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 .
DETAILED ACTION
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 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.
Status of the claims
Applicant’s amendments filed 02/11/2026 is acknowledged. In the amendments filed 02/11/2026, claim 54 has been canceled. Thus claims 1, 3-4, 7-8, 11-12, 14, 17-25, 27-28, 31, 33-34, 36-37, 41-42, 48, 53 and 55 are pending. Claims 33-34, 36-37 and 41-42 are withdrawn. See office action of 12/30/2024 for the withdrawal of the claims as being directed to non-elected invention. Therefore, claims 1, 3-4, 7-8, 11-12, 14, 17-25, 27-28, 31, 48, 53, and 55 are examined on merits in this office action.
Claim Rejections - 35 USC § 103
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 of this title, 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 1, 3, 14, 16, 18-25, 27, 31, and 48 are rejected under 35 U.S.C. 103 as obvious over Liu et al (mABs 2010) in view of Fong et al (US 2018/0327446A1) and Leister et al (US 2009/0252749).
In regards to claim 1, Lui discloses purification of monoclonal antibody using affinity chromatography followed by additional polishing steps (Abstract). Lui teaches that the monoclonal antibody includes IgG1 (page 487, 1st and last paragraph of 2nd col.). Lee discloses collecting IgG1 containing protein from suitable mammalian expression system and impurities, contacting the protein on to an affinity chromatography (e.g. protein A chromatograph) (page 484, 2nd col. to 2nd paragraph, 2nd col. of page 485) and applying the eluted IgG protein to an additional polishing step (Fig. 1), as for example mixed mode chromatography (page 489, last paragraph of 1st col.). Lui teaches Capto Adher (i.e. a multimodal chromatography or mixed mode chromatography) has been evaluated as a second antibody purification step after protein A chromatography to remove aggregate, hos cell protein and leached protein A (page 489, last paragraph of 1st col.).
As described above Liu teaches IgG purification (including IgG1) with protein A affinity chromatography followed by downstream polishing steps including mixed-mode chromatography. Lui however, does not mention performing mixed-mode chromatography performed in bind-elute mode and does not teach purification wherein the monoclonal antibody is CTLA4-Ig fusion protein.
Fong teaches purification of recombinant polypeptides (e.g. antibodies), the method includes affinity chromatography, mixed-mode chromatography and hydrophobic interaction chromatography (Abstract). the recombinant polypeptide preparation is a final purified product. Fong teaches that the recombinant polypeptide contained in the recombinant polypeptide sample is an antibody and the antibody is a multispecific antibody, a bispecific antibody, a half antibody or an antibody fragment and in some embodiments, the recombinant polypeptide is an IgG1, an IgG2, an IgG3, or an IgG4 (paragraphs [0020] and [0023]). Fong teaches that the method comprising the sequential steps of a) subjecting the composition to affinity chromatography to produce an affinity eluate, b) subjecting the affinity eluate to mixed-mode chromatography to generate a mixed-mode eluate, and c) subjecting the mixed-mode eluate to hydrophobic interaction chromatography and collecting a fraction comprising the polypeptide, wherein the method reduces the amount of product-specific impurities from the composition (paragraph [0029]). Fong teaches that the mixed-mode chromatography is a mixed-mode anion exchange chromatography and in some embodiments, the mixed-mode chromatography is carried out in bind and elute mode (paragraphs [0029]-[0031], [0036]-[0037]).
Leister discloses a fusion protein monomer comprising a CTLA4-Ig fusion protein wherein the Ig is a constant region from human IgG1 (paragraph [0262], [0265], [0266], [0291, [0446]). Leister discloses fusion monomer comprising CTLA4 and Fc domain of human immunoglobulin of IgG1 (paragraphs [0503] and [1214]). Leister disclosed pharmaceutical composition of CTLA4-Ig (para [00181], [0197] and [0208] and [0311]). Leister teaches population of CTLA4-Ig monomer wherein the composition is substantially free of CTLA4-Ig dimer and tetramer (Example 4; paragraphs [0013], [0152] and [0635]). Leister teaches that the invention provides for a composition consisting essentially of CTLA4-Ig monomers substantially free of CTLA4-Ig dimers and high molecular weight species (paragraph [0221]). Leister, as described above teaches CTLA4-Ig monomers and pharmaceutical composition with the monomers and also teaches CTLA4-Ig monomer wherein the composition is substantially free of CTLA4-Ig dimer and tetramer. In the reference of Leister, the term substantially free of CTLA4-Ig dimer and tetramer is referred for a population wherein less than 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of CTLA4-Ig dimer and tetramer (i.e. HMW impurities) are present in the population, which encompasses the recitation of purity of “at least 90%” or “more than 90%” or a purity of “more than about 99%”. Moreover, Leister taches Protein A chromatograph for CTLA4-Ig purification (para [1023]) followed by downstream chromatography polishing steps.
