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 .
Claim Status
Rejected Claims: 13, 21-22, 24, and 34-35
Cancelled Claims: 1-12, 14-20, 23, and 25-33
Response to Amendment
The amendment filed on 16 APRIL 2026 has been entered.
In view of the amendment to the claims, the amendment of claims 13 and 22 and the cancellation of claims 19-20, and 23 have been acknowledged.
In view of the amendment to the claims, the previous rejections under 35 U.S.C. 103 have been sustained.
Response to Arguments
Applicant’s arguments filed on 16 APRIL 2026 have been fully considered.
Applicant argues that the prior art does not teach the explicit combination of affinity matrices of protein A in a first column followed by protein G in a second column and because the prior art teaches additional types of columns, it would not be obvious to use protein A and then protein G in series and instant claim 13 is allowable (Arguments filed 16 APRIL 2026, Page 5 to Page 8, Paragraph 1, and Page 9, Paragraphs 2).
Regarding Applicant’s arguments, Afeyan teaches that protein A and protein G are known to allow different antibodies to be bound to a matrix surface (Col. 22, Lines 31-62), Konstantinov teaches protein A and protein G as exemplary capture mechanisms for chromatography columns in series (Paragraphs 0087-0088), and Tustian teaches that modifications can be made to antibodies such that protein A binding is middling for the heterodimeric antibody and the homodimeric antibody impurities have either a high affinity for protein A or a very weak affinity for protein A which allows for selective purification of the heterodimeric antibody (Paragraph 0002). Under the KSR rationale in MPEP 2141(III)(E), there are a finite number of identified, predictable solutions, with a reasonable expectation of success, because Afeyan and Konstantinov teach protein A and G for antibody binding and Tustian explicitly teaches protein A for specific substituted CH3 domain antibody purification. Assuming these limitations, the number of obvious combinations to try significantly reduces to Protein A and G, with only the order being unknown, which means four options (Protein A -> Protein A, Protein A -> Protein G, Protein G -> Protein A, or Protein G -> Protein G). Therefore instant claim 13 is not allowable.
Applicant argues, regarding instant claim 13, that Konstantinov does not teach or suggest that the first affinity matrix is capable of binding to a heterodimeric antibody and a first homodimeric antibody impurity, the first affinity matrix is not capable of substantially binding to a second homodimeric antibody impurity, the second affinity matrix is capable of binding to the second homodimeric antibody impurity, and the heterodimeric antibody has a lower affinity to the first affinity matrix than the first homodimeric antibody impurity as well as the newly added limitation of "the heterodimeric antibody comprises a first immunoglobulin CH3 domain and a second immunoglobulin CH3 domain ...the second immunoglobulin CH3 domain comprises H435R and Y436F amino acid substitutions” and so instant claim 13 is allowable (Arguments filed 16 APRIL 2026, Page 8, Paragraph 2).
Regarding Applicant’s argument, Konstantinov teaches the same structure of protein A and protein G as the system of instant claim 13. Tustian and the instant specification, as mentioned in the previous argument, teach that the protein A matrix and the protein G matrix are not actually modified to change the binding of the antibody to the matrix. Instead, the antibody is substituted such that the binding changes to protein A based upon the number of substituted CH3 domains versus original CH3 domains the antibody contains. Therefore, the prior art is capable of binding in the same manner as instant claim 13 and the newly amended limitations simply pertain to articles or material worked upon by the system and are not patentable limitations. The inclusion of material or article worked upon by a structure being claimed does not impart patentability to the claims (In re Young, 75 F.2d 996, 25 USPQ 69 (CCPA 1935) and thus holds no patentable weight. See MPEP §2115. Therefore, instant claim 13 is not allowable. If Applicant wished to differentiate the structure of the instant claims from the prior art, the inclusion of specific ligands/functional groups that have been modified on protein A or protein G would be necessary. Stating that the binding differences are due to the antibody structure appears to state that standard protein A and protein G matrices can be used and that the antibody is the inventive concept rather than the chromatography system.
