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 .
Application Status
Claims 1, 3-5, 7, 11, 22, 25-26, 31, 44-45, 49, 51-52, 54, 58, 62-63, 65, 72-73, 76, 78, 80-82, 85-86, 90-91, 93-95, 102, 109, and 112-113 are pending and examined on the merits herein.
Information Disclosure Statement
The information disclosure statement filed 12/02/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. Foreign patent documents A and D were not submitted. It has been placed in the application file, but the information referred to therein has not been considered.
Priority
Priority of the claim set is restored to 06/10/2019 for all claims in view of claim amendments.
Grounds of Rejection Withdrawn
All previous rejections of claims 4, 24, 27, 53 and 69 have been rendered moot by claim cancellation.
Previous rejection of claim 11 under 35 U.S.C. 112(d) is withdrawn in view of claim amendments.
Previous rejection of claim 22 under 35 U.S.C. 112(b) is withdrawn in view of claim amendments.
Previous rejection of claims 1, 3, 5, 7, 49, and 51 under 35 U.S.C. 102 is withdrawn in view of claim amendments.
Previous rejections of claims 22, 25-26, 31, 44-45, 52, 54, 58, 62-63, 65, 72-73, 76, 78, 80-82, 85-86, 90-91, 93-95, 102, 109, and 112-113 under 35 U.S.C. 103 are withdrawn in view of claim amendments.
Previous rejection of claims 1 and 7 under NSDP over copending application 17/596,418 is withdrawn in view of claim amendments.
Previous rejection of claims 22, 31, and 44-45 under NSDP over copending application 17/596,422 is withdrawn in view of claim amendments.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 80-81 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 80 is drawn to the method of 63, wherein the sample containing vedolizumab is derived from a mammalian cell culture following one or more chromatographic separation steps. However claim 63 already recites that the sample is derived from CHO cells, which are mammalian cells and that the sample is collected after contact with an anion exchange resin, which is a chromatographic separation step. Therefore claim 80 is not further limiting to claim 63.
Claim 81 is included in this rejection as it depends from claim 80.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
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, 3-5, 7, 11, 22, 31, 44-45, 49, 51, 113 are rejected under 35 U.S.C. 103 as being unpatented by Diluzio (US 2019/0076532 A1; cited in OA 05/29/2025), Felfoldi (US 2017/0058019 A1; cited in OA 05/29/2025) and Joshi (Biotechnology Journal, 9: 1195-1205; PTO-892).
Regarding claims 1, 3, 5, 7, 11, 22, 44-45, 49, 51, and 113, Diluzio teaches the anti-α4β7 antibody can be produced by expression of nucleic acid sequences encoding each chain in cell culture and subsequently purified (para 0137). Diluzio further teaches a method of making (claim 33) a stable formulation comprising an anti-α4β7 antibody (claim 1), wherein said antibody is vedolizumab (claim 33). Diluzio further teaches that bottles of frozen, high concentration anti-α4β7 antibody preparation (vedolizun 50 mM histidine, 125 mM arginine, 0.06% polysorbate 80, pH 6.3) are thawed at room temperature for 16-24 hours before mixing and dilution with buffer A & B for formulation (para 0199). Diluzio further teaches vector pLKTOK38D suitable for producing vedolizumab in CHO cells (Fig 5; para 0038). Diluzio further teaches that a stable anti- α4β7 antibody formulation has about 5% basic isoforms or about 10% basic isoforms as determined by CEX (para 0109). The instant specification teaches that “about” is defined as +/-5% of the value (page 25, lines 24-28) and therefore 6.3 would fall within the acceptable range for both claim 1 and claim 22.
Regarding claims 22 and 31, Diluzio further teaches purification using cation exchange chromatography (CEX) and that acidic isoforms elute before the major isoform (para 0212), it was within the skillset of one of ordinary skill in the art that the basic isoform could be quantified by determining the relative area of peaks that elute more slowly from a cation exchange (CEX) resin than a peak corresponding to the main isoform, because quantitation of protein under the peak area was well known in the art. Diluzio further teaches change in percent basic isoforms by CEX when stored at 25ºC/ 60% RH (table 16, page 23) by assessing charge heterogeneity using cation exchange chromatography (para 0103), this means the basic isoform species have a net positive charge relative to a main isoform of the anti- α4β7 antibody because the basic isoform elutes more slowly during CEX compared to the main isoform.
