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
Pursuant to a preliminary amendment filed November 25, 2025, claims 1-14 are currently pending in the instant application.
Response to Election/Restriction
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);
Species (C) – (E): species directed to Groups III-V were not elected, in the reply filed
February 20, 2026 is acknowledged.
Claims 12-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 3-6 and 9-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
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 reduced number of the CDR3, CDR2 and/or CDR1 sequences are false positives as compared to a control” and “wherein x is the length of the CDR3, CDR2 or CDR1 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.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on November 1, 2022; May 8, 2023 and October 28, 2024 have been considered. Initialed copies of the IDSs accompany this Office Action.
Claim Objections/Rejections
Claim Interpretation: the term “false positives” as recited in claim 1 is interpreted to refer to the incorrect identification of any nanobody sequences including CDR3, CDR2 and/or CDR1 sequences.
The term “digesting the nanobodies with trypsin or chymotrypsin” as recited in claim 1, line 10 is interpreted to refer to digesting nanobodies obtained from a blood sample from an immunized camelid (line 5); digesting nanobodies in the nanobody cDNA library (line 6), and/or digesting the nanobodies isolated from a blood sample from the same or a second blood sample from the camelid (line 8).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 7 and 8 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 is indefinite due to the use of use parentheses to comment on or qualify part of the sentences, for example: “(CDR3, CDR2 and/or CDR1 sequences)” in lines 2-3 because it is unclear whether the limitations in parentheses are meant to be limitations in the claims or whether they are only suggestions, examples of a preferred embodiment, or synonym. Accordingly, the metes and bounds of the claim are not clear.
Claim 1 is indefinite for the recitation of the term “reduced number” such as recited in claim 1, lines 3 and 25-26 because the term “reduced” is a relative term that renders the claim indefinite. Although claim 1, line 4 recites comparison to a “control”, the identity of the control is unspecified and it is not recited in the body of the claim. Thus, the term “reduced” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite reduction in number of false positive CDR sequences as compared to some other value that qualifies as a “reduced number of false positive” CDR sequences. Moreover, it is unclear how the selected CDR region sequences are determined to be ‘false positives’ (false positives compared to what?) such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention.
Claim 1 is indefinite for the recitation of the term “the CDR3, CDR2 and/or CDR1 sequences” such as recited in claim 1, lines 3 and 26. There is insufficient antecedent basis for the term “the CDR3, CDR2 and/or CDR1 sequences” in the claim because claim 1, line 2 recites the term “CDR3, CDR2 and/or CDR1 nanobody amino acid sequences”. The Examiner suggests that Applicant amend the claim to recite, for example, “wherein a reduced number of CDR3, CDR2 and/or CDR1 nanobody amino acid sequences are false positives.”
Claim 1 is indefinite for the recitation of the terms “the sequence” and “the sequences” such as recited in claim 1, lines 7 and 16. There is insufficient antecedent basis for the terms “the sequence” and “the sequences” in the claim.
Claim 1 is indefinite for the recitation of the term “the same or a second blood sample” such as recited in claim 1, line 8. There is insufficient antecedent basis for the term “the same or a second blood sample” in the claim because claim 1, line 5 recites the term “a blood sample”. Moreover, claim 1 does not recite obtaining a ‘plurality of blood samples’ and/or obtaining a ‘second blood sample’ and, thus, the metes and bounds of the claim cannot be determined. The Examiner suggests that Applicant amend the claim to recite, for example, “isolating nanobodies from the blood sample”.
Claim 1 is indefinite for the recitation of the term “the digestion products” such as recited in claim 1, line 12. There is insufficient antecedent basis for the term “the digestion products” in the claim because claim 1, lines 10-11 recite the term “a group of digestion products”. The Examiner suggests that Applicant amend the claim to recite, for example, “performing MS analysis of the group of digestion products”.
Claims 1 and 7 are indefinite for the recitation of the term “step” such as recited in claim 1, lines 14, 17, 18, 22, 23 and 25. There is insufficient antecedent basis for the terms “step” in the claim because claim 1 recites “a”, “b”, “c”, “d”, “e,” etc. such that claim 1 does not recite the term “step.”
