DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. A request for continued examination (RCE) under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/01/2025 has been entered.
Election/Restrictions
3. Applicant’s election without traverse of Group II claims 18-23 in the reply filed on 09/12/2024 is acknowledged. On 04/02/2025 applicant added new claim 25, and on 12/01/2025 applicant added new claims 26-42, the new claims belong to elected Group II.
Status of Claims
4. Claims 1-5, 7-8, 11-23 and 25-42 are pending. Applicant added a new claim 26-42 in amended claims filed on 12/01/2025.
5. Claims 1-5, 7-8, and 11-17 were withdrawn from consideration due to election/restriction requirement.
6. Claims 18-23 and 25-42 are under examination in this office action.
Priority
7. Acknowledgment is made of applicant’s claim for priority to U.S. provisional patent application serial no. 62/781,634, filed on 12/19/2018 which is related to the instant application 17/309,796 through a 371 application of PCT/IL2019/051392, filed on 12/19/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
8. The information disclosure statement (IDS) submitted on 01/05/2022 is acknowledged. The
submission is in-compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Claim Rejections
9. Withdrawn prior rejection of claim 21 under 35 USC § 112 (b) for claiming an improper Markush grouping of alternatives in view of applicant’s amendment of the instant claim 21.
Specification and Claim Objections
10. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. See specification dated 06/18/2021 that has 8 references listed on page numbers 1-2.
11. The applicant improperly amended the specification by specifying the amendment as a “substitute specification” filed 2 pages on 04/02/2025. See MEPE 714 37 CFT 1.121. The applicant did not provide what changes were introduced by providing a marked up copy and if the amendment filed as a “substitute specification” whether has introduced a new matter or not?
12. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
In the instant specification dated 03/28/2022 see page 38 for: http://www.imgt.org
Claim Interpretation
13. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification.
The instant claims 18-23 and 25-42 are methods claims (process of making a product or a product by process) and are interpreted to be directed to produce scFv or antibodies that are HCV E2 binder and the scFv or antibodies are derived from HCV spontaneous clearer (SC) subjects by a method of B cells repertoire sequencing, comparison of sequence of a with a reference HCV scFv neutralizing antibody associated with HCV clearance obtained from HCV SC subject. The claim 18 and dependent claims recite identifying stratifying clusters (based on using machine learning AI-artificial intelligence algorithm) and selecting scFv sequence with sequences similar to reference scFv for obtaining HCV E2 binder scFv. The claims under examination 18-23 and 25-42 are directed to genus of scFv binding to HCV E2 protein or genus of cluster(s) or clone(s) encompassing many species of scFv sequences that are not recited in the claims expressively.
The instant claim 18 and dependent claims limitation recites “stratifying clusters” from a “general repertoire” selecting an scFv sequence with “high similarity” to a sequence in a stratifying cluster from said general repertoire that is associated with HCV clearance and these claim elements are defined or elaborated in the specification. A “general repertoire” is interpreted as a “B-cell repertoire sequences” for V-gene, J-gene and CDR3 from HCV infected subjects that were not previously identified as HCV CI or SC or healthy not infected (Specification dated 03/28/2022, page 43). Based on the specification, a “stratifying cluster” is interpreted as analysis of a general B-cell repertoire or HCV SC B-cell repertoire or HCV CI B-cell repertoire sequences for identity or similarity or dis-similarity % level (amino acid sequence) by comparison a reference sequence from at least one HCV E2 binder scFv or antibody (broadly neutralizing scFv) obtained from a known HCV SC subject. A “high similarity” is defined as 95% or higher of total sequence identity is interpreted as a high similarity to the scFv heavy chain comprising CDR3 from the general repertoire or HCV SC or HCV CI subjects. High sequence similarity is defined herein as having 95% or higher (e.g. 96%, or 97%, or 98%, or 99% or 100%) of total sequence identity or junction’s identity. The full-length antibodies comprise a light chain of the selected scFv antibody and a heavy chain of one of the sequences that show high similarity to the scFv heavy chain from the general repertoire. (specification, page 7, 15). Similarity is defined as having the same V gene, J gene, and CDR3 sequence that are at least 75% identical at the amino acid level (page 48 of specification)
Claim Rejections - 35 USC § 112 (b)
14. 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 18-23 and 25-42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claim 18 comprise a generic limitation scFv (also reads an antibody) that binds to HCV E2.
The claims 21 and 26-42 are directed to the stratifying clusters e.g. IGHV1-18*IGHJ6*15**79, IGHV1-18*IGHJ6*24**16. The claims do not recite what the structure or sequence of the cluster is? The claims limitation does not clearly set forth the metes and bounds because one of the ordinary skills in the art is not clear how to compare the novelty, if any, of the recited clusters in absence of reciting the corresponding structure or sequence.
“The applicant, in response (12/01/2025) to the final rejection (07/30/2025), described that it is impossible to recite specific sequences since a cluster, by definition, comprises many sequences originating from a common "ancestor". One of ordinary skill in the art would understand that identifying a cluster using a definition such as "IGHV1-18*IGHJ6*15**79" or "IGHV1-18*IGHJ6*24**16" is the most recognized manner to refer to the clusters of clones detected in HCV-specific B cell repertoire and enriched in SC (spontaneous clearers) samples. The term "cluster" is defined as a group of antibody VDJ sequences that share the same IGHV and IGHJ genes and have highly similar CDR3 sequences (at least 75% amino-acid identity). In total 5,447, such clusters were identified, and the clusters that are significantly enriched in either the SC or Cl cohorts are explicitly stated to be listed in Tables 3 and 4. The "Clone" identifier in the table is the cluster identifier”.
