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 .
Priority
Applicant’s claim for the benefit of a prior-filed application (DIV of 16/486,653, filed 16 August 2019; which is a 371 of PCT/EP2018/053816, filed 15 February 2018) 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 (GB1703116.2, filed 27 February 2017) under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 16/486,653, filed on 16 August 2019.
Claim Interpretation
The claims recite a “KD” value. As defined in the Specification on pg. 5, lines 10-16:
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Thus, the “KD” value will be interpreted as KD = (VR – V0)/(Vt – V0) where VR is the retention volume (or elution volume) of the target analyte, V0 is the volume of the void fraction of the column, and Vt is the total liquid volume of the column.
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) 1-14 and 16-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over BRYNTESSON et al. (US 7,901,581) in view of JOHANSSON et al. (US 2014/0329995 A1), RAJENDRAN et al. (US 2016/0176921 A1), and BIOPHARMACEUTICAL PURIFICATION STRATEGIES (Genetic Engineering & Biotechnology News, Vol. 27, No. 11, 01 June 2007; https://www.genengnews.com/insights/biopharmaceutical-purification-strategies/; accessed 06 February 2026; hereafter BPS).
Regarding Claim 1, BRYNTESSON discloses a semi-continuous liquid chromatography method (c3/25-28). The method comprises a number of steps (c5/49-c6/10) involving the capture of target compounds using adsorbents, whereby the target compounds are antibodies (c6/39-41), the adsorbents are chromatography columns comprising the same kind of packing material, i.e., affinity resins, such as Protein A-based resins wherein Protein A is coupled to particles (i.e., a separation matrix comprising… particles to which antibody-binding protein ligands have been covalently immobilized; c5/31-35; c4/36-44):
“(a) passing feed comprising at least one target compound across a 1st adsorbent…” (i.e., conveying a process feed through at least a first chromatography column to adsorb antibodies from said feed);
“(b) …passing wash liquid across the 1st adsorbent to which target compound has bound” (i.e., optionally washing said first chromatography column);
“(d) regenerating the 1st adsorbent”, wherein the step of “regenerating” involves releasing the bound compounds and is also known as “elution of compounds” (i.e., conveying an eluent through said first chromatography column to elute antibodies; c4/23-29); and
“wherein at least one target compound is collected in step (d)” (i.e., recovering said eluent with antibodies).
BRYNTESSON is deficient in disclosing the claimed limitation that the separation matrix [comprises] porous particles, the density of ligands is above 5 mg/mL, the volume-weighted median diameter of said porous particles is at least 10 µm and below 30 µm and the said porous particles have a gel phase distribution coefficient, expressed as KD for dextran of molecular weight 110 kDa of 0.5-0.9.
JOHANSSON discloses a separation matrix/affinity chromatography matrix comprising polypeptide proteins capable of binding immunoglobulins or immunoglobulin-containing proteins (p0017). The polypeptide protein content in the separation matrix is 7-15 mg/mL, i.e., suitable for a high binding capacity for immunoglobulins (p0025), which reads on the claimed range of a ligand density above 5 mg/mL. The separation matrix comprises a solid support comprising spherical beads having a volume-weighted average diameter of 1-30 µm, i.e., suitable for high resolution analytical separations (p0028), which significantly overlaps with the claimed range of at least 10 µm and below 30 µm and therefore establishes a case of prima facie obviousness (MPEP 2144.05). JOHANSSON further discloses the Kay or Kd value of the porous separation matrix as the fraction of the pore volume available to a probe material of a particular size being 0.7-0.9 as measured with dextran of MW 110 kDa (p0029), which reads upon the claimed range of a KD of 0.5-0.9. Advantageously, such a separation matrix with this polypeptide having these defined properties is able to bind large amounts of immunoglobulins and has high alkali stability (p0011-0012); the high alkali stability addresses the problematic issue of the harsh conditions encountered by adsorbent ligands that results in lowered capacities due to their instabilities at high pH, especially encountered during the necessary cleaning/sanitizing of separation matrices with NaOH (p0005). Indeed, as is known to one of ordinary skill in the art (and even acknowledged by BRYNTESSON), during regeneration of the adsorbents, the columns and adsorbents require cleaning with highly aggressive sodium hydroxide alkaline solutions (BRYNTESSON; c8/26-31). Thus, prior to the effective filing date of the claimed invention, one of ordinary skill in the art would have found it obvious to provide a separation matrix having a ligand density, a volume-weighted median diameter of porous particles, and a gel phase distribution coefficient of porous particles as taught by JOHANSSON as the affinity chromatography matrix of the method disclosed by BRYNTESSON.