Claims 1 and 7 are indefinite for the recitation of the term “the CDR3, CDR2 and/or CDR1 region sequences” such as recited in claim 1, lines 18 and 24. There is insufficient antecedent basis for the term “the CDR3, CDR2 and/or CDR1 region sequences” in the claim.
Claim 1 is indefinite for the recitation of the term “the fragmentation coverage percentage” such as recited in claim 1, line 20. There is insufficient antecedent basis for the term “the fragmentation coverage percentage” in the claim because claim 1, line 19 recites the term “a required fragmentation coverage percentage”.
Claim 1 is indefinite for the recitation of the term “x[5,30]” such as recited in claim 1, lines 21 and 23 because the bracketed numbers “[5,30]” are not defined, such that it is unclear what the bracketed numbers represent; including whether they indicate a specific length of a CDR3, CDR2 and/or CDR1 peptide fragment (e.g., 5 amino acids, 30 amino acids); whether the numbers represent a range of fragment lengths (e.g., between 5 and 30 amino acids); or whether the numbers represent something else and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “the length” such as recited in claim 1, lines 23- 24. There is insufficient antecedent basis for the term “the length” in the claim.
Claim 1 is indefinite for the recitation of the term “the selected sequences” such as recited in claim 1, line 25. There is insufficient antecedent basis for the term “the selected sequences” in the claim.
Claim 7 is indefinite for the recitation of the term “each fraction” such as recited in claim 7, line 5. There is insufficient antecedent basis for the term “each fraction” in the claim because claim 7, line 4 recites the term “different nanobody fractions”.
Claim 1 is indefinite for the recitation of the term “the reduced number of false positive CDR3, CDR2 and/or CDR1 sequences” such as recited in claim 1, lines 3-4 and 25-26. There is insufficient antecedent basis for the term “the reduced number of false positive CDR3, CDR2 and/or CDR1” in the claim because claim 1, lines 3-4 recites the term “a reduced number of the CDR3, CDR2 and/or CDR1 sequences are false positives.”
Claim 7 is indefinite for the recitation of the term “the nanobody fractions” such as recited in claim 7, line 7. There is insufficient antecedent basis for the term “the nanobody fractions” 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 following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7 recites (in part): “wherein step d further comprises…and performing steps e. through i. on each fraction individually and estimating the affinity of each different step i.” in lines 1-6 because claim 7 depends from instant claim 1, wherein claim 1 does not recite step e., step i. and/or steps e. through i. 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.
Claims 1, 2 7 and 8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. An analysis with respect to the claims as a whole reveals that they do not include additional elements that are sufficient to amount to significantly more than the judicial exception. See Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 110 U.S.P.Q.2d 1976 (2014); Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116, 106 U.S.P.Q.2d 1972 (2013); Mayo Collaborative Svcs. v. Prometheus Laboratories, Inc., 132 S. Ct. 1289, 101 U.S.P.Q.2d 1961 (2012). See also 2014 Interim Guidance on Patent Subject Matter Eligibility, available at http://www.gpo.gov/fdsys/pkg/FR-2014-12-16/pdf/2014-29414.pdf (“2014 Interim Guidance”), and the Office’s examples to be considered in conjunction with the 2014 Interim Guidance in examination of nature-based products, available online at http://www.uspto.gov/patents/law/exam/mdc_examples_nature-based_products.pdf (“Nature-Based Products Examples”). This rejection is proper.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of three issues: (1) whether the claim is directed to one of the four categories recited in §101; (2) whether the claim recites or involves a judicial exception (i.e., 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, 2 and/or 1 nanobody amino acid sequences (CDR3, CDR2 and/or CDR1 sequences) wherein a reduced number of the CDR3, CDR2 and/or CDR1 sequences are false positives as compared to a control, 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 the sequence of each cDNA in the library; (d) isolating nanobodies from the same or a second blood sample from the camelid immunized with the antigen; (e) digesting the nanobodies with trypsin or chymotrypsin to create a group of digestion products; (f) performing a mass spectrometry analysis of the digestion products to obtain mass spectrometry data; (g) selecting sequences identified in step c. that correlate with the mass spectrometry data; (h) identifying sequences of CDR3, CDR2 and/or CDR1 regions in the sequences from step (g); and (i) selecting from the CDR3, CDR2 and/or CDRI region sequences of step (h) those sequences having 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 step (e), or a formula f(x,trypsin)=0.00006x2-0.00444x+0.9194, x[5,30] when trypsin is used in step (e), and wherein x is the length of the CDR3, CDR2 or CDR1 region sequence, respectively; and (j) wherein the selected sequences of step (i) comprise a group having the reduced number of false positive CDR3, CDR2 and/or CDRI sequences.