The cluster, for e.g. IGHV1-18*IGHJ6*15**79, IGHV1-18*IGHJ6*24**16 (as recited in the claims 21 and 26-42) are indefinite because the ordinary skill in the art cannot predict the structure or sequence of the clone(s) or the obtained broadly neutralizing antibodies. The ordinary skills in the art does not have access to the structure or sequence of the claimed stratified clusters or a cluster. For all of the above reasons, the claims 18-23 and 25-42 are indefinite for failing to particularly point out and distinctly claim the subject matter.
Applicant may recite a species of scFv or antibody along with the structure (SEQ ID NO) rather than cluster or clone to overcome the rejection under 35 USC 112(b).
Claim Rejections - 35 USC § 112 (a)
15. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 18-23 and 25-42 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The elected group of invention and the claims 18-23 and 25-42 requires in the specification the recitation of corresponding subject matter is accessible to one of the ordinary skills in the art that the claimed invention to have achieved reduction to the practice which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims 18-12 and 25-42 are methods claims (process of making a product or a product by process) and are interpreted to be directed to produce scFv or antibodies that are HCV E2 binder and the scFv or antibodies are derived from HCV spontaneous clearer (SC) subjects by a method of B cells repertoire sequencing, comparison of sequence of a with a reference HCV scFv neutralizing antibody associated with HCV clearance obtained from HCV SC subject and construction of scFv antibodies and making scFv antibodies. The claims recite identification and stratification of clusters using machine learning (AI-artificial intelligence algorithm) and selecting scFv sequence with sequences that are similar to reference scFv for obtaining or production of HCV E2 binder scFv antibody.
The instant claim 18 (and dependent claims) comprise a “genus” limitation (b) HCV E2 binder (scFV or scFv antibody or antibody) and does not provide a structure or sequence of an scFv or scFv antibody or antibody that binds to HCV E2 protein.
The instant claims 21 and 26-42 (dependent on claim 18) are directed or comprise limitations the B-cell repertoire “stratifying clusters” or “clusters”, e.g. IGHV1-18*IGHJ6*15**79, IGHV1-18*IGHJ6*24**16. The claims do not recite what the structure or sequence of the “cluster” is or the structure or sequence of an scFV or the structure or sequence an antibody is? The claim limitation does not clearly set forth the corresponding structure or sequence of the stratified clusters/cluster/clone/scFV/antibody. The claims 21 and 26-42 depends on claim 18, and thus inherit a limitation of a method of preparing neutralizing anti HCV scFv antibodies associated with HCV clearance. The prior arts by Merat et al 2016 (PLoS ONE, 2016, 11(10)) and Bailey et al 2017 (JCI Insight. 2017 May 4;2(9):e92872) as recited below in claim rejection, teaches HCV E2 protein binder broadly neutralizing antibody and the antibody sequences obtained from a spontaneously recovered HCV patient. The specification table 4 (see, page 49) has listed the recited for e.g. IGHV1-18*IGHJ6*15**79, IGHV1-18*IGHJ6*24**16 in a column as “Clone”. The nomenclature IGHV1-18\*IGHJ6\*15\*\*79 refers to a specific gene sequence within the immunoglobulin heavy chain variable region, part of the human immune system's antibody production process.
IGHV: Indicates the immunoglobulin heavy chain variable region. This region is crucial for antibody diversity, as it's where antibodies bind to antigens.
1-18: Refers to a specific gene within the IGHV family, in this case, IGHV1-18. This denotes a particular gene sequence associated with a specific protein.
IGHJ6: Specifies the immunoglobulin heavy chain joining region, specifically IGHJ6. This region connects the variable region to the constant region of the antibody.
15: Represents the allele number for the IGHJ6 gene. This is a specific version of the IGHJ6 gene.
79: Indicates the allele number for the IGHV1-18 gene. This is a specific version of the IGHV1-18 gene.
Therefore, the entire nomenclature describes a unique combination of variable and joining gene segments that contribute to a specific antibody.
However, the claims 21 and 26-42 do not recite the structure or sequence of the clone or the obtained broadly neutralizing antibodies. The ordinary skills in the art does not have access to the structure or sequence of the claimed stratified clusters or a cluster or the clone to practice the claimed methods and would require undue experimentation to achieve the same or similar results in absence of access to the same HCV SC, CI patients and healthy human subjects.
The following quotation from section 2163 of the Manual of Patent Examination
Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirement for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus (in the instant application claim 18 recites a genus of scFv or scFv antibody that is HCV E2 protein binder (binder reads on scFv or antibody), claims 21, and 26-42: genus is a cluster, clusters or clone or clones) may be satisfied through sufficient description of a representative number of species by actual reduction to practice..., reduction to drawings..., or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 'A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus (See, page 2 of applicant’s response on 12/01/2025, 25% difference in CDR3 sequence with 75% amino acid similarity), one must describe a sufficient variety of species to reflect the variation within the genus.
In the context of claimed invention, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) recently decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies (antibodies reads on scFv HCV E2 binder). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody (antibody reads on scFv HCV E2 binder). Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen (e.g. HCV E2 protein antigen) alone is not considered adequate written description of a claimed antibody (reads on HCV E2 binder scFv) to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Id.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
It is well known within the prior art that even the most minor differences can have significant effects on antigen binding ability of antibody or scFv. The art relating to antibodies for examples recognizes that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity that is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al 1982. (Proc Natl Acad Sci USA 79:1979-1983). Rudikoff et al 1982 teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. In the instant application the applicant’s response page 2 (12/01/2025) remarks 75% sequence identity in CDR3 amino acid sequence (25% difference in amino acid identity of CDR3). See e.g. MPEP 2161; 2163 and 2163.02.
Appropriate amendments to the claims 18, 21 and 26-42 is required by reciting the structure (SEQ ID NO) to overcome the rejection and for further examination.