Applicant argues that Tustian does not teach that the second affinity matrix is configured to bind to the second homodimeric antibody impurity, despite teaching that protein G and protein L may also be used for affinity chromatography, because Tustian only teaches examples with two protein A columns in series and no motivation to combine protein A and protein G. Therefore, instant claim 13 is allowable (Arguments filed 16 APRIL 2026, Page 8, Paragraph 3 and Page 9, Paragraph 3).
Regarding Applicant’s argument, the motivation to combine protein A and protein G columns in series comes from Konstantinov in that the combination of capture mechanisms is known to increase the percentage of recovery of recombinant therapeutic proteins (Paragraph 0213) under which bispecific heterodimeric antibodies are classified. Furthermore, Afeyan and Tustian both teach that specifically proteins A and G are well known matrices for chromatography antibody purification systems. Due to the wide variety of different antibodies and chromatography systems, there is naturally going to be a number of well-known starting materials based on the antibodies that one wishes to capture. While specific methods may be unknown, the use of standard chromatography materials in instant claim 13, such as a column of protein A followed by a column of protein G in a system, is not patentable over the current prior art.
Applicant argues that none of the prior art teaches the limitations of “a first mobile phase that contains a chaotropic agent having a pH of about 5.6 to about 7.4; a second mobile phase that contains a chaotropic agent having a pH of about 4.3 to about 5.6; and a third mobile phase that contains a chaotropic agent having a pH of about 2.0 to about 2.8” and so instant claim 13 is allowable (Arguments filed 16 APRIL 2026, Page 9, Paragraph 4).
Regarding Applicant’s argument, Tustian teaches a series sequential elution buffers having a pH gradient run from pH 6 to pH 2.5 in which the buffer contains a chaotropic agent where a first buffer is at a pH 7.2 (i.e., a first mobile phase that contains a chaotropic agent having a pH of about 5.6 to about 7.4; Paragraph 0020) and a sequential downward gradient of the range of pH 6 to 2.5 would encompass a second and third pH within the claimed pH ranges of 4.3 to 5.6 and 2.0 to 2.8 (i.e., a second mobile phase that contains a chaotropic agent having a pH of about 4.3 to about 5.6, a third mobile phase that contains a chaotropic agent having a pH of about 2.0 to about 2.8; Paragraph 0020). Therefore instant claim 13 is not allowable.
Applicant argues that instant claims 21-22, 24, and 34-35 are allowable because they depend upon instant claim 13 and instant claim 13 is allowable (Arguments filed 16 APRIL 2026, Page 9, Paragraph 5).
Regarding Applicant’s argument, instant claim 13 is not allowable and so instant claims 21-22, 24, and 34-35 are also not allowable.
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.
Claims 13, 21-22, 24, and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Afeyan et al US Patent No. 6344172 B1 (hereinafter Afeyan), in view of Konstantinov et al US Patent No. 20140255994 A1 (hereinafter Konstantinov), in view of Tustian et al US Patent No. 20160024147 A1 (hereinafter Tustian).
Regarding Claim 13, Afeyan discloses a separating column unit (Fig. 3, #130) in which a two column system has an output section (Fig. 3, #135) that includes pH, conductivity, and UV or other spectral absorbance or fluorescence detectors (i.e., a detector; Col. 8, Lines 35-54), where the chromatographic matrices separate components based on a specific affinity for the matrix binding sites thereon (i.e., a chromatography system; Col. 1, Lines 30-44) for the purpose of purifying components such as antibodies (Col. 12, Lines 21-30) and for the production of a profile of a mixture representative of the nature and relative concentration of structured variants of a given solute (i.e., for quantifying an amount and purity of a components of a heterodimeric antibody in a sample comprising a mixture of the heterodimeric antibody, a first homodimeric antibody impurity, and a second homodimeric antibody impurity; Col. 2, Lines 46-63). Afeyan further teaches that a first column (i.e., a first affinity matrix; Fig. 3, #131) and second column (i.e., a second affinity matrix; Fig. 3, #132) which utilizes a six port two-position valve (i.e., one switch valve; Fig. 3, #133) which operates in conjunction with a similar valve (Fig. 3, #134) to direct fluids from an inlet valve (Fig. 3, #151) to one of the separation columns