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
This is the Final Action for application 18/221934 response filed 04/06/2026.
Claims 1 & 3-7 are pending and have been fully considered.
Claim 2 has been cancelled.
Claim Rejections - 35 USC § 112
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.
Claim 6 is 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.
With respect to Claim 6, it is unclear if subjecting the charge variants to cIEF, is a further step from the reversed phase cIEF in Claim 1, or if instead applicant is broadening the claim from claim 1. This is unclear and requires correction. Further the part of the claim that states “to separate to separate the charge variant,” is confusing and unclear.
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, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3 & 6-7 are rejected under 35 U.S.C. 103 as being obvious over MICHELS in Imaged Capillary Isoelectric Focusing for Charge-Variant Analysis of Biopharmaceuticals in view of REN in Isoforms analysis of recombinant human erythropoietin by polarity-reversed capillary isoelectric focusing.
With respect to Claim 1, MICHELS teaches of using imaged capillary isoelectric focusing for charge variant analysis of therapeutic proteins (Page 48, column 1, paragraph 1). MICHELS further teaches that the proteins are separated primarily on the basis of a molecules pI intrinsic net charge (Page 48, column 3, paragraph 1 & 2).
Even more specifically, MICHELS teaches of subjecting a sample to imaged capillary isoelectric focusing (iCIEF) to separate an antibody-drug conjugate (Figure 1) and a rMAb protein (Figure 2) into acidic charge variants and basic charge variants, which means the antibody (protein)-drug conjugate contains “more than one charge variant species,” as instantly claimed.
MICHELS do not teach of basically repeating the analysis/enriching a selected charge variant species using reversed polarity capillary isoelectric focusing.
REN is used to remedy this. REN teaches of methods for analysis of proteins using isoelectric focusing and more specifically of using reversed polarity capillary isoelectric focusing, after a method is performed using regular capillary isoelectric focusing (abstract)—this reads on the claimed enriching and providing of an enriched sample through broadest reasonable interpretation. REN teaches that the second step is done to enable for better detection of acid proteins with pI < 5.5 (See Figure 1, figure 1 description, and Page 2057, column 1, first paragraph).
It would have been obvious to one of ordinary skill in the art to reverse polarity of the capillary isoelectric focusing after the first step as is done in REN in the method of MICHELS due to the advantage this offers in providing an improved method in giving higher resolution for the capillary isoelectric focusing and due to the advantage this offers for analyzing the acid part of the proteins (REN, abstract & 2057, column 1, paragraph 1).
With respect to Claim 3, MICHELS teaches of the claims as shown above but does not teach of repeating the analyses. REN teaches of repeating the analysis (Page 2060, column 1, paragraph). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to repeat the analyses as done in REN in the method of MICHELS due to the advantage this offers in showing if the method is consistent and due to the importance of this for quality control (REN, abstract & Page 2060, column 2, paragraph 1).
With respect to Claim 6, MICHELS teaches of using imaged capillary isoelectric focusing for charge variant analysis of therapeutic proteins (Page 48, column 1, paragraph 1). MICHELS further teaches that the proteins are separated primarily on the basis of a molecules pI intrinsic net charge (Page 48, column 3, paragraph 1 & 2).
Even more specifically, MICHELS teaches of subjecting a sample to imaged capillary isoelectric focusing (iCIEF) to separate an antibody-drug conjugate (Figure 1) and a rMAb protein (Figure 2) into acidic charge variants and basic charge variants, which means the antibody (protein)-drug conjugate contains “more than one charge variant species,” as instantly claimed.
MICHELS do not teach of basically repeating the analysis/enriching a selected charge variant species using a capillary isoelectric focusing.
REN is used to remedy this. REN teaches of methods for analysis of proteins using isoelectric focusing and more specifically of using reversed polarity capillary isoelectric focusing, after a method is performed using regular capillary isoelectric focusing (abstract)—this reads on the claimed enriching and providing of an enriched sample through broadest reasonable interpretation. REN teaches that the second step is done to enable for better detection of acid proteins with pI < 5.5 (See Figure 1, figure 1 description, and Page 2057, column 1, first paragraph).
It would have been obvious to one of ordinary skill in the art to reverse polarity of the capillary isoelectric focusing or use capillary isoelectric focusing again after the first step as is done in REN in the method of MICHELS due to the advantage this offers in providing an improved method in giving higher resolution for the capillary isoelectric focusing and due to the advantage this offers for analyzing the acid part of the proteins (REN, abstract & 2057, column 1, paragraph 1).
With respect to Claim 7, MICHELS teaches of the protein being an antibody (Figure 1) or of it being a rMAB (recombinant monoclonal antibody/protein (Figure 2).