Claim Rejections - 35 USC § 103
16. 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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
17. Claims 18-21 and 26-42 are rejected under 35 U.S.C. 103 as being unpatentable over Baran et al 2018 (Journal of Hepatology, 2018, 68: S799), and further in view of Merat et al 2016 (published in PLoS ONE 11(10), Lefranc et al 1999 (Nucleic Acids Res. 1999 Jan 1;27(1):209-12), Nahary et al 2009 (Methods in Molecular Biology™, vol 525. Humana Press. https://doi.org/10.1007/978-1-59745-554-1_3), Chan et al 1996 (published in Journal of General Virology, (1996), 77, 2531-2539), Wilson et al 2012 (published in Nature Review Immunol, 2012, 12(10):709-719), Racanelli et al 2011 (PLoS ONE, 2011 6(9): e25606), Georgiou et al 2014 (Nature Biotechnology, 2014, 32 (2), Chen et al 2010 (Immunome Research 2010, 6(Suppl 1):S4), Greiff et al 2015 (Genome Medicine (2015) 7:49), Kovaltsuk et al 2017 (Front. Immunol. 8:1753), Benichou et al 2011 (Immunology, 135, 183–191), Bailey et al 2017 (JCI Insight. 2017 May 4;2(9): e92872), Burioni 2014 (US8623363B2, 01/07/2014), and Grebely et al 2012 (Lancet Infect Dis 2012; 12: 408–14) and Parameswaran et al 2013 (Cell Host Microbe. 2013 Jun 12;13(6):691–700).
Regarding claim 18-21 and 26-42: Baran et al 2018 (according to incoming written opinion of ISA/PCT available on file 06/18/2021) is in the art and is directed to the development and characterization of unique hepatitis C virus neutralizing antibodies associated with infection outcome. Baran et al 2018 discloses obtaining sera and B cells from a panel of chronically infected (CI) and spontaneous clearers (SC) HCV patients and healthy controls were isolated. Sera were screened for HCV neutralization and binding whereas B cells were used for constructing two antibodies libraries, one from CI samples and second from SC samples, using phage display technology. Specific HCV-binding and neutralizing antibodies were isolated from these libraries and characterized (See, method section). Following five rounds of panning a panel of 10 unique antibodies have been isolated; 3 from CI library and 7 from SC library. Antibodies isolated from SC library demonstrate moderate binding to genotype la HCV envelope protein E2 by ELISA, but higher HCV neutralization efficiency, compared to those isolated from CI library (See, results section). This study suggests that SC patients exhibit unique, specific and efficient B cells response comparing to CI. Baran et al 2018 states that the isolation of unique antibodies may open new avenues to effective immunoglobulin- based therapies that could prove helpful in preventing or treating HCV-related liver disease and would benefit vaccine development effort (See, conclusion section). Baran et al 2018 discloses the means and approach to solve the problem of identifying broadly neutralizing antibodies from HCV SC and CI samples of subjects or patients having the same or similar properties as in the claimed antibodies (antibodies also reads on scFv antibodies) of instant claim 1. Baran et al 2018 also discloses the advantage of said antibodies for therapeutic use.
Baran et al 2018 does not teach each and every limitation of instant claim 18, that are providing specific CDRs or heavy and light chain variable regions sequences for the disclosed antibodies or sequencing of B-cell repertoires from total B-cells, HCV-specific B-cells of healthy, chronic HCV infected and individuals with spontaneous HCV clearance and identifying stratifying clusters based on antibody sequence features.
Merat et al 2016 teaches a method of preparing or obtaining neutralizing monoclonal antibodies from a participant’s peripheral blood mononuclear cells (PBMC) memory B cells immortalized, inter alia, introducing BCL6 and BCL-xL mediated gene transfer isolated after 25 years of spontaneous clearance of HCV. The transduced B cells secrete monoclonal antibodies (immunoglobulin) into the cell culture supernatant. The antibodies bound to E2 protein as it recognized linear epitopes on E2 (See, page 1, title, abstract; page 3, generation of immortalized B cells). The VH and VL of HCV neutralizing antibodies produced from memory B cells sequenced, cloned and recombinant antibodies were produced. In brief, total RNA was isolated from B cells and after generation of cDNA, the sequences were obtained from the heavy and light chain by PCR. To produce recombinant antibodies, the VH and VL sequences were cloned onto the human IgG1 and kappa constant regions in pcDNA3.1 (Invitrogen). 293T/17 cells were transiently transfected and recombinant antibodies were purified using the …… column (See, page 4, section on Soluble … and Antibodies, entire research paper).
Merat et al 2016 do not teach constructing a phage display scFv antibody library.
Lefranc et al 1999 discloses and offer sequence database and design tools for degenerative primer set design for phage display (See, abstract, entire article).
Nahary et al 2009 teaches a protocol for design of a human synthetic combinatorial library of single-chain antibodies (See, abstract, entire protocol).
Chan et al 1996 teaches human recombinant antibodies, from a patient suffering from chronic cirrhosis with chronic HCV infection, specific for HCV envelope E2 peptides from an immune phage display library, construction of a phage antibody display library, selection of scFv phage particles by binding to E2 peptides and purification of scFv, sequencing, compiling and analysis of VH and VL sequences compared to germline gene segments and sequences available in GenBank, scFv production and E2 peptide binders from the recombinatorial library constructed from the patient (See, title, abstract, page 2532-2533: methods, 2534, page 2533 table 1 E2 peptides; Results; page 2537 para 2, entire research paper).
Wilson et al 2012 teaches a method of scFv phage display applicable to Hepatitis C virus involving VH and VL RT-PCR of RNA isolated from B cells, combinatorial phage library of random VH and VL pairs, expression of scFv on phage, and screening of scFv phage library by binding to antigen of interest (See, page 710, col 1 para 1; col 2 para 2, page 711 Figure 1, a).