Therefore, from the above description in mind of Lui, Fong and Leister, it would be obvious to one of ordinary skilled in the art to easily envisage downstream purification of monoclonal antibody after protein A because the references teach downstream chromatographic polishing steps. From the reading in mind of Leister, on of ordinary skilled in the art would easily envisage including for the purification because Leister teaches purification from LMW and HMW impurities involving Protein A chromatograph for CTLA4-Ig purification followed by downstream chromatography polishing steps. One of ordinary skilled in the art from the description in mind of Fong, would envisage employing mixed-mode chromatography in bind-elute mode after affinity chromatography with the expectation of obtaining high purity IgG1 and IgG1 fusion protein CTLA4IgG1 with downstream polishing and removal step with a reasonable expectation of success. Since Fong teaches carrying out mixed-mode chromatography after protein A affinity chromatography and since Fong throughout the reference teaches that the mixed-mode chromatography can be in bind and elute mode, one of ordinary skilled in the art can easily envisage bind and elute mode for the downstream purification of mixed-mode chromatography envisaged by Lui. Font teaches that the process involving mixed-mode chromatography provides purification of antibody to above 90% (para [0630]; Table 26 and 35).
In regards to claim 3, Fong teaches various conditions of loading and elution of antibody on mixed-mode chromatography (e.g. Capto adhere) such as loading pH and conductivity, washing pH and eluting pH and/or conductivity (paragraphs [0639], [0643], [0646] and [0657]) and optimization with pH, conductivity, washing pH and elution pH based on desired purification would be within the purview of one of ordinary skilled in the art.
In regards to claim 14, as described above, Lui teaches Capto adhere mixed mode chromatography and protein A affinity chromatography and Fong also teaches protein A affinity chromatography and capto adhere mixed mode chromatography.
In regards to claim 16, as described above, Lui teaches reducing impurities as for example, high molecular weight (HMW) species, as for example, aggregates and high molecular weight proteins (page 492) from protein A elute utilizing additional polishing steps including multimodal chromatography.
In regards to claims 18-25, 27 and 31, Lui teaches various other additional polishing steps including ion exchange chromatography, which includes anion exchange chromatography (page 485). However, as claimed in claim 1, the other purification steps are optional and thus considered as not a required part of claimed invention.
In regards to claim 48, claim 48 recites “wherein the IgG1 containing protein is antibody and as described above, Lui teaches IgG1, which is an antibody.
Claims 1, 3-4, 7-8, 11-12 14, 16, 18-25, 27, 31, 48, 53 and 55 are rejected under 35 U.S.C. 103 as obvious over Liu et al (mABs 2010) in view of Fong et al (US 2018/0327446A1) and Leister et al (US 2009/0252748) as described for claims 1, 3, 14, 16, 18-25, 27, 31 and 48 above and further in view of GE Healthcare Multimodal Chromatography Handbook (J. Chromatography 2013).
Lui in view of Fong and Leister has been described above for claims 1, 3, 14, 16, 18-25, 27, 31 and 48 making it obvious for downstream purification step of IgG1 and IgG1 fusion protein using multimodal chromatography in bind-elute mode. Fong teaches bind-elute mode utilizing multimodal chromatography carrying out binding near neutral pH and eluting antibody with lower pH. Fong teaches conductivity but however, does not mention elution by increasing conductivity.
