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 .
Claims 1, 3, 5, 9, 10, 13, 15, 17-23 and 25 are pending.
Claims 5, 15 and 17 have been withdrawn.
Claims 1, 3, 9, 10, 13, 18-23 and 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, claims 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35 USC § 112 rejections withdrawn
The rejections of claims 1, 3, 7-10, 12, 13 and 18-25 under 35 U.S.C. 112(a) as failing to comply with the written description requirement are withdrawn in view of Applicant’s amendments to claim 1.
35 USC § 112 rejections maintained
The rejections of claims 1, 3, 9, 10, 13, 18-23 and 25 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 maintained.
Claim 1 recites “contacting the sample comprising the competing drug to a target of the anti-PD-1 therapeutic protein, a detection antibody that directly or indirectly binds to the anti-PD-1 therapeutic protein, and an anti-idiotypic monoclonal antibody mitigating agent that binds to the competing drug comprising pembrolizumab, nivolumab, or cemiplimab.
Given that the anti-idiotype antibody binds the antigen-binding site on pembrolizumab, nivolumab, or cemiplimab and that there is no other known antigen that pembrolizumab, nivolumab, or cemiplimab binds to other than PD-1, it is unclear how the target can be any other molecule besides PD-1.
35 USC § 103 rejections maintained
The rejections of claims 1, 3, 9-10, 13, 18-20 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 proteins 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 states that The Office acknowledges that Puszkiel does not disclose the claimed mitigating agent but alleges that one of ordinary skill in the art would have arrived at the claimed mitigating agent from Xu' s purported disclosure of a pretreatment procedure for removing therapeutic antibodies prior to an assay. Applicant argues that, Xu neither discloses a mitigating agent nor the specific removal of any therapeutic protein. Applicant argues that Xu discloses the specific extraction of the analyte itself - anti-drug antibodies - for subsequent analysis, which according to Xu, "remov[es] drug and other interfering factors from human serum samples." Applicant argues that Xu reduces interference only indirectly by isolating the analyte, not by neutralizing or removing a competing drug. Applicant argues that in Xu' s method the analyte - rather than the source of interference - is targeted by the binding agent in the pretreatment procedure: "ADAs [anti-drug antibodies], dissociated from drug product, would bind to biotin-drug and were then immobilized ... Bead-complexes were then captured ... the BEAD eluate samples (25μL) ... were filtered prior to injection into a high performance liquid chromatography system." Applicant argues that Xu does not teach or suggest an anti-idiotypic monoclonal antibody mitigating agent that binds to the competing drug to reduce binding of the competing drug to the target of the therapeutic protein, as set out in claim 1.
Applicant’s arguments have been considered but are not persuasive. In response to applicant's arguments against Puszkiel 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). In addition,
a prior art reference is relevant for all its teachings, not only its examples. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (holding that both preferred and unpreferred embodiments must be considered). In addition, Applicants point to narrow embodiments which are not the sum total of information conveyed by each. Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. MPEP § 2123. In this case, Xu disclose that monoclonal antibodies are dosed at high concentrations and have long half-lives they are typically present at high circulating levels in serum and may be removed. Given that prior treatment of pembrolizumab would result in concentrations of pembrolizumab that would interfere with the quantitation of nivolumab in a PD-1 capture ELISA, it would have been obvious to remove the pembrolizumab with Loo’s anti-idiotype antibody to pembrolizumab. Puszkiel disclose measuring levels of nivolumab in an ELISA using Fc/PD-1 (target) in the presence of antibody that may interfere in their ELISA. Thus, both Puszkiel and Xu disclose that residual antibodies in serum may interfere with the quantitation of a therapeutic antibody.
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.
In addition, Applicant’s argues that modification of the primary reference, Puszkiel, as suggested by the Office would have rendered Puszkiel unsatisfactory for its intended purpose. Applicant argues that the Office alleges that one of ordinary skill in the art would have modified Puszkiel's methods of quantifying nivolumab with Xu's pretreatment procedure using Loo's anti-pembrolizumab antibodies to analyze samples from patients administered the combination treatments disclosed in Cortellini and Baruah. Applicant argues that as explained above, Xu' s pretreatment procedure binds and isolates the analyte itself for subsequent analysis and incorporating such a procedure into Puszkiel would result in isolating and analyzing a competing drug rather than quantifying the anti-PD-1 therapeutic protein ( e.g., nivolumab ), which is the objective of Puszkiel. The MPEP states that" [i ]f a proposed modification would render the prior art invention being modified unsatisfactory for its intended purpose, then there is no suggestion or motivation to make the proposed modification." In re Gordon, 733 F.2d 900 (Fed. Cir. 1984); MPEP § 2143.0l(V). Applicant argues that modification of the primary reference, Puszkiel, as suggested by the Office, would render Puszkiel unsatisfactory for its purpose.