Burioni 2014 (US8623363B2) discloses the preparation of random combinatorial libraries displayed on surfaces of filamentous phages (phage display) represents a highly potent tool for selecting high affinity human monoclonal antibodies and identified and developed bnAb binding to HCV E2 protein (See, para [0026]-[0043]).
Racanelli et al 2011 teaches antibody V(h) repertoire differences between spontaneously resolving (spontaneous clearance) and chronically evolving (chronic infection) hepatitis C virus infections. To understand how HCV infection perturbs the antibody repertoire and to identify molecular features of antibody genes associated with either viral clearance or chronic infection, sequencing of V(D)J region of naïve and memory B cells of 6 persons who spontaneously resolved an HCV infection (SR), 9 patients with a newly diagnosed chronically evolving infection (CE), and 7 healthy donors. Compared to CE, SR antibody genes used fewer VH, D and JH gene segments in naïve B cells and fewer VH segments in memory B cells. SR and CE groups significantly differed in the frequency of use of 7 gene segments in naïve B cell clones and 3 gene segments in memory clones. The nucleotide mutation rates were similar among groups, but the pattern of replacement and silent mutations in memory B cell clones indicated greater antigen selection in SR than CE. Greater clonal evolution of SR than CE memory B cells was revealed by analysis of phylogenetic trees and CDR3 lengths. Pauciclonality of the peripheral memory B cell population is a distinguishing feature of persons who spontaneously resolved an HCV infection (See, abstract, entire article).
Chen et al 2010 teaches clustering-based identification of clonally-related immunoglobulin gene sequence sets. Chen et al developed and implemented an algorithm for identifying sets of clonally related sequences in large human immunoglobulin heavy chain gene variable region sequence sets, comparisons of CDR3 sequences and similarity in IGHV and IGHJ germline gene assignments, agglomerative hierarchical clustering to identify likely groups of clonally-related sequences. The program is available for download from website cse.unsw.edu.au/~ihmmune/ClonalRelate/ClonalRelate (See, abstract, entire article).
Greiff et al 2015 teaches a bioinformatic framework for immune repertoire diversity profiling enables detection of immunological status. Greiff et al developed an approach that coupled diversity profiles with unsupervised (hierarchical clustering) and supervised (support vector machine and feature selection) machine learning approaches in order to correlate patient’s immunological statuses with their B- and T-cell repertoire data. We could predict with high accuracy (greater than or equal to 80 %) a wide range of immunological statuses such as healthy, transplantation recipient, and lymphoid cancer, suggesting as a proof of principle that diversity profiling can recover a large amount of immunodiagnostic fingerprints from immune repertoire data (See, abstract, entire article).
Georgiou et al 2014 provides an overview of high-throughput sequencing of the antibody repertoire by teaching methods for high-throughput sequencing of the Ig sequence repertoire using B cell mRNA, sequence data analysis and clustering of the similar sequences for antibody discovery and understanding immune repertoire development against infectious diseases (See, abstract, entire article, Fig 3).
Kovaltsuk et al 2017 teaches B-cell receptor repertoire sequencing using next-generation sequencing of immunoglobulin gene repertoires (Ig-seq) allows the investigation of large-scale antibody dynamics at a sequence level and it can be enriched with structural antibody data (See, abstract, Fig 1-3, entire article). Kovaltsuk et al 2017 as recited below in the table columns 2-3 teaches V gene and J gene combination antibody features (See, Fig 2).
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The claim 21 recites e.g. stratified cluster or cluster IGHV1-18*IGHJ6*15**79 which is the nomenclature IGHV1-18\*IGHJ6\*15\*\*79 refers to a specific gene sequence within the immunoglobulin heavy chain variable region, part of the human immune system's antibody production process. The claim 21 do not recite amino acid sequence or nucleic acid sequence encoding the claimed stratified cluster or cluster (clones).
Benichou et al 2011 reviews Rep-Seq: uncovering the B and T cell immunological repertoire through next-generation sequencing for construction of synthetic antibody libraries for therapeutic antibody development (See, abstract, entire article, Fig 1, Table 1).
Bailey et al 2017 teaches isolation of broadly neutralizing mAbs (bNAbs) from persons with broadly neutralizing serum who spontaneously cleared hepatitis C virus (HCV) infection. We found that bNAbs from two donors bound the same epitope and were encoded by the same germline heavy chain variable gene segment. Remarkably, these bNAbs were encoded by antibody variable genes with sparse somatic mutations. For one of the most potent bNAbs, these somatic mutations were critical for antibody neutralizing breadth and for binding to autologous envelope variants circulating late in infection (See, abstract, entire article).
Grebely et al 2012 in a review on epidemiology of HCV infections in human teaches HCV infection will spontaneously clear in about 25% of people (See, abstract, entire article).
It would have been obvious to apply the prior art teachings as recited supra to obtain PBMCs from HCV SC, HCV CI and healthy individuals, obtain mRNA and perform sequencing of cDNA, and obtain large data sets and analyze the sequence data sets by comparing or aligning with the HCV E2 protein binder bnAb antibody sequence data HCV SC patient of Merat et al 2016 or Bailey et al 2017 and arrive at the stratified B cell repertoire cluster sequences (similar approach- different HCV patients with different phenotypic disease SC, CI and healthy (Racanelli et al 2011) to identify the sequence cluster with sequence features similar to known bnAb in the art, in particular from HCV Sc patients.
