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 .
Priority
The present application was filed on 09/30/2025. This application is a CON of 16/872,767, which claims benefit of U.S. Provisional Patent Application 62/846,872 filed on 05/13/2019 and 62/859,914 filed on 06/11/2019. The effective filing date of this application is 05/13/2019.
Claim status
Claims 1-3, 6-10, 17, 19-21, and 23 are amended. Claims 1-23 are pending and examined.
Objections/Rejections status
The rejection of claims 1-23 under 35 USC 112(b) is withdrawn in view of the amendment of the claims and the Applicant’s argument filed on 04/20/2026.
The rejections of claims 1-23 under Double Patenting is withdrawn in view of the abandon of the application 16/872,767.
New objections of claims 19 and 23 are made in view of the amendment of the claims.
The rejections of claims 1-23 under 35 USC 103 are updated in view of the amendment of the claims.
Claim Objections
Claim 19 is objected to because of the following informalities:
Claim 19, in lines 1-2, recites “wherein the labeled target or the labeled antibody drug comprise….” It appears that the subject and verb agreement is not correct. The word “comprise” should be replaced by -comprises- since the subject is singular.
Claim 23, in lines 5-6, the phrase “identifying the at least one lead antibody drug as the one or more antibody drug candidates” is not grammatically correct. It appears that the at least one lead antibody drug is identified from or among the one or more antibody drug candidates.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
Claims 1-16 and 18-23 are rejected under 35 U.S.C 103 as being unpatentable over Rajadhyaksha et al. (US20160252520) in view of Smith et al. (“Detection of antibodies against therapeutic proteins in the presence of residual therapeutic protein using a solid-phase extraction with acid dissociation (SPEAD) sample treatment prior to ELISA” Regulatory Toxicology and Pharmacology 49:230-237 2007), Mei et al. (Digital Microfluidic Platform for Human Plasma Protein Depletion, Anal. Chem. 2014, 86, 8466−8472), Grabert et al. (US20150226758) and GenScript (What is an Anti-Idiotypic Antibody?, 2018).
For claims 1-2, Rajadhyaksha teaches a method for detecting the presence of anti-drug antibodies (ADA) to an antibody drug in a sample (see Abstract, see par.7 teaching “method for detecting the presence of neutralizing antibodies to a biotherapeutic protein… the protein biotherapeutic is a monoclonal antibody”), the method comprising:
incubating the sample under acidic conditions to produce an acidified sample (see par.36: teaching that a sample is diluted in low pH condition (with acetic acid), which results in the dissociation of neutralizing antibody (NAb):drug and drug:target complexes present in serum samples, allowing for improved detection of NAb in the presence of excess drug in the serum);
combining the acidified sample with a pH buffered solution to make a combined sample (see par. 36: teaching that a sample is diluted in low pH condition and then neutralized using a Tris-base solution).
Rajadhyaksha teaches that the Tris-base solution contains Biotinylated-REGN88 (i.e., a labeled drug), so the NAb in the combined sample bound to the labeled drug. The combined sample was then added to the avidin precoated microplate, where the avidin captured the biotinylated-REGN88 along with any NAb that was bound to it. See paragraph 36. This step formed a drug coated solid support because the labeled drug in the combined sample was captured on the avidin precoated microplate. After that, ruthenium-REGN78 (i.e., a labeled target of the drug) was added to the microplate (see par.37). This step teaches the concept of incubating the depleted sample with the antibody drug and the labeled target of the antibody drug together to create a competitive binding assay between the NAb in the sample and the labeled target of the drug to the drug and then the drug is immobilized on the solid support (see par.37). The claimed invention is different from the prior art as the drug is pre-coated on the solid support. 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 method of Rajadhyaksha, pre-coating the antibody drug on the solid support because the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art, wherein the drug is eventually immobilized on the solid support via biotin-streptavidin link and the result is based on a detectable signal from the labeled target bound to the drug-coated solid support. The modification would yield a predictable result because the incubation methods taught by prior art and the claimed invention are functionally equivalent.
