DETAILED ACTION
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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-9, drawn to a method of identifying Hepatitis C virus (HCV) neutralizing antibodies, in the reply filed on 10/27/2025 is acknowledged. The traversal is on the ground(s) that the inventions may be searched and examined together without undue burden and notes that Connors et al. does not disclose Hepatitis C virus. This is not found persuasive because the requirement under 37 CFR 1.475 is based on whether the claimed inventions are linked by the same or corresponding special technical feature defining a contribution over the prior art, rather than merely whether the inventions may be searched together conveniently. Further, the Office Action expressly acknowledged that Connors et al. does not teach HCV and relied upon Merat et al. for the HCV-related teachings. Applicant has not identified a deficiency in the combined teachings of Connors et al. and Merat et al. or otherwise established that the inventions of Groups I-VI share a special technical feature constituting a contribution over the prior art. Accordingly, the requirement for restriction based on lack of unity of invention is maintained. The requirement is still deemed proper and is therefore made FINAL. Hence, claims 10-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Also, Applicant did not distinctly and specifically point out an error in the election of species requirement. Accordingly, the election of species requirement is maintained. Claims 1-9 are examined as readable on elected Group I and the elected species, namely: (1) measuring neutralization of HCV pseudoparticles (HCVpp) for the type of analyte being measured; and (2) neutralization profiles identifying individual antibodies that bind to distinct HCV epitopes for the type of antibody interaction.
Status of the Claims
Claims 1-15 are pending. Claims 10-15 are withdrawn. Claims 1-9 are examined herein in view of the restriction.
Priority
The present application, filed 01/25/2022, is a 371 of PCT/US2020/043429, filed 07/24/2020, which claims benefit of U.S. Provisional Patent Application 62/878,631, filed 07/25/2019. The benefit is acknowledged and the claims examined herein are treated as having an effective filing date of 07/25/2019.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 01/25/2022, 02/07/2023, and 02/16/2024 are acknowledged and have been considered. However, the reference “Law, Mansun, Hepatitis C Virus Protocols, Methods in Molecular Biology (1911)” was present in the file wrapper but was not listed on Information Disclosure Statement(s). Accordingly, the reference has not been considered.
Specification
The disclosure is objected to because of the following informalities: On page 17, the statement that exemplary doses and dosage regimens for the compositions in methods of treating muscle diseases or disorders appears inconsistent with the subject matter of the present application, which is directed to hepatitis C virus (HCV), including HCV neutralizing antibodies, vaccines, and methods of treating HCV infection. Applicant is required to correct or delete this inconsistent language. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 4 and 5 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.
Regarding claim 4, the claim recites the reference antibody neutralization profiles; however, claim 1, from which claim 4 depends, introduces only a reference antibody neutralization profile. Thus, it is unclear whether the reference antibody neutralization profiles recited in claim 4 refer to the singular reference antibody neutralization profile of claim 1 or to a plurality of separately generated reference antibody neutralization profiles. For purposes of compact prosecution, the reference antibody neutralization profiles will be interpreted as a plurality of reference antibody neutralization profiles generated for respective reference antibodies. Appropriate correction is required.
Regarding claim 5, the claim recites that “a specific combined reference antibody neutralization profile is correlated with each plasma neutralization profile”; however, claim 1, from which claim 5 depends, recites a biological sample and the biological sample’s neutralization profile, without requiring that the biological sample be plasma. Claim 2 further confirms that the biological sample may alternatively be whole blood, lymphocytes, serum, or plasma. Claim 5 does not depend from claim 2. Accordingly, it is unclear whether each plasma neutralization profile corresponds to the biological sample’s neutralization profile of claim 1, whether claim 5 intends to further limit the biological sample to plasma, or whether a separate plasma neutralization profile is intended. For purposes of compact prosecution, each plasma neutralization profile will be interpreted as the neutralization profile of the biological sample recited in claim 1, wherein the biological sample is plasma. Appropriate correction is required.
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 1-9 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to judicial exceptions, specifically a law of nature and an abstract idea in the form of mental processes, without significantly more. Claims 1–9 recite the naturally occurring relationship between an HCV-specific antibody’s biological characteristics, including its epitope-binding characteristics, and its ability to neutralize particular HCV variants, and evaluate neutralization information to identify the antibodies responsible for an observed neutralization response. Claims 1–9 further recite abstract evaluation of neutralization information through generation of neutralization profiles, ranking, combination of reference profiles, deconvolution, and correlation.
