DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Claims 1, 3, 5-13, 15 and 17-25 are pending.
Claims 5, 6, 11, 15 and 17 have been withdrawn.
Claims 1, 3, 7-10, 12, 13 and 18-25 are currently under examination.
Priority
The disclosure of the prior-filed application, Application No. 17/245,271, fails to
provide adequate support or enablement in the manner provided by the first paragraph
of 35 U.S.C. 112 for one or more claims of this application.
Particularly, the present claims are not supported by the prior-filed application
because the disclosure of Application No. 17/245,271 primarily involves diagnostic
assays for detecting neutralizing antibodies against therapeutic proteins and does not
disclose methods for quantifying therapeutic proteins in the presence of a competing
drug. Thus, claim 1, 3, 7-10, 12, 13 and 18-25 are hereby assigned the priority date of
May 2, 2022, the filing date of the present application.
35 USC § 112(b) rejections withdrawn
The rejections of claims 7 and 12 under 35 U.S.C. 112(b) 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in view of Applicant’s amendments to claim 1.
35 USC § 102(a1) rejections withdrawn
The rejections of claims 1, 3, 7-10, 12, 13, 18-20, 24 and 25 under 35 U.S.C. 102(a1) as being anticipated by Dengler et al (AAPS J 23:109, October 2021, IDS, cited previously) are withdrawn in view of Applicant’s amendments to claim 1.
35 USC § 103 rejections maintained
The rejection of claims 1, 3, 7-10, 12, 13, 18-20, 24 and 25 under 35 U.S.C. 103 as being unpatentable over Puszkiel et al (J Phar Biomed Anal 139:30-36, 2017, cited previously) in view of Lofgren et al (J Immunol Meth 308:101-108, 2006), Baruah et al (US 2017/0044260, published February 16, 2017) and Cortellini et al (Case Reports in Oncol Med 2018, pp 2783917, page 1-4, published March 8, 2018), de Zwart et al (Bioanalysis 8:2065-2070, 2016) in further view of Xu et al (J Immunol Meth 416:94-104, 2015) and Loo et al (US2017/0089914, published March 30, 2017) are maintained.
Puszkiel disclose measuring levels of nivolumab in an ELISA using Fc/PD-1 (target) in the presence of ipilimumab (competing drug) and the presence or absence of blocking buffer (mitigating agent) (section 2.4 on page 31; section 2.5.5 on page 32; section 3.1 on page 32). Puszkiel disclose ALP-conjugated anti-human IgG4 antibody (section 2.4 on page 31; page 35, 1st column, 2nd paragraph).
Puszkiel does not disclose that the competing drug binds the same antigen as the therapeutic protein and that the mitigating agent is an antibody
Cortellini disclose the administration of pembrolizumab followed by the administration of nivolumab to patients with melanoma.
Baruah disclose the simultaneous or sequential administration of the anti-PD-1 antibodies, pembrolizumab and nivolumab to melanoma patients (paragraphs 37,39, 41).
Lofgren disclose that therapeutic protein remain in the serum or plasma samples (page 102, 1st column). Lofgren further disclose that many of these therapeutic proteins, particularly the antibody therapeutic proteins, have a long half-life and a high concentration in the biologic system being tested (page 101, 2nd column). Lofgren disclose antibodies that bind to residual therapeutic antibodies (page 102, 1st column).
One of ordinary skill in the art would have been motivated to apply Cortellina and Baruah’s treatment of a cancer patient with pembrolizumab followed by treatment with nivolumab to Puszkiel’s method for detecting the anti-PD-1 antibody nivolumab because Cortellina, Baruah and Puszkiel disclose treatment with more than one checkpoint inhibitors. Furthermore, one of ordinary skill in the art would have been motivated to apply Lofgren’s disclosure that therapeutic antibodies have a long half-life to Cortellina, Baruah and Puszkiel treatment with a mixture of checkpoint inhibitors because Puszkiel was concerned with the concomitant use of nivolumab and ipilimumab and the interference of ipilimumab on the quantitation of nivolumab in the serum of a patient. Given that pembrolizumab binds to the same antigen as nivolumab it would be more imperative to ensure that any remaining pembrolizumab in a serum would be neutralized in order to accurately quantitate nivolumab as disclosed in Puszkiel. In addition, de Zwart discloses that co-medication with drugs having the same target antigen results in the cross-reactivity or interference in immunoassays of a therapeutic agent in serum from a patient that was previously exposed to a therapeutic that binds the same epitope (Abstract; page 2068, 2nd column to page 2069, 1st column; Figure 1).
