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 .
Priority
Applicant’s claim for the benefit of a prior-filed application (371 of PCT/IB2021/052739, filed 04/01/2021, which has PRO 63/009,080, filed 04/13/2020) under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claim Interpretation
The claimed invention recites the phrase “buffer exchange(s)”. Applicant has defined “exchange” in the disclosure as (pg. 6, lines 29-33):
"exchange" does not require changing the buffer. Although a buffer exchange may include a complete change in buffers (i.e., change of one buffer for another buffer) by known methods (e.g., Tangential Flow Filtration or Crossflow Filtration), an "exchange" can also include modifying a buffer by, e.g., changing the pH, changing the conductivity, and/or diluting the sample of interest. It may also be referred to as a buffer change or a buffer adjustment
Claim Rejections - 35 USC § 102/103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claim(s) 1, 4-6, 12, and 13 is/are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over XENOPOULOS et al. (US 2015/0133636 A1) with evidentiary support from KOZLOV et al. (US 2013/0245139 A1).
Regarding Claims 1 and 4, XENOPOULOS discloses a method for purifying a target molecule from a sample comprising depth filtration to remove one or more impurities and flow-through purification using two or more media (p0014; p0021; p0173-0179; see Table 1 on pg. 13). The target molecule is an antibody, e.g., monoclonal antibody (p0018), and the sample comprises cell culture (p0026). In some embodiments, XENOPOULOS teaches a solution change to adjust solution pH (p0034) or to add a precipitant to aid in impurity removal during depth filtration (p0113, p0119, p0180). The flow-through purification employs an anion exchange chromatography step (p0237) utilizing a porous membrane comprising polymeric materials (p0240-0241) and coated with suitable monomers/polymer ligands having appropriate moieties (p0242-245). The flow-through purification further employs an additional step, specifically a cation exchange chromatography step (p0247, p0253); said step employs a solid support containing one or more cation exchange binding groups (p0253). XENOPOULOS references Application No. 13/783941 (published KOZLOV et al. US 2013/0245139 A1 is referenced herein) for further details regarding the flow-through CEX process; KOZLOV discloses such solid supports for CEX include porous media, including polymeric porous membranes functionalized with negatively charged ionic binding groups (p0100-p0104; p0109-0110, p0114).
Although XENOPOULOS further discloses in p0255 the use of a pH adjustment to buffer solutions prior to the CEX step, XENOPOULOS teaches such a step as optional: “The use of a flow-through cation-exchange step (CEX) may necessitate a reduction of solution pH to increase affinity and capacity for impurities” (emphases added), i.e., a pH adjustment step is not required depending on the desired separation outcome. Indeed, the prior art further states in p0235: “In some embodiments… in-line static mixers… may be used”, i.e., buffer exchanges are optional and not required by the prior art. Furthermore, as noted earlier by the prior art, “[b]y reducing or eliminating steps, such as intermediate washing, the application of continuous chromatography for higher titers (target protein concentrations) is enabled… [and] simplifies the timing required for all titer conditions during continuous chromatography” (p0216). Thus, the prior art provides sufficient motivation for one of ordinary skill in the art to exclude a buffer exchange step between the AEX step and the CEX step.
Regarding the limitation “salt-tolerant” with respect to the anion exchange filter element, the limitation is broad and includes any AEX filter element; thus, the prior art disclosure of an AEX filter element reads on this limitation.
Regarding Claim 5, XENOPOULOS discloses or makes obvious the flow-through process of Claim 1. The prior art further discloses the target molecule is an antibody, e.g., monoclonal antibody (p0018).
Regarding Claim 6, XENOPOULOS discloses or makes obvious the flow-through process of Claim 1. Prior to the flow-through purification steps, XENOPOULOS discloses viral inactivation of the depth filtered cell culture solution (p0228-0233).
Regarding Claims 12 and 13, XENOPOULOS discloses or makes obvious the flow-through process of Claim 1. XENOPOULOS further discloses exemplary AEX media include ligands such as those based on quaternary ammonium ions and weak anion exchangers based on primary, secondary, and tertiary amines (p0239).
Claim Rejections - 35 USC § 103
Claim(s) 2, 3, and 7-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over XENOPOULOS et al. (US 2015/0133636 A1), as applied to Claim 1 above, and further in view of BOTHOF et al. (US 8,846,203 B2).
