DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 20 March 2026 has been entered.
Priority
Applicant’s claim for the benefit of a prior-filed application (371 of PCT/KR2021/001523, filed 02/05/2021) under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority (KR10-2020-0021724, filed 02/21/2020) under 35 U.S.C. 119 (a)-(d) Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Amendment
Applicant’s amendments filed 20 March 2026 and 15 April 2026 have been fully considered.
Applicant has amended Claim 1 to include limitations of now-canceled Claim 2; and new Claim 11 has been added. Claims 1, 5, and 9-11 are pending.
In response to these amendments, the rejections of Claims 1 and 5 under 35 U.S.C. 103 as being unpatentable over KIM et al. (US 2016/0122384 A1) in view of VON HIRSCHHEYDT et al. (WO 2019/122054 A1, hereafter ‘054) are unchanged.
Response to Arguments
Applicant's arguments filed 15 April 2026 have been fully considered but they are not persuasive.
Applicant traverses the prior art rejection under KIM in view of ‘054 arguing that “the Office has failed to establish that one of ordinary skill in the art would have a reasonable expectation of success from the alleged combination” (pg. 5, par. 5) and instead argues that the results from the practice of the claimed method would not have been predictable (par. spanning pg. 5-6). Applicant that the as-amended Claim 1 now recites preliminary washing steps and therefore, the claim is now commensurate in scope with the unexpected results demonstrated in Example 2 of the instant application (pg. 6, par. 1).
Applicant further argues that the KIM reference is owned by the Applicant, and “the column volumes in Comparative Example 1, explicitly taught in the specification as reproducing the methods of Kim, were not made on arbitrary assumptions. Instead, the inventors strictly followed the actual process conditions disclosed in Kim” (pg. 6, par. 3); and further, “The composition and amount of buffer used in this Comparative Example are the buffers and volumes of Kim. As is evident by Table 3 of the application, the methods described in Kim require a buffer solution in the amount of 20 times or more the column volume be applied at least two times in the elution step” (pg. 7, par. 2). Applicant argues that “As described in Example 2 and the Comparative Example described in Table 6, the methods as instantly claimed result in excellent yields and charge variant profile. Specifically, in Table 6, the data shows that the purification steps of the methods of Kim result in only ~50% yield, while the instantly claimed methods yield greater than 60% while using less buffer and a shortened processing time. Specifically, the comparative experiment of Example 6 of the present application thus shows that the addition of a first elution step with 40-50mM NaCl, which is not disclosed by Kim, is associated with an increased yield” (pg. 8, par. 3-4; emphasis Applicant’s). Therefore, Applicant argues, “because Kim fails to teach or suggest adding a first elution step with 40-50mM NaCl, let alone that such additional elution step can increase the yield and allow for using smaller amounts of buffer, the Applicant submits the claims are allowable” (pg. 8, par. 5).
Applicant further argues secondary considerations with respect to price competitiveness in the production of biosimilar products utilizing the claimed method yielding reduced manufacturing cost and time (par. spanning pg. 8-9).
Applicant further argues that the claimed methods “proceed against conventional wisdom in the field”: “The conventional wisdom in the field of separating and purifying antibodies is that increasing the amount of buffer in the elution step increases the antibody yield. However, the presently claimed methods use less buffer and shorten the purification time, while improving the antibody yield. Proceeding contrary to accepted wisdom in the art is evidence of nonobviousness. In re Hedges” (pg. 9, par. 1). Applicant continues, arguing that “Nothing in either Kim nor '054 teaches or suggests the increased yield shown in the instant application, to which the claims correspond” (pg. 9, par. 3).
In light of these arguments, Applicant argues Claim 1 and depending claims are nonobvious, and the prior art rejections should be withdrawn. (pg. 10, par. 1-3).
The Examiner respectfully disagrees.
Applicant’s amendments to Claim 1 incorporating the preliminary washing steps of Claim 2 have been noted. The prior art rejection has been updated accordingly.
It is appreciated that Applicant has indicated the differences between the primary prior art KIM and the disclosed examples in the instant application; however, despite Applicant’s insistence that the prior art KIM discloses uses of column volumes (see Table 3) of 30 and 20 in a “Washing 4 Step” and an “Elution 1 Step”, respectively, and that such CVs differ from the claimed invention (see Table 2) and amount to evidence of improvement of the claimed invention over the prior art, such purported column volume values are nowhere to be found in the disclosure of KIM. A review of KIM indicates no such column volume numbers are disclosed, nor any volume. It is unclear how Applicant could interpret KIM to disclose any such column volume as argued. It is further noted that ‘054 does disclose a column volume range overlapping the claimed inventive column volumes and thereby renders obvious the claimed purification method.
Even if arguendo, KIM did disclose column volumes having values as those argued by the Applicant, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, KIM discloses a method for purifying bevacizumab antibody utilizing various wash and elution steps with specific buffers and under specific conditions; KIM is silent as to the column volumes of the elution buffers; however, ‘054 discloses column volumes and even further, discloses the advantages and benefits to step-wise gradient elution. Thus, the claimed invention is rejected over the combination of KIM and ‘054.