The method further comprises measuring a detectable signal from the labeled target bound to the drug-coated solid support, wherein a decreased signal relative to a control sample indicates the presence of anti-drug antibodies in the sample. (See par.37: “the avidin captured biotinylated-REGN88 binds to the ruthenium-REGN78 forming a biotinylated-REGN88:ruthenium-REGN78 complex on the surface of the microplate… In the presence of NAb, the NAb will bind the biotinylated-REGN88 preventing the formation of the biotinylated-REGN88:ruthenium-REGN78 complex which in turn reduces the electrochemiluminescent signal. Hence, the measured electrochemiluminescence (i.e., counts) is inversely proportional to the amount of NAb in the sample.”)
Rajadhyaksha does not teach using a labeled non-blocking anti-idiotypic antibody specific for the drug to produce non-blocking anti-idiotypic antibody: antibody drug complexes, wherein the labeled non-blocking anti-idiotypic antibody comprises a selectable label; removing the non-blocking anti-idiotypic antibody: antibody drug complexes from the sample using the selectable label to produce a depleted sample.
Smith discloses the detection of antibodies against therapeutic proteins (i.e., neutralizing antibody (NAb) or anti-drug antibody (ADA)) in the presence of residual therapeutic protein (i.e., drug) using a solid-phase extraction with acid dissociation (SPEAD) sample treatment prior to ELISA. The method comprises removing the interfering therapeutic protein “drug” from the sample prior to perform an immunoassay for detection of anti-drug antibodies (ADA). See Abstract. Smith teaches that the residual drug in the sample when analyzing the ADA can cause false negatives and make it difficult to detect ADA in most immunoassay formats. See page 231 column 1 paragraphs 1-2. Therefore, removing the interference improves assay tolerance to residual drug in samples (see Abstract).
Briefly, the sample containing a biotin-drug and ADA is incubated with a streptavidin solid phase. The complex of biotin-drug and ADA is immobilized on the solid phase. ADA is dissociated from the complex by incubating the solid phase with an acidic solution. The acid-treated solution is then collected, and ADA is measured. See page 232 and Table 1. This step encompasses the step of removing the drug out of the sample to form a depleted sample (i.e., sample containing ADA without the drug). This step also encompasses the use of a selectable label to produce a depleted sample because the biotin label can bind to streptavidin solid phase, so the drug is captured in the solid phase to produce a drug depleted sample.
While Smith emphasizes the need to remove the drug interference from the sample before detecting ADA, Smith does not teach using a labeled non-blocking anti-idiotypic antibody to bind to the drug.
Mei discloses a method for isolating a target analyte from an interference non-analyte in human serum. The method comprises the use of superparamagnetic beads coated with a non-analyte binding agent. The method has 95% depletion efficiency and increases the sensitivity of biomarker identification assay because the reduction of interference non-analyte reduces the complexity of plasma. See Abstract and page 8466 column 1. The samples can be manipulated using antibody-functionalized superparamagnetic particles, which can be controlled with magnetic fields, allowing for separation of specific molecules bound to the particles from the remainder of the supernatant (see page 8469 col.2).
Grabert teaches the methods of reducing or eliminating the problems caused by interference, e.g., drug or target in ADA detection (see par.7) or reducing interference in a drug assay due to the presence of an ADA in a sample in drug detection (see par.18). The methods comprise producing a depleted sample by dissociating drug and ADA apart and immobilizing the dissociated ADAs or drug on a substrate for further analysis (see par(s).17-18 and 86). Grabert demonstrates that acid treatment alone does not eliminate drug tolerance in ADA assays (see par.63). Reducing the interference from the detection assay can minimize the false negative and false positive results, thus improving assay sensitivity and ADA recovery (see par(s).5, 61, 118).
Grabert also teaches the drug can be detected using an anti-idiotype antibody labeled with a detectable label (see par.19). Grabert does not teach the anti-idiotype antibody is a non-blocking anti-idiotype antibody.
GenScript teaches that an anti-idiotypic (Anti-ID) antibody binds to the idiotype of another antibody, usually an antibody drug (see page 1). There are three main types of anti-ID antibodies based on the way they interact and detect an antibody drug. One of them is a non-blocking anti-ID antibody because the antibody drug's paratope and idiotope do not overlap. Therefore, the anti-ID antibody and the antigen can simultaneously bind to the antibody drug without affecting one another's binding capability. Because of this, non-blocking anti-ID antibodies are used to detect all forms of available antibody drug (free and antigen bound). See GenScript page 2, paragraph 1.