Regarding Claims 2 and 3, as applied to the rejection of Claim 1 XENOPOULOS discloses or makes obvious a flow through process for purifying a target molecule from a biological solution. XENOPOULOS further discloses that although the overall disclosed method includes 4 steps, i.e., clarification, bind and elute chromatography, virus inactivation, and flow-through purification, any of these process steps can be removed without affecting other process steps (p0099). Furthermore, XENOPOULOS notes “[b]y reducing or eliminating steps, such as intermediate washing, the application of continuous chromatography for higher titers (target protein concentrations) is enabled… [and] simplifies the timing required for all titer conditions during continuous chromatography” (p0216). Thus, absent showings of criticality or non-obviousness beyond the advantage disclosed by XENOPOULOS, one of ordinary skill in the art would find it obvious to perform depth filtration immediately followed by anion exchange and immediately followed by cation exchange as cited in Claim 2 or to include a buffer exchange after the step of depth filtration as cited in Claim 3.
XENOPOULOS is deficient in disclosing the adsorptive depth filter is an anion exchange adsorptive depth filter.
BOTHOF discloses the functionalization of porous substrates with ligands for use in selectively binding and removing biological materials from biological samples (c1/17-21). Such ligands have an affinity for binding negatively charged biomaterials (c2/28-29). Advantageously, compared with non-modified porous substrates, the functionalization of such porous substrates with these ligands enhances the affinity for negatively charged biological materials, such as host cell proteins, DNA, RNA, and viruses and more importantly allows for the positively charged materials, especially antibodies, to be purified (c4/24-28). The nature of the problem to be solved would have led one of ordinary skill in the art to combine the elements as claimed by known methods with no change in their respective, individual functions, and the combination would have yielded nothing more than predictable results (MPEP §2143.01 A). It is further noted that the BOTHOF prior art constitutes Applicant-admitted prior art as it pertains to grafted ligand-functional polymers disclosed by Applicant (see Specification, pg. 8, lines 29-32).
Regarding Claim 7, XENOPOULOS discloses or makes obvious the flow-through process of Claim 1. While XENOPOULOS teaches the use of depth filters having graded layers of polymeric non-woven fibers with an anisotropic pore distribution to filter cellular debris and particulate matter from cell culture (e.g., p0174-0176, p0178), the prior art is deficient in disclosing the depth filter further comprises immobilized anion exchange ligands.
BOTHOF discloses the functionalization of porous substrates with ligands for use in selectively binding and removing biological materials from biological samples (c1/17-21). Such ligands have an affinity for binding negatively charged biomaterials (c2/28-29). Advantageously, compared with non-modified porous substrates, the functionalization of such porous substrates with these ligands enhances the affinity for negatively charged biological materials, such as host cell proteins, DNA, RNA, and viruses and more importantly allows for the positively charged materials, especially antibodies, to be purified (c4/24-28). The nature of the problem to be solved would have led one of ordinary skill in the art to combine the elements as claimed by known methods with no change in their respective, individual functions, and the combination would have yielded nothing more than predictable results (MPEP §2143.01 A). It is further noted that the BOTHOF prior art constitutes Applicant-admitted prior art as it pertains to grafted ligand-functional polymers disclosed by Applicant (see Specification, pg. 8, lines 29-32).
Regarding Claims 8-11, modified XENOPOULOS makes obvious the flow-through process of Claim 7. BOTHOF further discloses the ligand-functionalized substrates comprises a number of components including (a) a grafted photoinitiator group extending from the surface of the base substrate; (b) one or more ligand monomers of Formula II (see column 3 middle); (c) optionally one or more monomers having at least one acryloyl group; and (d) optionally one or more hydrophilic monomers (c4/35-43), e.g., of the form (c13/23-32):
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Ligand monomers of Formula II (column 3, middle):
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Such a formula is disclosed by BOTHOF to include cationic nitrogen-containing ligands, including a number of primary amines and quaternary ammonium salts (Formula X; c16/31-55).
Regarding Claim 16, XENOPOULOS discloses or makes obvious the flow-through process of Claim 12. XENOPOULOS is deficient in explicitly disclosing the salt-tolerant anion exchange nonfibrous porous filter element comprises a nonfibrous porous filter element and a ligand-functional polymer grafted thereto having the claimed formula.
BOTHOF discloses the functionalization of porous substrates with ligands for use in selectively binding and removing biological materials from biological samples (c1/17-21). Such ligands have an affinity for binding negatively charged biomaterials (c2/28-29). Porous substrates include microporous membranes, e.g., those formed by thermally-induced phase separation (c5/48-52). These substrates are functionalized with grafted groups comprising a number of components including one or more ligand monomers of Formula II (see column 3 middle); (c) optionally one or more monomers having at least one acryloyl group; and (d) optionally one or more hydrophilic monomers (c4/35-43), e.g., of the form (c13/23-32):
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Ligand monomers of Formula II (column 3, middle):
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Advantageously, compared with non-modified porous substrates, the functionalization of such porous substrates with these ligands enhances the affinity for negatively charged biological materials, such as host cell proteins, DNA, RNA, and viruses and more importantly allows for the positively charged materials, especially antibodies, to be purified (c4/24-28).