Regarding claim 90, Diluzio teaches a formulation of the invention is administered in an effective amount which inhibits binding of α4β7 integrin to a ligand thereof, that can be administered subcutaneously (para 0172).
Diluzio does not teach wherein the incubation is performed during purification prior to UF/DF.
Regarding claim 1, Felfoldi teaches a method for purifying an immunoglobulin from a sample comprising the immunoglobulin and at least one impurity (claim 37) and the immunoglobulin may be vedolizumab (para 0207). Felfoldi further teaches that universal large scale purification methods for protein purification end with final formulation through an ultrafiltration/ diafiltration step (para 0265; figures 1-4).
Regarding claim 1, Joshi teaches an approach based on empirical modeling and least squares regression is suggested for establishing hold times for process intermediates during production of monoclonal antibody (Mab) therapeutics (abstract). Joshi further teaches that platform processes typically involve Protein A affinity chromatography followed by low-pH elution and hold, ion-exchange chromatography, and viral inactivation (page 1196, col 1, para 3). Joshi further teaches that it has been observed that both time and pH play a significant role in formation of charged variants (Fig 3B) and further demonstrated by Fig 3A where it is seen that while there is negligible change in main peak content for the case of phosphate buffer at pH 7.5, significant changes occur with the same buffer at pH 6.5. An interesting observation made at pH 6.5 is that the main peak content first decreases and then increases with time. Upon careful review of the data it was found that during early time points, the main peak consistently decreases but after a point, the basic species reduce and convert back to the native product, thus, the basic antibody species is known to increase then decrease over time back to the main peak.
It would be obvious to one of ordinary skill in the art before the filing date of the instant application to incubate the composition comprising CHO derived anti-α4β7 antibody at a pH greater than about 6.5 for 16-24 hours prior to formulation as taught by Diluzio during the purification process as taught by Felfoldi and Joshi. The ordinary artisan would be motivated to do so as Joshi teaches an approach based on empirical modeling and least squares regression is suggested for establishing hold times for process intermediates during production of monoclonal antibody (Mab) therapeutics and further that it is known that the basic antibody species are known to increase then decrease over time back to the main peak at pH 6.5. Diluzio also teaches for a protein to remain biologically active, a formulation must preserve the conformational integrity of at least a core sequence of the protein's amino asides, while at the same time protecting, the protein's multiple functional groups from degradation. Felfoldi teaches that a method of purifying vedolizumab from impurities and ending the purification with formulation through ultrafiltration while Diluzio teaches a stable final formulation of vedolizumab. The ordinary artisan would have a reasonable expectation of success of optimizing the holds of the intermediates during purification to avoid aggregation and maintain charge variants by incubating the antibody vedolizumab at a pH about 6.5 during the purification process to reduce basic isoforms to produce a stable final formulation with a pH of 6.3 and basic isoforms of about 10%.
Claims 25-26, 52, 54, 58, 62 are rejected under 35 U.S.C. 103 as being unpatentable over Diluzio (US 2019/0076532 A1; cited in OA 05/29/2025), Felfoldi (US 2017/0058019 A1; cited in OA 05/29/2025) and Joshi (Biotechnology Journal, 9: 1195-1205; PTO-892) as applied to claims 22, 24, 27, 31, 44-45, and 113 above and further in view of Wang (US 2015/0110803 A1; cited in OA 05/29/2025) and Trappe (J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Sep 15;1095:166-176; PTO-892).
The teachings of Diluzio, Felfoldi, and Joshi are detailed above.
Diluzio, Felfoldi, and Joshi do not teach that the pharmaceutical composition comprise 2 basic isoform peaks or the specific ratios of those peaks.
