DETAILED ACTION
Status of Application
Claims 1-44, 46, and 50-60 are pending
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
The following amendments, additions, and cancelations as submitted on 05/26/2026 are acknowledged:
Claims 45, 47, and 48 are cancelled.
Claims 1, 17-30, 37-44, and 46 are amended.
Claims 49 and 51-60 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/21/2025.
Claims 1-44, 46, and 50 are being examined.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/26/2026 and 05/26/2026 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
The previous objection of claim 46 due to the recitation of “before and/or after the cation exchange chromatography step, one or more unit operations for purifying the multispecific protein, comprising affinity chromatography, ion exchange chromatography, hydrophobic interaction chromatography column, and/or mixed-mode chromatography column” is hereby withdrawn by virtue of Applicant’s amendment.
Claim 44 is objected to due to the recitation of “wherein the sample comprises at least one product-related impurity, and at least one product-related impurity is a homodimer”. It should be amended to recite “wherein the sample comprises at least one product-related impurity, wherein said impurity is a homodimer…”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
(previous rejection, withdrawn) Claims 1-47 were previously rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly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. In view of the amendment of claims 1, 30, 37-43, 46-47, and cancellation of claims 45, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 102 (AIA )
Claims 1-3,17,30-34, 44-45, 47, and 50 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yosuke et al. (JP-2016183113 Published 10/20/2016) as evidenced by the Fisher Scientific Catalog (product No. 50-851-205, 2026) and as evidenced by Brinkmann et. al (mAbs, VOL 9, pages 182-212, 2017). The examiner will use the English translation provided when referring to specific teachings relevant to the instant claims.
Response to Arguments
Applicant’s arguments with respect to the rejection(s) of claims 1-3,17,30-34, 44-45, 47, and 50 under 35 U.S.C. 102(a)(1) have been fully considered and are persuasive. Applicant has amended claim 1, to recite “a method for purifying a bispecific antibody”, rendering the rejection of 1-3,17,30-34, 44-45, and 50 moot. In addition, the Applicant has canceled claims 45 and 47 rendering the rejections of claims 45 and 47 moot. In addition, the Applicant has canceled claims 45 and 47 rendering the rejections of claims 45 and 47 moot. Therefore, the rejections have been withdrawn.
Claim Rejections - 35 USC § 103 (AIA )
Claims 4-6, 18-20, 29, 35-43, and 48 were rejected under 35 U.S.C. 103 as being unpatentable over Yosuke et al. (JP2016183113A published 10/20/2016) as evidenced by the Fisher Catalog (product No. 50-851-205, 2026).
Claims 7-16, 21-28, and 46 were rejected under 35 U.S.C. 103 as being unpatentable over Yosuke et al. (JP2016183113A published 10/20/2016) in view of Kang et al. (WO/2018/190677 filed on 4/13/2018).
Claim 48 was rejected under 35 U.S.C. 103 as being unpatentable over Yosuke et al. (JP2016183113A published 10/20/2016) in view of Spiess et al. (The Journal of Biological Chemistry, Vol. 288, pages 26593-26593, 2013, published on 9/13/2013).
Response to Arguments
Applicant’s arguments, with respect to the rejection(s) of claims 4-6, 7-16, 18-20, 21-28, 29, 35-43, 46, and 48 under 35 U.S.C. 102(a)(1) have been fully considered and are persuasive. Applicant has amended claim 1, to recite “a method for purifying a bispecific antibody”, rendering the rejections of 4-6, 7-16, 18-20, 21-28, 29, 35-43, 46, and 48 moot. In addition, the Applicant has canceled claim 48 rendering the rejection of claim 48 moot. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Applicant’s amendment of claim 1.
(new rejection, necessitated by amendment) Claims 1-6, 17-20, 29-44, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over unpatentable over Yosuke et al. (JP-2016183113 Published 10/20/2016), hereinafter referred to as “Yosuke”, in view of Giese et al. (WO-2017218977-A2 Published 12/21/2017), hereinafter referred to as “Giese”, as evidenced by the Fisher Scientific Catalog (product No. 50-851-205, 2026), hereinafter referred to as “Fisher”, and as evidenced by Brinkmann et. al (mAbs, VOL 9, pages 182-212, 2017), hereinafter referred to as “Brinkmann”.