Regarding the argument of an unexpected result of increased yield, Applicant has argued that “the addition of a first elution step with 40-50mM NaCl, which is not disclosed by Kim, is associated with an increased yield” (emphasis Applicant’s; Arguments, pg. 8, par. 4). However, such a salt concentration range is not recited in independent Claim 1; the claim has required a broader range of 38-50 mM NaCl in the first elution step. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). While such a difference is relatively minor, it must be noted for the sake of delineating the metes and bounds of the claimed invention. Furthermore, even though KIM may not have explicitly disclosed the argued narrow salt concentration range, KIM does disclose a broader range that encompasses both the claimed and disclosed ranges; while Applicant has argued that specific unexpected results were due to this salt range such arguments lack nexus with independent Claim 1. Therefore, the prima facie case of obviousness has not been overcome.
Regarding Applicant’s arguments for secondary consideration, because the prima facie case of obviousness has not been overcome, such arguments are moot with respect to the rejection of Claim 1; however, they are noted and will be considered by the Examiner.
Regarding Applicant’s argument that the use of lower column volumes is contrary to accepted wisdom and is therefore evidence of nonobviousness, the Examiner respectfully disagrees. ‘054 discloses that the utilization of a step gradient advantageously speeds up separation times and reduces buffer consumption (pg. 49, lines 20-28). As such, Applicant’s reasoning is known to one of ordinary skill in the art and would be obvious to apply, i.e., such a methodology would not be “contrary to accepted wisdom”.
Thus, it is concluded that Applicant has not overcome the prior art rejections of the claimed invention.
Claim Objections
The claims fail to provide the appropriate status identifiers. After each claim number, the status identifier of the claim must be presented in a parenthetical expression, and the text of each claim under examination as well as all withdrawn claims (each with markings if any, to show current changes) must be presented. The listing will serve to replace all prior versions of the claims in the application (MPEP §714 IIC). Acceptable status identifiers and alternatives as set forth in 37 CFR 1.121(c) are listed in MPEP §714 IIC(E).
In this case, regarding Claim 1, it seems that the limitations of Claim 2 have been incorporated into Claim 1; however, no markings have been included in the as-amended text of Claim 1 to indicate that Claim 1 has been amended.
Canceled claims should not be removed from the amended document nor should newly added claims be assigned with claim numbers of canceled claims. Each amendment document that includes a change to an existing claim, including the deletion of an existing claim, or submission of a new claim, must include a complete listing of all claims ever presented (including previously canceled and non-entered claims) in the application. The listing will serve to replace all prior versions of the claims in the application (MPEP §714 IIC).
Claim 8 has seemingly been canceled in a prior claim set but is not listed in the as-filed claims.
Claim Rejections - 35 USC § 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 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, 5, and 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over KIM et al. (US 2016/0122384 A1) in view of VON HIRSCHHEYDT et al. (WO 2019/122054 A1, hereafter ‘054).
Regarding Claim 1, KIM discloses a purification method for monoclonal antibodies (abstract), including Bevacizumab (i.e., [a] method of purifying bevacizumab; p0022).
Briefly, a sample comprising the antibody to be purified and at least one host cell protein (HCP) is loaded onto a cation exchange column to remove the HCP from the sample; sample loading is conducted at pH 5.5-7.0 and conductivity 5-7 mS/cm onto an equilibrated cation exchange column (i.e., the method comprising: a step of loading a sample… and one or more host cell proteins (HCPs) and having a pH of 5.5 to 7.0… into an equilibrated cation exchange column; p0016). The disclosure of 5-7 mS/cm conductivity overlaps with the claimed range of a conductivity of 7 mS/cm to 8 mS/cm and therefore, establishes a case of prima facie obviousness (MPEP 2144.05).
After loading, the column is washed once with a 20 mM phosphate buffer at pH 6.0 (i.e., without salt) and then washed again with a 20 mM phosphate buffer (pH 6.5) with 30 mM sodium chloride (i.e., a primary washing step of washing… with a washing buffer comprising a 10 mM to 50 mM phosphate having a pH of 5.5 to 7.0 that does not comprise sodium chloride; a tertiary washing step of washing… with a washing buffer comprising a 10 mM to 50 mM phosphate having a pH of 6.0 to 7.0 that comprises 20 to 38 mM sodium chloride; p0056). Although KIM fails to disclose a “secondary washing step of washing the antibody with a washing buffer including a 10 mM to 50 mM phosphate having a pH of 5.5 to 7.0 that does not comprise sodium chloride”, this secondary washing step is identical to the first washing step. The mere duplication of parts or process steps has no patentable significance unless a new and unexpected result is produced (In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960); MPEP §2144.04).
Subsequently, the antibody is eluted with an elution buffer comprising 10-50 mM phosphate at pH 6.0-7.0 (i.e., a second elution step of eluting… with a buffer comprising a 10 mM to 50 mM phosphate with a pH of 6.0 to 7.0; p0027). KIM further discloses the elution buffer comprises 50-200 mM sodium chloride (p0027), which overlaps with the claimed range of a buffer comprising 50 mM to 60 mM sodium chloride of a second elution step (and also overlaps with the claimed range of a buffer comprising 38 mM to 50 mM sodium chloride of a first elution step) and therefore, establishes a case of prima facie obviousness (MPEP 2144.05).
