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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/23/2025 has been entered.
Application Status
Claims 1-7, 9-15, 18, 21-24, and 27-29 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
Previous rejection of claims 1-7, 9-15, 18, 21-24, and 27-29 under 35 U.S.C. 103 are withdrawn in view of applicant’s arguments.
Claim Rejections - 35 USC § 103
New Rejection
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 11, 15, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Igawa (US 2009/0263392 A1; IDS entered July 2, 2024), Goyon (J Chromatogr B Analyt Technol Biomed Life Sci, 2017 Oct 15, 1065-1066: 119-128; cited in OA 01/28/2025), and Raju (Expert Opinion on Biological Therapy, 13(10): 1347-1352; PTO-892).
Regarding claims 1 and 27-29, Igawa teaches a method for producing a multispecific antibody comprising a first polypeptide and a second polypeptide, wherein the method comprises the steps of: (a) modifying both or either one of a nucleic acid encoding the amino acid residues of the first polypeptide and a nucleic acid encoding the amino acid residues of the second polypeptide, such that the difference between the isoelectric point of the first polypeptide and that of the second polypeptide will be increased; (b) culturing host cells to express the nucleic acids; and (c) collecting the multispecific antibody from the host cell culture (claim 1). Igawa further teaches a method for purifying a multispecific antibody comprising a first polypeptide and a second polypeptide, wherein the method comprises the steps of: (a) modifying both or either one of a nucleic acid encoding the amino acid residues of the first polypeptide and a nucleic acid encoding the amino acid residues of the second polypeptide, such that the difference between the isoelectric point of the first polypeptide and that of the second polypeptide will be increased; (b) culturing host cells to express the nucleic acids; and (c) purifying said multispecific antibody from the host cell culture by standard chromatography (claim 10), wherein the modification of step (a) is modifying the nucleic acids so that the peaks of the homomultimer of the first polypeptide, the homomultimer of the second polypeptide, and the heteromultimer of the first polypeptide and the second polypeptide will be separated in standard chromatography analysis (claim 11). Igawa further teaches that examples of standard chromatography in the present invention include cation exchange chromatography, anion exchange chromatography, hydrophobic chromatography, hydroxyapatite chromatography, hydrophobic charge interaction chromatography, and chromatofocusing (paragraph 0121). The separation of 2 homomultimers in claim 11 results in the production and isolation of at least 2 monospecific antibodies.
Regarding claim 2, Igawa teaches the polypeptides of the present invention can be collected and purified from recombinant cell cultures using known methods, including ammonium sulfate or ethanol precipitation, acidic extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxyapatite chromatography, and lectin chromatography (paragraph 0084).
Regarding claim 15, Igawa teaches wherein the heavy chain constant regions with different isoelectric points are IgG1 and IgG4, or IgG1 and IgG2 (claim 28).
Igawa does not teach that the at least two antibodies exhibit IEX retention times that deviate by 10% or less from the average of the retention times of the individual antibodies under the IEX conditions used.
Regarding claims 1 and 11, Goyon teaches that the ionic properties of the mAbs are a crucial parameter for their purification, as most processes include at least one ion exchange step and that for antibodies with a pI < 7.5, anion exchange chromatography (AEX) can be used in flow-through mode to remove process-related impurities, then CEX is subsequently used to remove charged process-related impurities for mAbs with a pI > 7.0 (page 122, column 2, paragraph 1). Goyon further teaches that cationic mAbs (pI > 7.0) and especially those with a pI > 7.5 may be selected during developability studies, to avoid specific purification processes (e.g. host cell proteins removal and viral inactivation steps (page 122, column 2, paragraph 1). Goyon further teaches that acidic or basic species correspond to the ones with lower or higher pI values than the main one respectively and acidic or basic species measured by CEX are those with lower or higher retention times than the main chromatographic peak (section 3.2, 1st paragraph). Goyon further teaches that modifications that form acidic species include sialic acid
addition, deamidation, non-classical disulfide linkage, trisulfide bonds, high mannose content, thiosulfide modification, glycation, modification by maleuric acid, cysteinylation, reduced disulfide bonds, non-reduced species and fragments and on the other hand, basic species are due to the presence of C-terminal Lys, N-terminal Glu, isomerization of Asp, succinimide, Met oxidation, amidation, incomplete disulfide bonds,
incomplete removal of leader sequence, mutation from Ser to Arg, aglycosylation, fragments and aggregates (section 3.2, first paragraph).