Applicant’s argument has been considered but is not persuasive. In response to Applicant’s argument that Xu' s pretreatment procedure binds and isolates the analyte itself for subsequent analysis and incorporating such a procedure into Puszkiel would result in isolating and analyzing a competing drug rather than quantifying the anti-PD-1 therapeutic protein ( e.g., nivolumab ), which is the objective of Puszkiel, Puszkiel involved the interference of the monoclonal antibody ipilimumab that binds CTLA-4 on the quantitation of levels of nivolumab in an ELISA using Fc/PD-1 (target). Given that ipilimumab doesn’t bind PD-1, it would not directly interfere in the binding of nivolumab to it’s target, PD-1. However, a different strategy would be involved if the interfering monoclonal antibody binds the same target, as is the case for sequential treatment of a patient with pembrolizumab followed by treatment with nivolumab. One of ordinary skill in the art would readily recognize that a different procedure must be used when the interfering antibody binds the same target as the measured antibody in a ligand binding assay. Thus, one would look at Xu that disclose a pretreatment procedure for removing therapeutic antibodies prior to an assay and Loo that disclose anti-pembrolizumab antibodies. 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.
Puszkiel does not does not criticize, discredit, or otherwise discourage the solution claimed, using the anti-idiotype antibodies to pembrolizumab to remove the previously administered pembrolizumab when measuring levels of nivolumab in a ligand binding assay.
MPEP 2143.01 (I)states that
The disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention. In In re Fulton, 391 F.3d 1195, 73 USPQ2d 1141 (Fed. Cir. 2004), the claims of a utility patent application were directed to a shoe sole with increased traction having hexagonal projections in a "facing orientation." 391 F.3d at 1196-97, 73 USPQ2d at 1142. The Board combined a design patent having hexagonal projections in a facing orientation with a utility patent having other limitations of the independent claim. 391 F.3d at 1199, 73 USPQ2d at 1144. Applicant argued that the combination was improper because (1) the prior art did not suggest having the hexagonal projections in a facing (as opposed to a "pointing") orientation was the "most desirable" configuration for the projections, and (2) the prior art "taught away" by showing desirability of the "pointing orientation." 391 F.3d at 1200-01, 73 USPQ2d at 1145-46. The court stated that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." Id. In affirming the Board’s obviousness rejection, the court held that the prior art as a whole suggested the desirability of the combination of shoe sole limitations claimed, thus providing a motivation to combine, which need not be supported by a finding that the prior art suggested that the combination claimed by the applicant was the preferred, or most desirable combination over the other alternatives. Id. See also In re Urbanski, 809 F.3d 1237, 1244, 117 USPQ2d 1499, 1504 (Fed. Cir. 2016).
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.
The rejections of claims 1, 3, 9, 10, 13, 18-23 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, 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.
The rejections of claims 1, 3, 9, 10, 13, 18-20 and 25 under 35 U.S.C. 103(a) as being unpatentable over Dengler et al (AAPS J 23:109, October 2021, IDS, cited previously) are maintained.
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 is not prior art to the instant application under 35 U.S.C. 102(b)(l)(A) and 35 U.S.C. 102(b)(2)(A) because the Dengler disclosure was jointly made by common inventors with the present application (Michael Partridge and Susan Irvin) and because Dengler was published on October 4, 2021, which is one year or less before the instant application's filing date of May 2, 2022.
Applicant’s argument has been considered but is not persuasive.
Dengler has 13 authors of which Michael Partridge and Susan Irvin are two of the authors. Applicant must file a declaration under 1.130(a) indicating that Dengler is the inventors’ work.
Summary
Claims 1, 3, 9-10, 13, 18-23 and 25 stand rejected
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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