Regarding claims 25-26, 52, 54, and 58, Wang teaches the present invention relates to low acidic species (AR) compositions comprising a protein, e.g., an antibody, or antigen-binding portion thereof, and methods for producing such low AR compositions using displacement chromatography (abstract) and all peaks eluting prior to the Main Isoform peak were summed as the acidic region, and all peaks eluting after the Main peak were summed as the basic region (para 0427). Figure 2 shows 2 basic species peaks after the main isoform peak for adalimumab. Wang further teaches the purification and/or pooling techniques described herein allow for modulation of the concentration of product-related substances in the purified sample, e.g., increasing or decreasing the amount of AR and/or basic species (para 0212). Wang further teaches that reduction of charge variants and/or product- or process-related impurities is particularly advantageous in the context of commercially produced recombinant biotherapeutics, as they have the potential to impact numerous product characteristics, including, but not limited to, product stability, product safety and product efficacy (para 003).
Trappe teaches that development of the optimal gradient slope, separation temperature and gradient length for each, pH and salt elution modes was performed with a view to determining the most selective and sufficiently resolved charge variant separation of NIST mAb within a reasonable analysis time (section 3.1, para 1). As seen in figure 2, the NIST antibody demonstrated multiple basic species peaks, and further in figure 3 that numerous other commercial antibodies also have multiple basic antibody species that are able to be resolved by this generic protocol. Trappe further teaches that the protocol is suitable for the analysis of in-process samples and demonstrates reproducibility of the process in Fig 4. Trappe further teaches that different cell lines and expression methods effected the charge variant profile as well as the various purification steps that the antibodies were exposed to (page 173; Fig 7).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application that the antibody composition of Diluzio, Felfoldi, and Joshi could comprise basic isoforms that produce a first basic isoform peak (BP1) and a second basic isoform peak (BP2) according to Wang and Trappe. Trappe also teaches quantification of the basic variant peaks that can be used during in process purification reproducibly and that cell culture and purification process changes effect that profile. Wang teaches that BP1 and BP2 peaks could be quantitated to determine their relative levels. Wang further teaches the purification and/or pooling techniques described herein allow for modulation of the concentration of product-related substances in the purified sample, e.g., increasing or decreasing the amount of AR and/or basic species that may be particularly advantageous in the context of commercially produced recombinant biotherapeutics, as they have the potential to impact numerous product characteristics, including, but not limited to, product stability, product safety and product efficacy. It would be within the skillset of the ordinary artisan to optimize the purification method to obtain a composition with the desired level of basic species peaks by percentage and ratio.
Claims 63, 65, 69, 72-73, 76, 78, 80-82, 91, 93-95, 102, 109, and 112 are rejected under 35 U.S.C. 103 as being unpatentable over Felfoldi (US 2017/0058019 A1; cited in OA 05/29/2025), Gagnon (BioProcess International, 4(2), 50-60; cited in OA 05/29/2025), Ichihara (MABS, 2018, 10(2):325–334; PTO-892), and Grönberg (Biopharmaceutical Processing, Ch 18, 2018; PTO-892).
Regarding claims 63, 78, 80-81, and 91, Felfoldi teaches a method for purifying an immunoglobulin from a sample comprising the immunoglobulin and at least one impurity, the method comprising the following steps in the following order: (a) exposing the sample to anion exchange chromatography and obtaining the immunoglobulin, which is not bound to the anion exchange chromatography resin, in the flow-through; (b) exposing the flow-through obtained in step (a) either to Protein A affinity chromatography, wherein the immunoglobulin is bound to the Protein A affinity chromatography resin, and obtaining the immunoglobulin in the eluate by eluting the protein from the Protein A affinity chromatography resin, or to Mixed Mode chromatography, wherein the immunoglobulin is bound to the Mixed Mode chromatography resin, and obtaining the immunoglobulin in the eluate by eluting the protein from the Mixed Mode chromatography resin; (c) incubating the eluate obtained in step (b) at low pH of 2.5 to 4.5 for a defined time wherein the method results in a cumulative log10 reduction factor for steps (a) and (c) of at least 10 with respect to enveloped viruses (claim 37). Felfoldi further teaches cation exchange chromatography was used for the ability to separate residual HCP and product-related impurities (acid (charge variants) and basic (aggregates) fractions) (para 0244). Felfoldi further teaches the immunoglobulin may be vedolizumab (para 0207). Felfoldi further teaches that in the first polishing step which is an anion exchange step in flow through mode (figure 2) that the conditions depend on the pI of the immunoglobulin (para 0150). Felfoldi further teaches in a preferred embodiment, the sample is derived from a cell culture supernatant which is obtained from recombinant CHO cell culture (para 0221). Felfoldi teaches that AEX follows protein A and cation exchange purification steps (figure 1).