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, CDR2 and/or CDR1 regions in the sequences; identifying sequences of CDR3, CDR2 and/or CDR1 regions; selecting from the CDR3, CDR2 and/or CDR1 region sequences having a 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, such that the selected sequences have reduced false positive CER3, CDR2 and/or CDR1 sequences; 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 the sequence of each cDNA in the library” in lines 1-3 (encompassing a generic computer that carries out general computer functions” in lines 5-7; “(d) isolating nanobodies from the same or a second blood sample from the camelid immunized with the antigen; (e) digesting the nanobodies with trypsin or chymotrypsin to create a group of digestion products; (f) performing a mass spectrometry analysis of the digestion products to obtain mass spectrometry data” in lines 8-13; “(g) selecting sequences identified in step (c) that correlate with the mass spectrometry data; (h) identifying sequences of CDR3, CDR2 and/or CDR1 regions in the sequences from step (g)” in lines 14-17; and “(i) selecting from the CDR3, CDR2 and/or CDRI region sequences of step (h) those sequences having 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 step (e), or a formula f(x,trypsin)=0.00006x2-0.00444x+0.9194, x[5,30] when trypsin is used in step (e), and wherein x is the length of the CDR3, CDR2 or CDR1 region sequence, respectively; and (j) wherein the selected sequences of step (i) comprise a group having the reduced number of false positive CDR3, CDR2 and/or CDRI sequences” in lines 16-26, 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 step (d) further comprises a functional selection step 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 steps e. through i. on each fraction individually and estimating an affinity of each different step (i)” in lines 1-6, 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, CDR2 and/or CDR1 sequences as false positives, 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 steps that provide 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 CDR region sequences; the required fragmentation coverage percentage; how the formulas were derived; the meaning of [5,30]; the lengths of the CDR region sequences; the group having reduced number of false positives; the number of false positive CDR sequences, 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; 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). 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). Moreover, methods for identifying sequence regions of the antibodies produced by camelids from which nanobodies are derived, and recombinant methods for producing nanobodies that bind with specificity to the antigen(s) (Ag-specific nanobodies), wherein the nanobodies are a heavy chain only IgG class of antibodies (HCAbs), and thus contain heavy chain homodimers and do not contain antibody light chains, wherein HCAbs are typically about 110 amino acids long and comprise a single variable domain (VHH) and two constant domains (CH2 and CH3), such that the single variable domain comprises three complementarity-determining regions (CDRs); and that by utilizing the diversity of the nanobody population and mapping binding epitopes, it was possible to design ultra-high affinity dimeric nanobodies with Kd down to ~30 pM was known in the art as evidenced by Rout (US11447891; col 6, lines 32-43; and col 7, lines 13-16); 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; 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).
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, 7 and 8 are rejected 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.
The Examiner suggests that Applicant amend the claims to clarify the process steps including the purpose of the process, the identity of the control, the identity of the nanobodies digested, and clarifying the purpose of isolating nanobodies from a second blood sample.
It is not clear whether: (1) the method is directed to removing sequence fragments obtained via mass spectrometry (spurious sequence fragments?, in silico sequence fragments?) that do not correlate to known CDR3, CDR2 and/or CDR1 sequence fragments such as in a database obtained through trypsin and chymotrypsin digestion of a sample; or (2) the method is directed to removing sequence fragments obtained from a different llama used to produce a ‘decoy’ database and, therefore, reduce false sequences not related to the CDR sequences obtained from a sample from the first llama.
Conclusion
Claims 1, 2, 7 and 8 are rejected.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684