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 .
Claims 5, 12, 18-19, 24-108 and are cancelled.
Claims 1-4, 6-11, 13-17, and 20-23 are pending.
Applicant’s election without traverse of Group 1, claims 1-4, 6-11, 13-17, and 21-23 in the reply filed on 10/31/2025 is acknowledged.
Claims 1-4, 6-11, 13-17, and 20-23 are under examination on the merits.
Priority
This application is a CON of PCT/US2021/044704, filed 08/05/2021, which claims benefit of US Provisional Application No. 63/215,199, filed 06/25/2021, and claims benefit of US Provisional Application No. 63/062,991, filed 08/07/2020.
IDS
The information disclosure statements (IDS’) filed 06/12/2023 and 09/03/2025 have been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: “…then…” in line 2 of the wherein clause following step (e) should read “…than…”. Appropriate correction is required.
Drawings
The drawings are objected to because the color/grayscale denoting different donors is illegible because it does not clearly allow the viewer to determine which data point is associated with which donor (see exemplary figure 4, but not that the problem persists throughout the figures). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-3, 6, 10-11, 13-17, 20, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schultz et al (PLoS One. 2017 May 31;12(5):e0178544. doi: 10.1371/journal.pone.0178544.) in view of Stuber et al (The Journal of Experimental Medicine; 9 Volume 183, March 1996, 979-989) and Shindo et al (Biol Blood Marrow Transplant. 2008 Mar;14(3):268-81. doi: 10.1016/j.bbmt.2007.12.004).
Regarding claim 1, Schultz et al teach a major concern regarding treatment with biopharmaceuticals (BPs) that are therapeutic proteins (such as antibodies) is the risk of provoking an unwanted immune response, such as the development of anti-drug antibodies (ADAs). ADAs can potentially decrease the efficacy of the BPs, modify clearance, induce hypersensitivity reactions or cause severe adverse events. Regardless of how immunogenicity is triggered, it is evident that the formation of high affinity antibodies (Abs) to BPs is CD4+ T cell dependent. A T cell dependent Ab response relies on T cell recognition of protein-derived epitopes that have been taken up, processed and displayed by HLA class II on antigen presenting cells (APCs). Because of polymorphisms in the HLA class II genes, the CD4 + T cell epitopes can differ between individuals. Detection of BP-specific T cells in healthy naive donors is considered as one of the major approaches to assess immunogenicity risk (see for example, page 2 [understood by the artisan to be the propensity of a composition to elicit ADA production]). Schultz et al teach an assay where blood donations from healthy donors, from which PBMCs were purified. A fraction of the PBMCs was γ-irradiated at 3000 rads to prevent cell division to ensure that the responses seen solely are CD4+ T cell-mediated. From the remaining fraction, CD4+ T cells were isolated using a CD4+ T cell enrichment kit. CD4+ T cell purity was assessed by flow cytometry (see for example the T cell Assay Setup section of page 3). To assess T cell proliferation, 1x105 CD4+ T cells were co-cultured with 2x105 autologous PBMCs in 96-well plates in the absence or presence of BPs and control antigens (see for example, pages 3 bridging page 4). BP exposed and non-BP exposed conditions were compared and a stimulation index value (SI value) was calculated (see for example, page 4).
Schultz et al, predominantly looking at T cell proliferation/responsiveness and teaching that regardless of how immunogenicity is triggered, it is evident that the formation of high affinity antibodies (Abs) to BPs is CD4 + T cell dependent, does not teach that the CD4+ T cells are measured for CD134 (also called OX40) expression or that a count of CD4+, CD134+/OX40+ T cells are measured in the assay.
However, Stuber et al teach that in vitro studies have established that activated B cells express OX40 ligand (OX40L), a member of the tumor necrosis factor/nerve growth factor family of cytokines, and become stimulated to proliferate and secrete immunoglobulin (Ig) after cross-linking of OX40L by its counterreceptor OX40, which is expressed on activated T cells (see for example, the abstract at page 979). Stuber et al teach that T cells were analyzed for OX40 and CD4 expression using an anti-OX40 polyclonal antibody and an anti-CD4-FITC antibody for flow cytometry analysis (see for example, column 1 of page 980).
