Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
Claims 1-7, 9-15, 18, 21-24, and 27-29 are pending and examined on the merits herein.
Claim Interpretation
Claim 1 is drawn to a method of producing wherein the method is characterized in that 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. The language “characterized in that” does not constitute an active method step and therefore the limitation that follows is not a required limitation of the method but a result of the recited active method steps.
Further, claim 1 is drawn to a method of producing “at least two antibodies”; this language leaves the claim open to multiple interpretations including but not limited to: two separate antibodies as identified by sequence, two copies of the same antibody as identified by sequence, etc.
Claims 2-6, 9-15, and 21-24, recite the same language and depend from claim 1, therefore they are subject to the same interpretation.
Claim Rejections - 35 USC § 112(b)
New Rejection
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12-13 are 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.
Regarding claim 12, the claim recites wherein the at least two antibodies are selected for having heavy and light chain combination that have retention times that are significantly different from their retention times under the IEX conditions used. It is unclear what the first recitation of retention times is referring to. Retention times on a column is the time from when the sample is injected to when it is detected at the end of the column. In the instant claim what column is the first recitation of “retention time” referring to that should be significantly different from the retention times under IEX conditions used? There is only one column recited in the independent claim 1 and that is the IEX column, as such it is unclear how the at least two antibodies can be selected for having heavy and light chain combination that have retention times that are significantly different from their retention times under the IEX conditions used. Is this meant to be a comparison between different IEX conditions? Or between the different combinations of antibodies formed?
Claim 13 depends from claim 12 and does not rectify this issue, therefore it is included in this rejection.
Claim Rejections - 35 USC § 102
New Rejection
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 15, and 27-29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Igawa (US 2009/0263392 A1; IDS entered July 2, 2024).
Regarding claims 1, 18, 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 the recitation of the method characterized in that the at least two antibodies exhibit IEX retention times that deviate by 10% or less from the average of the retention time of the individual antibodies under the IEX conditions used; as detailed in the interpretation above this is not an active method step and therefore not a required limitation of the method.
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).
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 3 and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Igawa (US 2009/0263392 A1; IDS entered July 2, 2024) as applied to claims above 1-3, 15, and 27-29 and further in view of Sharkey (mAbs, 2017, 9(2): 257-268; cited in OA 01/28/2025), 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; cited in OA 02/10/2026), and Nielson (Mol Biotechnol (2010) 45:257–266; PTO-892).
The teachings of Igawa regarding claims 1-3, 15, and 27-29 are detailed above.
Igawa does not teach sequential affinity purification combined with size exclusion chromatography and/ or ion exchange chromatography; separation of the half
wherein the at least two antibodies have pI that differ by 0.4 units or less than the average pI of the at least two antibodies.
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).
Regarding claim 11, Sharkey teaches that as the pI difference between the two parent antibodies for the bispecific gets smaller (Figs. 2B to 2E), the individual peaks are less resolved and once this difference is as small as 0.10 (Figs. 2F and 2G), no separation between the two homodimers and the heterodimer in the mixture can be
achieved under the chosen purification conditions.
Regarding claims 12-13, Sharkey teaches in Fig. 3A, the BsAb#2 mixture of homodimeric antibodies with a difference in pI of 0.59 pH units and the corresponding heterodimer was purified using a MonoS 5/50 GL column and a full pH gradient (from pH 4.0 to 11.0).
Regarding claim 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).
Regarding claim 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 these antibody mixtures may provide advantages over antibody monotherapy because the individual antibody components present in the mixture may complement each other to target the diseases (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).
Nielson teaches development and implementation of production of recombinant polyclonal antibodies (rpAb) in single batches (abstract). Nielson further teaches that target-specific rpAb is a new generation of antibodies mimicking the diversity, specificity, and binding capability of the natural human immune system which is accomplished by an rpAb preparation that contains several specific antibodies, and for economic reasons a manufacturing procedure with all antibodies being produced in the same culture vessel will be preferable (page 258, col 1, para 2). Nielson further teaches proof of principal in the development and production of Sym001 (Rozrolimupab) which is a rpAb against the RhD antigen consisting of 25 individual antibodies (page 258, col 1, para 3). Nielson further teaches that while demand for the RhD antibody product is small the higher demand for cancer targeted products require a high production level than achieved in this system (page 258, col 1, para 3). Nielson further teaches that different alternatives could be thought of regarding production of rpAbs (page 265, col 2, para 3).
Regarding claim 3: 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. 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.
Regarding claims 11-13: 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 to optimize the retention times of the heavy and light chains as taught by Goyon and Sharkey to the method of producing multiple antibodies as taught by Igawa with reasoning as taught by Raju and Nielson. 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 to reduce the cost of goods (COGs). Nielson teaches that target-specific rpAb is a new generation of antibodies mimicking the diversity, specificity, and binding capability of the natural human immune system which is accomplished by an rpAb preparation that contains several specific antibodies, and for economic reasons a manufacturing procedure with all antibodies being produced in the same culture vessel will be preferable. 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, while Sharkey demonstrates how these principles can be applied to purify fractions with combinations of antibodies or to optimize for their separation. 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 and demonstrated by Sharkey to allow purification by IEX with less than 0.4 units of difference in pI between the 2 antibodies, or less than 0.4 units of opI of difference between te heavy and light combinations under the conditions used in the method of producing antibodies as taught by Igawa. Raju and Nielson teaches that mixtures of antibodies can be superior to single target antibody therapy and reduction of cost of goods can be achieved by utilizing a single batch production platform.