This rejection is made in accordance with Patent Subject Matter Eligibility as set forth in MPEP §2106. Analysis of subject-matter eligibility under 35 U.S.C. §101 requires consideration under these steps as followed:
Step 1 – Statutory Category (Refer to MPEP § 2106.03): Claims 1–9 are drawn to a process, which falls within a statutory category under 35 U.S.C. § 101.
Step 2A, Prong One – Recitation of a Judicial Exception (Refer to MPEP § 2106.04): Regarding claim 1, the claim recites obtaining a biological sample from a subject having been infected with HCV; measuring neutralization of HCV pseudoparticles (HCVpp) by HCV-specific antibodies in the biological sample; generating a neutralization profile; generating a reference-antibody neutralization profile to deconvolute HCV-specific neutralizing antibodies; correlating the reference-antibody neutralization profile with the biological-sample neutralization profile; and identifying the HCV neutralizing antibodies.
Claim 1 therefore recites a law of nature, namely the naturally occurring relationship between an HCV-specific antibody’s biological characteristics, including its epitope-binding characteristics, and its ability to neutralize particular HCV variants. The neutralizing activity observed when antibodies from an HCV-infected subject encounter HCVpp reveals the underlying naturally existing biological relationship between the antibody’s characteristics and its neutralizing activity against HCV variants. The claim does not create the antibody’s biological characteristics, epitope-binding characteristics, or resulting neutralizing capability; rather, the claim measures neutralization resulting from that underlying relationship and uses the resulting information to identify the antibodies responsible for the observed neutralization.
Claim 1 additionally recites an abstract idea in the mental-process grouping. Once neutralization measurements are available, the recited acts of generating a neutralization profile, generating a reference-antibody neutralization profile, correlating the reference profile with the biological-sample profile, deconvoluting the HCV-specific neutralizing antibodies from those profiles, and identifying the antibodies constitute evaluation, comparison, and interpretation of information. The claimed profile comparison and correlation therefore constitute the type of observation, evaluation, judgment, and opinion that falls within the mental-process grouping identified in MPEP § 2106.04(a)(2).
Claim 2 specifies that the biological sample is whole blood, lymphocytes, serum, or plasma. This limitation specifies the source of the biological information used in the claimed neutralization analysis, but retains the same naturally occurring relationship between the antibody’s biological characteristics and HCV neutralization and the same profile-based evaluation recited in claim 1.Claim 3 specifies that the neutralization profile comprises a ranking of relative neutralization of each HCVpp by each reference antibody or biological sample. Ranking measured neutralization results constitutes further organization and evaluation of information and therefore does not remove the underlying law of nature or mental-process limitations from the claim. Claim 4 specifies that reference-antibody neutralization profiles are added in various proportions to generate an array of possible combined antibody neutralization profiles. The limitation further manipulates and organizes neutralization information by combining reference profiles in differing proportions. It therefore constitutes additional abstract mathematical/informational analysis used to perform the claimed deconvolution and does not remove the underlying judicial exceptions.
Claim 5 specifies correlating a particular combined reference-antibody neutralization profile with each plasma neutralization profile to identify the proportion of each reference antibody contributing to the neutralization profile of the biological sample. This limitation further specifies the comparison and evaluation of the biological neutralization information to infer the relative contribution of reference-antibody specificities. It therefore retains the same natural biological relationship while further reciting abstract evaluation and correlation of information. Claim 6 further recites identifying HCV epitope specificities for each neutralizing antibody. The particular HCV epitope to which an antibody binds is a naturally existing molecular characteristic of the antibody-antigen interaction. Identifying that specificity from the neutralization information does not create or alter the antibody’s epitope specificity, but instead determines information concerning that naturally occurring biological property.
Claim 7 specifies that the neutralization profiles identify individual antibodies that bind distinct HCV epitopes. The binding of an antibody toward HCV epitopes arise from the antibody’s naturally existing molecular structure and its interaction with the viral antigen. The use of neutralization profiles to identify that characteristic therefore continues to recite the natural biological relationship and abstract evaluation of information. Claim 8 further recites isolating the HCV neutralizing antibodies. The claim nevertheless retains claim 1’s judicial exceptions because the antibody to be isolated is identified through the claimed neutralization-profile generation, deconvolution, and correlation. The isolation limitation constitutes additional physical activity following identification of the antibody but does not eliminate the recited natural relationship or abstract profile analysis. Claim 9 specifies that the method comprises a high-throughput format. This limitation specifies the format in which the claimed activities are carried out but does not alter the underlying naturally occurring relationship between antibody characteristics and HCV neutralization or the profile generation, deconvolution, correlation, and identification constituting the abstract evaluation of neutralization information. Accordingly, claims 1–9 recite judicial exceptions in the form of a law of nature and abstract mental processes.