Felfoldi does not teach the conductivity of the loading buffer for the AEX.
Regarding claims 63 and 65, Gagnon teaches that AEX operated in flow through mode for purification of a monoclonal IgG was done in a load buffer with a conductivity of 7.5mS/cm (page 6; Three-step inset, step 2). Gagnon further teaches that in most cases, antibodies will flow through the column during sample application. If not, conductivity may be raised to 12 mS/cm and conditions will still be within the
published range shown to remove retroviruses (page 6; Three-step inset, step 2).
Regarding claims 72, 73 and 76, Gagnon teaches equilibration and wash with buffer A: 0.05M Tris, 0.05M NaCl, pH 7.0 (page 3; AEX inset).The calculated conductivity of this buffer is tris: At 0.05 M, the conductivity is likely to be around 2.15 mS/cm combined with NaCl: At 0.05 M, the conductivity is around 2.38 mS/cm for a total conductivity of 4.53 mS/cm, which is less than 11 mS/cm.
Regarding claims 82 and 93, it would be obvious that the results would naturally flow from the method to produce in a reduction of HCP by at least 50% or to a specific measurement of ppm as all the active steps of the method are taught by references.
Regarding claims 94-95, 109, and 112, Gagnon teaches use of ceramic hydroxyapatite (CHT) that is a mixed mode chromatography technique as a secondary purification step after protein A to effectively purify most monoclonal antibodies from leached protein A and aggregates on a platform style basis (page 2, introduction). Gagnon further teaches that buffer A in the NaPO4 and NaCl elution systema have a pH 6.5 and are used as both the wash and equilibration buffer (hydroxyapatite protocol inset, page 3). Gagnon further teaches that use of a CHT column is economically compelling in that it reduces the number of process steps to be developed, validated, and run in the course of every manufacturing campaign while reducing requirements for hardware, chromatography media, buffer, and water (page 7, col 1, para 4). The ordinary artisan would understand that a pH of 6.5 is not significantly different from a pH of 6.6 regarding the process of purification.
Regarding claims 94 and 102, Gagnon teaches that traditional applications of hydroxyapatite have almost exclusively used phosphate gradients but although convenient, their use sacrifices independent control over the two dominant retention mechanisms: ion exchange and calcium affinity (page 5, col 1, last para- col 2, 2nd para). Gagnon further teaches that NaCl only affects ion exchange interactions but the phosphate required to control calcium interactions also affects electrostatic interactions, so in order to control the proportional contribution of ach mechanism a NaCl gradient can be used while maintain a constant concentration of phosphate that can be optimized to separate the IgG from its major contaminants and that phosphate concentration can be adjusted incrementally (5 mM is a practical place) (page 5, col 2-col 3). Gagnon further teaches that use of a NaCl gradient facilitates a better resolution than a phosphate gradient (figure 3 and 4).
Grönberg teaches that load conductivity, load pH, operating flow rate, and protein load are critical process parameters for AEX, that have an impact on a critical quality attribute such as purity or activity of the target protein (section 18.8, para 2, page 391). Grönberg further teaches that while the highest dynamic binding capacity (DBC) for a target protein in IEC is expected to occur at low conductivity and at a pH far away from its pI, under some conditions it has been found that unexpected behavior occurs, with capacity going through a maximum with increasing conductivity and also decreasing protein charge (section 18.10, page 392). Grönberg further teaches that careful investigation of the effect of pH and salt concentration on DBC should be undertaken in order to reveal such behavior and locate conditions for the highest binding capacity (section 18.10, 1st para, pages 392-3). Grönberg further teaches that to be able to utilize the high capacity of modern chromatography resins, investigation of binding conditions—pH and conductivity for optimal binding—is a prerequisite (section 18.11, para 2, page 395).