Schultz et al and Stuber et al do not teach that antigen/BP contact with T cells leads to an increase in OX40 expression/CD4+ T cells that are OX40+.
However, Shindo et al teach that CD4+OX40+ T cells with IL-2-producing potential are expected to be privileged for growth and differentiation in lymph nodes upon antigen (reading upon, in the instant case, composition/BP) presentation (see for example, the abstract).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to develop a method for determining the propensity of a composition (BP) to elicit the production of antibodies (anti-drug antibodies; also called ADAs) against the composition (BP). The artisan would have found it obvious to use art known techniques, such as flow cytometry, to look at the relative number of CD4+ OX40+ T cells in BP exposed conditions relative to BP-naïve conditions as an indicator of the BP’s propensity to elicit ADA production because the cited references teach that antigen exposure drives T cells to upregulate OX40 and that CD4+ T cells drive ADA production through their interaction with OX40L-expressing B cells, causing said B cells to produce the antibodies. Where the SI value is calculated, the artisan would have expected that a stimulation value index greater than the control (BP-naïve) SI value would indicate an increased propensity to elicit ADAs and an SI value lower than the control to be indicative of a lower propensity to elicit ADA production. This assay could be used to identify BPs with less immunogenic epitopes or to personalized a therapy for a particular patient to select for a BP less likely to elicit ADA production in that patient for personalized medicine. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 2, Schultz et al teach that an SI value above 2 was defined a positive response, which is equivalent to other similar studies that have defined their SI cut-off value ranging from 1.8 to 3 (see for example, page 12). Note that the reference/reference value stimulation index value/reference stimulation index value is never provided with a clear and closed definition. The closest description is provided at lines 20-26 of page 4 of the instant specification, which states that the reference SI value may be about 1-4 or about 1.8 or greater. In light of this description and absent a preclusive definition, the teachings of Schultz are deemed to meet the claim limitations as drafted.
Regarding claim 3, ‘about’ is never provided with a closed and clear definition. The closest description is provided at page 10 bridging page 11 of the instant specification provides that about “…can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation, per the practice in the given value. Where particular values are described in the application and claims, unless otherwise stated the term "about" can mean an acceptable error range for the particular value, such as ±10% of the value modified by
the term "about." The teaching of Schultz et al that an SI value above 2 was defined a positive response, which is equivalent to other similar studies that have defined their SI cut-off value ranging from 1.8 to 3 (see for example, page 12) is deemed to meet the instant claim limitation because 2 is greater than 1.8 and, alternatively, is reasonably deemed to be ‘about 1.8’.
Regarding claim 6, as discussed above, Schultz et al begins with PBMCs taken from donors and purifies T cells from said PBMCs, as discussed in greater detail above, such that the lymphocytes used in Schultz et al are understood to comprise T cells.
Regarding claim 10, as discussed above, Schultz et al begins with PBMCs taken from donors. Schultz et al further teach that because of polymorphisms in the HLA class II genes, the CD4 + T cell epitopes can differ between individuals. Detection of BP-specific T cells in healthy naive donors is considered as one of the major approaches to assess immunogenicity risk (see for example, page 2 [understood by the artisan to be the propensity of a composition to elicit ADA production]). Using a single donor allows for personalized medicine, such that BPs/compositions can be screened for their propensity to elicit ADAs in that specific person, where it is known that there can be significant individual variation in CD4+ epitopes/immunogenicity. For example, Schultz et al teach that one of the donors had a very high SI value for rituximab, which skewed the result in the plot, indicating that this donor had an idiosyncratic ADA-response to rituximab, further suggesting the desirability of individual screening for personalized medical care in selectin less immunogenic treatment options (see for example, page 10 at the Responding Donors paragraph). Furthermore, the number of donors used does not clearly alter the active steps or calculations of the method and, as such, would have been expected to function as claimed with a reasonable expectation of success.