In addition, Parameswaran et al 2013 is in the virology art and is directed to identification of convergent antibody signatures in human dengue and teaches approach to identify patterns that could be used for sequence-based monitoring of the antibody response to dengue, we examined antibody heavy-chain gene rearrangements in longitudinal peripheral blood samples from 60 dengue patients. Comparing signatures between acute dengue, post-recovery and healthy samples, we find increased expansion of B cell clones in acute dengue patients, with higher overall clonality in secondary infection. Parameswaran et al 2013 observed consistent antibody sequence features in acute dengue in the major antigen-binding determinant Complementarity Determining Region-3 (CDR3), with specific CDR3 sequences highly enriched in acute samples compared to post-recovery, healthy or non-dengue samples. Dengue thus provides a striking example of a human viral infection where convergent immune signatures can be identified in multiple individuals. Such signatures could facilitate surveillance of immunological memory in communities (See, abstract, entire article).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teachings of Baran et al 2018 by incorporating the teachings of Merat et al 2016, Bailey et al 2017, Lefranc et al 1999, Nahary et al 2009, Chan et al 1996, Wilson et al 2012 (anti-HCV scFv phage display library), Racanelli et al 2011 (antibody V(h) repertoire differences between spontaneously resolving (spontaneous clearance) and chronically evolving (chronic infection) hepatitis C virus infections), Chen et al 2010, Georgiou et al 2014 (clustering of the similar sequences or stratification of clustered sequences), Greiff et al 2015 (B and T cell repertoire sequence analysis), Bailey et al 2017 (bnAbs in serum of spontaneously cleared hepatitis C virus (HCV) patients and sequence features of the heavy chain variable gene segment) and teachings approach of Parameswaran et al 2013 on dengue virus B-cell repertoire based antibodies to arrive at the resulting invention of instant claim 18-21 and 26-42. The motivation would be to identify the scFv sequences from HCV infected patients having different immunogenetics and HCV infection outcome in patients (chronic HCV infected, Cleared HCV infection, spontaneous clearer) that have high homology with scFv of HCV neutralizing antibodies obtained from HCV spontaneous clearer (SC) individuals and use it to develop broadly neutralizing anti-HCV scFv/ antibody therapeutics and commercial success (Burioni 2014, US8623363B2, teaches a bnAb binding to HCV E2 for therapeutics, Grebely et al 2012 teaches HCV infection scenario). This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 18-21 and 26-42. There would have been a reasonable expectation of success to arrive at the inventions of claims 18-21 and 26-42 given the applied prior arts. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales A-G).
18. Claim 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Baran et al 2018 (Journal of Hepatology, 2018, 68: S799), Merat et al 2016 (published in PLoS ONE 11(10), Chan et al 1996 (published in Journal of General Virology, (1996), 77, 2531-2539), Wilson et al 2012 (published in Nature Review Immunol, 2012, 12(10):709-719), Racanelli et al 2011 (PLoS ONE, 2011 6(9): e25606), Georgiou et al 2014 (Nature Biotechnology, 2014, 32 (2), Chen et al 2010 (Immunome Research 2010, 6(Suppl 1):S4), Greiff et al 2015 (Genome Medicine (2015) 7:49), Kovaltsuk et al 2017 (Front. Immunol. 8:1753), Benichou et al 2011 (Immunology, 135, 183–191), Bailey et al 2017 (JCI Insight. 2017 May 4;2(9):e92872), Burioni 2014 (US8623363B2, 01/07/2014), and Grebely et al 2012 (Lancet Infect Dis 2012; 12: 408–14), and Parameswaran et al 2013 (Cell Host Microbe. 2013 Jun 12;13(6):691–700) as applied to claims 18-21 and 26-42 above and further in view of Mazor et al 2007 (J Immunol Methods, 2007 Apr 10;321(1-2):41-59), Keck et al 2012 (published in PLoS Pathogens, 2012, vol 8, no. 4), Xiao et al 2017 (published in MABS, 2017, 9 (6) 996-1006) and Bujak et al 2014 (published in Vincent Ossipow and Nicolas Fischer (eds.), Monoclonal Antibodies: Methods and Protocols, Methods in Molecular Biology, vol. 1131, Springer Science+Business Media New York 2014).
Claims 22-23: The combined teachings of Baran et al 2018, Merat et al 2016, Chan et al 1996, Wilson et al 2012, Racanelli et al 2011, Georgiou et al 2014, Chen et al 2010, Greiff et al 2015, Kovaltsuk et al 2017, Benichou et al 2011, Bailey et al 2017, Burioni 2014, and Grebely et al 2012 and Parameswaran et al 2013 teaches/renders obvious claims 18-21 and 26-42 as recited supra and the teachings that render obvious claim 18 are incorporated in entirety here.
The combined prior art teachings as recited supra do not teach the claim 22 limitation, the step of converting the scFv to full-length antibodies; and claim 23 limitations wherein the full-length antibodies comprise a light chain of the selected scFv antibody and a heavy chain of one of the sequences that show high similarity to the scFv heavy chain from the general repertoire.
Mazor et al 2007 teaches expression and purification of full-length chimeric antibodies by disclosing mammalian vector pMAZ-IgH for human γ1 heavy chain expression and pMAZ-IgL for human κ light chain expression were designed for production of human IgG1 antibodies in mammalian cell culture (See, methods, entire article).
Keck et al 2012 teaches neutralizing human monoclonal antibodies with to a novel cluster of conformational epitopes on HCV E2 protein. Keck et al 2012 teaches steps of production of scFv and converting scFv to IgG human monoclonal antibodies that neutralize HCV by binding to E2. In brief, VH and VL genes were PCR-amplified using primers to restore the human framework and append restriction sites. The resulting fragments were cloned into Ig gamma, Igk or Ig lambda mammalian expression vectors containing the signal peptide and constant region genes. IgG1 was expressed by co-transfection of 293 T cells and cultured in serum-free medium. The expression levels were measured by ELISA and the resulting IgG1 were purified using protein A affinity chromatography (See, abstract; page 17, col 2, section on Production of scFvs and IgG1 HMAbs, entire research paper).