The teachings of Yosuke have been discussed in the 02/27/2026 office action. The evidence of Fisher and Brinkmann have also been discussed in the 02/27/2026 office action.
Yosuke teaches a method for purifying an Fc binding protein using a cation chromatography resin, wherein the method requires at least one wash with a buffer comprises 100mM of sodium chloride (page 5, paragraph 0018, line 12). Yosuke also teaches using two washes with two buffers (page 5, paragraph 0018, line 5). Yosuke teaches elution with a salt gradient that is step gradient (paragraph 0011, page 4, line 10) with an elution buffer having an NaCl concentration of 250 mM (page 5, paragraph 0019, line 1). Yosuke teaches a TOYOPEARL CM-650M cation exchange medium (Page 5, paragraph 0017, line 3) which is a resin as evidenced by Fisher. Yosuke teaches a method for purifying fc-binding proteins (Page 3, paragraph 0001, line 1) which can be a bispecific protein as evidenced by Brinkmann (page 183, right column, first paragraph). Yosuke teaches using two wash buffers to remove contaminants (page 5, paragraph 0018) and teach that at least one wash buffer comprises 150mM or less of sodium chloride (page 4, paragraph 0011, line 7). Yosuke teaches elution with a salt gradient that is step gradient (paragraph 0011, page 4, line 10) with an elution buffer having an NaCl concentration of 250 mM (page 5, paragraph 0019, line 1). Yosuke teaches a method for purifying an Fc binding protein using a cation chromatography resin, wherein the sample comes from an E.coli supernatant, which would comprise intracellular components such as amino acids, saccharides, and metabolites that are considered low molecular weight species (page 10, paragraph 0029, line 21). Yosuke teaches that the wash buffer comprises less than 150 mM of sodium chloride (page 4, paragraph 0011, line 7). Yosuke does not explicitly teach a method for purifying bispecific antibodies.
Giese teaches a method for purifying multispecific antibodies (abstract). Giese teaches that method can be used for purifying bispecific antibodies for the manufacture of a medicament for the treatment of cancer or eye disease (Page 9, [0032]). Giese teaches that method can be used for the purification of an Fc-containing heterodimeric polypeptide (Page 9, [0033]). Giese teaches that the loading buffer, the equilibration buffer, and/or the wash buffer comprises sodium chloride and/or sodium acetate (Page 34, [0153]). Giese teaches antibody loading densities greater than 10g/L (Page 35 [0158]).
Claims 1-6, and 50 as interpreted are directed in part to a method for purifying a bispecific antibody onto a cation exchange chromatography medium, wherein said method comprises (a) washing the cation exchange medium with at least one wash buffer comprising 100 - 147 mM sodium chloride, (b) eluting the bispecific protein from the cation exchange chromatography medium, wherein at least one wash buffer comprises 100-125mM, 100-105 mM, 105-147mM, 105-125mM, or 125-147mM of sodium chloride, wherein the cation exchange chromatography medium is a resin.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the cation wash conditions of Yosuke in the purification methods of Giese to purify a bispecific protein. Any concentration below 150 mM is clearly suggested by Yosuke. A person of ordinary skill in the art is motivated to use these concentrations on a chromatography resin to purify a bispecific protein because the wash conditions taught by Yosuke would remove impurities while maintaining the binding of Fc-containing bispecific antibodies to the resin. One of ordinary skill in the art has a reasonable expectation of success at arriving to these concentrations because all that is required is adjusting the amount of NaCl used in the preparation of the wash buffers. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 17 as interpreted is directed to the process of claim 1, as described above, wherein the cation exchange medium is washed with at least two buffers. Claim 18 as interpreted is directed in part to the process of claim 1 wherein the cation exchange buffer is washed with at least three wash buffers.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate and modify the cation wash steps of Yosuke in the purification methods of Giese to purify a bispecific protein. A person of ordinary skill in the art is motivated to wash with two or three wash buffers for the benefit of removing additional contaminants from the resin to purify a bispecific protein because the wash conditions taught by Yosuke would remove impurities while maintaining the binding of Fc-containing bispecific antibodies to the resin. One of ordinary skill in the art has a reasonable expectation of success at using two or three buffers to purify a bispecific protein because all that is required is adding the wash steps as taught by Yosuke to the purification of bispecific antibodies as taught by Giese, and adding additional wash steps to further purify the protein. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 19 is directed in part to the process of claim 18 wherein the cation exchange buffer is washed with at least two wash buffers, at least one of the wash buffers comprising 0-147 mM sodium chloride. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use two wash buffers having a concentration within the recited NaCl concentration range in the purification methods of Giese to purify a bispecific protein. A person of ordinary skill in the art is motivated to use these concentrations to purify a bispecific protein because they are also lower than 150 mM which can be used to remove impurities during cation exchange chromatography of Fc-binding proteins as taught by Yosuke. Any concentration below 150 mM and the use of two buffers are clearly suggested by Yosuke. A person of ordinary skill in the art would have reasonably expected that applying the known wash conditions of Yosuke to the purification of the Fc-containing bispecific antibody of Giese would likewise remove impurities. One of ordinary skill in the art has a reasonable expectation of success at arriving to using two wash buffers with this concentration range to purify a bispecific protein because all that is required is adjusting the amount of NaCl used in the preparation of the wash buffers, along with changing the amount of wash buffers used. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 20 is directed in part to the process of claim 19 wherein the cation exchange buffer is washed with at least two wash buffers, at least one of the wash buffers comprising 0-70 mM sodium chloride. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use two wash buffers having a concentration within the recited NaCl concentration range in the purification methods of Giese to purify a bispecific protein. A person of ordinary skill in the art is motivated to use these concentrations to purify a bispecific protein because they are also lower than 150mM. Any concentration below 150 mM and the use of two buffers are clearly suggested by Yosuke to remove impurities during cation exchange chromatography of Fc-binding proteins. A person of ordinary skill in the art would have reasonably expected that applying the known wash conditions of Yosuke to the purification of the Fc-containing bispecific antibody of Giese would likewise remove impurities. One of ordinary skill in the art has a reasonable expectation of success at arriving to using two wash buffers with this concentration range to purify a bispecific protein because all that is required is adjusting the amount of NaCl used in the preparation of the wash buffers. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 29 is directed in part to the process of claim 1 wherein the cation exchange medium is washed with 2.5 mM/CV of a wash buffer comprising 147 mM sodium chloride. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use two wash buffers having a concentration within the recited NaCl concentration range in the purification methods of Giese to purify a bispecific protein. A person of ordinary skill in the art is motivated to use these concentrations to purify a bispecific protein because they are also lower than 150mM which can be used to remove impurities during cation exchange chromatography of Fc-binding proteins as taught by Yosuke. Any concentration below 150 mM and the use of two buffers are clearly suggested by Yosuke. A person of ordinary skill in the art would have reasonably expected that applying the known wash conditions of Yosuke to the purification of the Fc-containing bispecific antibody of Giese would likewise remove impurities. One of ordinary skill in the art has a reasonable expectation of success at arriving to using buffers with this concentration range to purify a bispecific antibody because all that is required is adjusting the amount of NaCl used in the preparation of the wash buffers. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 30-34 as interpreted are directed to the process of claim 1, as described above, wherein the protein is eluted from the cation exchange medium by a salt gradient that is a linear or step gradient with an elution buffer that comprises 0-1 M NaCL or 70-500 mM NaCl.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to elute bispecific antibodies from a cation exchange medium by a salt gradient that is a linear or step gradient with an elution buffer that comprises 0-1 M NaCL or 70-500 mM NaCl. A person of ordinary skill in the art is motivated to apply the elution methods taught by Yosuke to elute the Fc-containing bispecific antibodies of Giese because Yosuke teaches that these elution concentrations and steps work on Fc-containing proteins. One of ordinary skill in the art has a reasonable expectation of success at arriving to using Yosuke elution methods because all that is required is adjusting the amount of NaCl used in the elution of the protein. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 44 as interpreted is directed to the process of claim 1, as described above, wherein at least one product-impurity is a homodimer, high molecular weight species, half antibody, aggregate, low molecular weight species, antibody fragment, or a light chain mis-assembly.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have one of the product-impurities mentioned in Yosuke. A person of ordinary skill in the art is motivated to incorporate the purification steps of Yosuke in the purification of bispecific antibodies as taught by Giese and expect at least one product-impurity being a low molecular weight species because Yosuke teaches that the Fc-containing protein sample comes from an E.coli supernatant with low molecular weight species and Giese teaches the purification of Fc-containing bispecific antibodies. One of ordinary skill in the art has a reasonable expectation of success at arriving to expecting that a product-impurity of bispecific antibody purification would be a low molecular weight species because low molecular weight species are known impurities that are washed out of the resin during chromatography. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 35 is directed in part to the process of claim 33 wherein at least one elution buffer comprises 125mM of sodium chloride.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to elute bispecific antibodies by using an elution buffer that comprises 125 mM of sodium chloride. A person of ordinary skill in the art is motivated to use this concentration because the choice of NaCl concentration would depend on the nature of the protein to be purified. Different proteins would elute at different NaCl concentrations depending on their charge. A person of ordinary skill in the art is motivated to using the elution methods as taught by Yosuke to elute the Fc-containing bispecific antibody of Giese because Yosuke teaches that these elution concentrations and steps work on Fc-containing proteins. One of ordinary skill in the art has a reasonable expectation of success at arriving to using Yosuke elution concentrations because all that is required is adjusting the amount of NaCl used in the preparation of the elution buffer. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 36 is directed in part to the process of claim 1 wherein at least one wash buffer and one elution buffer comprises 125mM of sodium chloride. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use a wash buffer having a concentration within the recited NaCl concentration range and to use an elution buffer that comprises 125 mM of sodium chloride in the purification methods of Giese to purify a bispecific protein. A person of ordinary skill in the art is motivated to use these wash buffer concentrations to purify a bispecific protein because they are also lower than 150 mM which can be used to remove impurities during cation exchange chromatography of Fc-binding proteins as taught by Yosuke and Giese teaches the purification of Fc-containing bispecific antibodies using chromatography. Any wash buffer concentration below 150 mM is clearly suggested by Yosuke. A person of ordinary skill in the art is motivated to use the recited elution concentration because the choice of NaCl concentration would depend on the nature of the protein to be purified. Different proteins would elute at different NaCl concentrations depending on their charge. One of ordinary skill in the art has a reasonable expectation of success at arriving to using one wash buffer and one elution buffer comprising 125mM NaCl because all that is required is adjusting the amount of NaCl used in the preparation of the wash buffers, along with adjusting the amount of NaCl used in elution buffers. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 37-40 are directed in part to the process of claim 1 wherein the cation exchange medium is loaded with 10 g/L, 10 g/L to 40g/L, 15g/L to 30g/L, and 25g/L to 40g/L of the bispecific antibody. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to load the column with 10 g/L, 10 g/L to 40g/L, 15g/L to 30g/L, or 25g/L of the bispecific antibody taught by Giese to be purified with the method taught by Yosuke. A person of ordinary skill in the art is motivated to use any of the recited concentrations because the choice of protein concentration would depend on how much purified protein is desired, the binding capacity of the resin, and the protein concentration obtained from the process that generates the protein. One of ordinary skill in the art has a reasonable expectation of success at using different protein concentrations because all that is required is adjusting the amount of resin used. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 41 is directed in part to the process of claim 1 wherein the cation exchange medium is loaded with 10g/L of the bispecific protein, washed with a wash buffer comprising 105 mM sodium chloride and eluted in a salt gradient at 8 mM/CV. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use a cation exchange medium with 10g/L of the bispecific protein, to wash the column medium with 105 mM sodium chloride and to elute in a salt gradient at 8 mM/CV to purify the bispecific antibodies taught in Giese. A person of ordinary skill in the art is motivated to use the recited protein concentrations because the choice of protein concentration would depend on how much purified protein is desired, the binding capacity of the resin, and the protein concentration obtained from the process that generates the protein. A person of ordinary skill in the art is motivated to use a salt gradient at 8 mM/CV because the choice of salt gradient would depend on the nature of the protein to be purified, the level of impurities in the sample loaded to the column, the type of resin used and the degree of purity desired. A person of ordinary skill in the art is motivated to use these concentrations because they are also lower than 150 mM. Any concentration below 150 mM is clearly suggested by Yosuke. Any protein loading concentration above 10g/L is suggested by Giese. One of ordinary skill in the art has a reasonable expectation of success at using the recited protein concentration, desired gradient, and desired NaCl concentration to purify bispecific antibodies because all that is required is adjusting the amount of resin used, the NaCl concentration of the elution buffer and the flow rate, and the amount of NaCl used in the preparation of the elution buffer. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 42 is directed in part to the process of claim 1 wherein the cation exchange medium is loaded with 15g/L to 30g/L of the bispecific antibody, washed with a wash buffer comprising 147 mM sodium chloride to purify the bispecific antibody taught in Giese. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to load the column with 15g/L to 30g/L of the protein to be purified. A person of ordinary skill in the art is motivated to use the recited concentrations because the choice of protein concentration would depend on how much purified protein is desired, the binding capacity of the resin, and the protein concentration obtained from the process that generates the protein. One of ordinary skill in the art has a reasonable expectation of success at using different protein concentrations because all that is required is adjusting the amount of resin used. A person of ordinary skill in the art is motivated to use the recited concentration because it is lower than 150 mM. Any concentration below 150 mM and the use of two buffers are clearly suggested by Yosuke. Any protein loading concentration above 10g/L is suggested by Giese. One of ordinary skill in the art has a reasonable expectation of success at using different protein concentrations with two wash buffers comprising the desired amount of NaCl, because all that is required is adjusting the amount of resin used and the amount of NaCl used in the preparation of the wash buffers. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 43 is directed in part to the process of claim 1 wherein the cation exchange medium is loaded with 25g/L to 40g/L of the bispecific antibody, washed with a wash buffer and an elution buffer comprising 125 mM sodium chloride. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to load the column with 25g/L to 40g/L of the protein to be purified. A person of ordinary skill in the art is motivated to use the recited concentrations because the choice of protein concentration would depend on how much purified protein is desired, the binding capacity of the resin, and the protein concentration obtained from the process that generates the protein. A person of ordinary skill in the art is motivated to use the recited concentration because it so lower than 150 mM. Any concentration below 150 mM are clearly suggested by Yosuke. Any protein loading concentration above 10g/L is suggested by Giese. One of ordinary skill in the art has a reasonable expectation of success at arriving to using different protein concentrations and wash buffers with the recited concentration, because all that is required is adjusting the amount of resin used and NaCl used in the preparation of the wash buffers. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
(new rejection, necessitated by amendment) Claims 7-16, 21-28, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Yosuke et al. (JP-2016183113 Published 10/20/2016), hereinafter referred to as “Yosuke”, in view of Giese et al. (WO-2017218977-A2 Published 12/21/2017), hereinafter referred to as “Giese”, as applied to claim 1 above, and in further view of Kang et al. (WO/2018/190677 filed on 4/13/2018), hereinafter referred to as “Kang”.
The teachings of Yosuke have been discussed above. Yosuke does not explicitly teach a method for purifying bispecific antibodies or the use of a buffer comprising acetate. The teachings of Giese have been discussed above.