and to direct the output to the output monitoring system (i.e., each of the first affinity matrix, the second affinity matrix, and the detector are connected via the switch valve; Col. 10, Lines 8-15) where the column is operated such that after a sample is provided through the separation column, solvent flow may be varied to perform the steps of washing (i.e., the chromatography system is configured such that the sample is applied to the first affinity matrix and a series of washes is applied; Col. 1, Lines 1-7). Afeyan further discloses that a three valve, two column apparatus (Fig. 3) can be configured such that the input goes to the top of the first column (Fig. 3, #131), the output to the top of the second column (Fig. 3, #132), and then output to the detector in the output section (Fig. 3, #135), among other configurations (i.e., wherein the switch valve is configured to allow an eluent to flow from the first affinity matrix to the second affinity matrix and, subsequently, to the detector; Fig. 5; Col. 10, Lines 16-27). Afeyan also discloses a configuration of the valves in which the valve (Fig. 3, #133) is in state 2 and the other valve (Fig. 3, #134) is in state 2 such that only the first column is on-line and flows directly to the output section (i.e., or to be switched to another position to allow eluent to flow from the first affinity matrix directly to the detector, bypassing the second affinity matrix; Fig. 5; Col. 10, Lines 16-27). Afeyan further teaches that protein A (i.e., an affinity matrix comprising protein A) or protein G (i.e., an affinity matrix comprising protein G) may be covalently bound to the matrix surface for the purpose of allowing multiple different solute specific antibodies to be bound to the matrix in turn (Col. 22, Lines 31-62) and that a mixture is first passed through a column capable of separating components in the mixture (Col. 18, Lines 57-63) and then a method of passing different samples of a first effluent through a second column capable of selectively extracting different solutes of interest (Col. 19, Lines 47-65).
Afeyan does not explicitly teach that a first affinity matrix comprises protein A and a second affinity matrix comprises protein G.
However, Konstantinov teaches that the columns in a multi-chromatography column system are known in the art that contains a first column with a protein A-binding capture mechanism (i.e., a first affinity matrix comprises protein A; Paragraph 0088) and a second column with a protein G-binding capture mechanism and that it is known to combine different resins (i.e., a second affinity matrix comprises protein G; Paragraph 0094). Konstantinov teaches that the processes can result in an increased percentage of recovery of the recombinant therapeutic protein (Paragraph 0213).
Konstantinov is analogous to the claimed invention because it pertains to multi-column chromatography systems to continuously produce therapeutic protein drug substances (Paragraph 0004). It would have been obvious to one of ordinary skill in the art to use the protein A affinity matrix and protein G affinity matrix taught by Afeyan together as taught by Konstantinov because the two different protein matrices would result in an increased antibody recovery.
Afeyan in view of Konstantinov does not explicitly teach wherein the first affinity matrix is capable of binding to a heterodimeric antibody and a first homodimeric antibody impurity, the first affinity matrix is not capable of substantially binding to a second homodimeric antibody impurity, the second affinity matrix is capable of binding to the second homodimeric antibody impurity, and the heterodimeric antibody has a lower affinity to the first affinity matrix than the first homodimeric antibody impurity and a first mobile phase that contains a chaotropic agent having a pH of about 5.6 to about 7.4, a second mobile phase that contains a chaotropic agent having a pH of about 4.3 to about 5.6, a third mobile phase that contains a chaotropic agent having a pH of about 2.0 to about 2.8. Afeyan in view of Konstantinov does not teach the heterodimeric antibody comprises a first immunoglobulin CH3 domain and a second immunoglobulin CH3 domain, said first and second immunoglobulin domains are different in their affinity to the first affinity matrix, the first homodimeric antibody impurity comprises two of the first immunoglobulin CH3 domains, and the second homodimeric antibody impurity comprises two of the second immunoglobulin CH3 domains, the second immunoglobulin CH3 domain comprises H435R and Y436F amino acid substitutions.