BRYNTESSON further discloses a primary capture step of monoclonal antibodies in Example 2 having a “load” of 56 g/L (Example 2, Table 2, c11/30-62). BRYNTESSON also reports a “feed” of 0.85 g/L in the same Example 2. Such a disclosure is differentiated from the presently claimed invention, which requires that the process “feed” comprise at least 4 mg/mL antibodies. BRYNTESSON disclosure of a “load” of 56 g/L is directed toward the amount of antibodies capably “loaded” onto the separation column and is not considered the mAb concentration in the feed. Thus, modified BRYNTESSON is deficient in disclosing said process feed comprises at least 4 mg/mL antibodies.
However, different mAb “feed” concentrations are known in the art. For example, RAJENDRAN discloses capturing recombinant protein through the use of affinity chromatography, specifically, Protein A binding for antibody recombinant proteins (p0084-0086). Such recombinant proteins include monoclonal antibodies (p0003; p0004). The feed medium includes between about 0.05 mg/mL to about 100 mg/mL recombinant protein or even between about 0.5 mg/mL to about 10 mg/mL recombinant protein (p0087), which overlaps with the claimed range of said process feed comprises at least 4 mg/mL antibodies and therefore, establishes a case of prima facie obviousness (MPEP 2144.05). Absent showings of unexpected results or criticality to the claimed range of at least 4 mg/mL antibodies, such a limitation would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention because all claimed elements were known in the prior art and the combination would have yielded nothing more than predictable results (MPEP §2143.01 A). Thus, the claimed process flow of at least 4 mg/mL antibodies is obvious over RAJENDRAN and would have been obvious to combine with the antibody separation method made obvious by modified BRYNTESSON.
Modified BRYNTESSON is deficient in disclosing that the first chromatography column has a packed bed height not exceeding 10 cm.
BRS discloses considerations for optimizing a packed bed height in a chromatography column (§Optimizing Bed Height, §Manufacturing-scale Considerations, pg. 3-5) wherein bed heights are typically in the range 10-20 cm (FIG. 1, top of pg. 3; FIG. 2 bottom of pg. 4; §Optimizing Bed Height, par. 1).
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While the disclosed range overlaps with the claimed range of “not exceeding 10 cm”, BRS further discloses bed height is optimizable and dependent on a number of factors, including volumetric flow rate, residence time, column dimensions (i.e., diameter), and compressibility of adsorbent resin/matrix. As taught by BRYNTESSON, the adsorbents utilized in the semi-continuous liquid chromatography method are used in a packed bed (c5/24-25) and further, JOHANSSON discloses high-binding capacity adsorbents comprising agarose (p0025, p0026); these types of adsorbents are taught by BRS as exemplary compressible chromatography media with decreased bed heights, e.g., less than 10 cm (§Optimizing Bed Height, par. 2; FIG. 2, bottom of pg. 4). Thus, prior to the effective filing date of the claimed invention, one of ordinary skill in the art would have found it obvious to limit the packed bed of the first chromatography column to a bed height not exceeding 10 cm as taught by BRS for the method of antibody separation made obvious by modified BRYNTESSON.
Regarding Claim 2, modified BRYNTESSON makes obvious the method of Claim 1. JOHANSSON further discloses qb10% (mg/mL) data for IgG (Table 1, p0067) for the disclosed separation matrices; all tested samples showed qb10% of at least 31.2 mg/mL, which reads upon the claimed range of a dynamic IgG capacity q10% of at least 20 mg/mL. While JOHANSSON reported these values at longer residence times (i.e., at least 2.4 minutes), the claimed limitation requiring that the q10% value at residence time of 0.5 min is at least 20 mg/mL is directed toward a functional limitation of the claimed separation matrix (i.e., the ability to retain/adsorb target analyte up to a certain threshold for a certain period of time). There is nothing in the Specification or the disclosure of the claimed invention that correlates such a measurement to a physical property of the claimed separation matrix. Because Applicant has claimed other physical properties of the separation matrix, i.e., ligand density range and particle diameter range, and because the prior art separation matrix also possesses such claimed physical properties and ranges, then the functional limitation of a q10% of at least 20 mg/mL at 0.5 min residence time is inherent. The burden shifts to Applicant to establish that the prior art does not possess the characteristic relied on. In re Schreiber, 128 F.3d at 1478, 44 USPQ2d at 1432; In re Swinehart, 439 F.2d 210, 213, 169 USPQ 226, 228 (CCPA 1971) (MPEP 2114 I).