Ichihara teaches that the effects of pH and conductivity on HCP clearance were observed to be mAb dependent and that this may be a result of differences in HCP isoelectric points, as well as the difference of HCP concentration and populations that ultimately manifest as differences in the adsorption isotherms (discussion, para 2). Ichihara further teaches that binding capacity for a highly charged HCP may be reduced by protein-protein electrostatic repulsion at low conductivities such that an optimum HCP clearance condition may be defined with combinations of pH and conductivity (discussion, para 2).
It would be obvious to one of ordinary skill in the art before the effective filing date of the instant application to optimize the buffer conductivity for AEX and CHT as taught by Gagnon and Ichihara in the method of vedolizumab purification as taught by Felfoldi. The ordinary artisan would be motivated to do so as Gagnon teaches that the buffers should be optimized for CHT and that CHT purification yields similar results to the 3 step protocol regarding impurities and Ichihara teaches that an optimum HCP clearance condition may be defined with combinations of pH and conductivity Grönberg also teaches that careful investigation of the effect of pH and salt concentration (conductivity) on DBC should be undertaken in order to determine conditions for the highest binding capacity. Ichihara teaches that the effects of pH and conductivity on HCP clearance were observed to be mAb dependent and that optimum HCP clearance condition may be defined with combinations of pH and conductivity. It would be obvious to one of ordinary skill in the art that optimizing the buffer and reducing the number of columns would increase the yield and that this would be facilitated by optimizing the pH and conductivity of the buffers, as well as lower contaminants such as HCP. The ordinary artisan has a reasonable expectation of success in using the buffers and protocols from the 2 or 3 step protocol as published with routine optimization.
Response to Arguments
Applicant's arguments filed 12/01/2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references 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).
Applicant submits: Based on the combined teachings of Diluzio, Felfoldi, and Lan, one of ordinary skill would not have been able to predict that providing a vedolizumab composition derived from a CHO cell culture expressing vedolizumab at a pH of about 6.5-8.5 and incubating the vedolizumab composition for a period of at least 10 hours during purification and prior to formulation of vedolizumab in a pharmaceutically acceptable buffer would produce a vedolizumab composition having less than 16% basic vedolizumab isoform species.
In sum, Diluzio describes lyophilized antibody formulation storage, which is distinct from a purification method involving incubation prior to formulation, as claimed. Further, Diluzio does not teach or suggest that formulation storage would apply to a purification method. Felfoldi describes a purification process involving low pH incubation (e.g., between pH 3 and 4), which is below the claimed range. Felfoldi describes that low pH is preferred for viral inactivation. Further, Lan describes a one-minute hold at pH of at most pH 6.4, which is both a shorter period of time and below the claimed pH range. Thus, one of ordinary skill would not arrive at the claimed methods based on the combined teachings of Diluzio, Felfoldi and Lan, as none of the references teach or suggest that the claimed combination of a pH between about 6.5-8.5 and an incubation period of at least 10 hours would provide an unexpected result, i.e., an vedolizumab composition having less than 16% basic vedolizumab isoform species.
In response: Diluzio also teaches incubation prior to formulation as addressed in the new rejection detailed above.
Contrary to the argument that the ordinary artisan could not have a reasonable expectation of success to achieve a reduced basic species of vedolizumab by incubating in a pH of about 6.5 or greater the teachings of new reference Joshi detailed above demonstrate that it was known in the art that at pH 6.5 the main peak consistently decreases but after a point, the basic species reduce and convert back to the native product, thus, the basic antibody species is known to increase then decrease over time back to the main peak. Therefore the ordinary artisan would have a reasonable expectation of reducing basic species by utilizing such an incubation at any point in the purification process, even at formulation.