Neither Lofgren, Cortellina, Baruah nor Puszkiel disclose a method for neutralizing the previously administered pembrolizumab when quantitating the levels of nivolumab in a serum sample from a patient.
Xu disclose that since monoclonal antibodies are dosed at high concentrations and have long half-lives they are typically present at high circulating levels in serum (page 95, 1st column). Xu disclose a pretreatment procedure for removing therapeutic antibodies prior to an assay (Abstract; page 97, 2nd column to page 99, 2nd column; Table 1).
Loo disclose anti-pembrolizumab antibodies for detecting remaining pembrolizumab in a sample prior to performing an assay (paragraphs 3-11).
One of ordinary skill in the art would have been motivated to apply Xu’s method of removing a therapeutic antibody from serum using Loo’s anti- pembrolizumab antibodies to Lofgren, Cortellina, Baruah, de Zwart, and Puszkiel method of quantitating the levels of nivolumab in serum from patients previously administered pembrolizumab because Puszkiel, de Zwart and Lofgren all disclose that residual antibodies in serum interfere with quantitating the levels of a therapeutic antibody. It would have been prima facie obvious to combine Lofgren, Cortellina, Baruah, de Zwart, and Puszkiel method of quantitating the levels of nivolumab in serum from patients previously administered pembrolizumab with Xu’s method of removing a therapeutic antibody from serum using Loo’s anti- pembrolizumab antibodies to have a method for quantifying a concentration of nivolumab in a sample, comprising contacting said sample having pembrolizumab, PD-1, an antibody that binds nivolumab, and an anti-pembrolizumab antibody and measuring a binding of nivolumab to PD-1 to quantify the concentration of nivolumab.
Applicant argues that none of the cited references, alone or combination, discloses contacting a sample having a competing drug to a therapeutic protein, a target of said therapeutic protein, a detection antibody, and a mitigating agent, as recited in claim 1. Applicant argues that Puszkiel generally discloses an ELISA method for assaying nivolumab concentration in patient plasma. In Puszkiel, levels of nivolumab are measured in an ELISA in the presence of ipilimumab and a blocking buffer. Applicant argues that the Office Action appears to equate the ipilimumab of Puszkiel with the "competing drug" recited in claim 1 and the blocking buffer of Puszkiel with the "mitigating agent". Applicant argues that the PBS-based blocking buffer of Puszkiel does not include a monoclonal antibody that is used to reduce a binding of the ipilimumab to a target of nivolumab. Applicant argues that the blocking buffer of Puszkiel is not equivalent to the claimed mitigating agent.
Lofgren discloses a study in which solid beads were used to capture a therapeutic protein and an anti-therapeutic protein within a single assay such that the beads with the therapeutic protein adhered thereto could be removed from the sample. Applicant argues that in Lofgren, a mitigating agent is not added to a sample to a reduce a binding of a competing drug to a target of a therapeutic protein. Rather, in Lofgren, beads, the formation of complexes, and subsequent dissociation is used to remove a therapeutic protein from a sample having competing molecules therein. Applicant argues that Lofgren fails to disclose the claimed mitigating agent.
Applicant argues that Xu discloses a study in which a solid phase or bead extraction was utilized, with acid dissociation, to extract anti-drug antibodies. Applicant argues that Xu explains that the anti-drug antibodies bind to biotin-drug and become immobilized to streptavidin-coated magnetic beads. The bead complexes were treated with acid so that the ADA-containing acid solution could be transferred to a new plate and subsequently neutralized. Applicant argues that in Xu, a mitigating agent is not added to a sample to a reduce a binding of a competing drug to a target of a therapeutic protein. Applicant argues that in Xu, beads, the formation of complexes, and subsequent dissociation is used to remove a therapeutic protein from a sample having
competing molecules therein. Applicant argues that Xu fails to disclose the claimed mitigating agent.
Applicant argues that Cortellini discloses a case study in which a melanoma patient was administered with sequential ipilimumab, pembrolizumab, and nivolumab. Cortellini, p. 2. Applicant argues that Cortellini is unrelated to neutralizing antibody assays and fails to disclose the claimed mitigating agent.