Regarding claims 11 and 13, Schultz et al do not explicitly teach the number of donors for the assay at any given time. However, they focus on the use of 26 donors who provided blood samples from which PBMCs (understood by the artisan to include lymphocytes)(see for example, page 2 and page 10 at the Responding Donors paragraph) were isolated and used. Schultz et al show the percentage of responding donors to 4 different BPs/compositions at figure 8 of page 11. Use of multiple donors allows for this type of analysis such that a composition’s immunogenicity for the general population may be more readily extrapolated to determine a gestalt risk of the composition for safety/efficacy balancing. Schultz et al further teach that Karle et al. observed that the mAbs had the ability to initiate a T cell response in 10, 14 and 20% of the donors for rituximab, adalimumab and infliximab, respectively (see for example, page 13). The use of multiple donors in the assay of Schultz et al is therefore presumed useful to avoid missing the potential of a composition/BP to elicit ADA production by increasing the likelihood that a responder in present in the donor pool and by enhancing how representative/generalizable the assay results are to the general population. The number of donors used does not clearly alter the active steps or calculations of the method and, as such, would have been expected to function as claimed with a reasonable expectation of success.
Regarding claim 14, Schultz et al teach that, to assess T cell proliferation, 1x105 CD4+ T cells were co-cultured with 2x105 autologous PBMCs in 96-well plates in the absence or presence of BPs and control antigens (see for example, pages 3 bridging page 4). The artisan, modifying the assay of Schultz et al according to Stuber et al and Shindo et al to use the number of CD4+,OX40+ T cells after BP exposure/ the number of CD4+,OX40+ T cells with no BP exposure as a measure of the propensity of a BP/composition to elicit ADA production would have further found it obvious to use the starting rations of CD4+ T cells to irradiated autologous PBMCs of Schultz et al because Schultz et al teach that this novel ration was a major point of optimization yielding increased sensitivity and reduced background (see for example, the rejection of claim1 above as well as pages 2 bridging 3 and 5 of Schultz et al).
Regarding claim 15, Shultz et al teach that the lymphocytes are cultured with KLH (30 µg/ml), CMV (2 µl/ml), infliximab, rituximab, adalimumab and natalizumab (all 45 µg/ml). The artisan would have found it obvious to use a concentration of 30-40 µg/ml of BP/composition because Shultz et al teach that this concentration is sufficient to stimulate the CD4+ T cells in the assay to determine the immunogenicity (propensity to elicit ADA production) of the BP/composition. This range is encompassed by the claimed range and therefore reads upon the claimed range, making obvious the claim as presently drafted.
Regarding claims 16-17 and 20, as discussed above, Schultz et al teach that the assay can be used to determine the immunogenicity of polypeptides, including antibodies (see for example, the caption of figure 1 at page 5). Schultz et al also suggest that smaller peptides may also be presented to T cells as antigens (see for example, page 12). Schultz et al does not explicitly limit the biological class of molecule which may be assay as the BP for immunogenicity. Therefore, absent evidence to the contrary, the artisan would have found it prima facie obvious to use the assay of Schultz et al as modified by Stuber et al and Shindo et al to assay any class of BP, including peptides, small molecules, neoantigens, antibody fragments, or antibody-drug conjugates (ADCs), for immunogenicity with a reasonable expectation of success in light of the combined references prior to the effective filing date.
Regarding claim 22, as discussed above, the combined references teach and make obvious claim 1 where Stuber et al teach that T cells were analyzed for OX40 and CD4 expression using an anti-OX40 polyclonal antibody and an anti-CD4-FITC antibody for flow cytometry analysis (see for example, column 1 of page 980). The artisan looking to modify the assay of Schultz et al to use the number of CD4+,OX40+ T cells after BP exposure/ the number of CD4+,OX40+ T cells with no BP exposure as a measure of the propensity of a BP/composition to elicit ADA production would have found it obvious to measure the number of said cells using art-known techniques, such as the flow cytometry method taught by Stuber et al.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schultz et al, Stuber et al, and Shindo et al, as applied to claims 1-3, 6, 10-11, 13-17, 20, and 22 above, in further view of Brinke et al (Front. Immunol. 8:1870. doi: 10.3389/fimmu.2017.01870).
Regarding claim 4, Schultz et al teach that the empirical threshold was based on a stimulation index (SI)>2, where SI was calculated from counts per minute (cpm)Ag/cpmbaseline or spots per well (spw)Ag/spwbaseline for ELISA.