The nature of the problem to be solved would have led one of ordinary skill in the art to combine the elements as claimed by known methods with no change in their respective, individual functions, and the combination would have yielded nothing more than predictable results (MPEP §2143.01 A). It is further noted that the BOTHOF prior art constitutes Applicant-admitted prior art as it pertains to salt-tolerant membrane filters that are “made using standard techniques” as disclosed by Applicant (see Specification, pg. 18, lines 21-23).
Claim(s) 14 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over XENOPOULOS et al. (US 2015/0133636 A1), as applied to Claim 13 above, and further in view of RASMUSSEN et al. (US 10,239,828 B2).
Regarding Claims 14 and 15, XENOPOULOS discloses or makes obvious the flow-through process of Claim 13. XENOPOULOS is deficient in explicitly disclosing the cationic nitrogen-containing ligands of the salt-tolerant anion exchange nonfibrous porous filter element comprises guanidinyl-containing ligands (Claim 14) or that the ligands further comprise interpolymerized monomer units comprising a guanidinyl-containing ligand monomer, an amide monomer, an oxy monomer (selected from epoxy and alkyl ether functional monomer units), and a polyalkylene oxide monomer (Claim 15).
RASMUSSEN discloses guanidino-functional polymers used to bind negatively charged biomaterials for the separation and purification of various target biomaterials (c1/50-53; c1/33-47). The polymers are represented by the general formula (column 3, top):
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wherein R1 is selected from hydrogen, alkyl, aryl, and combinations thereof; R2 is selected from hydrocarbylene, heterohydrocarbylene, and combinations thereof; each R3 is independently selected from hydrogen, hydrocarbyl, heterohydrocarbyl, and combinations thereof; R4 is selected from hydrogen, hydrocarbyl, heterohydrocarbyl (for example, R4 can comprise -R2-NH-C(=NR3)-N(R3)2, so as to provide a compound having more than one guanidino moiety), and combinations thereof; and R5 is selected from hydrocarbylene, heterohydrocarbylene, and combinations thereof (c3/12-26).
It is further noted that the RASMUSSEN prior art constitutes Applicant-admitted prior art as it pertains to salt-tolerant membrane filters that “can be made using standard techniques” as disclosed by Applicant (see Specification, pg. 18, lines 21-23).
Claim(s) 17 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over XENOPOULOS et al. (US 2015/0133636 A1), as applied to Claim 1 above, and further in view of COLAK ATAN et al. (US 2019/0194250 A1).
Regarding Claim 17, XENOPOULOS discloses or makes obvious the flow-through process of Claim 1. As noted earlier, evidentiary support KOZLOV discloses such CEX filter elements are porous media, including polymeric porous membranes functionalized with negatively charged ionic binding groups (p0100-p0104; p0109-0110, p0114). However, XENOPOULOS is deficient in disclosing the instant limitations directed toward the cation exchange nonfibrous porous filter element.
COLAK ATAN discloses processes for separating target proteins in a biological solution (abstract), e.g., monoclonal antibodies from a protein solution (p0006), utilizing filter media comprising porous substrate membranes functionalized with negatively charged binding groups (p0008; p0077). These filter media include a porous substrate and disposed on the porous substrate, a polymer that includes a hydrocarbon backbone and a plurality of pendant groups attached to the hydrocarbon backbone; said pendant groups including at least one acidic group or salt thereof and a spacer group that directly links the at least one acidic group or salt thereof to the hydrocarbon backbone by a chain of at least six catenated atoms (p0008-0010). At the time of the filing of the invention, one of ordinary skill in the art would have found it obvious to include the filter media taught by COLAK ATAN as the cation exchange nonfibrous porous filter element disclosed or made obvious by XENOPOULOS. The nature of the problem to be solved would have led one of ordinary skill in the art to combine the elements as claimed by known methods with no change in their respective, individual functions, and the combination would have yielded nothing more than predictable results (MPEP §2143.01 A). It is further noted that the COLAK ATAN prior art constitutes Applicant-admitted prior art as it pertains to cation exchange membrane filters that “can be made using standard techniques” as disclosed by Applicant (see Specification, pg. 20, lines 24-26).
Regarding Claim 18, modified XENOPOULOS makes obvious the flow-through process of Claim 17. COLAK ATAN further discloses the polymer disposed on the porous substrate includes interpolymerized units of at least one monomer (p0055), i.e., copolymerized with other monomers having other types of ligands to advantageously adjust binding capacities and/or to achieve special properties (p0135-0138).