However, Tustian teaches the isolation of a heterodimer (i.e., heterodimeric antibody) from a mixture of homodimers via affinity chromatography (Paragraph 0001) in which a second homodimer (i.e., a second homodimeric antibody impurity) is first removed from a mixture by a first affinity matrix that binds the first homodimer (i.e., first homodimeric antibody impurity) and the heterodimer (i.e., wherein the first affinity matrix is capable of binding to a heterodimeric antibody and a first homodimeric antibody impurity, the first affinity matrix is not capable of substantially binding to a second homodimeric antibody impurity; Paragraph 0014) and then the first homodimer and the heterodimer are differentially bound to the second affinity matrix such that the pH or ionic strength of solution can be passed over the affinity matrix to selectively elute each of the dimer species, where the heterodimer is released in a first pH range (i.e., the heterodimeric antibody has a lower affinity to the first affinity matrix than the first homodimeric antibody impurity; Paragraph 0017). Tustian also teaches that the second homodimer may bind to the affinity matrix and be eluted in a third pH range (i.e., the second affinity matrix is capable of binding to the second homodimeric antibody impurity; Paragraph 0007). Due to the fact that the affinity is conditional, the different antibodies have differing affinities to the affinity matrix, both higher and lower, in the different conditions and so they satisfy the requirement of the heterodimeric antibody having a lower affinity to the first affinity matrix than the first homodimeric antibody. Tustian teaches that the process is capable of good resolution among the heterodimer, the first homodimer, and the second homodimer for the purpose of commercial scale purification (Paragraph 0003).
Tustian further teaches a series sequential elution buffers having a pH gradient run from pH 6 to pH 2.5 in which the buffer contains a chaotropic agent where a first buffer is at a pH 7.2 (i.e., a first mobile phase that contains a chaotropic agent having a pH of about 5.6 to about 7.4; Paragraph 0020) and a sequential downward gradient of the range of pH 6 to 2.5 would encompass a second and third pH within the claimed pH ranges of 4.3 to 5.6 and 2.0 to 2.8 (i.e., a second mobile phase that contains a chaotropic agent having a pH of about 4.3 to about 5.6, a third mobile phase that contains a chaotropic agent having a pH of about 2.0 to about 2.8; Paragraph 0020).
Tustian further teaches that a heavy chain (Fc) can be substituted such that the CH3 domain contains H435R/Y436F (now Fc*) which reduces the binding capacity of the antibody to protein A and, during the purification of the heterodimeric bispecific antibody (FcFc*), the unsubstituted homodimer (FcFc) has high affinity to protein A, the substituted homodimer (Fc*Fc*) has low affinity to protein A, and the heterodimer (FcFc*) has an intermediate binding affinity to protein A (i.e., the heterodimeric antibody comprises a first immunoglobulin CH3 domain and a second immunoglobulin CH3 domain, said first and second immunoglobulin domains are different in their affinity to the first affinity matrix, the first homodimeric antibody impurity comprises two of the first immunoglobulin CH3 domains, and the second homodimeric antibody impurity comprises two of the second immunoglobulin CH3 domains, the second immunoglobulin CH3 domain comprises H435R and Y436F amino acid substitutions; Paragraph 0002).
Tustian is analogous to the claimed invention because it pertains to a method for purifying a specific multimeric protein from a complex mixture of proteins via affinity chromatography (Paragraph 0001). It would have been obvious to one of ordinary skill in the art to modify the chromatography columns made obvious by Afeyan in view of Konstantinov with the differentially binding affinity matrices taught by Tustian because the affinity matrices would improve the resolution among the heterodimer, the first homodimer, and the second homodimer for the purpose of commercial scale purification.
Afeyan in view of Konstantinov in view of Tustian does not teach the explicit range pH ranges of 4.3 to 5.6 and 2.0 to 2.8. However, a prima facie case of obviousness exists for claimed ranges that overlap or lie inside ranges disclosed by prior art (In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976))(See MPEP 2144.05(I)). It would have been obvious to one of ordinary skill in the art to have selected the pH ranges that correspond with the claimed ranges when experimenting with pH ranges of the eluting steps as taught by Afeyan in view of Konstantinov in view of Tustian.