Claim 5 is rejected under 35 U.S.C. 103 as being obvious over MICHELS in Imaged Capillary Isoelectric Focusing for Charge-Variant Analysis of Biopharmaceuticals in view of REN in Isoforms analysis of recombinant human erythropoietin by polarity-reversed capillary isoelectric focusing and further in view of GENTALEN in US 20210181148.
With respect to Claim 5, MICHELS and REN teach of the claims as shown above, but do not teach of using ion exchange chromatography with the isoelectric focusing.
GENTALEN is used to remedy this. GENTALEN teaches of a method for characterization of analyte mixtures. Some methods described herein include performing enrichment steps on a device before expelling enriched analyte fractions from the device for subsequent analysis (abstract). More specifically, GENTALEN teaches that the method is for separating a mixture of charge variants of one or more biologics (Claim 31) (which reads on 2 to 10), which can be proteins (paragraph 0009-0010).
GENTALEN more specifically teaches that ion exchange chromatography can be used for chromatographic separation (paragraph 0045-0046), and that enriching the sample can include ion exchange chromatography and isoelectric focusing (paragraph 0076, 0100, 0101). GENTALEN further teaches that any combination of components and features described therein can be used together (paragraph 0137).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use ion exchange chromatography in addition to isoelectric focusing as is done in GENTALEN in the methods of MICHELS and REN due to the advantage ion exchange offers for capturing analytes based on charge (GENTALEN, paragraph 0046, 0101).
Claim 4 is rejected under 35 U.S.C. 103 as being obvious over MICHELS in Imaged Capillary Isoelectric Focusing for Charge-Variant Analysis of Biopharmaceuticals in view of REN in Isoforms analysis of recombinant human erythropoietin by polarity-reversed capillary isoelectric focusing and further in view of LIU in US 20080206102.
With respect to Claim 4, MICHELS and REN teach of the claims as shown above, but do not teach of combining the fractions for an enriched sample.
LIU teaches of a method and device for simultaneous separation, fractionation, and collection of samples simultaneously (abstract). LIU further teaches that the method uses isoelectric focusing (IEF) in capillary tubes (paragraph 0023)—so reads on capillary isoelectric focusing. LIU teaches that the separation is based on the charge properties (charges and charge variants) of the protein and sample (paragraph 0004).
LIU further teaches the IEF sample is prepared by mixing ampholytes with a protein sample (paragraph 0025-0027), the sample is the loaded into the continuous capillary (the thin-line of FIG. 1A) (paragraph 0029), and then the IEF is run (paragraph 0030) that the sample including protein of interest is subjected to isoelectric focusing to separate said charge variant of protein of interest as claimed.
The proteins are collected inside the segmented capillaries. It is noted that although the sample is "split" into 100 fractions, proteins of similar pI are "focused" in one or two (combined) fractions after IEF (paragraphs 0030-0031, & 0023 & 0025). This reads on the instant step b), which requires collecting, “at least one,” fraction, and also instant step c) which requires repeating steps a) and b) “at least once,” since the 100 initial fractions read on repeating the IEF, and collecting “two,” fractions reads on repeating the collecting. Since the 100 fractions are narrowed down to two collected samples, this means that from the 100 samples the proteins of interested are collected and combined into one or two samples as claimed for instant step d).
Protein “enrichment,” is the concentrating of specific proteins or making them more abundant for analysis. LIU teaches of concentration of the proteins by IEF so this reads on the claimed “method for enriching,” (paragraph 0016). The protein separated is the “charge variant,” of the protein of interest (paragraph 0004).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to collect the protein samples as is done in LIU in the methods of MICHELS and REN due to the advantage this offers for retaining resolution of IEF (paragraph 0031).
Response to Arguments
Applicant's arguments filed 04/06/2026 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to claim(s) have been considered but are moot because the new ground of rejection does not rely on the combination of references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Specifically the claims were significantly amended 04/06/2026--- and new primary references used are MICHELS in view of REN. LIU and GENTALEN are used only as supporting references now instead of primary references. Therefore, applicant’s arguments are not commensurate in scope with the instant rejections made.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
MADDEN in Reverse Isoelectric Focusing Procedure Resolves Charge Variants of Basic Proteins
MADDEN is used to remedy this. MADDEN further teaches of reverse isoelectric focusing for resolving charge variants of basic proteins (title). MADDEN further teaches that NEPHGE, nonequilibrium pH gradient electrophoresis is used (Page 203, column 2, paragraphs 1-2), and that they have chosen to call this procedure “reverse IEF,” (page 203, column 1, paragraph 1) and that this technique resolves/separates charge variants of basic proteins (title). NEPHGE, which MADDEN names reverse IEF, is the same method used in LIU.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
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