This does not explicitly read upon the use of the percentage of cells to calculate the SI value.
However, Brinke et al teach that the stimulation index for T cells against auto antigens was calculated by % proliferating cells stimulated/% proliferating cells non-stimulated (see for example, column 2 of page 10).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have found the method of Brinke et al and the method of Schultz et al for calculating SI values to be equivalent calculations for arriving at SI value, where the use of the cpm/spw of the in the test divided by control or baseline. This would have been an obvious variant of the % cells of interest in the test divided by the % cells of interest in the control (bassline or non-stimulated), the choice between the two variations being a mere matter of choice yielding no more than predictable results. As part of determining obviousness, it is to be considered that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. (see MPEP 2141. I.)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schultz et al, Stuber et al, and Shindo et al, as applied to claims 1-3, 6, 10-11, 13-17, 20, and 22 above, in further view of Kleiveland et al (Peripheral Blood Mononuclear Cells. In: Verhoeckx K, Cotter P, López-Expósito I, et al., editors. The Impact of Food Bioactives on Health: in vitro and ex vivo models [Internet]. Cham (CH): Springer; 2015. Chapter 15. Available from: https://www.ncbi.nlm.nih.gov/books/NBK500157/ doi: 10.1007/978-3-319-16104-4_15).
Regarding claim 7, Schultz et al do not explicitly teach that 30% of more of the lymphocytes comprise T cells. However, To develop a sensitive and high throughput T cell assay we combined and optimized the current assays used by contract research organizations (CRO), including PBMC and DC:T cell assays from Antitope Ltd (EpiScreenTM), Lonza (EpiBaseTM), ProImmuneLtd (REVEAL1), EpiVax Inc. and ImmunXperts. The parameters considered were media, cell culture conditions, cell number ratio, antigen-presenting cells (APCs), culture time, bulk culture vs single well, co-stimulation, concentration, number of BP stimulations, readouts and analyses. The main novelty with the assay is the combination and ratio of purified CD4+ T cells and the use of irradiated PBMCs as APCs (see for example, the Development of a Novel T cell: PBMC Assay paragraph at the bottom of page 4). Schultz et al emphasize that the amount of CD4+ T cells added to each well can be controlled, which is needed for T cell repertoire frequency calculations (see for example, page 11).
Additionally, Kleiveland et al evidence teachings that human peripheral blood mononuclear cells (PBMCs) are isolated from peripheral blood and include lymphocytes, the lymphocyte population including 70–85 % CD3 + T cells, where the CD3 + lymphocytes are composed of CD4 + and CD8 + T cells, roughly in a 2:1 ratio (see for example, section 15.1 spanning pages 161-162).
Therefore, from a pool of donor PBMCs (see for example, page 3 of Schultz et al), the artisan would have expected 70–85 % of the lymphocyte population to comprise T cells, even without any enrichment step.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed first, because where Schulz et al teach the use of PBMCs, even without T cell enrichment, which is taught to be done and is thus presumed logically to increase the % of lymphocytes in the assay which are T cells, the artisan would have expected at least 30% of the lymphocytes to be T cells as evidenced by Kleiveland et al teaching that 70–85 % of the lymphocyte population from PBMCs are T cells. Additionally, from the teachings of Schultz et al, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to perform routine optimization of the % of lymphocytes in the assay that are T cells to make and use the claimed invention. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Routine optimization is not considered inventive and no evidence has been presented that arriving at the claimed % of lymphocytes that are T cells was anything other than routine, that the properties of the assay having the claimed % of lymphocytes that are T cells from the optimization has any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art. Optimization of parameters is a routine practice that would be obvious for the artisan to employ (see MPEP § 2144.05). The artisan would have had a reasonable expectation of success based on the cumulative disclosure the cumulative cited prior art references prior to the effective filing date.
Claim(s) 8-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schultz et al, Stuber et al, Shindo et al, and Kleiveland et al as applied to claim 7 above, in further view of Clenet et al (Sci Rep 7, 11612 (2017). https://doi.org/10.1038/s41598-017-11926-2).
