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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/23/2025 has been entered.
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, 19-24, and 34-35 is 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.
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).
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.
Applicant has only generically claimed “a heterodimeric antibody”, “a first homodimeric antibody impurity”, and “a second homodimeric antibody impurity” where there are no distinguishing factors for any of the antibodies. As nothing specific regarding the antibodies is claimed, and because Afeyan teaches that two columns with different matrices, possibly containing protein A and protein G, can be used to separate different solutes of interest, these specified matrices can bind to a different relative degree to each other. While Afeyan is not explicit with the differences in antibody attachment, the chromatography system with two columns that differentially capture two different solutes makes obvious the differential binding of “a heterodimeric antibody”, “a first homodimeric antibody impurity”, and “a second homodimeric antibody impurity” within the “first affinity matrix” and the “second affinity matrix”.
Regarding Claim 19, Afeyan in view of Konstantinov in view of Tustian makes obvious the chromatography system of claim 13. Tustian further teaches the application of separation involving an antibody with two distinct heavy chains in which one heavy chain has substitutions which reduces or eliminates the binding of the substituted heavy chain to Protein A and the other does not (i.e., wherein the heterodimeric antibody comprises a first immunoglobulin CH3 domain and a second immunoglobulin CH3 domain, wherein said first and second immunoglobulin CH3 domains are different in their affinity to the first affinity matrix), which causes two homodimeric antibodies, one containing two unsubstituted heavy chains (i.e., wherein the first homodimeric antibody impurity comprises two of the first immunoglobulin CH3 domains) and the other containing two substituted heavy chains (i.e., wherein the second homodimeric antibody impurity comprises two of the second immunoglobulin CH3 domains; Paragraph 0002).
Furthermore, the limitation “wherein the heterodimeric antibody comprises a first immunoglobulin CH3 domain and a second immunoglobulin CH3 domain, wherein said first and second immunoglobulin CH3 domains are different in their affinity to the protein A matrix, wherein the first homodimeric antibody impurity comprises two of the first immunoglobulin CH3 domains, and wherein the second homodimeric antibody impurity comprises two of the second immunoglobulin CH3 domains” 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 20, Afeyan in view of Konstantinov in view of Tustian makes obvious the chromatography system of claim 19. Tustian further teaches that the substituted sequence on the heavy chain is at the H435R/Y436F location in the CH3 domain (i.e., wherein the second immunoglobulin CH3 domain comprises H435R and Y436F amino acid substitutions; Paragraph 0002).
Furthermore, the limitation “wherein 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, Afeyan in view of Konstantinov in view of Tustian makes obvious the chromatography system of claim 13. 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, Afeyan in view of Konstantinov in view of Tustian makes obvious the chromatography system of claim 13. 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* (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; 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 23, Afeyan in view of Konstantinov in view of Tustian makes obvious the chromatography system of claim 22. Tustian further teaches that the heavy chain with an unsubstituted sequence is called Fc and that the heavy chain with a substituted sequence, called Fc*, is created by substituting the H435R/Y436F location in the CH3 domain (i.e., Fc* denotes a heavy chain having a H435R/Y436F substituted immunoglobulin CH3 domain; Paragraph 0002).
Furthermore, the limitation “wherein Fc* denotes a heavy chain having a H435R/Y436F substituted immunoglobulin CH3 domain” 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 in view of Konstantinov in view of Tustian makes obvious the chromatography system of claim 13. 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, Afeyan in view of Konstantinov in view of Tustian makes obvious the chromatography system of claim 13. 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, Afeyan in view of Konstantinov in view of Tustian makes obvious the chromatography system of claim 13. 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.
Response to Amendment
The amendment filed on 06/23/2025 has been entered.
In view of the amendment to the claims, the amendment of claims 13 and 34 and the cancellation of claim 33 have been acknowledged.
In view of the amendment to claim 34, the rejection under 35 U.S.C. 112(b) has been withdrawn.
In view of the amendment to claim 13 and the cancellation of claim 33, the rejection of claim 13 under 35 U.S.C. 103 has been modified to incorporate the limitations that were moved from the previous claim 33 to claim 13 and the rejection under 35 U.S.C. 103 of claim 33 has been withdrawn.
Response to Arguments
Applicant’s arguments filed on 06/23/2025 have been fully considered.
Applicant argues, regarding claim 13, that the claimed chromatography system utilizes a switch valve that allows the detector to remain online in any configuration (Arguments filed 06/23/2025, Page 5, Paragraph 8 to Page 6, Paragraph 1).
Applicant argues, regarding Afeyan et al (US Patent No. 6344172 B1) hereinafter Afeyan, that Afeyan teaches a specific method of use of the columns involving a preparative parameter being specified in the first column and specifying an analytical parameter in the second column, which is different from the instant application because the instant specification separates and analyzes with the first column and only analyzes with the second column (Arguments filed 06/23/2025, Page 6, Paragraph 2).
Applicant argues, regarding claim 13, that the prior art of 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 fails to teach the newly added limitations of claim 13 that were in the previous claim 33 that has been cancelled (Arguments filed 06/23/2025, Page 6, Paragraph 3).
Applicant argues, regarding claim 13, that Afeyan teaches the use of multiple switch valves and so the amendment of terminology from “a switch valve” to “one switch valve” causes the prior art to no longer read upon claim 13 (Arguments filed 06/23/2025, Page 6, Paragraph 4).
Applicant argues, regarding the dependent claims, that claim 13 is now allowable and so the dependent claims are also allowable (Arguments filed 06/23/2025, Page 7, Paragraph 2).
The Examiner respectfully disagrees.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a switch valve that allows the detector to remain online in any configuration) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, if a switch valve is capable of operating in the given configurations, the use of the switch valve to always align with the detector becomes an intended use of the switch valve and is thus not patentable in an apparatus claim. The manner or method in which an apparatus is to be utilized is not subject to the issue of patentability of the apparatus itself (In re Casey, 370 F.2d 576, 152 USPQ 235 (CCPA 1967) and thus holds no patentable weight. See MPEP §2115.
In response to applicant's argument that Afeyan teaches a specific method of use of the columns involving a preparative parameter being specified in the first column and specifying an analytical parameter in the second column, which is different from the instant application because the instant specification separates and analyzes with the first column and only analyzes with the second column, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Regarding the newly amended limitations of claim 13 moved from cancelled claim 33, 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) and also that there are specifically three different wash buffers used to elute dimer species from affinity matrices (Paragraph 0007). 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.
Regarding Applicant’s argument about the change from “a switch valve” to “one switch valve”, claim 13 uses ‘comprising’ terminology, meaning that the apparatus must only include at least one switch valve and does not exclude unrecited elements. See MPEP 2111.03(I).
Regarding Applicant’s argument for the dependent claims, claim 13 is not allowable and so the dependent claims are also not allowable.
Applicant’s arguments have been fully considered but are not persuasive. All other arguments have been indirectly addressed.
Conclusion
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/A.A.G./ Examiner, Art Unit 1777 /VICKIE Y KIM/Supervisory Patent Examiner, Art Unit 1777