Therefore, it would have been obvious to integrate the drug interference depletion step taught by Smith or Mei or Grabert into the anti-drug antibody detecting method of Rajadhyaksha for the following reasons: Grabert demonstrates that acid treatment alone does not eliminate drug tolerance in ADA assays (see par.63); Smith, Mei and Grabert all teach that the step of removing drug interference will improve the sensitivity of the anti-drug antibody detection assay because it reduces false negative and increases the drug tolerance of the anti-drug antibody in the assay as discussed above. (Smith in Abstract, Grabert in par(s).5, 61 and 118, and Mei in Abstract).
Accordingly, to remove the drug interference from the sample in the detecting method of Rajadhyaksha, it would have been obvious to apply the isolating method of Smith and Mei, by capturing the drug on the solid phase via a label, e.g., biotin label or magnetic label (as taught by Smith in Abstract and Mei in Abstract). One having an ordinary skill in the art would have been motivated to use a superparamagnetic beads coated with non-analyte binding agent and the magnetic field to separate the drug bound on the beads from the supernatant as taught by Mei (See Mei Abstract, page 8466 column 1, and page 8469 col.2) because the drug depletion would be more efficient to produce a depleted sample as taught by Mei in Abstract. Moreover, the interference drug in the method of Rajadhyaksha can be separated from the combined solution (comprising biotin-drugs, ADAs and labeled targets) by using the magnetic field. Therefore, the biotin-drug is still retained in the combined solution for downstream detection step.
It would have been obvious to one having an ordinary skill in the art before the effective filing date of the claimed invention to use a non-blocking anti-idiotypic antibody specific for the drug as a substitute for the non-analyte binding agent on superparamagnetic beads in the method of Rajadhyaksha, Smith and Mei, as an obvious matter to try, namely choosing from a finite list of suitable, art recognized/known binding agent for recognizing the drug from the mixture of drug, target, anti-drug antibody and the complex thereof from the supernatant as taught by Grabert and GenScript. One having an ordinary skill in the art would have been motivated to use a non-blocking anti-idiotypic antibody specific for the drug, because GenScript teaches that the non-blocking anti-idiotypic antibody can bind to the drug in both free form and bound form with the target (see GenScript page 2 paragraph 1), so the drug depletion would be more efficient because the non-blocking anti-idiotypic antibody can detect all forms of the antibody drug (free and antigen bound) if there are some complexes of drug:target or drug:ADA left in the solution after acidification step.
A person having an ordinary skill in the art would have had a reasonable expectation of success in combining Rajadhyaksha, Smith, Mei, Grabert and GenScript because they are directed to a detection method (e.g., detecting drug or anti-drug antibody in a sample comprising a mixture of drug, anti-drug antibody and target of the drug), wherein the interferences (e.g., anti-drug antibody or drug or target) should be eliminated or reduced to improve the sensitivity and accuracy of the test.
For claim 2, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein the depleted sample is incubated with a labeled target of the drug on the antibody drug-coated solid support and the detectable signal is measured from the labeled target bound to the drug-coated solid support. See discussion in claim 1 above.
For claims 3-5, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, further comprising incubating the acidified sample or the depleted sample with an anti-target blocking reagent or an antigen binding fragment thereof that specifically binds to the target of the antibody drug. (Rajadhyaksha, in par.36, teaches that the samples are diluted in low pH conditions (with acetic acid) and then neutralized using a Tris-base solution containing Biotinylated-REGN88 and REGN17. In order to mitigate target interference, REGN17 is used to bind free target released by the low pH treatment. This teaching encompasses incubating the acidified sample with an anti-target blocking reagent that binds to the target of the drug.)
Smith and Grabert teach that there is a need in the art for methods to more accurately and reproducibly detect the presence of ADA in samples (see Smith Introduction and Grabert in Abstract). One of the methods is reducing or eliminating the problems caused by interference by drug or target prior to performing the ADA detection (Smith in Abstract and Grabert par.7).