Xiao et al 2017 is in the art in the field of high-throughput platform for population reformatting and mammalian expression of scFV phage display libraries to enable functional screening as full-length IgG (See, abstract, page 998 figure 1, page 1001-1002 figure 6-7 entire research paper) and teaches a high-throughput method to convert scFv to full length antibodies and the method can be applied to the HCV to the invention of instant claim 22.
Bujak et al 2014 is in the art in the field of reformatting of scFv antibodies into the scFv-Fc format and their downstream purification. Bujak et al 2014 teaches a method and steps to convert scFv antibodies to scFv-Fc format and the method can be applied to the HCV to the invention of instant claim 22 (See, abstract and entire book chapter page 315-334).
The instant claim 23 limitations wherein the full-length antibodies comprise a light chain of the selected scFv antibody and a heavy chain of one of the sequences that show high similarity to the scFv heavy chain from the general repertoire are taught by the combined teachings of Merat et al 2016, Chan et al 1996 and Wilson et al 2012 and further by Keck et al 2012, Xiao et al 2017 and Bujak et al 2014 as recited supra.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teachings of Baran et al 2018, Merat et al 2016, Chan et al 1996, Wilson et al 2012, Racanelli et al 2011, Georgiou et al 2014, Chen et al 2010, Greiff et al 2015, Kovaltsuk et al 2017, Benichou et al 2011, Bailey et al 2017, Burioni 2014, and Grebely et al 2012 and Parameswaran et al 2013 as applied to claim 18 by incorporating teachings of Mazor et al 2007, Keck et al 2012, Xiao et al 2017 and Bujak et al 2014 to arrive at the resulting invention of instant claim 22-23. There would have been a reasonable expectation of success given the disclosures of the recited combined teachings of the prior arts as outlined above to convert scFv to full-length antibodies. The motivation would be the full-length antibodies will comprise Fc domain required for effector function of antibody mediated cellular cytotoxic (ADCC) response and full-length antibodies are bivalent that could bind E2 protein neutralizing epitopes of more than one adjoining virus particle for effective and efficient neutralization of the HCV. The combination of light chain of the selected scFv antibody and a heavy chain of one of the sequences that shows high similarity to the scFv heavy chain from the general repertoire would likely improve stability, confer broad binding to variant HCV E2 and neutralizing activity against HCV. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 22-23. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
19. Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of
Baran et al 2018 (Journal of Hepatology, 2018, 68: S799), Merat et al 2016 (published in PLoS ONE 11(10), Chan et al 1996 (published in Journal of General Virology, (1996), 77, 2531-2539), Wilson et al 2012 (published in Nature Review Immunol, 2012, 12(10):709-719), Racanelli et al 2011 (PLoS ONE, 2011 6(9): e25606), Georgiou et al 2014 (Nature Biotechnology, 2014, 32 (2), Chen et al 2010 (Immunome Research 2010, 6(Suppl 1):S4), Greiff et al 2015 (Genome Medicine (2015) 7:49), Kovaltsuk et al 2017 (Front. Immunol. 8:1753), Benichou et al 2011 (Immunology, 135, 183–191), Bailey et al 2017 (JCI Insight. 2017 May 4;2(9):e92872), Burioni 2014 (US8623363B2, 01/07/2014), and Grebely et al 2012 (Lancet Infect Dis 2012; 12: 408–14), and Parameswaran et al 2013 (Cell Host Microbe. 2013 Jun 12;13(6):691–700) as applied to claims 18-21 and 26-42 above and further in view of Yari et al 2015 (Genome Medicine (2015) 7:121), Emerson et l 2015 (bioRxiv 2015), Lopez et al 2018 (Journal of Biomedical Informatics 85 (2018) 30–39), Ralph et al 2016 (PLoS Comput Biol 12(10): e1005086), Miho et al 2018 (Front. Immunol., 20 February 2018 (9), Sec. B Cell Biology) and Hofree et al 2013 (Nat Methods 10, 1108–1115 (2013)).
Claim 25: The method of claim 18 wherein said step (c) of identifying stratifying clusters based on antibody sequence features is performed using a machine learning model.
The combined teachings of Baran et al 2018, Merat et al 2016, Chan et al 1996, Wilson et al 2012, Racanelli et al 2011, Georgiou et al 2014, Chen et al 2010, Greiff et al 2015, Kovaltsuk et al 2017, Benichou et al 2011, Bailey et al 2017, Burioni 2014, and Grebely et al 2012 and Parameswaran et al 2013 teaches/renders obvious claims 18-21 and 26-42 as recited supra and the teachings that render obvious claim 18 are incorporated in entirety here.
The combined teachings, however, do not teach machine learning approach for B cell antibody repertoire stratifying clusters based on sequence features of antibody.
Yari et al 2015 provides practical guidelines for B-cell receptor repertoire sequencing analysis and the methods involving machine learning and statistics adapted to this problem (See, Fig 1-3, abstract, entire article).
Ralph et al 2016 teaches likelihood-based inference of B cell clonal families based on B cell receptor sequence diversity into clusters based on a multi-hidden Markov Model (multi-HMM) framework for B cell receptor sequences using two real data sets (See, abstract, entire article).
Emerson et al 2015 teaches immunosequencing reveals diagnostic signatures of chronic viral infection in T cell memory (See, abstract, entire article).
Hofree et al 2013 teaches a network (machine learning) based stratification of tumor mutations (See, abstract, entire article).
Miho et al 2018 reviews and teaches the adaptive immune system recognizes antigens via an immense array of antigen-binding antibodies and T-cell receptors, the immune repertoire. Miho et al review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic, and (iv) machine learning methods applied to dissect, quantify, and compare the architecture, evolution, and specificity of immune repertoires and propose future directions for systems immunology toward coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics.
