Enzyme”
x is the length of CDR3 that the peptide mapped” (pg. 12, lines 33-37).
Additionally, Figure 1 teaches:
“1d) In-silica digestion of the Nb database by two proteases and a cumulative plot of corresponding peptide masses. 1e) The length distributions for both trypsin and chymotrypsin digested CDR3 peptides. 1f) Complementarity of trypsin and chymotrypsin for Nb mapping based on simulation. 10,000 Nbs with unique CDR3 sequences were randomly selected and in silico digested to produce CDR3 peptides. Peptides with molecular weights of 0.8-3 kDa and with sufficient CDR3 coverage (~ 30%) were used for Nb mapping. 1g)-1h) Evaluations of unique CDR3 peptide identifications (lg: trypsin; 1h: chymotrypsin) based on the percentage of CDR3 fragment ions that were matched in the MS/MS spectra” (pg. 2, lines 5-12)
Figure 2 teaches:
“c) identifications of unique CDR combinations and unique CDR3 sequences for different antigens. d) a comparison between trypsin and chymotrypsin for CDR3 mapping of high-quality NbGST” (pg. 2, lines 26-28).
Instant claim 1 does not disclose the limitations as recited in the prior applications. The priority date of the instant claims is (at best) April 29, 2021. Thus, Xiang is prior art with respect to the filing date of US Patent Application 17/922,685. The claims remain rejected.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 2, 7 and 8 is maintained under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Xiang et al. (hereinafter “Xiang”) (bioRxiv, 2020, 1-44).
Regarding claims 1 and 2, Xiang teaches a platform for comprehensive quantitative Nb proteomics and high-throughput structural characterizations of antigen-Nb complexes (Fig, 2A), wherein a domestic camelid was immunized with the antigens of interest, wherein the Nb cDNA library was then prepared from the blood and bone marrow of the immunized camelid (Fridy et al., 2014); and NGS was performed to create a rich database of >107 unique Nb protein sequences (Fig. S2D-E) (interpreted as obtaining a blood sample from a camelid immunized with an antigen; and using the blood sample to obtain a Nb cDNA library, claim 1a-b) (pg. 3, first full paragraph, lines 1-4; and Figures 2A and S2D-E). Xiang teaches that variable domains of HcAb (VHH/Nb) cDNA libraries from the B lymphocytes of two lama glamas were amplified, and 13.6 million unique Nb sequences in the databases by NGS sequencing (interpreting llamas as a camelid; a cDNA library; and identifying the sequence of each cDNA in the library, claim 1a-c) (pg. 2, last full paragraph, lines 1-3). Xiang teaches that antigen-specific Nbs were isolated from the sera and eluted using step-wise gradients of salts or pH buffers wherein fractionated HcAbs were efficiently digested with trypsin or chymotrypsin to release Nb CDR peptides for identification and quantification by nanoflow liquid chromatography coupled to high-resolution MS. Initial candidates that pass database searches were annotated for CDR identifications (interpreted as isolating nanobodies; and digesting with trypsin and chymotrypsin to obtain digestion products, claim 1d-e) (pg. 3, first full paragraph, lines 4-7). Xiang teaches that for chymotrypsin digestion samples, 1:50 (w/w) chymotrypsin was added and digested at 37 °C for 4 hrs, such that after proteolysis, the peptide mixtures were desalted by self-packed stage-tips or Sep-pak C18 columns (Waters) and analyzed with a nano-LC 1200 that is coupled online with a Q Exactive HF-X Hybrid Quadrupole Orbitrap mass spectrometer (interpreted as performing mass spectrometry to obtain MS data, claim 1f) (pg. 43, last partial paragraph, lines 10-13). Xiang teaches that the complementarity of trypsin and chymotrypsin for Nb mapping based on simulation, wherein 10,000 Nbs with unique CDR3 sequences were randomly selected and in silico digested to produce CDR3 peptides, wherein the peptides with molecular weights of 0.8- 3 kDa and with sufficient CDR3 coverage (≥ 30%) were used for Nb mapping (interpreted as a percentage of coverage of about 30%, claims 1g-h and 2) (pg. 8, Fig. 1, F). Xiang teaches that evaluations of unique CDR3 peptide identifications (G: trypsin; H: chymotrypsin) based on the percentage of CDR3 fragment ions that were matched in the MS/MS spectra, wherein CDR3 peptides were identified by database search using either the “target” database (in salmon) or the “decoy” database (in grey) (interpreted as selecting sequences identified in step (c) that correlate with MS data; and identifying CDR regions, claim 1g-h) (pg. 8, Figure 1, G-H). Xiang teaches that 3D plots of the normalized CDR3 peptide identifications from the target database search, the percentages of CDR3 fragmentations, and CDR3 length, wherein FDR: false discovery rate; and that FDRs of CDR3 identifications are colored on the 3D plots, wherein the color bar shows the scale of FDR, such that FDR below 5% are presented in gradient red. I: analysis by trypsin; J: analysis by chymotrypsin (interpreted as selecting from the CDR region sequences; and selected sequences comprise a group having a reduced number of false positive CDR sequences, claim 1i-j) (pg. 8, Figure 1, I-J).
Regarding claims 7 and 8, Xiang teaches in (b) ELISA analysis of the camelid immune responses of three different antigens; (c) the identifications of unique CDR combinations and unique CDR3 sequences for different antigens; (d) a comparison between trypsin and chymotrypsin for CDR3 mapping of NbGST; and (e) phylogenetic analysis and logo plots of CDR3 sequences from three antigen-specific repertoires (interpreted as a functional selection step, claim 7) (pg. 10, Fig. 2, B-E). Xiang teaches that to purify antigen-specific VHH antibodies, the GST or HSA-conjugated CNBr resin was incubated with the VHH mixture for 1 hr at 4°C and extensively washed with high salt buffer (1xPBS and 350 mM NaCl) to remove non-specific binders, wherein specific VHH antibodies were then released from the resin by using one of the following elution conditions: alkaline (1-100 mM NaOH, pH 11, 12 and 13), acidic (0.1 M glycine, pH 3, 2 and 1) or salt elution (1M – 4.5 M MgCl2 in neutral pH buffer) (interpreted as affinity chromatography with a resin, claim 7 and 8) (pg. 33, second full paragraph).
Xiang meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Response to Arguments
Applicant’s arguments filed June 18, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) the Xiang reference is not a prior art reference to amended claim 1 (Applicant Remarks, pg. 11, first full paragraph).
Regarding (a), please see the discussion supra regarding teachings regarding the formula provided in US Provisional Patent Application 63018559 (as well as, with regard to WO2021222546, filed April 29, 2021). Xiang is prior art with respect to the instant Application. Thus, the claims remain rejected.
The Examiner suggests that Applicant amend claim 1 to provide a nexus between the improvements and the steps recited in instant claim 1; amend claim 1 to recite the definition of “x”; include the limitation of instant claim 2 (e.g., providing a required fragmentation coverage percentage); and indicate how the formula of claim 1 is connected to the improvement. The Examiner also suggests that Applicant review all of the claims for any remaining 35 USC 112(b) issues.
Conclusion
Claims 1, 2, 7 and 8 are rejected.
THIS ACTION IS MADE FINAL. 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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