Step 2A, Prong Two – Integration into a Practical Application (Refer to MPEP § 2106.04(d)): Regarding claim 1, the additional physical activity principally consists of obtaining a biological sample from an HCV-infected subject and measuring HCVpp neutralization by antibodies in that sample. These activities obtain the biological information upon which the claimed neutralization-profile analysis operates. The claim does not recite an improvement to HCVpp technology, an improved neutralization assay, an improved laboratory instrument, a new biological-sample-processing technique, or another technological improvement attributable to the claimed method. Rather, the measured neutralization results provide the information that is subsequently organized into profiles, deconvoluted, correlated, and interpreted to identify HCV neutralizing antibodies.
The biological sample does not meaningfully integrate the judicial exceptions merely because the neutralization information originates from a physical specimen. The sample is used to acquire the biological information necessary for the subsequent profile comparison and inference. Likewise, exposing HCVpp to antibodies and measuring neutralization obtains the data upon which the claimed analysis operates. Claim 1 ends with identification of the HCV neutralizing antibodies and does not require administration of an identified antibody, vaccination, treatment of HCV infection, alteration of therapy, or another action that applies the resulting identification to effect a particular treatment or prophylaxis.
Claim 2’s recitation of whole blood, lymphocytes, serum, or plasma merely specifies the biological source from which the antibody information is obtained. It does not impose a meaningful application of the judicial exceptions beyond the acquisition of biological data. Claim 3’s ranking of relative HCVpp neutralization further organizes the neutralization information used in the claimed analysis. Claim 4’s addition of reference-antibody profiles in various proportions to generate possible combined profiles further manipulates the reference information. Claim 5’s correlation of a selected combined reference profile with a plasma profile to identify antibody proportions further specifies how the neutralization information is evaluated. These limitations refine the information processing used to perform the claimed identification rather than improve an assay, laboratory instrument, or other technology.
Claims 6 and 7 further specify the biological information obtained from the analysis—HCV epitope specificity and whether individual antibodies bind distinct HCV epitopes. Those limitations provide additional characterization of the naturally occurring antibody-antigen interactions rather than impose a treatment or technological transformation responsive to the identification. Regarding claim 8, physically isolating an identified HCV neutralizing antibody is additional activity beyond the profile analysis. However, the claim does not recite a new antibody-isolation technique, require modification of the antibody, or apply the isolated antibody therapeutically. The isolation step merely collects the antibody identified through the recited natural relationship and abstract analysis and does not, in the context of the claim as a whole, transform the claimed profile-based identification into an improvement to another technology or technical field. Claim 9’s high-throughput format merely specifies the scale or format in which the same neutralization measurement and profile analysis are performed. The claim does not recite a particular improved high-throughput apparatus, architecture, assay configuration, or technological improvement resulting from that format.
Accordingly, when claims 1–9 are considered as a whole, the additional limitations obtain the biological material and neutralization information, perform or format the analysis, and, in claim 8, collect the identified antibody. They do not meaningfully apply the naturally occurring relationship between the biological characteristics of HCV-specific antibodies and their ability to neutralize particular HCV variants or abstract profile evaluation in a manner that integrates the judicial exceptions into a practical application.
Step 2B, Inventive Concept (Refer to MPEP § 2106.05): The additional elements are considered individually and as an ordered combination to determine whether they amount to significantly more than the judicial exceptions. One consideration is whether the additional elements merely constitute well-understood, routine, conventional activities previously engaged in within the relevant field. The evidence discussed below is relied upon for this limited Step 2B purpose. The references are not relied upon to establish the judicial exceptions themselves, but rather to demonstrate the conventional nature of the additional HCV sample acquisition, neutralization-assay, antibody-isolation, and high-throughput activities surrounding those exceptions.