Applicant further argues that Zwart, Baruah, Loo, McCutcheon, and Matsuki do not cure the deficiencies of Puszkiel, Dees, Lofgren, Cortellini, and Xu discussed above.
Applicant’s arguments have been considered but are not persuasive. In response to applicant's arguments against Puszkiel, Dees, Lofgren, Cortellini, and Xu individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The interference for measuring the amount of one antibody by another antibody was known in the art. The ability to mitigate that interference was known in the art. The treatment of patients by antibodies that bind to the same target, such as pembrolizumab and nivolumab, was known in the art. The fact that antibodies have a long half-life in the blood and thus an antibody such as the anti-PD-1 antibody, nivolumab, would interfere with the determination of the concentration another anti-PD-1 antibody, such as pembrolizumab in a target-capture format was known in the art. Given that pembrolizumab and nivolumab were known to be used to treat a cancer patient, given that pembrolizumab and nivolumab both bind PD-1, one of skill in the art would know that to measure the concentration of either pembrolizumab or nivolumab in a target-capture format it would require inhibiting the binding of the anti-PD-1 antibody not being measured to PD-1. Given that anti-idiotype antibodies were known for both pembrolizumab and nivolumab it would have been obvious to neutralize the specific binding of the interfering anti-PD-1 antibody with its anti-idiotype antibodies. As discussed above, all the limitations and antibodies were known in the art and the motivation to combine the cited art was discussed above.
Puszkiel, Lofgren, and Xu all disclose interfering agents, including antibodies that may disrupt the accurate quantitation of therapeutic antibodies. Puszkiel disclose measuring levels of nivolumab in an ELISA in the presence of another therapeutic antibody, ipilimumab and used methods to prevent the interference by ipilimumab for the accurate quantitation of nivolumab. Puszkiel disclose the treatment of cancer patients with both nivolumab and ipilimumab. Puszkiel was concerned that ipilimumab would interfere with the quantitation of nivolumab in an ELISA. The ELISA used in the quantitation of nivolumab in Puszkiel had PD-1 as the target antigen for nivolumab.
Lofgren and Xu disclose that many of these therapeutic proteins, particularly the antibody therapeutic proteins, have a long half-life and a high concentration in the biologic system being tested. Xu disclose a pretreatment procedure for removing therapeutic antibodies prior to an assay with antibodies to the therapeutic proteins. Cortellini and Baruah disclose the administration of pembrolizumab followed by the administration of nivolumab to patients with cancer. de Zwart discloses that co-medication with drugs having the same target antigen results in the cross-reactivity or interference in immunoassays of a therapeutic agent in serum from a patient that was previously exposed to a therapeutic that binds the same epitope (Abstract; page 2068, 2nd column to page 2069, 1st column; Figure 1).
Given that it was known that pembrolizumab and nivolumab are routinely used together to treat cancer patients, given that it was known that antibodies have a long half-life in the patients, given that de Zwart discloses that co-medication with drugs having the same target antigen results in the cross-reactivity or interference in immunoassays of a therapeutic agent in serum from a patient that was previously exposed to a therapeutic that binds the same epitope, given that pembrolizumab and nivolumab bind the same antigen, PD-1, it would have been prima facie obvious to use anti- idiotype, anti-pembrolizumab antibodies to remove or neutralize pembrolizumab from a patient’s serum sample to have a method for quantitating levels of nivolumab in a patient’s serum sample in a ligand binding ELISA. Pembrolizumab would be the competing antibody while nivolumab would be the therapeutic protein. The target would be PD-1 which would be attached to a surface and used in an ELISA to detect nivolumab. The mitigating agent would be the anti- pembrolizumab antibodies which could be used with Xu’s method to remove pembrolizumab from the patient’s sample or added directly to the sample to block binding of the pembrolizumab to PD-1 in the ligand binding assay for quantitating levels of nivolumab.
In response to Applicant’s argues that Xu, a mitigating agent is not added to a sample to a reduce a binding of a competing drug to a target of a therapeutic protein it would have been obvious to added coated beads to a sample and then remove the beads prior to quantitating the therapeutic antibody, nivolumab, Xu is primarily used to disclose that Xu disclose that since monoclonal antibodies are dosed at high concentrations and have long half-lives they are typically present at high circulating levels in serum (page 95, 1st column). Furthermore, given that the anti-pembrolizumab antibody would be an anti-idiotype antibody adding the anti-pembrolizumab antibody would prevent the binding of pembrolizumab to PD-1 and not interfere in the quantitation of nivolumab.