While Rajadhyaksha does not teach to incubate an anti-target blocking reagent in the depleted sample, it would have been obvious to modify the method of Rajadhyaksha, incubating an anti-target blocking reagent in the depleted sample because it can remove the target interference from the sample prior detecting the ADA. The change in sequence of adding the anti-target blocking reagent does not change the concept of the method of ADA detection. Removing the interferences (e.g., removing a target of a drug or a drug from the sample prior to performing an immunoassay for detection of ADA) will increase residual drug tolerance of ADA, and improve the sensitivity and accuracy of the test (see Smith in Abstract and Introduction, Grabert in at least par.42). Therefore, the modification would result in a predictable outcome.
For claims 6 and 22, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein the depleted sample is incubated with a labeled antibody drug on the target-coated solid support, and the detectable signal is measured from the labeled antibody drug bound to the target-coated solid support, and wherein the target-coated solid support comprises biotinylated target bound to an avidin or streptavidin coated solid support.
While Rajadhyaksha, Smith, Mei, Grabert and GenScript do not teach using a labeled drug on target coated solid support, 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 method of Rajadhyaksha, Smith, Grabert and GenScript, and Mei, using a labeled drug on target coated solid support to detect the ADA in the sample because the differences between the claimed invention and the prior art were encompassed in known variations or in a principle known in the prior art.
The detection of ADA in the solution is based on the competition of ADA and the target to bind the drug. Therefore, replacing the labeled target on drug coated solid support by a labeled drug on target coated solid support is just an alternative way to detect the ADA. One of ordinary skill in the art, in view of the identified design incentives, could have implemented the claimed variation of the prior art, and the claimed variation would have been predictable to one of ordinary skill in the art.
For claim 7, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, further comprising washing the antibody drug-coated solid support or the target-coated solid support after incubation with the depleted sample. (Rajadhyaksha teaches that the acidic pH treated samples were then added to the avidin precoated microplate, where the avidin captured the biotinylated-REGN88 along with any NAb that was bound to it. After incubation and washing, a labeled target was added to the microplate. See par.36-37.)
For claim 8, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein the anti-drug antibodies comprise neutralizing antibodies that specifically bind to the antibody drug (see Rajadhyaksha in par.5, teaching that applicants have developed a sensitive and reliable CLB assay that can detect a neutralizing antibody (NAbs) response to a biotherapeutic drug molecule, in a patient).
For claim 9, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein the antibody drug is a monoclonal antibody (see Rajadhyaksha par.5-7: teaching that the drug is biotherapeutic protein, e.g., a monoclonal antibody (mAb)).
For claim 10, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 9. Rajadhyaksha teaches that the detection of antibodies, such as neutralizing antibodies (NAbs), is part of the immunogenicity assessment that this performed for patients treated with a biotherapeutic agent because neutralizing antibodies neutralize the function of the drug thereby negatively impacting the efficacy of the drug (see par.2).
Rajadhyaksha does not teach the drug is an antigen binding fragment.
Grabert teaches while the introduction of biotherapeutics (e.g., biologic agents such as proteins, peptides, nucleotides, etc.) has given a major boost to the treatment of diseases, biologic agents, including therapeutic antibodies, are known to have immunogenic potential, and administration of therapeutic proteins to a patient can induce immune response leading to the formation of anti-drug antibodies which may reduce the effectiveness of the therapeutic protein (see par.3). In some patients, the clinical benefits provided by such therapeutic proteins diminishes over time due to the formation of ADAs. Immunogenicity risk assessment is critical to understand the frequency and severity of drug induced ADA. See paragraph 3.
Grabert teaches the methods of reducing or eliminating the problems caused by interference, e.g., drug in ADA detection (see par.7), wherein the drug comprises an antibody or fragment thereof, a dual affinity antibody, diabody, multiple domain biologics (see par.22).