Regarding claims 1–7, obtaining biological specimens from HCV-infected subjects and measuring HCV neutralization do not supply an inventive concept. Osburn et al. (Clearance of Hepatitis C Infection Is Associated with the Early Appearance of Broad Neutralizing Antibody Responses. Hepatology. Vol. 59, No. 6, June 2014 – IDS dated 02/07/2023) demonstrates that plasma samples obtained from HCV-infected subjects were used in HCV studies and that heat-inactivated plasma samples were tested for neutralization of library HCVpp at a single dilution (p. 2141–2142). Osburn further demonstrates use of a high-throughput production and screening approach for an HCVpp library (p. 2141) and reports that the use of an HCVpp library for screening for neutralizing antibody (nAb) responses during acute infection is a more sensitive approach than screening with a single HCVpp (p. 2144). Thus, the sample-acquisition and HCV neutralization measurements surrounding the claimed profile analysis were established HCV laboratory activities rather than an inventive concept.
Claims 6 and 7 likewise do not acquire an inventive concept merely by identifying epitope specificity or distinct HCV epitope binding. Sabo et al. (Neutralizing Monoclonal Antibodies against Hepatitis C Virus E2 Protein Bind Discontinuous Epitopes and Inhibit Infection at a Postattachment Step. Journal of Virology. Vol. 85, No. 14, July 2011 – IDS dated 02/07/2023) demonstrates established HCV antibody characterization using high-throughput focus-forming reduction or luciferase-based neutralization assays and reports that using yeast surface display, the authors localized epitopes for the neutralizing MAbs on the E2 protein (p. 7005). Sabo further describes identifying neutralizing antibodies that bound to distinct regions of E2 using a high-throughput yeast surface display mapping strategy (p. 7006).These established antibody-characterization activities do not transform the underlying natural antibody/epitope relationship and profile analysis into significantly more.
Claim 8’s antibody-isolation limitation likewise does not supply an inventive concept. Merat et al. (Hepatitis C Virus Broadly Neutralizing Monoclonal Antibodies Isolated 25 Years after Spontaneous Clearance. Plos One. Vol. 11, No. 10, October 2016 – IDS dated 01/25/2022) demonstrates that human CD27+IgG+ memory B cells were isolated and expressly describes isolation of cross-reactive antibodies (p. 3). Merat further reports that five E1E2 broadly reactive antibodies were isolated and that three showed potent neutralization of genotype 1 to 4 using HCV pseudotyped particles (p. 1). Thus, isolation of HCV neutralizing antibodies following their identification represents established laboratory activity rather than an inventive concept. Claim 9’s high-throughput format also does not supply significantly more. Sabo expressly teaches for high-throughput screening, the authors adapted an FFU assay with Huh-7.5 cells and assessed reduction in infectious foci after preincubation of virus with individual monoclonal antibodies (p. 7010, Fig. 1A). Osburn similarly reports constructing HCVpp from HCV-infected-subject plasma using a high-throughput production and screening approach (p. 2141). Accordingly, merely carrying out the claimed neutralization-based analysis in a high-throughput format does not constitute an inventive concept.
When the additional limitations of claims 1–9 are considered as an ordered combination rather than in isolation, the claims still amount to obtaining antibody-containing biological material, measuring established HCV neutralization activity, organizing the resulting neutralization information into profiles, evaluating and correlating those profiles to identify naturally existing antibody characteristics, and, in claims 6–9, further characterizing, isolating, or processing the identified antibodies in established formats. No unconventional laboratory arrangement, improvement to HCV neutralization technology, or other technological improvement is recited. Accordingly, the ordered combination does not provide an inventive concept sufficient to transform the claimed judicial exceptions into patent-eligible subject matter.
Ultimately, claims 1–9 are therefore rejected under 35 U.S.C. 101 because the claimed inventions are directed to a law of nature and an abstract idea without additional elements that integrate the judicial exceptions into a practical application or amount to significantly more than the exceptions themselves.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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.
Claims 1-2 and 4-9 are rejected under 35 U.S.C. 103 as being unpatentable over Georgiev et al. (Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization. Science. Vol. 340, No. 6133, May 2013 – IDS dated 02/07/2023) in view of Osburn et al (Clearance of Hepatitis C Infection Is Associated with the Early Appearance of Broad Neutralizing Antibody Responses. Hepatology. Vol. 59, No. 6, June 2014 – IDS dated 02/07/2023).
Regarding claim 1, for a method of identifying Hepatitis C virus (HCV) neutralizing antibodies, Georgiev teaches a method for determining neutralizing-antibody specificities from serum neutralization patterns. Specifically, Georgiev teaches that epitope specificities of HIV-1–neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates, that the authors determined neutralization fingerprints for 30 neutralizing antibodies on a panel of 34 diverse HIV-1 strains, and used these fingerprints to delineate specificities of polyclonal sera (p. 751). Regarding obtaining a biological sample from a subject having been infected with HCV, Georgiev teaches obtaining and analyzing biological samples from virus-infected subjects, specifically neutralization data for sera from HIV-infected donors ( p. 752).