Raju teaches that mixtures of rMAbs, that contain two or more antibodies directed against either a single antigen or different antigens, are now being developed as human therapeutics (page 1349 last paragraph – page 1350 first paragraph). Raju further teaches that Sym013, or Pan-HER antibody mixture, contains six humanized antibodies targeting three different antigens, that is, EGFR, HER2 and HER3 and has been shown to simultaneously downmodulate the EGFR, HER2and HER3 antigens and appears to circumvent the acquired resistance to anti-HER2 drugs due to upregulation of other receptor tyrosine kinases (page 1350, column 1 paragraph 2- column 2 paragraph 1). Raju further teaches several advantages of antibody mixtures in Table 1 including synergistic effects of multiple antibodies, possibility to engineer multiple functions, increased target clearance, and superior internalization. Raju further teaches that new platform technologies have been developed that makes it easier to produce antibody mixtures either using multiple cell lines or by using one cell line for each antibody molecule in order to reduce the effect of cost of goods (COGs) on the marketed products (page 1350, column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the pI of the antibodies so that the retention times of the antibodies is within 10% of the average as taught by Goyon to the method of producing multiple antibodies as taught by Igawa with reasoning as taught by Raju. The ordinary artisan would have been motivated to do so because Raju teaches that mixtures of rMAbs, that contain two or more antibodies directed against either a single antigen or different antigens, are now being developed as human therapeutics and that new platform technologies have been developed that makes it easier to produce antibody mixtures either using multiple cell lines or by using one cell line for each antibody molecule in order to reduce the effect of cost of goods (COGs) on the marketed products. Goyon teaches that specific modifications can be made to form acidic or basic species and that the amount of these species determines the pI which further determines the appropriate type of ion exchange chromatography. Having a pI that differs by less than 0.4 units from the average would allow the antibodies to be purified in the same fraction by IEX. Both Igawa and Goyon teach modification of the isoelectric point to facilitate purification of antibodies so the ordinary artisan has a reasonable expectation of success to alter the isoelectric point as taught by Goyon to allow purification by IEX with less than 10% deviation from the average retention of the individual antibodies under the conditions used for the method producing antibodies as taught by Igawa and Raju teaches that mixtures of antibodies produced in a single platform can be useful for therapy and reduction of cost of goods.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Igawa (US 2009/0263392 A1; IDS entered July 2, 2024), Goyon (J Chromatogr B Analyt Technol Biomed Life Sci, 2017 Oct 15, 1065-1066: 119-128; cited in OA 01/28/2025) and Raju (Expert Opinion on Biological Therapy, 13(10): 1347-1352; PTO-892) as applied to claims 1-2, 5, 11, 15, and 27-29 above, and further in view of Sharkey (mAbs, 2017, 9(2): 257-268; cited in OA 01/28/2025).
The teachings of Igawa, Goyon, and Raju are detailed above.
Igawa, Goyon, and Raju do not teach sequential affinity purification combined with size exclusion chromatography and/ or ion exchange chromatography; separation of the half
Regarding claim 3, Sharkey teaches a standard purification scheme for mAbs usually contains a Protein A capture step followed by AEX or CEX or a combination of both (page 260, column 2, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the standard purification protocol as taught by Sharkey to the method of purification of multiple antibodies as taught by Igawa, Goyon, and Raju. The ordinary artisan would have been motivated to do so because as Sharkey teaches this is a standard purification scheme for mAbs and therefore an ordinary artisan has a reasonable expectation of success using this scheme.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Igawa (US 2009/0263392 A1; IDS entered July 2, 2024), Goyon (J Chromatogr B Analyt Technol Biomed Life Sci, 2017 Oct 15, 1065-1066: 119-128; cited in OA 01/28/2025), and Raju (Expert Opinion on Biological Therapy, 13(10): 1347-1352; PTO-892) as applied to claims 1-2, 11, 15, and 27 above, and further in view of Fekete (J Pharm Biomed Anal. 2016 Oct 25;130:3-18; cited in OA 01/28/2025).
The teachings of Igawa, Goyon, and Raju as applied to claims 1-2, 11, 15, and 27 are detailed above.
Regarding claim 5, Igawa teaches the binding specificity of the antibody produced from these hybridomas can be measured using known analysis methods including enzyme-linked immunosorbent assay (ELISA) (paragraph 0184).
Igawa, Goyon, and Raju do not teach subsequent to IEX the at least 2 antibodies are quantitively analyzed for relative expression levels by hydrophobic interaction chromatography (HIC).