Therefore, it would have been obvious to one having an ordinary skill in the art before the effective filing date of the claimed invention to apply the modified method of Rajadhyaksha to assess the immunogenicity in the patients treated with the drug comprising antigen binding fragment because Rajadhyaksha and Grabert teach that the immunogenicity assessment is critical to understand if the therapeutic drug can induce immune response to the formation of anti-drug antibodies which may reduce the effectiveness of the therapeutic protein overtime (Rajadhyaksha par.2 and Grabert par.3).
A person having an ordinary skill in the art would have had a reasonable expectation of success in combining Rajadhyaksha, Smith, Grabert and GenScript, and Mei because they are directed to a detection method (e.g., detecting drug or anti-drug antibody in a sample comprising a mixture of drug, anti-drug antibody and target of the drug), wherein the interferences (e.g., anti-drug antibody or drug or target) should be eliminated or reduced to improve the sensitivity and accuracy of the test.
For claims 11-13, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein the acidic conditions comprise a pH of about 2.0 to about 4.0; wherein the combining results in a sample pH of 4.0-5.5; wherein the incubating of the depleted sample is performed at a pH of about 7.0.
It is noted that the term “about” is defined in the instant specification on page 8, which the value in a range of approx. +/- 10% or 5% or 2% or 1%.
Rajadhyaksha teaches that 300 mM acetic acid is used for dissociation step, which is equivalent to the pH 2.6 (see par.44). The acidic sample is incubated with 0.2M Tris (see par.44). Rajadhyaksha does not specifically teach the same pH value for each step.
Grabert teaches the pH of acid range from 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or 6.5. The pH of the base for neutralizing step can be, for example, about 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5 and 13.0. The sample is contacted with an acid or base for an amount of time sufficient to dissociate preformed drug/ADA complexes. See par.74-77. The selection of an acidic or basic solution will depend on the parameters of the drug (e.g., the biologic drug), such as pI, or the presence of certain conjugating bonds, and the selection will have minimal effect on the integrity and structure of the drug (see par.10). Grabert also teaches wherein the incubating of the depleted sample is performed at a pH of about 7.0 (see par.97: a solution comprising sample is neutralized to pH 7.0 before doing immunoassay).
While Rajadhyaksha and Grabert do not specifically teach the same pH value for each step, Grabert suggests selecting pH of the acidic solution and base solution for the method of ADA or drug detection based on the parameters of the drug.
Since Applicant has not disclosed that the specific limitations recited in instant claims 11-13 are for any particular purpose or solve any stated problem and the prior art teaches that pH value of the solution often varies according to the parameters of sample being analyzed, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the pH solutions by normal optimization procedures known in the art to define the appropriate pH using in the detection method. The optimal pH will have minimal effect on the integrity and structure of the drug. Thus, the sensitivity of the ADA/drug detecting immunoassay is improved.
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 method of Rajadhyaksha, Smith, Grabert and GenScript, and Mei, incubating of the depleted sample in a pH 7.0 solution so that the immunoassay can be performed as taught by Grabert (see Grabert par.61 and par.97)
A person having an ordinary skill in the art would have had a reasonable expectation of success in combining Rajadhyaksha, Smith, Grabert and GenScript, and Mei because they are directed to a detection method (e.g., detecting drug or anti-drug antibody in a sample comprising a mixture of drug, anti-drug antibody and target of the drug), wherein the interferences (e.g., anti-drug antibody or drug or target) should be eliminated or reduced to improve the sensitivity and accuracy of the test.
For claims 14-16, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein the selectable label comprises a magnetic label, e.g., superparamagnetic particles (see Mei page 8469 col.2).
It would have been obvious to combine the concept taught by Smith, Grabert, and Mei, isolating an interference non-analyte from the analyte (e.g., drug from ADA) by using a magnetic-labeled non-blocking anti-idiotypic antibody specific for the drug because: Grabert and GenScript provides a method to detect the drug by a labeled non-blocking anti-idiotypic antibody specific for the drug, Smith provides a method to isolate the drug by capturing the drug on the solid phase via the label, Mei provides a method to isolate the interference by using a superparamagnetic beads coated with non-analyte binding agent and the magnetic field to separate the interference bound on the beads from the supernatant. As such, the labeled non-blocking anti-idiotypic antibody can be a non-blocking anti-idiotypic antibody attached to superparamagnetic beads. By doing that, the drug depletion would be more efficient to produce a depleted sample as taught by Mei in Abstract. Moreover, Grabert also teaches that the non-blocking anti-idiotypic antibody can bind to the drug in free form or in bound form with the target, so the drug depletion would be more efficient. By substituting the label of non-blocking anti-idiotypic antibody with a magnetic bead as taught by Mei (not with the biotin label as taught by Smith), the interference drug in the method of Rajadhyaksha can be separated from the combined solution (comprising biotin-drug, ADA and labeled target) by using the magnetic field, thereby the biotin-drug is still retained in the combined solution for downstream detection step.