KIM is deficient in explicitly disclosing that the eluting further comprises a first elution step of eluting with a buffer comprising a 10 mM to 50 mM phosphate with a pH of 6.0 to 7.0, comprising 38 mM to 50 mM sodium chloride. KIM is also deficient in disclosing 10 to 20 column volumes of buffer used in the first elution step and 5 to 12 column volumes of buffer used in the second elution step.
However, such a first elution step is considered obvious to one of ordinary skill in the art because the claimed elution comprises repeated elution steps with increasing buffer salt concentration and is considered a step gradient elution in the art. As disclosed by ‘054, the use of a step gradient elution advantageously speeds up separation times and reduces buffer consumption (pg. 49, lines 20-28). Indeed, even KIM seems to implies the use of multiple elution steps in Example 1-2 whereby after eluting with a 20 mM phosphate buffer comprising 60 mM sodium chloride, a “primary eluate” is obtained suggesting further elution steps to obtain secondary eluates (Example 1-2, p0056). The obvious expected result from the use of multiple elution steps would be the higher recovery of the target antibody—which is especially desired in view of the significant economic incentives in maximizing recovery and removing HCP contaminants (p0004-0005). Thus, prior to the effective filing date of the claimed invention, one of ordinary skill in the art would have found it obvious to apply a step gradient elution, i.e., performing at least two elution steps with increasing salt concentration, as taught by ‘054 in the purification method for monoclonal antibodies disclosed by KIM. Even though the prior art is deficient in explicitly disclosing the specific range of sodium chloride concentration utilized in a step gradient elution, such claimed ranges are obtainable by optimization. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation absent unexpected results or evidence indicating such optimum or workable ranges are critical (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); MPEP§2144.05).
‘054 further discloses 10-30 column volumes of eluting buffer in the disclosed stepwise gradient (pg. 49, lines 16-17). Although the prior art is deficient in explicitly disclosing treating with 10 to 20 column volumes of buffer (Claim 3) or 5 to 12 column volumes of buffer (Claim 4), such claimed ranges are obtainable by optimization. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation absent unexpected results or evidence indicating such optimum or workable ranges are critical (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); MPEP§2144.05).
Regarding Claim 5, modified KIM makes obvious the method of Claim 1. KIM further discloses bevacizumab has an isoelectric point of 8.3 in a neutral pH buffer (i.e., wherein the antibody has an isoelectric point of 6 to 11; p0058).
Regarding Claim 11, modified KIM makes obvious the method of Claim 1. KIM further discloses that the disclosed antibody purification method efficiently removes host cell protein impurities and purifies the antibody to “high purity and high yield” (p0048). KIM is deficient in explicitly disclosing a yield of at least 60% of the bevacizumab.
However, while KIM is deficient in disclosing a specific range, it is noted that both KIM and the present application utilize the term “high yield”, e.g., “when the method according to the present invention was used, a high yield of about 60% or more was shown…” (p0125, Specification). Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation absent unexpected results or evidence indicating such optimum or workable ranges are critical (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); MPEP§2144.05). Even further, it is well-understood in the art that a number of factors influence purification yields, especially initial sample compositions which have not been claimed or limited. As such, because the prior art states that the practice of the disclosed method would result in a “high yield” of antibody, one of ordinary skill in the art would be capable of achieving such high yield through routine optimization.
Claim(s) 9 and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over KIM et al. (US 2016/0122384 A1) in view of VON HIRSCHHEYDT et al. (WO 2019/122054 A1, hereafter ‘054) as applied to Claim 1 above, and further in view of JORGENSEN et al. (US 2021/0355215 A1).
Regarding Claim 9, modified KIM makes obvious the method of Claim 1. KIM further discloses a subsequent second purification step using a multilayer filter (p0032); said multilayer filter is an ultrafiltration (i.e., a step of subjecting a filtrate recovered by the elution step to ultrafiltration…; and a step of recovering the filtrate by allowing the filtrate to pass through a multi-layer filtration filter; p0060; Table 1, Step 3). KIM or modified KIM is deficient in disclosing diafiltration.
JORGENSEN discloses that after antibody purification to remove HCP (p0123), further purification steps of ultrafiltration and diafiltration are performed to advantageously further purify and concentrate the antibody sample (p0125). Thus, prior to the effective filing date of the claimed invention, one of ordinary skill in the art would have found it obvious to perform both ultrafiltration and diafiltration as taught by JORGENSEN after the disclosed cation exchange step in the method made obvious by KIM or modified KIM.
Regarding Claim 10, modified KIM makes obvious the method of Claim 9. KIM further discloses after the recovering a filtrate from the second purification step using a multilayer filter, a third purification step of passing the filtrate through an anion exchange column is performed (i.e., further comprising: removing the host cell protein using an anion exchange column after the step of recovering the filtrate by allowing the filtrate to pass through a multi-layer filtration filter; p0041).
Conclusion
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
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