However, Fekete teaches that hydrophobic interaction chromatography (HIC) is a historical strategy used for the analytical purification and characterization of proteins (abstract). Fekete further teaches that with the strong development of protein biopharmaceuticals (mainly mAbs and ADCs), HIC comes back on the forefront as an analytical technique with the advantage of performing separations under non denaturing conditions (conclusion). Fekete further teaches that HIC has been used for several applications, including (1) the determination of mAbs or ADCs hydrophobicity, (2) the determination of ADCs’ average DAR and DAR distribution and (3) the monitoring of various posttranslational modifications (conclusion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the HIC as an analyzation tool after purification as taught by Fekete to the method of purification of multiple antibodies as taught by Igawa, Goyon, and Raju. The ordinary artisan would have been motivated to do so because as Fekete teaches that HIC is a historical strategy used for the analytical purification and characterization of proteins and has the advantage for therapeutic antibodies performing separations under non denaturing conditions and can therefore by used for (1) the determination of mAbs or ADCs hydrophobicity, (2) the determination of ADCs’ average DAR and DAR distribution and (3) the monitoring of various posttranslational modifications.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Igawa (US 2009/0263392 A1; IDS entered July 2, 2024), Goyon (J Chromatogr B Analyt Technol Biomed Life Sci, 2017 Oct 15, 1065-1066: 119-128; cited in OA 01/28/2025), and Raju (Expert Opinion on Biological Therapy, 13(10): 1347-1352; PTO-892) as applied to claims 1-2, 5, 11, 15, and 27-29 above, and further in view of Birck-Wilson (WO 2004/026427 A2; IDS entered August 13, 2021).
The teachings of Igawa, Goyon, and Raju as applied to claims 1-2, 11, 15, and 27 are detailed above.
Igawa, Goyon, and Raju do not teach wherein the retention times of the one or more half antibodies are outside the range spanned by the retention times of the at least two antibodies.
Birck-Wilson teaches a method for separating IgG half antibodies from IgG whole antibodies, wherein the half antibodies and the whole antibodies are of the same isotype, comprising: obtaining a sample that contains a mixture of IgG half antibodies and IgG whole antibodies of the same isotype; reducing the pH of the sample such that the half antibodies dissociate from one another to form a resulting solution;
applying the resulting solution to an ion exchange column such that both the IgG half antibodies and IgG whole antibodies are retained by the column; adding a buffer to the column such that the pH of the buffer present within the column increases to a level sufficient to selectively elute the IgG half antibodies; and subsequently adding a buffer to the column such that the ionic strength of the buffer present within the column increases to an amount sufficient to elute the IgG whole antibodies (claim 31). Figure 5 shows the retention time of the 80kDa species or half-antibody is separated from the whole antibody species at 150kD.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the steps of separating half- from whole-antibodies as taught by Birck-Wilson to the method of purification of multiple antibodies as taught by Igawa, Goyon, and Raju. The ordinary artisan would have been motivated to do so because as Birch-Wilson has a demonstrated IEX method to separate the whole from half antibodies and as the half antibodies are not a desired product this is a necessary step in the production process.
Claims 7, 9-10, 14, 18, and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Igawa (US 2009/0263392 A1; IDS entered July 2, 2024), Goyon (J Chromatogr B Analyt Technol Biomed Life Sci, 2017 Oct 15, 1065-1066: 119-128; cited in OA 01/28/2025), Raju (Expert Opinion on Biological Therapy, 13(10): 1347-1352; PTO-892) and Birck-Wilson (WO 2004/026427 A2; IDS entered August 13, 2021) as applied to claims 1-2, 6, 11, 15, and 27-29 above, and further in view of de Kruif (US 9,248,181 B2; IDS entered August 13, 2021).
The teachings of Igawa, Goyon, Raju, and Birck-Wilson as applied to claims 1-2, 6, 11, 15, and 27 are detailed above.
Igawa, Goyon, Raju and Birck-Wilson do not teach wherein the plurality of cells produces 3 heavy chains; wherein at least 2 of the at least 2 antibodies are bispecific antibodies; wherein at least 2 of the at least 2 antibodies share an identical heavy chain;
Regarding claims 7, 9-10, and 22-24, de Kruif teaches that the art provides a variety of technologies and methods for generating monoclonal antibodies, bispecific antibodies, mixtures of monoclonal antibodies, or mixtures of monospecific and bispecific antibodies that can subsequently be used for therapeutic application in patients (column 3, lines 32-36). De Kruif further teaches that in the art, it has been shown that combinations of 2 monoclonal antibodies may have additive or synergistic effects and recruit effector mechanisms that are not associated with either antibody alone, for example, mixtures of 2 monoclonal antibodies against the EGFR or HER2 were shown to more potently kill tumor cells based on a combination of activities including enhanced receptor internalization, improved blockade of signaling pathways downstream of the receptors as well as enhanced immune effector-mediated cytotoxicity (column 2, lines 24-33). de Kruif further teaches that therapies based on a single bispecific antibody are facilitated by a less complicated and cost-effective drug development process while providing more efficacious antibody therapies versus mixtures of monoclonal antibodies (Column 2, line 66- column 3 line 2). de Kruif further teaches that the invention provides methods and means for improved and/or alternative technologies for producing biological therapeutics in the form of mixtures or bispecific approaches for targeting multiple disease-modifying molecules, as well as products and uses resulting from these methods and means (column 3, lines 46-50). de Kruif further teaches that a mixture of more than one bispecific antibody is also particularly useful for the treatment of certain diseases such as cancer where more than 2 disease- and escape related target molecules or epitopes can be involved, therefore a mixture of bispecific antibodies provides an innovative and attractive therapeutic format (column 6, lines 4-5 and 12-15) de Kruif further teaches that the present invention provides a method for producing at least two different Ig-like molecules from a single host cell, wherein each of said two Ig-like molecules comprises two CH3 domains that are capable of forming an interface, said method comprising providing in said cell a) a first nucleic acid molecule encoding a 1st CH3 domain comprising polypeptide chain, b) a second nucleic acid molecule encoding a 2nd CH3 domain-comprising polypeptide chain, c) a third nucleic acid molecule encoding a 3rd CH3 domain comprising polypeptide chain, and d) a fourth nucleic acid molecule encoding a 4th CH3 domain comprising polypeptide chain, wherein at least two of said nucleic acid molecules are provided with means for preferential pairing of said 1st and 2nd CH3 domain-comprising polypeptides and said 3rd and 4th CH3-domain comprising polypeptides, said method further comprising the step of culturing said host cell and allowing for expression of said at least four nucleic acid molecules and harvesting said at least two different Ig-like molecules from the culture (column 5, lines 45-65). It would be obvious to the ordinary artisan that generating 3 heavy chains with 3 antigen targets would also be possible by this methodology so that the resulting bispecific molecules would share 1 antigen target.