A person having an ordinary skill in the art would have had a reasonable expectation of success in combining Rajadhyaksha, Smith, Grabert and GenScript, and Mei because they are directed to a detection method (e.g., detecting drug or anti-drug antibody in a sample comprising a mixture of drug, anti-drug antibody and target of the drug), wherein the interferences (e.g., anti-drug antibody or drug or target) should be eliminated or reduced to improve the sensitivity and accuracy of the test.
For claim 18, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein the sample is agitated during the incubating (see Rajadhyaksha in par.41: teaching that shaking was performed during the incubation steps).
For claims 19-20, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein the labeled target or the labeled drug comprises a fluorophore or an electrochemiluminescence probe (see Rajadhyaksha par.37, teaching the label is ruthenium emitting electrochemiluminescent signal).
For claim 21, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein the antibody drug-coated solid support comprises biotinylated drug bound to an avidin or streptavidin coated solid support (Rajadhyaksha par.36-37).
For claim 23, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1. They teaches a method for identifying a lead antibody drug comprising: administering one or more antibody drug candidates to a subject (see Rajadhyaksha in abstract teaches that the subject has been administered the biotherapeutic protein); performing the method of claim 1 on a sample obtained from the subject (see discussion of Rajadhyaksha, Smith, Grabert and GenScript in claim 1 above); and identifying the at least one lead antibody drug in the one or more antibody drug candidates that produce little or no anti-drug antibodies (Rajadhyaksha in par.2 teaches that detection of antibodies, such as neutralizing antibodies (NAbs), is part of the immunogenicity assessment for patients treated with a biotherapeutic agent. Neutralizing antibodies neutralize the function of the drug, thereby negatively impacting the efficacy of the drug.)
Grabert teaches while the introduction of biotherapeutics (e.g., biologic agents such as proteins, peptides, nucleotides, etc.) has given a major boost to the treatment of diseases, biologic agents, including therapeutic antibodies, are known to have immunogenic potential, and administration of therapeutic proteins to a patient can induce immune response leading to the formation of anti-drug antibodies which may reduce the effectiveness of the therapeutic protein (see par.3). In some patients, the clinical benefits provided by such therapeutic proteins diminishes over time due to the formation of ADAs. Immunogenicity risk assessment is critical to understand the frequency and severity for drug induced ADA. See paragraph 3.
Therefore, it would have been obvious to apply the method of detecting NAbs taught by Rajadhyaksha, Smith, Grabert and GenScript for identifying the lead antibody drug candidate that produces little or no anti-drug antibodies for the benefit of finding the most effective drug, because anti-drug antibodies can reduce the effectiveness of the therapeutic protein overtime by neutralizing the function of the drug as taught by Grabert and Rajadhyaksha as discussed above.
Claim 17 is rejected under 35 U.S.C 103 as being unpatentable over Rajadhyaksha et al. in view of Smith et al., Mei et al., Grabert et al. as evidenced by GenScript, as applied to claim 1 above, and further in view of Seegraber et al. (Dupilumab for treatment of atopic dermatitis, Drug Profile, pages 467-474, 2018).
For claim 17, Rajadhyaksha, Smith, Mei, Grabert and GenScript teach the method of claim 1, wherein drug tolerance of the method is at least 10-fold greater in a depleted sample compared to a non-depleted sample.
Rajadhyaksha teaches the method improves drug tolerance, while target interference was mitigated (see par.27). Smith teaches that the method results in a >10–100-fold increase in residual drug tolerance as compared to an immunoassay without the sample treatment, wherein the sample treatment includes the acidic dissociation step and the physical separation ADA and ADA:Drug complexes from the drug and the sample matrix (see Abstract).