Response to Amendments
Applicant’s amendments filed 18 December 2025 have been fully considered.
Regarding the objections of Claims 11, 16, and 18, Applicant’s amendments are persuasive; these objections have been withdrawn.
Regarding the rejections of Claims 11 and 15-18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, Applicant’s amendments to Claims 11, 15, 16, and 17 are persuasive; these rejections have been withdrawn.
Regarding the rejections of Claim(s) 1, 4-6, 12, and 13 under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over XENOPOULOS et al. (US 2015/0133636 A1) with evidentiary support from KOZLOV et al. (US 2013/0245139 A1); Claim(s) 2, 3, and 7-11 under 35 U.S.C. 103 as being unpatentable over XENOPOULOS et al. (US 2015/0133636 A1) in view of BOTHOF et al. (US 8,846,203 B2); Claim(s) 14 and 15 under 35 U.S.C. 103 as being unpatentable over XENOPOULOS et al. (US 2015/0133636 A1), in view of RASMUSSEN et al. (US 10,239,828 B2); and Claim(s) 17 and 18 under 35 U.S.C. 103 as being unpatentable over XENOPOULOS et al. (US 2015/0133636 A1) in view of COLAK ATAN et al. (US 2019/0194250 A1), no substantial amendments have been filed. The grounds of rejection are maintained.
Response to Arguments
Applicant’s arguments filed 18 December 2025 have been fully considered but are not persuasive.
Applicant argues the following:
Regarding the rejection of Claim 1, “Xenopoulos does not disclose all the limitations of independent claim 1. For example, Xenopoulos does not teach a flow-through process for purifying a target molecule wherein the flow-through process comprises one or two buffer exchanges, with no buffer exchange between the sample contacting the salt-tolerance anion exchange nonfibrous porous filter element and the cation exchange nonfibrous porous filter element, as encompassed by independent claim 1” (pg. 13, top).
“Xenopoulos discloses a method comprising buffer exchanges between contacting anion exchange and cation exchange filter elements, which is in direct contrast to independent claim 1” (pg. 13, middle);
“It appears as though the Office Action construes the pH adjustment step disclosed in Xenopoulos as being optional or not required. This is in direct contrast with what is disclosed in Xenopoulos when taken as a whole” (pg. 13, bottom); Applicant then cites p0348 of XENOPOULOS arguing that “The step of pH adjustment disclosed in Xenopoulos can only be omitted when the pH of the sample is already at a pH of 5, otherwise it is required”
Regarding the rejection of Claim 4, “Xenopoulos does not disclose all the limitations of independent claim 4. For example, Xenopoulos does not teach a flow-through process for purifying a target molecule comprising contacting a sample with a salt-tolerant anion exchange nonfibrous porous filter element and immediately thereafter, contacting the sample with a cation exchange nonfibrous porous filter element” (pg. 15, top).
Applicant summarizes the points made regarding the rejection of Claim 1;
“Based on the plain language of claim 4, notably the phase "immediately thereafter", the processes recited would necessarily exclude a buffer exchange between contacting a sample with an anion exchange and subsequently contacting the sample with a cation exchange” (pg. 15, middle).
The Examiner respectfully disagrees.
The Examiner will address Arguments (1) and (2) because both arguments are directed toward the same reasoning. It is noted that Applicant is citing one of the examples provided by XENOPOULOS, namely Example 9, which describes an embodiment where a surge tank is utilized in the flow-through purification to adjust the buffer pH before the CEX step (p0347-0351). Applicant has misinterpreted this embodiment to be a “required” condition for the entire XENOPOULOS prior art as a whole. However, XENOPOULOS clearly states in p0287 in describing the subsequently presented examples (of which Example 9—the Applicant-cited example—is part of): “This invention is further illustrated by the following examples which should not be construed as limiting” (emphasis added). Even earlier, XENOPOULOS states that “[i]n some preferred embodiments, the systems described herein include one or more static mixers for buffer exchange and/or in-line dilution” (p0283), i.e., the disclosure of a buffer exchange prior to CEX utilizing static mixers as cited by Applicant in Example 9 of XENOPOULOS is merely a preferred embodiment and does not constitute teaching away from the broader disclosure or nonpreferred embodiments (In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use” (In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994); MPEP §2123 II).
Applicant’s further arguments pertaining to the remaining prior art rejections are dependent on the arguments as presented above.
Conclusion
THIS ACTION IS MADE FINAL. 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 RYAN B HUANG whose telephone number is (571)270-0327. The examiner can normally be reached 9 am-5 pm EST.
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/Ryan B Huang/Primary Examiner, Art Unit 1777