Regarding measuring neutralization of HCV pseudoparticles (HCVpp) by antibodies specific for an HCV in the biological sample, Georgiev teaches measuring neutralization across a diverse virus panel, using neutralization data for a panel of 34 diverse HIV-1 isolates and 30 monoclonal antibodies recognizing diverse epitopes on HIV-1 Env to generate antibody neutralization fingerprints (p. 751). Regarding generating a neutralization profile of each biological sample, Georgiev teaches serum neutralization patterns and explains that neutralization patterns of a polyclonal serum could be viewed as the combined effect of the neutralization fingerprints of component monoclonal antibodies (p. 751). Figure 1 further teaches using patterns of neutralization from polyclonal sera as the serum-neutralization pattern analyzed using antibody neutralization fingerprints (Fig. 1, p. 752).
Regarding deconvoluting the HCV-specific neutralizing antibodies by generating a reference antibody neutralization profile, Georgiev teaches determining whether the neutralization signal from polyclonal sera could be deconvoluted into component-antibody specificities and generating a reference set of 10 epitope-specific neutralization fingerprints, one for each antibody cluster (p. 752). Figure 1 likewise teaches that a database of neutralization fingerprints for known antibodies can be constructed and that deconvolution of the serum-neutralization pattern into epitope-specific fingerprints identifies epitope specificity of the component antibodies (Fig. 1, p. 752). Regarding correlating the reference antibody neutralization profile to the biological sample’s neutralization profile, Georgiev teaches that neutralization fingerprints for antibodies known to target similar epitopes correlated significantly better (Spearman correlation) than fingerprints of antibodies targeting different epitopes (p. 751). Figure 1 further teaches that the correlations between antibody neutralization fingerprints are used to establish epitope-specific antibody clusters whose resultant fingerprints are used to interrogate polyclonal-serum neutralization patterns (Fig. 1, p. 752).
Regarding identifying the HCV neutralizing antibodies, Georgiev teaches that its neutralization-based method for delineating component-antibody epitopes was successful in identifying major antibody responses for sera with confirmed specificities, with at least one of the top two neutralization-delineated specificities identified by standard mapping in approximately ~85% of the tested sera (p. 752; Fig. 3). Georgiev further teaches that neutralization fingerprints allow for prospective prediction of monoclonal antibody epitopes (p. 753).
Georgiev also provides an express bridge for applying its methodology to another viral system. Georgiev recognizes monoclonal antibodies against HIV-1, influenza, hepatitis C, and other viruses, explains that viral genetic diversity can be an integral mechanism of immune evasion; this same diversity may, however, also provide a means by which to understand antibody responses, and teaches that diverse viral isolates provide characteristic neutralization patterns or neutralization fingerprints (p. 751). Georgiev further concludes that epitope delineation based on neutralization fingerprints may provide a transformative strategy for screening sera or characterizing antibody specificities induced upon infection or vaccination against HIV-1 as well as other viruses (p. 755).
However, Georgiev does not specifically teach applying its neutralization-fingerprint/deconvolution methodology to a biological sample from an HCV-infected subject and measuring neutralization of HCV pseudoparticles, as required by the elected species.