Regarding claims 8-9, Schultz et al do not teach what percentage of the T cells are
CD8-. Schultz et al do teach that their assay was compared to a commonly used CD8 T cell-depleted PBMC assay as a control (see page 2 bridging 3, for example). Kleiveland et all teach that human peripheral blood mononuclear cells (PBMCs) are isolated from peripheral blood and include lymphocytes, the lymphocyte population including 70–85 % CD3 + T cells, where the CD3 + lymphocytes are composed of CD4 + and CD8 + T cells, roughly in a 2:1 ratio (see for example, section 15.1 spanning pages 161-162).
The combined references do not teach explicitly the percentage of PBMC lymphocytes that are CD8- or what percentage of CD4+ T cells are CD8-.
However, Clenet et al teach that CD4+CD8+ T lymphocytes account for 1–2% of circulating human T lymphocytes (see for example, page 1). This implicitly teaches that 99-98% of CD4+ T lymphocytes are CD8-.
Therefore, even before any enrichment for CD4+ T cells (which is taught to be done in the assay of Schultz et al) starting with PBMCs, as taught by Schultz et al, the artisan would have expected 70–85 % of the lymphocytes in the PBMCs to be CD3 + T cells, where the CD3 + lymphocytes are composed of CD4 + and CD8 + T cells, roughly in a 2:1 ratio (see for example, section 15.1 spanning pages 161-162 of Kleiveland et al), such that approximately 46.7-56.7% of the CD3+ T cells are CD4+ and 45.7-55.6% of CD3+ T cells are CD4+ and CD8- (where Schultz et al teach that 1x105 CD4+ T cells were co-cultured with 2x105 autologous PBMCs in 96-well plates in the absence or presence of BPs and control antigens (see for example, pages 3 bridging page 4) are used, the artisan would have understood that 1.89X105-2.095X105 cells in the assay would have been expected to be CD4+, CD8- T lymphocytes, representing well over 10% of the total cells or even the lymphocytes used in the assay). Therefore, approximately 65% of the CD3+ T cells from the numbers provided by Kleiveland et al would have been logically expected by the artisan to be CD8-. Enrichment of CD4+ T cells would only be expected to increase the percent of T cells that are CD8- in the assay.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because Schultz et al teach using PBMCs with CD4+ T cell enrichment, where the ration of cells is a variable for routine optimization (see for example, pages 4 and 11 of Schultz et al and See MPEP § 2144.05) and where Kleiveland et al and Clenet et al support that the artisan using PBMCs would have arrived at the instant claim limitations. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schultz et al, Stuber et al, and Shindo et al, as applied to claims 1-3, 6, 10-11, 13-17, 20, and 22 above, in further view of Yu et al (The Journal of Immunology, Volume 176, Issue 4, February 2006, Pages 2486–2495, https://doi.org/10.4049/jimmunol.176.4.2486).
Regarding claim 21 as discussed above, the combined references make obvious claim 1.
The combined references do not teach that the cells (T lymphocytes) are cultured with the BP/composition for 48 hours of less.
However, Yu et al teach that OX40 has a unique pattern of expression which is expressed on activated CD4+ T cells. The expression of OX40 on activated naive T cells peaks within 24–48 h of engagement of the TCR by peptide Ag in the context of MHC class II, and returns to baseline levels 120 h later (see for example, column 2 of page 2486).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because Schultz et al, Stuber et al, and Shindo et al teach the assay of instant claim 1 wherein the artisan, being motivated to shorten the duration of the assay (the wait time before a conclusion for general immunogenicity or for a personalized medicine determination of personal immunogenicity may be rendered) would have found it obvious to shorten the incubation period of the cells with the BP/composition to 24-48hrs because Yu et al teach that expression of OX40 on activated naive T cells peaks within 24–48 h of engagement of the TCR by peptide Ag in the context of MHC class II, which the artisan would understand to be the presentation used to present the BP/composition to the CD4+ T cell , resulting in upregulation of OX40 expression as a measure of its activation and therefore ability to participate with B cells to induce ADA production in response to the BP/composition. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schultz et al, Stuber et al, and Shindo et al, as applied to claims 1-3, 6, 10-11, 13-17, 20, and 22 above, in further view of Ito et al (J Immunotoxicol. 2019 Dec;16(1):125-132. doi: 10.1080/1547691X.2019.1604586).