Therefore, it would have been obvious to integrate the drug interference depletion step taught by Smith to the anti-drug antibody detecting method of Rajadhyaksha because Smith teaches that it will improve the sensitivity of the anti-drug antibody detection assay because it reduces false negative and increases the drug tolerance of the anti-drug antibody in the assay (see Smith Abstract).
A person having an ordinary skill in the art would have had a reasonable expectation of success in combining Rajadhyaksha, Smith, Grabert and GenScript because they are directed to a detection method (e.g., detecting drug or anti-drug antibody in a sample comprising a mixture of drug, anti-drug antibody and target of the drug), wherein the interferences (e.g., anti-drug antibody or drug or target) should be eliminated or reduced to improve the sensitivity and accuracy of the test.
Rajadhyaksha does not teach the antibody drug comprising dupilumab or aflibercept.
Rajadhyaksha teaches that the detection of antibodies, such as neutralizing antibodies (NAbs), is part of the immunogenicity assessment that is performed on patients treated with a biotherapeutic agent, because neutralizing antibodies neutralize the function of the drug, thereby negatively impacting the efficacy of the drug (see par.2).
Grabert teaches while the introduction of biotherapeutics (e.g., biologic agents such as proteins, peptides, nucleotides, etc.) has given a major boost to the treatment of diseases, biologic agents, including therapeutic antibodies, are known to have immunogenic potential, and administration of therapeutic proteins to a patient can induce immune response leading to the formation of anti-drug antibodies which may reduce the effectiveness of the therapeutic protein (see par.3). In some patients, the clinical benefits provided by such therapeutic proteins diminishes over time due to the formation of ADAs. Immunogenicity risk assessment is critical to understand frequency and severity for drug induced ADA. See paragraph 3.
Seegraber teaches that Dupilumab is a new treatment option for patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable (see Abstract).
Therefore, it would have been obvious to one having an ordinary skill in the art before the effective filing date of the claimed invention to apply the modified method of Rajadhyaksha for assessing the immunogenicity in the patients treated with Dupilumab because Seegraber teaches that Dupilumab is a new therapeutic drug for patients with moderate-to-severe atopic dermatitis and Rajadhyaksha and Grabert teach that the immunogenicity assessment is critical to understand if the therapeutic drug can induce immune response to the formation of anti-drug antibodies which may reduce the effectiveness of the therapeutic protein overtime (Rajadhyaksha par.2 and Grabert par.3).
Response to Arguments
Applicant’s arguments, see Remarks, filed 04/20/2026, with respect to the rejections of claims 1-23 under 35 U.S.C. 112 (b) have been fully considered and are persuasive. The rejections has been withdrawn.
Applicant's arguments, see Remarks, filed 04/20/2026, with respect to the rejections of claims 1-23 under 35 U.S.C.103 and Double Patenting have been fully considered but they are not persuasive.
Applicant argues, on pages 7, 8 (par.1), 9 (par.1), that the cited references, alone or in combination, do not teach or suggest the claimed methods, including the labeled non-blocking anti-idiotypic antibody for producing a drug depleted sample. In fact, Rajadhyaksha, Smith, and Mei are silent on an anti-idiotypic antibody in general, and while Grabert is said to disclose an anti-idiotypic antibody, this reference merely discloses an anti-idiotypic antibody for determining the presence, absence, or amount of the drug in the sample-not for drug depletion. Grabert only teaches only that the anti-idiotypic antibody has a detectible, and not a selectable, label, as claimed.