Osburn remedies this deficiency. Osburn teaches a representative genotype 1 HCV pseudoparticle (HCVpp) library, consisting of 19 genetically distinct genotype 1 HCVpp that comprise the natural variability of genotype 1 E1E2 sequences, and expressly measures neutralization of individual library HCVpp by the last viremic plasma sample (p. 2140). Osburn teaches plasma samples obtained from HCV-infected subjects (p. 2141) and that heat-inactivated plasma samples were tested for neutralization of library HCVpp (p. 2142). Regarding the sample neutralization profile, Osburn’s Figure 2A provides a heat map illustrating neutralization results against each HCVpp for Persistence and Clearance subjects, wherein each square represents negative (white) or positive (gray) neutralization of that particular HCVpp (Fig. 2A, p. 2145). Osburn further provides a specific technical reason for the modification. Osburn explains that neutralizing antibody (nAb) studies using a single isolate may underestimate the incidence or magnitude of nAb responses due to this high level of sequence diversity, and addresses this problem using an HCVpp library that models the natural envelope sequence variability (p. 2141). Osburn experimentally demonstrates that the use of an HCVpp library for screening for nAb responses during acute infection is a more sensitive approach than screening with a single HCVpp (p. 2144).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Georgiev’s neutralization-fingerprint/deconvolution method by applying the method to plasma from HCV-infected subjects and measuring neutralization across the representative HCVpp library taught by Osburn. Georgiev itself suggests extension of its approach beyond HIV, expressly identifies hepatitis C among viruses for which monoclonal neutralizing antibodies were being studied, and teaches use of neutralization fingerprints for HIV-1 as well as other viruses. Osburn provides the HCV-specific technical reason for the modification because single-isolate HCV studies may underestimate the incidence or magnitude of nAb responses, whereas its representative HCVpp library models natural envelope diversity and provides a more sensitive approach than screening with a single HCVpp. Thus, one of ordinary skill would have been motivated to use Osburn’s HCVpp/plasma system in Georgiev’s method to obtain a more representative and sensitive HCV neutralization pattern from which component HCV-neutralizing-antibody specificities could be delineated. A skilled artisan would have reasonably expected success because Georgiev successfully deconvoluted serum neutralization patterns into component-antibody specificities, while Osburn demonstrated that plasma from HCV-infected subjects reproducibly neutralizes members of a representative HCVpp panel; accordingly, the modification preserves Georgiev’s established diverse-virus neutralization-pattern analysis while applying it to Osburn’s demonstrated HCVpp assay.
Regarding claim 2, refer to the discussion above, Osburn expressly teaches plasma samples obtained from HCV-infected subjects and testing those plasma samples for neutralization of library HCVpp pp. 2141–2142). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use Osburn’s plasma samples as the biological sample in the Georgiev/Osburn method because Osburn specifically demonstrates that plasma from HCV-infected subjects contains measurable HCV-neutralizing-antibody activity against the representative HCVpp library. A skilled artisan would have reasonably expected success because Osburn actually obtained and tested such plasma samples and detected HCVpp neutralization therein. Thus, using plasma provides the sample medium already demonstrated by Osburn to carry the HCV-neutralizing-antibody activity required for the modified Georgiev analysis.
Regarding claim 4, refer to the discussion above, Georgiev teaches that the neutralization pattern for each serum was taken to be a linear combination of the reference-set fingerprints, resulting in an estimate of the relative contribution to serum neutralization (i.e., neutralization prevalence) of the respective component-antibody specificities (p. 752). Figure 3 further represents the predicted relative prevalence of the different reference-set antibody clusters as fractional contributions wherein numbers in each row add up to 1.00 ( Fig. 3, p. 754).
Regarding claim 5, refer to the discussion above, Georgiev teaches taking each serum neutralization pattern as a linear combination of the reference-set fingerprints, thereby obtaining an estimate of the relative contribution to serum neutralization of the respective component-antibody specificities (p. 752). Figure 3 expressly reports the predicted relative prevalence of the different reference-set antibody clusters, using a higher fractional number corresponding to a stronger neutralization signal (Fig. 3, p. 754).
Regarding claim 6, refer to the discussion above, Georgiev further teaches identifying epitope specificities for neutralizing antibodies. Specifically, Georgiev teaches that epitope specificities of HIV-1–neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates, and that similarity in neutralization fingerprint correlated with similarity in epitope (p. 751). Georgiev further teaches that clustering of antibodies based on neutralization fingerprints can be an accurate delineator of antibody-epitope specificity and generates 10 epitope-specific neutralization fingerprints for deconvolution of serum into component-antibody specificities (p. 752, Fig. 1). Georgiev’s Figure 1 expressly teaches that Deconvolution of the serum-neutralization pattern into epitope-specific fingerprints identifies epitope specificity of the component antibodies (p. 752, Fig. 1).
Regarding claim 7, refer to the discussion above, Georgiev further teaches neutralization profiles that distinguish individual antibodies according to distinct epitopes. Georgiev teaches that neutralization fingerprints for antibodies known to target similar epitopes correlated significantly better than fingerprints of antibodies targeting different epitopes and that neutralization fingerprints appeared to exhibit sufficient specificity to successfully distinguish between antibodies targeting different epitopes (pp. 751–752). Georgiev further teaches a reference set of 10 epitope-specific neutralization fingerprints, one for each antibody cluster, thereby permitting serum neutralization to be deconvoluted into distinct component-antibody specificities (p. 752, Fig. 1).