Regarding claim 23, as discussed above, Schultz et al teach a major concern regarding treatment with biopharmaceuticals (BPs) that are therapeutic proteins (such as antibodies) is the risk of provoking an unwanted immune response, such as the development of anti-drug antibodies (ADAs). ADAs can potentially decrease the efficacy of the BPs, modify clearance, induce hypersensitivity reactions or cause severe adverse events. Regardless of how immunogenicity is triggered, it is evident that the formation of high affinity antibodies (Abs) to BPs is CD4+ T cell dependent. A T cell dependent Ab response relies on T cell recognition of protein-derived epitopes that have been taken up, processed and displayed by HLA class II on antigen presenting cells (APCs). Because of polymorphisms in the HLA class II genes, the CD4 + T cell epitopes can differ between individuals. Detection of BP-specific T cells in healthy naive donors is considered as one of the major approaches to assess immunogenicity risk (see for example, page 2 [understood by the artisan to be the propensity of a composition to elicit ADA production]). Schultz et al teach an assay where blood donations from healthy donors, from which PBMCs were purified. A fraction of the PBMCs was γ-irradiated at 3000 rads to prevent cell division to ensure that the responses seen solely are CD4+ T cell-mediated. From the remaining fraction, CD4+ T cells were isolated using a CD4+ T cell enrichment kit. CD4+ T cell purity was assessed by flow cytometry (see for example the T cell Assay Setup section of page 3). To assess T cell proliferation, 1x105 CD4+ T cells were co-cultured with 2x105 autologous PBMCs in 96-well plates in the absence or presence of BPs and control antigens (see for example, pages 3 bridging page 4). BP exposed and non-BP exposed conditions were compared and a stimulation index value (SI value) was calculated (see for example, page 4).
Schultz et al, predominantly looking at T cell proliferation/responsiveness and teaching that regardless of how immunogenicity is triggered, it is evident that the formation of high affinity antibodies (Abs) to BPs is CD4 + T cell dependent, does not teach that the CD4+ T cells are measured for CD134 (also called OX40) expression or that a count of CD4+, CD134+/OX40+ T cells are measured in the assay.
However, Stuber et al teach that in vitro studies have established that activated B cells express OX40 ligand (OX40L), a member of the tumor necrosis factor/nerve growth factor family of cytokines, and become stimulated to proliferate and secrete immunoglobulin (Ig) after cross-linking of OX40L by its counterreceptor OX40, which is expressed on activated T cells (see for example, the abstract at page 979). Stuber et al teach that T cells were analyzed for OX40 and CD4 expression using an anti-OX40 polyclonal antibody and an anti-CD4-FITC antibody for flow cytometry analysis (see for example, column 1 of page 980).
Schultz et al and Stuber et al do not teach that antigen/BP contact with T cells leads to an increase in OX40 expression/CD4+ T cells that are OX40+.
However, Shindo et al teach that CD4+OX40+ T cells with IL-2-producing potential are expected to be privileged for growth and differentiation in lymph nodes upon antigen (reading upon, in the instant case, composition/BP) presentation (see for example, the abstract).
Notably, step (f) only recites the active step of calculating the percentages of reactive lymphocyte donors and non-reactive lymphocyte donors. The recitations regarding the respective calculated SI values relative to a reference value do not require and active step, but are instead directed towards results obtained from practicing the active steps with encompassed or equivalent reagents.
The combined references do not teach that 30% or more of donors responding indicates a high propensity of eliciting ADA and/or that 20% or less of donors responding indicates a low propensity of eliciting ADA.