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), Sharkey (mAbs, 2017, 9(2): 257-268; cited in OA 01/28/2025), 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; cited in OA 02/10/2026) and Nielson (Mol Biotechnol (2010) 45:257–266; PTO-892) as applied to claims 1-3, 11-13, 15, and 27-29 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, Sharkey, Goyon, Raju, and Nielson as applied to claims 1-3, 11-13, 15, and 27-29 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, Sharkey, Goyon, Raju, and Nielson 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, Sharkey, Goyon, Raju, and Nielson. 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), Sharkey (mAbs, 2017, 9(2): 257-268; cited in OA 01/28/2025), 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; cited in OA 02/10/2026) and Nielson (Mol Biotechnol (2010) 45:257–266; PTO-892) as applied to claims 1-3, 11-13, 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, Sharkey, Goyon, Raju, and Nielson as applied to claims 1-3, 11-13, 15, and 27-29 are detailed above.
Igawa, Sharkey, Goyon, Raju, and Nielson 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, Sharkey, Goyon, Raju, and Nielson. 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), Sharkey (mAbs, 2017, 9(2): 257-268; cited in OA 01/28/2025), 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; cited in OA 02/10/2026), Nielson (Mol Biotechnol (2010) 45:257–266; PTO-892) and Birck-Wilson (WO 2004/026427 A2; IDS entered August 13, 2021) as applied to claims 1-3, 6, 11-13, 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, Sharkey, Goyon, Raju, Nielson, and Birck-Wilson as applied to claims 1-3, 6, 11-13, 15, and 27-29 are detailed above.
Igawa, Sharkey, Goyon, Raju, Nielson, 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 points 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, Sharkey, Goyon, Raju, Nielson, 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 filed 06/30/2026 have been fully considered but they are not persuasive.
All arguments with regard to claims 1-2, 15, and 27-29 are no longer considered as the rejection has been changed to a 102 and no longer relies on Raju as a reference.
Applicant submits: The Office asserts that it would have been obvious to modify the combined teachings of Igawa and Goyon in view of Raju to arrive at the claimed invention. In particular, the Office relies on Raju as allegedly providing a motivation to purify mixtures of antibodies based on the general proposition that combinations of antibodies are being developed as therapeutics. For the reasons set forth below, Raju does not provide the requisite motivation, and the rejection is therefore improper.
The Office's position rests on the conclusion that, because Raju discusses the potential therapeutic benefits of antibody mixtures, a person of ordinary skill in the art would have been motivated to modify purification processes to yield mixtures of antibodies in a common fraction. This reasoning is legally insufficient. The courts have consistently required that a motivation to combine must be tied to the specific modification claimed, not merely to a general goal in the field. See, e.g., KSRint'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007) (requiring an "apparent reason to combine the known elements in the fashion claimed"); and Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1073 (Fed. Cir. 2015) (motivation must relate to the particular combination). Here, Raju does not disclose or suggest modifying antibody physicochemical properties (e.g., isoelectric point) or chromatographic conditions to achieve co-elution or co-purification of multiple distinct antibodies. Instead, Raju merely recognizes that antibody mixtures can have therapeutic utility. Such a general observation does not supply a motivation to implement the specific purification strategy recited in the claims.
In Response: The updated rejection relies on Raju and Nielson for teaching the benefits of production of mixtures of antibodies as well as the benefit of doing so in a single batch platform. Igawa, Sharkey and Goyon are relied upon for teaching not only the technical know how of optimizing the pI of antibodies but demonstration of co-purification of antibodies with known pI. Although it was not the goal of Sharkey, Goyon or Igawa to produce a mixture of antibodies the technical knowledge and resulting co-purification was well established in the art. Therefore, the ordinary artisan had only to recognize the benefit as taught by Raju and Nielson to have motivation to apply the knowledge with the specific examples seen in Sharkey as proof of principal.
Applicant submits: Moreover, while Raju addresses the advantages of antibody mixtures, it is silent with respect to how such mixtures should be purified. In fact, the approaches contemplated in Raju are entirely consistent with the conventional paradigm in the art, namely: (1) producing individual antibodies (e.g., in separate cell lines or production systems); (2) purifying each antibody independently to achieve homogeneity; and (3) combining the purified antibodies into a final formulation. Nothing in Raju suggests that distinct antibodies that have similar chromatographic behavior should be copurified or that purification processes should be modified to intentionally prevent their separation. Thus, Raju does not provide any teaching or suggestion to achieve such mixtures via co-purification in a single chromatographic fraction, as required by the claims.
In Response: Raju was not relied upon for the active method steps. Igawa as the primary reference provides most of these steps, while Sharkey and Goyon were further used as analogous purification protocols with specific teachings as to pI modifications.
Applicant submits: The Office's rationale further fails because it disregards the teachings of the primary references. Igawa teaches modifying antibodies to create differences in physicochemical properties ( e.g., pl) to enable separation of species. Goyon similarly teaches leveraging charge differences to resolve variants and impurities during chromatography. Collectively, these references teach that purification processes should be optimized to separate distinct antibody species and improve product homogeneity. In contrast, the claims require selecting or engineering antibodies such that they exhibit highly similar chromatographic properties; and achieving co-elution within a narrowly defined retention window. This represents the opposite design principle of the cited art. Where the prior art teaches away from the claimed invention, a motivation to combine cannot be established. WL. Gore & Assocs., Inc. v. Garlock, Inc., 721 F.2d 1540, 1550 (Fed. Cir. 1983). The Office has not identified any disclosure in Raju that would overcome or counteract this strong teaching toward separation.
In Response: Igawa and Goyon teach methodology to separate antibodies by modification of pI after Sharkey so clearly demonstrated that a bispecific with parental antibodies that have similar pI will purify together by IEX unless a linear pH gradient is used. The motivation to use this knowledge to leave the antibodies together is taught by Raju and Nielson in the updated rejection.
Conclusion
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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