The teachings of Kang have been discussed in the previous 02/27/2026 office action. Kang teaches purifying antibodies using buffers with other salts including, but not limited to, NaCl (page 6, paragraph 64) and different chromatography steps (page 9, paragraph 94, line 2). Kang teaches a protein purification process with the use of acetate wash buffers to wash the column medium (page 6, paragraphs 57-63). Kang teaches a protein purification process with the use of acetate wash buffers to wash the column medium, pH 4.5-5.2 (page 9, paragraph 93, Table 1). Kang teaches a protein purification process with the use of acetate wash buffers to remove impurities from the column medium (page 9, paragraph 93, Table 1). Kang teaches the use of affinity chromatography before cation exchange chromatography to obtain high purity antibody fragments (page 9, paragraph 94, line 2).
Claims 7-11 are directed in part to the process of claim 1 having at least one wash buffer that comprises acetate, wherein the acetate pH is 5.0 ±0.05% to pH 5.0 ±0.1%, pH 4.91-5.1, 4.9, 5.0, or 5.1 and the concentration of acetate is 100mM . It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use wash buffers comprising acetate with the recited pHs and concentration. A person of ordinary skill in the art is motivated to modify the methods in Yosuke and Giese to incorporate acetate to widen the range of impurities removed from the column medium beyond what could be removed with sodium chloride. One of ordinary skill in the art has a reasonable expectation of success at arriving to using acetate at the recited pHs and concentration in cation exchange chromatography because all that is required is adding another column medium preparation step to the method used in Yosuke and Giese to remove different impurities during the purification of bispecific antibodies. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 12-16 are directed in part to the process of claim 1 wherein at least one wash buffer comprises acetate, and 100-125mM, 100-105mM, 105-147mM, 105-125mM, or 125-147mM of NaCl. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use wash buffers comprising acetate with the recited NaCl concentrations. A person of ordinary skill in the art is motivated to use these concentrations because they are also lower than 150 mM. Any concentration below 150 mM is clearly suggested by Yosuke to remove impurities for the purification of Fc-containing proteins. A person of ordinary skill in the art is motivated to modify the method in Yosuke and Giese, and incorporate acetate to widen the range of impurities removed from the column medium beyond what could be removed with sodium chloride alone. One of ordinary skill in the art has a reasonable expectation of success at arriving to these NaCl concentrations with the addition of acetate because all that is required is adjusting the amount of NaCl used in the preparation of the wash buffers in addition to acetate to remove different impurities. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 21-28 are directed in part to the process of claim 1 wherein the cation exchange medium is washed with at least two wash buffers, at least one wash buffer comprising acetate, 0 mM sodium chloride, followed by a wash buffer comprising acetate and different concentrations of sodium chloride. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the recited number of wash buffers having the recited NaCl concentrations with acetate to purify the bispecific antibodies taught in Giese. A person of ordinary skill in the art is motivated to use these concentrations because they are also lower than 150 mM. Any concentration below 150 mM is clearly suggested by Yosuke. A person of ordinary skill in the art is motivated to modify the method in Yosuke and Giese, and incorporate acetate to widen the range of impurities removed from the column medium beyond what could be removed with sodium chloride alone. One of ordinary skill in the art has a reasonable expectation of success at arriving to these NaCl concentrations with the addition of acetate because all that is required is adjusting the amount of NaCl used in the preparation of the wash buffers in addition to acetate to remove different impurities. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 46 is directed in part to the process of claim 1 further comprising, before and/or after the cation exchange chromatography step, one or more unit operations for purifying the bispecific protein, comprising affinity chromatography, ion exchange chromatography, hydrophobic interaction chromatography column, and/or mixed-mode chromatography column. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the additional affinity chromatography in Kang before the chromatography methods in Yosuke and Giese. It is suggested by Kang to use affinity chromatography before cation exchange chromatography. A person of ordinary skill in the art is motivated to use another form of chromatography for the benefit of increasing the purity of the protein. One of ordinary skill in the art has a reasonable expectation of success at using another form of chromatography because all that is required is adding an additional chromatography step to the method of Yosuke and Giese. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is in condition for allowance
THIS ACTION IS MADE FINAL. 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 SYNPHANE SHELTON whose telephone number is (571)272-6318. The examiner can normally be reached 8:30am-6pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. /S.L.S./Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652
Prosecution Insights