Applicant submits: Based on the combined teachings of Diluzio, Abhyankar, Wang 2014, Khwali, and Lan, one of ordinary skill would not have been able to arrive at a low basic species composition comprising an anti-a47 antibody having less than 16% total basic isoform species of the anti-a47 antibody, and less than 2% a second basic isoform peak (BP2).
Wang 2014 is focused on using column chromatography to purify the main isoform antibody from other isoforms. (see e.g., page 2, line 29 to page 3, line 4, and the last paragraph of 4.4.4, bridging pages 33-34). However, in the Examples of the instant application, incubation conditions are used that prevent the formation of a basic isoform.
In response: The techniques for altering the charge variant profile are taught by Diluzio, Felfoldi and Joshi. Trappe and Wang further teach various factors that affect the charge variant profile including the cell line used, the expression mechanism (transient or stable), and the purification protocol. Trappe and Wang also teach methods for assessing the charge variant profile and that this process can reliably be used in process so that the ordinary artisan would be able to alter the profile as needed to obtain the desired profile.
Applicant submits: The claimed method is based, at least in part, on the discovery that charged isoform content can be impacted by controlling pH and incubation time during vedolizumab purification.
The claimed method is based, at least in part, on the discovery that HCP content can be impacted by controlling certain conditions during vedolizumab purification, such as the conductivity of the loading buffer contacted with an anion exchange resin
In response: Controlling charged isoform content was known to be affected by controlling pH and hold times for monoclonal antibody production as taught above by Joshi who teaches that it has been observed that both time and pH play a significant role in formation of charged variants.
HCP content was also known in the art to be impacted by controlling pH and conductivity of the buffers during AEX purification of monoclonal antibody as taught by Ichihara optimum HCP clearance condition may be defined with combinations of pH and conductivity.
Applicant’s arguments with respect to claim(s) 22, 24, 27, 31, 44, 45 and 113 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant submits: Based on the combined teachings of Felfoldi and Gagnon, one of ordinary skill would not have been able to predict that contacting a sample having vedolizumab and HCP with an anion exchange resin in the presence of a loading buffer having a specific conductivity range of 9 mS/cm to 11 mS/cm would provide a composition comprising vedolizumab having a reduced amount of HCP.
Gagnon teaches a loading buffer having a conductivity of 7.5 mS/cm for purifying a monoclonal IgG using AEX operated in flow through mode. Despite, contemplating an increase in conductivity, Gagnon describes that conductivity may be raised to 12 mS/cm, which is higher than the claimed conductivity. Thus, both loading buffer conductivities described by Gagnon fall outside the range of the claimed loading buffer conductivity.
There is nothing in Gagnon that would lead one of ordinary skill to the particular claimed loading buffer conductivity range of 9 mS/cm to 11 mS/cm.
In response: The argument for obviousness was drawn to routine optimization of the pH and conductivity of the buffers as taught by Gagnon. This is further supported by the teachings of Grönberg and Ichihara as detailed above.
Grönberg teaches that careful investigation of the effect of pH and salt concentration (conductivity) on DBC should be undertaken in order to determine conditions for the highest binding capacity. Ichihara teaches that the effects of pH and conductivity on HCP clearance were observed to be mAb dependent and that optimum HCP clearance condition may be defined with combinations of pH and conductivity.
Applicant submits: Based on the combined teachings of Felfoldi and Gagnon, one of ordinary skill would not have been able to predict that the use of an equilibration buffer, loading buffer, and wash buffer having a pH of 6.6 to 6.8 would provide an increased yield of vedolizumab recovered following elution from a mixed mode chromatography resin.
In response: One of ordinary skill in the art would understand that most parameters are given a margin of error, in the instant case 5% give or take, and that a pH of 6.5 is about a pH of 6.6. Even though the claim does not recite the term about, it still comes with a reasonable expectation of success of adjusting the pH from the 6.5 of Gagnon to 6.6 as recited in the claim in the purification protocol.
Further, the argument for obviousness was drawn to routine optimization of the pH and conductivity of the buffers as taught by Gagnon.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643