GE Healthcare Handbook teaches multimodal Chromatography. The handbook teaches that after capture stage, purification further involves intermediate purification stage and/or polishing steps. Intermediate stage is for removing most of the bulk impurities, such as other proteins and nucleic acids, endotoxins, and viruses and polishing step is for removing remaining impurities (page 9). The handbook teaches that the multimodal chromatography can be utilized in bind/elute or flowthrough mode and bind/elute mode of separation works by binding the sample components to the chromatography medium based on electrostatic charges. If the medium has negatively charged functional groups (as in CIEX), sample components with positively charged ions will bind to it; if the medium has positively charged functional groups (as in AIEX), then protein sample components with negatively charged ions will bind to it. Once sample components are bound, the medium is washed, and non-bound material is washed through, after which the bound material is eluted under conditions of increasing ionic strength or change in pH. With increasing salt concentration, salt ions in the buffer compete for binding with the charges on the medium, and the bound material is displaced and eluted. Alternatively, when pH is changed, bound proteins are titrated and eventually become noncharged or have the same charge as the ligand, leading to repulsion and elution of the bound protein ((page 10). The handbook teaches that the importance of each parameter will vary depending on whether a purification step is used for capture, intermediate purification, or polishing and purification methods should be selected and optimized to meet the objectives for each purification step. The handbook teaches that multimodal chromatography media using the multimodal ligand approach, ligands that have multiple modes of interaction are immobilized on the chromatography matrix and the current multimodal product offering from GE Healthcare consists of Capto MMC, Capto MMC ImpRes, Capto adhere, Capto adhere ImpRes, and Capto Core 700 (page 18). The healtcare teaches screening a pH and conductivity for binding and for binding and screen pH gradient and conductivity gradient for elution (page 21). The handbook teaches various different salt types and additives that modulate the interactions of target molecule with multimodal chromatography (page 22). The handbook teaches various medium suitable for additional purification and/or polishing steps in bind/elute mode, as for example, Capto adhere ImpRes, Capto MMC ImpRes (Table 3.1, page 24), and Capto adhere (page 25, 4th paragraph: “in cases where low molecular weight impurities, such as antibody fragments, are present, Capto adhere in bind/elute mode might give higher purity”). The handbook, throughout the disclosure, teaches optimization with pH, conductivity and additive for binding and elution, which is based on the medium used proteins to be purified in bind/elute mode (pages 25-38).
Therefore, since the basic concept of purification of IgG1 involving initial capture by protein A chromatography and downstream additional purification/polishing steps utilizing various mixed-mode chromatography (multimodal chromatography) in bind/elute mode has been established by Liu in view of Fong and since the GE Healthcare Handbbook teaches various multimodal medium for bind/elute mode for downstream purification of proteins including IgG1 with guidance for optimization with pH, conductivity, additives, pH gradient and conductivity gradient for binding and elution, it would be obvious to one of ordinary skilled in the art to easily obtain various optimized conditions of pH, conductivity, additives, pH gradient, and conductivity gradient, for binding and elution of IgG1 in the process of additional purification/polishing with a reasonable expectation of success. In regards to claims 53-55, as described in GE Healthcare Handbook, optimized pH, conductivity, additives, pH gradient and conductivity gradient, are as all based on the medium used and can be optimized by routine optimization. “[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” Application of Aller, 220 F.2d 454,456, 105 USPQ 223, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. At 458,105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable is a known process is ordinary within the skill of the art.” Application of Boesch, 617 F.2d 272,276,205 USPQ 215, 218-219 (C.C.P.A. 1980).
Response to argument
Applicant's arguments and amendments filed 02/11/2026 have fully been considered but the arguments are rendered moot in view of the new grounds of rejection as described in this office action that are necessitated by Applicant’s amendments. However, an argument has been addressed here. Applicant at page 10, argued that the combination of resin chemistry and precise elution buffer conditions (e.g. 0.3 M Arginine HCl at pH 7.2) achieve superior impurity profiles (e.g. <0.2% aggregates) for the mammalian-derived CTLA4IgG1 fusion protein and none of the references, alone or in combination teaches or suggest such a method, let alone the superior impurity profiles resulting from the presently claimed methods.
The above arguments have fully been considered but are not found persuasive because Applicant is kindly reminded that, according to MPEP 2145 “Consideration of Applicant's Rebuttal Arguments,” arguing limitations which are not claimed is not proper:
“Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993) (Claims to a superconducting magnet which generates a "uniform magnetic field" were not limited to the degree of magnetic field uniformity required for Nuclear Magnetic Resonance (NMR) imaging. Although the specification disclosed that the claimed magnet may be used in an NMR apparatus, the claims were not so limited.); Constant v. Advanced Micro-Devices, Inc., 848 F.2d 1560, 1571-72, 7 USPQ2d 1057, 1064-1065 (Fed. Cir.), cert. denied, 488 U.S. 892 (1988) (Various limitations on which appellant relied were not stated in the claims; the specification did not provide evidence indicating these limitations must be read into the claims to give meaning to the disputed terms.); Ex parte McCullough, 7 USPQ2d 1889, 1891 (Bd. Pat. App. & Inter. 1987) (Claimed electrode was rejected as obvious despite assertions that electrode functions differently than would be expected when used in nonaqueous battery since "although the demonstrated results may be germane to the patentability of a battery containing appellant's electrode, they are not germane to the patentability of the invention claimed on appeal.").”
Moreover, If Applicant is trying to assert unexpected advantages with a particular conditions of elution buffer, the examiner notes that according to MPEP 716.02(d) unexpected results shall commensurate in scope with claimed invention:
“Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).”
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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