Regarding claim 14, de Kruif teaches a heterodimeric antibody comprising two CH3 domains, wherein one of said two CH3 domains comprises the amino acid substitutions L351D and L368E and wherein the other of said two CH3 domains comprises the amino acid substitutions T366K and L351K (claim 24). de Kruif further teaches that an approach for the production of a given bispecific antibody of interest is based on electrostatic engineering of contact residues within the CH3-CH3 interface that are naturally charged and that within the CH3-CH3 interface four unique charges residue pairs are involved in the domain-domain interaction, therefore expression of different CH3 domains comprising different, complementary charge reversions, could drive heterodimerization, resulting in an increased proportion of the bispecific species in the mixture to 76-96% (column 5, lines 1-37).
Regarding claims 18 and 21, de Kruif teaches a pharmaceutical composition comprising a heterodimeric antibody according to claims 22 or 24, and a pharmaceutically acceptable carrier (claim 27). The teachings of Goyon regarding isoelectric point are detailed above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the heavy chain substitutions for heterodimer pairing and bispecific antibody mixture as taught by de Kruif to the method of purification of multiple antibodies as taught by Igawa, Goyon, Raju, and Birck-Wilson. The ordinary artisan would have been motivated to do so because as de Kruif teaches that a mixture of more than one bispecific antibody is also particularly useful for the treatment of certain diseases such as cancer as an innovative and attractive therapeutic format and single bispecific antibody are facilitated by a less complicated and cost-effective drug development process while providing more efficacious antibody therapies versus mixtures of monoclonal antibodies. de Kruif further teaches that through electrostatic engineering of contact residues within the CH3-CH3 interface that drive heterodimerization, production of the bispecific species in the mixture can be increased to 76-96%. The production of a mixture of bispecific antibodies would provide a benefit to cancer patients through more efficacious and cost effective treatments.
Response to Arguments
Applicant’s arguments, see page 8, filed 12/23/2025, with respect to claim 1 have been fully considered and are persuasive. The rejection of 09/23/2025 has been withdrawn.
Applicant submits: As explained previously, Igawa discloses a method for purifying bispecific antibodies using a chromatography column based on the difference in isoelectric points of the heavy chains of two types of antibodies, and the difference is introduced by modifying the amino acids present on the surface of the variable regions of the two types of antibodies that constitute a bi specific antibody. Therefore, Igawa teaches a method to purify individual antibodies that constitute a bispecific antibody. The Office asserts that an ordinary artisan would have the skill set to modify the isoelectric points of antibodies as provided by Goyon but again does not explain why a skilled artisan would do so. To the contrary, Goyon merely discloses the ionic properties of 23 FDAapproved monoclonal antibodies. It also provides no motivation for a skilled artisan to make mixtures of antibodies, nor does the Office point to any teaching in Goyon for such motivation.
Applicant respectfully asserts that the question is not whether a skilled artisan would have the capacity to modify an isoelectric point to achieve a purification goal by IEX (Office action, p. 15), but rather why they would do so to arrive at the claimed mixture of antibodies when the prior art taught separation to provide homogenous populations. None of Sharkey, Fekete, Birck-Wilson, or De Kruif, either alone or in combination provide such motivation. Accordingly, Applicant respectfully asserts that the claimed invention is not unpatentable and request that the rejection be reconsidered and withdrawn.
In response: The lack of motivation to produce a mixture of antibodies is provided by Raju as detailed in the new rejection above.
Conclusion
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.
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, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643