The rejections of claims 1-4, 7-10, 12, 13 and 18-25 under 35 U.S.C. 103 as being unpatentable over Puszkiel et al (J Phar Biomed Anal 139:30-36, 2017, cited previously) in view of Lofgren et al (J Immunol Meth 308:101-108, 2006, cited previously), Baruah et al (US 2017/0044260, published February 16, 2017, cited previously), Cortellini et al (Case Reports in Oncol Med 2018, pp 2783917, page 1-4, published March 8, 2018, cited previously), de Zwart et al (Bioanalysis 8:2065-2070, 2016, cited previously), Xu et al (J Immunol Meth 416:94-104, 2015, cited previously) and Loo et al (US2017/0089914, published March 30, 2017, cited previously) in further view of view of Dees et al (US 2010/0285490.published November 11, 2010, cited previously) are maintained.
Neither Puszkiel, Lofgren, Baruah, Cortellini, de Zwart, Xu nor Loo specifically disclose a detection system that using a secondary antibody linked with a biotin moiety and a streptavidin-horseradish peroxidase detection moiety.
Dees disclose an ELISA detection system using a biotin-linked secondary antibody and horseradish peroxidase detection enzyme (paragraph 212, 335).
One of ordinary skill in the art would have been motivated to apply Dees’s detection system comprising a biotin-linked secondary antibody and a streptavidin-horseradish peroxidase to Puszkiel, Lofgren, Baruah, Cortellini, de Zwart, Xu and Loo’s method for detecting the anti-PD-1 antibody nivolumab because both Dees and Puszkiel use ELISA detection systems for measuring therapeutic proteins.
Applicant argues that Baruah, Zwart, Loo, and Dees do not cure the deficiencies of Puszkiel, Lofgren, Cortellini, and Xu discussed above.
In response, for the reasons set forth above and the reasons of record, the rejections are maintained.
NEW REJECTIONS:
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.
Claims 1, 3, 7-10, 13 and 18-25 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites that the competing drug is pembrolizumab, nivolumab, or cemiplimab. Claim 1 further recites that the therapeutic protein comprises an anti-PD-1 antibody. Claim 7-9 recite that the target is an antigen, a receptor, or a ligand, cell surface receptor or a recombinant protein. Claim 12 recites that the target is PD-1. It is not clear how the target could be anything other than PD-1, given that the competing drugs and therapeutic protein are all anti-PD-1 antibodies.
In addition, claim 1 recites “measuring a second binding of said therapeutic protein to said target in an absence of said mitigating agent”. However, claim 1 also recites “contacting said sample having a competing drug to said therapeutic protein, a
target of said therapeutic protein, a detection antibody, and a mitigating agent, wherein said mitigating agent includes a monoclonal antibody that reduces a binding of said competing drug to said target of said therapeutic protein”. Thus claim 1 does not recite contacting said sample having a competing drug to said therapeutic protein, a
target of said therapeutic protein, a detection antibody in the absence of a mitigating agent.
In addition, claim 1 recites “based on a comparison of the first binding to the second binding, quantifying to quantify the concentration of said therapeutic protein”. However, quantifying the concentration of the first anti-PD-1 antibody would not require such a comparison. The concentration of the first anti-PD-1 antibody could be established in the presence of anti-idiotype antibodies to other previously administered anti-PD-1 antibodies.
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.
Claims 1, 3, 7-10, 12, 13 and 18-25 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter 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. This is a new matter rejection.
The specification as filed does not have support for the limitation “comparing the first binding to the second binding; and based on a comparison of the first binding to the second binding, quantifying to quantify the concentration of said therapeutic protein”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
Claims 1, 3, 7-10, 12, 13, 18-20, 24 and 25 are rejected under 35 U.S.C. 103(a) as being unpatentable over Dengler et al (AAPS J 23:109, October 2021, IDS, cited previously).