Lopez et al 2015 teaches an unsupervised machine learning method for discovering patient clusters based on genetic signatures (See, abstract, entire article).
Kovaltsuk et al 2017 teaches B-cell receptor repertoire sequencing using next-generation sequencing of immunoglobulin gene repertoires (Ig-seq) allows the investigation of large-scale antibody dynamics at a sequence level and it can be enriched with structural antibody data (See, abstract, Fig 1-3, entire article).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teachings of Baran et al 2018, Merat et al 2016, Chan et al 1996, Wilson et al 2012, Racanelli et al 2011, Georgiou et al 2014, Chen et al 2010, Greiff et al 2015, Kovaltsuk et al 2017, Benichou et al 2011, Bailey et al 2017, Burioni 2014, and Grebely et al 2012 and Parameswaran et al 2013 and incorporate machine learning based algorithm and statistical analysis-based approach taught by Yari et al 2015, Ralph et al 2016, Emerson et al 2015, Hofree et al 2013, and Lopez et al 2015 for analysis of large sequence data sets of B cell antibody repertoire (optionally T cell repertoire) from HCV SC, CI patients and healthy individuals and compare or align it with the HCV E2 protein binder bnAb antibody sequence data HCV SC patient of Merat et al 2016 or Bailey et al 2017 and arrive at the stratified B cell repertoire cluster sequences (similar approach- different HCV patients with different phenotypic disease SC, CI and healthy (Racanelli et al 2011) to identify the sequence cluster with sequence features similar to known bnAb in the art, in particular from HCV Sc patients to arrive at the resulting invention of instant claim 25. The motivation would be to identify the scFv sequences from HCV infected patients having different immunogenetics and HCV infection outcome in patients (chronic HCV infected, Cleared HCV infection, spontaneous clearer) that have high homology with scFv of HCV neutralizing antibodies obtained from HCV spontaneous clearer (SC) individuals and use it to develop broadly neutralizing anti-HCV scFv/ antibody therapeutics for commercial success. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 25. There would have been a reasonable expectation of success to arrive at the inventions of claim 25 given the applied prior arts. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales A-G).
Response to Arguments
20. Applicant's arguments filed on 12/01/2025 regarding claims 18-23 and 25-42 have been fully considered but they are not persuasive in view of additional search and amended office action incorporating additional prior arts as recited supra in response to the RCE filed on 12/01/2025.
The applicant has amended claim 21 and added new claims 26-42.
Applicant’s argument 1: The applicant filed arguments/remarks on 12/01/2025 (please refer pages 1-17). The applicant disagreed and traversed the rejection under 35 USC § 103 of the claims 18-21 deemed unpatentable/obvious over Merat et al 2016, and further in view of Chan et al 1996, Wilson et al 2012, Racanelli et al 2011, Georgiou et al 2014, Chen et al 2010, Greiff et al 2015, Kovaltsuk et al 2017, Benichou et al 2011, Bailey et al 2017, Burioni 2014 (US862336382), and Grebely et al 2012, beginning on page 8 of the Office Action
Claim 21 has been cancelled without prejudice or disclaimer, thus rendering this rejection moot as to this claim.
The applicant argued that (please see applicant’s arguments/remarks filed on 12/01/2025, see pages 2-12) the cited references, alone and in combination, do not teach or suggest each of the elements of the claimed invention. Applicant provided a summary (See, pages 2-12) of each cited document including what the document discloses and, critically, what is not disclosed, in relation to the presently claimed invention.
In Response 1: The applicant’s arguments made against the rejections under 35 USC § 103: Claims 18-21 have been fully considered but are not persuasive in view of the combined prior art teachings as applied of record for any teaching or matter specifically challenged in the argument. The applicant has amended claim 21 but, in the remarks, recites that claim 21 is cancelled. The applicant amended claim 21 (dependent on claim 18) and introduced new claims 26-42 to overcome the 112(a)-rejection based on improper Markush grouping and recited the different “stratified clusters” in claims 26-42 being dependent on claim 18.
The applicant has claimed first a genus of scFV or antibody as an HCV E2 binder (binder reads on scFv or antibody). The applicant has claimed a second genus “stratified cluster(s)” or “cluster(s)” or also defined as “clone(s) to derive scFv that would have a function of binding to a HCV E2, i.e. “HCV E2 binder”. The genus claimed by the applicant are expected to comprise thousands of species of scFv with a function of binding to HCV E2 i.e. HCV E2 binder.
Georgiou et al 2014 provides an overview of high-throughput sequencing of the antibody repertoire (See, office action page 18).
Xiao et al 2017 is in the art in the field of high-throughput platform for population reformatting and mammalian expression of scFV phage display libraries to enable functional screening as full-length IgG (See, office action page 24).
The prior arts from other viruses or general molecular biology teaching the claim limitations are equally applicable for the 35 USC 103 obviousness rejection because the claimed inventions have two components a virus (a virus species can be any virus e.g. HIV, influenza, measles, etc), more specifically an HCV virus infection of a host that may be a human or a mammalian species. The molecular biology techniques and software or algorithm applications are within the skill of ordinary in the art to modify and apply to the claimed problem solving.
The claims 18-23 and 26-42 are very broad. The claim rejection that are based on prior arts are under 35 USC 103 obviousness and certain claim limitations becomes obvious to one of the ordinary skills based on the combined teachings of the applied prior arts and knowledge, skills of the ordinary in the art with a reasonable expectation of success and a motivation to modify the prior arts of record to arrive at the claimed invention. Because the applicant did not claim the invention at a species level (scFv or a specific antibody with structure (SEQ ID NO) in the claim, the applied prior arts are also broad that provide the ordinary skills in the art a reasonable expectation of success to arrive at the claimed inventions. The claim limitations that recite genus is not searchable to find a specific prior art. The applicant has put an enormous burden on the examiner and the ordinary skills to find a prior art having claimed the methods of inventions making a product without claiming or reciting structure of a product (scFV antibody, cluster(s), clone(s) at the species level. Please see KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales A-G) as applied to render obvious the claims 18-21 and 26-42.