Regarding claim 8, refer to the discussion above, Georgiev further teaches isolating antibodies identified through neutralization-based analysis. Specifically, Georgiev teaches that the antibody specificities delineated from serum neutralization patterns were further confirmed by antibody isolation for two sera and that such serologic analysis can further lead to the isolation of new monoclonal antibodies (p. 751). Georgiev further recognizes that recent years have seen a surge in the isolation of monoclonal antibodies against HIV-1, influenza, hepatitis C, and other viruses (p. 751). Georgiev demonstrates this approach by selecting sera having predicted antibody specificities and then teaches cloning CD4bs antibodies from donor 127/C peripheral blood mononuclear cells (PBMCs) (p. 752), and, for donor N27, used single B cell culture and recovered one neutralizing antibody, VRC24 (p. 753). Georgiev concludes that for both donors 127/C and N27, the authors successfully confirmed the existence of antibodies with specificities predicted by the neutralization-based method (p. 753).
Regarding claim 9, refer to the discussion above, Osburn further expressly teaches a high-throughput production and screening approach for constructing the genotype 1 HCVpp library from samples obtained from HCV-infected subjects (p. 2141). Osburn further expressly identifies high-throughput HCVpp production and infectivity screening and teaches producing HCVpp in a 96-well plate (p. 2142). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the Georgiev/Osburn method in a high-throughput format using Osburn’s expressly taught high-throughput HCVpp production and screening approach. The modification would facilitate efficient generation and analysis of the numerous HCVpp neutralization measurements required by the diverse-virus fingerprint method. A skilled artisan would have reasonably expected success because Osburn actually implements high-throughput HCVpp production and screening in a 96-well format.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Georgiev et al. and Osburn et al., as applied to claim 1 above, and further in view of Doria-Rose et al. (Developmental Pathway for Potent V1V2-Directed HIV-Neutralizing Antibodies. Nature. Vol. 509, No. 7498, May 2014)
With respect to the teachings of Georgiev and Osburn, refer to the discussion above, which applies equally here. However, Georgiev and Osburn do not expressly teach or specify that the neutralization profile comprises a ranking of relative neutralization of each HCVpp by each reference antibody or biological sample.
Doria-Rose teaches the use of a single round of replication Env-pseudoviruses and a panel of 194 geographically and genetically diverse Env-pseudoviruses. Doria-Rose further explains that different viral strains may exhibit different neutralization sensitivities to the same antibody, that this pattern of neutralization variation can be used to define the neutralization fingerprint for a given antibody, and expressly defines the neutralization fingerprint of an antibody as the rank-order of neutralization potencies for the antibody against a set of diverse viral strains (Methods, p. 9). Doria-Rose additionally computes correlations between antibody fingerprints and longitudinal serum neutralization patterns.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the Georgiev/Osburn HCVpp neutralization profiles by representing relative neutralization of the diverse HCVpp panel as the rank order of neutralization potency taught by Doria-Rose. Doria-Rose expressly provides the reason for doing so: variation in neutralization sensitivity among diverse viral strains defines a characteristic antibody fingerprint, and rank ordering those potencies provides the fingerprint used for comparison and correlation. This directly complements Osburn’s teaching that HCV diversity makes a diverse HCVpp panel advantageous for characterizing neutralizing-antibody responses. A skilled artisan would have reasonably expected success because Doria-Rose actually used rank-ordered pseudovirus neutralization fingerprints for individual antibodies and correlated such fingerprints with serum neutralization patterns, while Osburn demonstrates that corresponding diverse pseudoparticle neutralization measurements are obtainable for HCV.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 1-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 13-15, 17, and 25 of copending Application No. 18/998,411 in view Georgiev et al., Doria-Rose et al., and Osburn et al., as applicable.
Regarding claim 1, claim 1 of the copending application claims measuring plasma antibody neutralization of a heterologous hepatitis virus panel and deconvoluting the plasma neutralizing antibodies to identify neutralizing antibodies having increased plasma neutralizing breadth and potency in hepatitis C virus infected or reinfected subjects. Claims 3–5 further require neutralization assays using pseudoviral particles, determining infectivity of the particles, incubating infectious pseudoviral particles with the biological sample, and determining percent neutralization values. Claims 13, 15, and 17 further claim HCV-specific subject matter comprising converting percent neutralization values to a neutralization profile for each biological sample, comparing the neutralization profiles to reference profiles, conducting a deconvolution analysis, and identifying neutralizing antibodies relative to control reference antibodies.