Dengler disclose quantifying the anti-PD-1 antibody cemiplimab in the presence of pembrolizumab or nivolumab and anti- pembrolizumab or anti- nivolumab antibodies in a target-capture immunoassay (page 3, 1st column to page 6, 1st column; Figs. 1, 3). Dengler disclose that analysis of in vitro serum samples spiked with therapies including cemiplimab, pembrolizumab, and nivolumab established that both pembrolizumab and nivolumab could be detected in the target-capture cemiplimab drug concentration assay (page 2, column 2; page 4, 2nd column). Dengler disclose that a strategy to minimize cross-reactivity of pembrolizumab and nivolumab in the cemiplimab ELISA is to use anti-idiotypic antibodies to block binding of the other therapeutic mAbs to PD-1 on the plate (Id). Dengler demonstrated that the addition of antibodies specific to either pembrolizumab or nivolumab could block detection of the drugs in the assay, thus providing a potential strategy to mitigate this cross-reactivity (Id). Dengler disclose that mock serum samples were created by spiking serum with cemiplimab, pembrolizumab, and nivolumab (Id). Dengler demonstrates the anti-idiotypic blocking antibodies specifically inhibited binding of the corresponding drug to PD-1 on the plate diminishing detection in the cemiplimab ELISA (Fig. 3b through d). Dengler disclose that the anti-idiotypic antibodies did not cross-react or interfere with quantification of the other mAbs in the assay. Dengler also disclose that their strategy could also be used to confirm the identity of any anti-PD-1 mAb in baseline clinical samples from patients previously treated with an anti-PD-1 mAb (Id). Dengler disclose that baseline samples collected from patients with prior anti-PD-1 exposure to either pembrolizumab or nivolumab were analyzed in the presence and absence of each of the three anti-idiotypic antibodies (Fig. 3e). Dengler disclose that the assay signal was markedly inhibited (greater than 80%) by only the anti-idiotypic antibody that corresponded to each patient’s anti-PD-1 medication history (Id). Thus, Dengler discloses a method for quantifying a concentration of an anti-PD-1 antibody in a sample, comprising contacting the sample having a second anti-PD-1 antibody, a PD-1 protein, a detection antibody, and anti-idiotype antibody to the second anti-PD-1 antibody and measuring the binding of the first anti-PD-1 antibody to PD-1 in the presence of the anti-idiotype antibody to the second anti-PD-1 antibody. Dengler does not directly compare the binding of the first anti-PD-1 antibody in the presence and absence of anti-idiotype antibodies to the other administered anti-PD-1 antibodies but does indirectly disclose measuring levels of cemiplimab in the presence and absence of anti-idiotype antibodies to pembrolizumab, and nivolumab (Figure 3a). It would have been obvious to compare the concentrations of the anti-PD-1 antibodies in the presence of anti-idiotype antibodies to other anti-PD-1 antibodies. This could be done mentally by looking at Figure 3a. By measuring levels of binding to cemiplimab in the presence and absence of the anti-idiotype antibodies to cemiplimab, pembrolizumab, and nivolumab, one could determine the relative concentrations of pembrolizumab, and nivolumab in the serum of a patient.
In addition, Dengler disclose biotin linked to horseradish peroxidase to quantify concentrations of cemiplimab. Dengler discloses further discloses determining the percent inhibition of binding measuring the baseline clinical samples with detectable responses in the cemiplimab ELISA from patients with prior exposure to pembrolizumab or nivolumab were evaluated in the presence of each of the three anti-idiotypic antibodies to demonstrate specific signal inhibition
Applicant argues that Dengler generally relates to a method of detecting a presence of antibodies, such as pembrolizumab and nivolumab, in a target-capture cemiplimab drug concentration assay. Applicant argues that cemiplimab is quantified in the presence of pembrolizumab or nivolumab and anti-pembrolizumab or anti-nivolumab antibodies in the assay. Applicant argues that Dengler does not disclose comparing a binding of a therapeutic protein to a target in a presence of a mitigating agent with a binding of the therapeutic protein to the target in an absence of the mitigating agent to quantify a concentration of the therapeutic protein.
In response, Dengler does disclose measuring concentrations of cemiplimab in the presence and absence of anti-pembrolizumab or anti-nivolumab antibodies. In addition, as discussed above, it would have been obvious to compare the binding of the first anti-PD-1 antibody in the presence and absence of anti-idiotype antibodies to the other administered anti-PD-1 antibodies.
Summary
Claims 1, 3, 7-10, 12, 13 and 18-25 stand rejected
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/MARK HALVORSON/ Primary Examiner, Art Unit 1646
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