Applicant's arguments filed on 12/01/2025 regarding claims 18-21 have been fully considered (because of amendment to claim 21, this response is applicable to the instant claims 18-21 and 26-42) have been fully considered but are not persuasive.
Applicant’s argument 2: Rejection under 35 USC § 103: Claims 22 and 23 are unpatentable/obvious over Merat et al 2016, and further in view of Chan et al 1996, Wilson et al 2012, Racanelli et al 2011, Georgiou et al 2014, Chen et al 2010, Greiff et al 2015, Kovaltsuk et al 2017, Benichou et al 2011, Bailey et al 2017, Burioni 2014 (US8623363B2), and Grebely et al 2012, and further in view of Keck et al 2012 (published in PloS Pathogens, 2012, vol 8, no. 4), Xiao et al 2017 (published in MABS, 2017, 9 (6) 996-1006) and Bujak et al 2014 (published in Vincent Ossipow and Nicolas Fischer (eds.), Monoclonal Antibodies: Methods and Protocols, Methods in Molecular Biology, vol. 1131, Springer Science+Business Media New York 2014), beginning on page 14 of the Office Action
In Response 2: The applicant’s arguments made against the rejections under 35 USC § 103 (See, arguments/remarks filed on 12/01/2025 pages 12-14): Claims 22-23 have been fully considered but are not persuasive in view of the combined prior art teachings as applied of record for any teaching or matter specifically challenged in the argument.
The applicant has claimed added limitations in claims 22-23 (dependent on claim 18) that are generic in the recombinant antibody or scFv art and within the skills of the ordinary based on the related prior arts. The rejection of the claims 22-23 that are based on prior arts are under 35 USC 103 obviousness and certain claim limitations becomes obvious to one of the ordinary skills based on the combined teachings of the applied prior arts and knowledge, skills of the ordinary in the art with a reasonable expectation of success and a motivation to modify the prior arts of record to arrive at the claimed invention. The applied prior arts teachings as recited supra are provide the ordinary skills a reasonable expectation of success to arrive at the claimed inventions. The claim limitations that recite genus which is not searchable to find a specific prior art at species level. The applicant has put an enormous burden on the examiner and the ordinary skills to find a prior art without having claimed the inventions at the species level. Please see KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales A-G) as applied to render obvious the claims 22-23.
Applicant's arguments filed on 12/01/2025 regarding claims 22-23 have been fully considered but are not persuasive.
Applicant’s argument 3: Rejection under 35 USC§ 103: Claim 25 is unpatentable/obvious over Merat et al 2016 (published in PLoS ONE 11(10), Chan et al 1996 (published in Journal of General Virology, (1996), 77, 2531-2539) and Wilson et al 2012 (published in Nature Review lmmunol, 2012, 12(10):709-719), Racanelli et al 2011 (PLoS ONE, 2011 6(9): e25606), Georgiou et al 2014 (Nature Biotechnology, 2014, 32 (2), Chen et al 2010 (lmmunome Research 2010, 6(Suppl 1):54), Greiff et al 2015 (Genome Medicine (2015) 7:49), Bailey et al 2017 (JCI Insight. 2017 May 4;2(9):e92872), Kovaltsuk et al 2017 (Front. lmmunol. 8:1753), Benichou et al 2011 (Immunology, 135, 183-191), Burioni 2014 (US8623363B2, 01/07/2014) and Grebely et al 2012 (Lancet Infect Dis 2012; 12: 408-14) as applied to claims 18-21 above and further in view of Yaari et al 2015 (Genome Medicine (2015) 7:121), Emerson et I 2015 (bioRxiv 2015), Lopez et al 2018 (Journal of Biomedical Informatics 85 (2018) 30-39), Ralph et al 2016 (PLoS Comput Biol 12(10): e1005086), Miho et al 2018 (Front. lmmunol., 20 February 2018 (9), Sec. B Cell Biology) and Hofree et al 2013 (Nat Methods 10, 1108-1115 (2013)), beginning on page 16 of the Office Action.
In Response 3: The applicant’s arguments made against the rejections under 35 USC § 103 (See, arguments/remarks filed on 12/01/2025 pages 14-17): Claim 25 have been fully considered but are not persuasive in view of the combined prior art teachings as applied of record for any teaching or matter specifically challenged in the argument.
The applicant has claimed added limitation in claims 25 (dependent on claim 18) that is generic in the B cell repertoire analysis for identifying an antibody scFv art and is within the skills of the ordinary based on the related prior arts. The rejection of the claim 25 is based on 35 that are based on prior arts are under 35 USC 103 obviousness and certain claim limitations becomes obvious to one of the ordinary skills based on the combined teachings of the applied prior arts and knowledge, skills of the ordinary in the art with a reasonable expectation of success and a motivation to modify the prior arts of record to arrive at the claimed invention. The applied prior arts teachings as recited supra provide the ordinary skills a reasonable expectation of success to arrive at the claimed inventions. Please see KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales A-G) as applied to render obvious the claim 25.
Applicant's arguments filed on 12/01/2025 regarding claim 25 have been fully considered but are not persuasive.
21. Relevant Prior Arts:
Foung et al 2013. (US20130084301A1, 04/04/2013). Cluster of Neutralizing Antibodies to Hepatitis C Virus.
Wu et al 2011. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science. 2011 Sep 16;333(6049):1593-602.
Conclusion
22. No claim is allowed.
23. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600