However, Ito et al, discussing in vitro human helper T cell assays to screen for antibody drug candidates for immunogenicity, teach that considering the reality of monoclonal antibody (mAb) drug development, an ADA incidence of < 10% would be acceptable, >30% would often be unacceptable, and 10–30%would require an evaluation on a case-by-case basis. Ito et al further teach that Infliximab elicited a response in 50% of healthy donors, Adalimumab elicited a response in 29.4% of healthy donors, and Abciximab elicited a response in 17.8% of healthy donors.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to optimize the cutoff points for low and high propensity to elicit AD A for antibody therapies, where optimizing cutoff points allows for optimized risk/benefit determinations. Where Schultz et al teach that the assay uses PBMCs from donors in a 96 well plate, the artisan would have found it obvious to keep the donor PBMCs separate (non-pooled) either to allow for personalized screening for personalized medicine or merely to determine the number of donors who exhibited a positive response (an increased number of CD4+, CD134_ T cells after stimulation and/or an SI value of 2 or more as taught by Schultz et al in view of Stuber et al and Shindo et al), where culturing lymphocytes form the donors in a BP/composition exposed and BP/composition naïve condition would have been understood to be desirable to allow for calculation of the SI value as taught by Schultz et al and/or to allow for observance of the change caused by the independent variable (BP/composition incubation) relative to baseline. Where the donor samples are not pooled, it is clearly possible to calculate an individual SI value for each donor, which would have been desirable to deliver personalized recommendations about the personalized propensity of a BP/composition to elicit ADA for personalized medicine. Note that the reference/reference value stimulation index value/reference stimulation index value is never provided with a clear and closed definition. The closest description is provided at lines 20-26 of page 4 of the instant specification, which states that the reference SI value may be about 1-4 or about 1.8 or greater. In light of this description and absent a preclusive definition, the teachings of Schultz et al that an SI value above 2 was defined a positive response, which is equivalent to other similar studies that have defined their SI cut-off value ranging from 1.8 to 3 (see for example, page 12) is deemed to teach and make obvious that a reference SI value of 2 or more indicates a high immunogenicity. The calculated SI value of a donor relative to the reference is passively obtained result, but the artisan would have found it obvious to place donors with an individually calculated SI value that is higher than the reference SI value of 2 in the category of responders (likely to have and ADA reaction to the BP/composition) and vice a versa. Schultz et al do teach plotting and calculating the percentage of responding donors (see for example, pages 10-11). Where Schultz et al, Stuber et al, and Shindo et al do not discuss a threshold of 20% or less of donors responding to indicate low propensity and 30%+ of donors responding to indicate high propensity, Ito et al step in to show that, while 10% or less of donors responding is considered acceptable and 30%+ of donors responding is unacceptable, several noted mAb therapies exhibit a percentage of responding donors that is intermediate between 10% and 30%, motivating the artisan to determine a lower limit between 10 and 30% at which a percentage of responding donors is still considered low propensity on a case-by-case basis (perhaps eve a disease by disease basis). Where the lower limit threshold is drawn between 10-30% is a result effective variable for the artisan to optimize so as to allow for more therapies to be given a more reflective balancing of their therapeutic benefit relative to their immunogenic risk (see MPEP § 2144.05). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references, prior to the effective filing date.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Pratt (Antibodies (Basel). 2018 May 31;7(2):19. doi: 10.3390/antib7020019; as cited on the 05/03/2023 IDS) teaches that the development of anti-drug antibodies (ADAs) following administration of biotherapeutics to patients is a vexing problem that is attracting increasing attention from pharmaceutical and biotechnology companies. This serious clinical problem is also spawning creative research into novel approaches to predict, avoid, and in some cases even reverse such deleterious immune responses. CD4+ T cells are essential players in the development of most ADAs, while memory B-cell and long-lived plasma cells amplify and maintain these responses (see the abstract, for example, at page). Additionally, Pratt teaches that the need for standardized assays utilizing predictive biomarkers of ADAs against any biologics to improve clinical decision-making has been pointed out (see for example, section 6. Prediction of Immunogenicity and Patient Outcomes at page 9 bridging 10).
Duke et al (J Pharm Innov 15, 202–218 (2020). https://doi.org/10.1007/s12247-019-09412-5) review in vitro assays for predicting T cell mediated immunogenicity.
Taraban et al (Eur J Immunol. 2002 Dec;32(12):3617-27. doi: 10.1002/1521-4141(200212)32:12<3617::AID-IMMU3617>3.0.CO;2-M. PMID: 1251654; as cited on the 07/17/2026 IDS) teaches the relative importance of CD134 (OX40) and CD137 (4-1BB) in the costimulation of CD4+ and CD8+ T cells under comparable conditions of antigenic stimulation.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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