Examiner respectfully disagreed. Examiner does not use Rajadhyaksha, Smith, and Mei for the teaching of an anti-idiotypic antibody. Smith, Mei and Grabert are used to provide a concept of removing interference (i.e., drug interference in ADA assay) for the benefit of improving the sensitivity of the anti-drug antibody detection assay, because it reduces false negative and increases the drug tolerance of the anti-drug antibody in the assay (Smith in Abstract, Grabert in par(s).5, 61 and 118, and Mei in Abstract). Smith and Mei are used to provide the methods of removing the interference from the sample, for example, capturing the drug on the solid phase via a label, e.g., biotin label or magnetic label. Particularly, Mei is generic to the method of removing the protein interference from the sample by using a superparamagnetic beads coated with non-analyte binding agent and the magnetic field to separate the protein interference from the supernatants. Grabert is used to provide a specific non-analyte binding agent, e.g., anti-idiotypic antibody specific for the antibody drug, which the anti-idiotypic antibody specific for the antibody drug can be used to replace the non-analyte binding agent of Mei on the superparamagnetic bead to recognize the drug and isolate the drug interference from the sample.
Applicant argues, on page 8, that there is no motivation to make a modification by using anti-idiotype antibody taught by Grabert for the depleting an antibody drug step. Since Grabert discloses detection using labeled anti-idiotype antibody that would occur after the dissociation of the precipitated complexes, the Office has not established that Grabert necessarily teaches that the labeled anti-idiotype antibody can bind to the drug in complex with its target, as alleged. Moreover, Grabert is silent on any effect for an anti-idiotype antibody, and Rajadhyaksha, Smith, and Mei are silent on both anti-idiotype antibodies and non-blocking antibodies.
Examiner respectfully disagreed. First, Mei teaches a method of removing the protein interference from the sample by using a superparamagnetic beads coated with non-analyte binding agent. Grabert specifically teaches that a non-analyte binding agent can be an anti-idiotypic antibody specific for the antibody drug. Thus, it would have been obvious to use the anti-idiotypic antibody specific for the drug (taught by Grabert) as a substitute for the non-analyte binding agent on superparamagnetic beads in the method Mei because the anti-idiotypic antibody specific for the drug is functionally equivalent to the non-analyte binding agent.
Second, GenScript teaches that an anti-idiotypic (Anti-ID) antibody binds to the idiotype of another antibody, usually an antibody drug (see page 1). There are three main types of anti-ID antibodies based on the way they interact and detect an antibody drug. One of them is non-blocking anti-ID antibody because the antibody drug's paratope and idiotope do not overlap. Therefore, the anti-ID antibody and the antigen can simultaneously bind to the antibody drug without affecting one another's binding capability. Because of this, non-blocking anti-ID antibodies are used to detect all forms of available antibody drug (free and antigen bound). See GenScript page 2 paragraph 1.
One having an ordinary skill in the art would have been motivated to use a non-blocking anti-idiotypic antibody specific for the drug because GenScript teaches that the non-blocking anti-idiotypic antibody can bind to the drug in free form or in bound form with the target (see GenScript page 2 paragraph 1), so the drug depletion would be more efficient because the non-blocking anti-idiotypic antibody can detect all forms of the antibody drug (free and antigen bound) if there are some complexes of drug:target or drug:ADA left in the solution after acidification step.
While Grabert is silent on any effect for an anti-idiotype antibody, GenScript teaches about the effect of an anti-idiotype antibody and a non-blocking anti-idiotype antibody.
Applicant argues, on page 9 (par.2), that the claimed methods achieve improved sensitivity by using the non-blocking anti-idiotypic antibody for producing a drug depleted sample because of reduced false positive response and increased drug tolerance. Moreover, the use of a non-blocking anti-idiotype antibody versus a blocking anti-idiotype antibody in the drug depletion step resulted in significantly reduced percent inhibition in a neutralizing antibody assay. (See FIG. 3C).
Examiner respectfully disagreed. Smith, Mei and Grabert all teach that the step of removing drug interference will improve the sensitivity of the anti-drug antibody detection assay because it reduces false negative and increases the drug tolerance of the anti-drug antibody (Smith in Abstract, Grabert in par(s).5, 61 and 118, and Mei in Abstract). By using the non-blocking anti-idiotype antibody in the method of removing drug interference taught by Smith, Mei and Grabert, it would results in a predictable increased sensitivity of the anti-drug antibody detection assay because GenScript teaches that the non-blocking anti-idiotypic antibody can bind to the drug in free form or in bound form with the target, so the drug depletion would be more efficient.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CHAU N.B. TRAN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 May 19, 2026
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