Furthermore, the limitation “the heterodimeric antibody comprises a first immunoglobulin CH3 domain and a second immunoglobulin CH3 domain, said first and second immunoglobulin domains are different in their affinity to the first affinity matrix, the first homodimeric antibody impurity comprises two of the first immunoglobulin CH3 domains, and the second homodimeric antibody impurity comprises two of the second immunoglobulin CH3 domains, the second immunoglobulin CH3 domain comprises H435R and Y436F amino acid substitutions” is directed toward materials or articles worked upon by the claimed invention and is therefore not subject to patentability. The inclusion of material or article worked upon by a structure being claimed does not impart patentability to the claims (In re Young, 75 F.2d 996, 25 USPQ 69 (CCPA 1935) and thus holds no patentable weight. See MPEP §2115.
Regarding Claim 21, Tustian further teaches that the antibody is bispecific due to the distinct heavy chains (i.e., wherein the heterodimeric antibody is a bispecific antibody; Paragraph 0002).
Furthermore, the limitation “wherein the heterodimeric antibody is a bispecific antibody” is directed toward materials or articles worked upon by the claimed invention and is therefore not subject to patentability. The inclusion of material or article worked upon by a structure being claimed does not impart patentability to the claims (In re Young, 75 F.2d 996, 25 USPQ 69 (CCPA 1935) and thus holds no patentable weight. See MPEP §2115.
Regarding Claim 22, Tustian further teaches that one of the heavy chains in the heterodimeric antibody is an Fc sequence and the other is a substituted Fc sequence, called Fc*, and that the homodimeric antibodies contain FcFc or Fc*Fc* and the substituted CH3 domain contains H435R/Y436F substitutions (i.e., wherein the heterodimeric antibody comprises FcFc*, the first homodimeric antibody impurity comprises FcFc, and the second homodimeric antibody impurity comprises Fc*Fc*, wherein Fc denotes a heavy chain having an unsubstituted immunoglobulin CH3 domain and Fc* denotes a heavy chain having a substituted immunoglobulin CH3 domain, and Fc* denotes a heavy chain having a H435R/Y436F substituted immunoglobulin CH3 domain; Paragraph 0002).
Furthermore, the limitation “wherein the heterodimeric antibody comprises FcFc*, the first homodimeric antibody comprises FcFc, and the second homodimeric antibody comprises Fc*Fc*” is directed toward materials or articles worked upon by the claimed invention and is therefore not subject to patentability. The inclusion of material or article worked upon by a structure being claimed does not impart patentability to the claims (In re Young, 75 F.2d 996, 25 USPQ 69 (CCPA 1935) and thus holds no patentable weight. See MPEP §2115.
Regarding Claim 24, Afeyan further teaches, within Example 5, the use of an HPLC system followed by a UV absorbance detector for sample analysis (i.e., wherein the detector comprises an HPLC column equipped with a UV detector, a charge aerosol detector, and/or a mass spectrometer; Fig. 3, #136; Col. 30, Lines 64-67 to Col. 31, Lines 1-15).
Regarding Claim 34, Tustian further teaches that the chaotropic agent in the elution buffer includes salts comprising the cations of lithium, magnesium, and calcium and the anion is selected from chloride (i.e., wherein the mobile phase modifier is a salt buffer selected from LiCl, MgCl2 and CaCl2 buffer; Paragraph 0020).
Regarding Claim 35, Tustian further teaches that affinity chromatography can be used for binding IgG1 and IgG4 antibodies (Paragraph 0046) of human antibodies (i.e., wherein: the heterodimeric antibody is a human IgG1 or IgG4 antibody, the first homodimeric antibody impurity is a human IgG1 or IgG4 antibody, and the second homodimeric antibody impurity is a human IgG1 or IgG4 antibody; Paragraph 0045).
Furthermore, the limitation “wherein: the heterodimeric antibody is a human IgG1 or IgG4 antibody, the first homodimeric antibody impurity is a human IgG1 or IgG4 antibody, and the second homodimeric antibody impurity is a human IgG1 or IgG4 antibody” is directed toward materials or articles worked upon by the claimed invention and is therefore not subject to patentability. The inclusion of material or article worked upon by a structure being claimed does not impart patentability to the claims (In re Young, 75 F.2d 996, 25 USPQ 69 (CCPA 1935) and thus holds no patentable weight. See MPEP §2115.
Conclusion
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.
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/A.A.G./ Examiner, Art Unit 1777
/Ryan B Huang/ Primary Examiner, Art Unit 1777
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