The copending claims differ principally from instant claim 1 in not expressly requiring that deconvolution be performed by generating a reference antibody neutralization profile and correlating that profile with the biological sample’s neutralization profile. Georgiev teaches determining whether a neutralization signal from polyclonal serum could be deconvoluted into component-antibody specificities, generating a reference set of 10 epitope-specific neutralization fingerprints, and using correlations between antibody neutralization fingerprints to interrogate serum-neutralization patterns. It would therefore have been obvious to employ Georgiev’s reference-antibody fingerprint and correlation methodology in the deconvolution analysis already claimed by the copending application to identify the component HCV-neutralizing antibodies represented in the biological-sample neutralization profile, with a reasonable expectation of success because Georgiev demonstrates successful deconvolution of polyclonal neutralization patterns into component-antibody specificities.
Regarding claim 2, claim 1 of the copending application already expressly requires plasma antibody neutralization from HCV-infected or reinfected subjects. Thus, the claimed plasma species is already encompassed by the copending claims.
Regarding claim 3, the discussion above applies. The copending claims and Georgiev do not expressly require that the neutralization profile comprise a ranking of relative neutralization of each HCVpp by each reference antibody or biological sample. Doria-Rose teaches neutralization fingerprints based on a diverse pseudovirus panel and expressly defines the neutralization fingerprint of an antibody as the rank-order of neutralization potencies against diverse viral strains. It would therefore have been obvious to represent the relative neutralization measurements of the claimed HCV pseudovirus panel according to Doria-Rose’s rank-order methodology because such ranking provides the characteristic neutralization fingerprint used for comparison and correlation.
Regarding claim 4, the discussion of claim 1 applies. Georgiev further teaches that each serum neutralization pattern was taken to be a linear combination of the reference-set fingerprints, thereby providing combinations of reference-antibody neutralization fingerprints representing possible component-antibody mixtures. Thus, employing various proportions of the reference profiles to generate possible combined profiles would have been an obvious implementation of Georgiev’s expressly taught deconvolution methodology.
Regarding claim 5, Georgiev further teaches that the linear combination of reference-set fingerprints provides an estimate of the relative contribution to serum neutralization of the respective component-antibody specificities, and Figure 3 reports the predicted relative prevalence of the reference-set antibody clusters as fractional contributions. Thus, correlating a combined reference profile with the biological-sample profile to identify the proportion contributed by each reference antibody would have been an obvious application of Georgiev’s expressly taught analysis.
Regarding claim 6, Georgiev teaches that epitope specificities of HIV-1-neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization and that clustering antibodies based on neutralization fingerprints delineates antibody-epitope specificity. Applying this expressly taught output to the HCV-neutralizing antibodies already claimed by the copending application would have predictably identified their HCV epitope specificities.
Regarding claim 7, the discussion of claim 6 applies. Georgiev further teaches that antibody neutralization fingerprints exhibit sufficient specificity to distinguish between antibodies targeting different epitopes and provides a reference set of epitope-specific neutralization fingerprints. Thus, identifying individual antibodies binding distinct HCV epitopes would have been an obvious consequence of applying Georgiev’s epitope-specific deconvolution to the HCV system claimed in the copending application.
Regarding claim 8, claim 25 of the copending application already claims an isolated hybrid cell producing a Hepatitis C virus (HCV) neutralizing antibody identified by the method of claim 1. Georgiev additionally teaches that antibody specificities delineated from serum-neutralization patterns were confirmed by antibody isolation and that the analysis may lead to the isolation of new monoclonal antibodies. It would therefore have been obvious to isolate the HCV-neutralizing antibodies identified by the claimed deconvolution method.
Regarding claim 9, the copending claims, as modified by Georgiev, do not expressly require performance in a high throughput format. Osburn teaches high-throughput HCVpp production and infectivity screening, including production of HCVpp in a 96-well plate. It would therefore have been obvious to implement the claimed HCV neutralization/deconvolution method in Osburn’s high-throughput format to facilitate efficient production, screening, and analysis of the numerous HCV pseudoparticle neutralization measurements required by the diverse-virus-panel method, with a reasonable expectation of success because Osburn actually performs high-throughput HCVpp production and screening in a 96-well format.
Accordingly, claims 1–9 are not patentably distinct from the claims of the copending application in view of the cited prior art. This is a provisional nonstatutory double patenting rejection.
Conclusion
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 September 17, 2026
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