Furthermore, BRYNTESSON acknowledges that the breakthrough point can be optimized in the process: “it will be easy to determine the point of time either by volumes of outflow or simply be measuring the time passed since applying the feed” (c7/19-24) further indicating that “after a suitable period of time, the outflow is directed to the next adsorbent in series whereby essential loss of target compound is avoided” (c7/2-5). One of ordinary skill in the art immediately recognizes that BRYNTESSON discloses that the breakthrough point and time of a sample can be optimized. 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). Thus, the claimed q10% value at a residence time of 0.5 min would have been obvious to optimize to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Regarding Claim 3, modified BRYNTESSON makes obvious the method of Claim 2. Both BRYNTESSON and JOHANSSON disclose Protein A binding ligands (e.g., BRYNTESSON, c5/35-36; JOHANSSON, p0017). Such a ligand binds to the Fc region (i.e., wherein the antibody-binding protein ligands comprise an Fc-binding protein; JOHANSSON, p0017).
Regarding Claim 4, modified BRYNTESSON makes obvious the method of Claim 1. BRYNTESSON discloses at least three chromatography columns (i.e., wherein the process feed is conveyed through a chromatography system comprising a plurality of chromatography columns; c3/25-28).
Regarding Claim 5, modified BRYNTESSON makes obvious the method of Claim 1. BRYNTESSON discloses other steps in the process that wholly read on the claimed method (c5/49-c6/10).
“(a) passing feed comprising at least one target compound across a 1st adsorbent, and directing the outflow from the 1st adsorbent to a 2nd adsorbent” (i.e., in step a) an effluent from said first chromatography column is passed through a second chromatography column);
“(b) redirecting the feed to the 2nd adsorbent, and passing wash liquid across the 1st adsorbent to which target compound has bound” (i.e., after step a), in a step a’), the process feed is redirected to the second chromatography column…);
“(c) directing the wash liquid outflow to the 3rd adsorbent and subsequently directing the outflow from the 2nd adsorbent to a 3rd adsorbent” (i.e., …and an effluent from the second chromatography column is passed through a third chromatography column);
“(d) regenerating the 1st adsorbent” (i.e., step c); step c) is performed before step a’’));
“(e) redirecting the feed to said 3rd adsorbent, and passing wash liquid across the 2nd adsorbent to which target compound has bound” (i.e., after step a’), in a step a’’), the process feed is redirected to the third chromatography column…);
“(f) directing the wash liquid outflow to the 1st adsorbent, and subsequently directing the outflow from the 3rd adsorbent to the 1st adsorbent” (i.e., … and an effluent from the third chromatography column is passed through the first chromatography column);
“(g) regenerating the 2nd adsorbent” (i.e., after step a’), in a step c’), the eluent is conveyed through the second chromatography column to elute antibodies);
“(h) redirecting the feed to said 1st adsorbent, and passing wash liquid across the 3rd adsorbent to which target compound has bound”;
“(i) directing the wash liquid outflow to the 2nd adsorbent, and subsequently directing the outflow from the 1st adsorbent to the 2nd adsorbent”;
“(j) regenerating the 3rd adsorbent” (i.e., after step a’’), in a step c’’), the eluent is conveyed through the third chromatography column to elute antibodies); and
“(k) repeating steps (b)-(j)” (i.e., the sequence of steps a), a’), a’’), c), c’), and c’’) is optionally repeated one or more times).
Regarding Claims 6-11, modified BRYNTESSON makes obvious the methods of Claims 5 and 9. BRYNTESSON acknowledges that the breakthrough point can be optimized in the process: “it will be easy to determine the point of time either by volumes of outflow or simply be measuring the time passed since applying the feed” (c7/19-24) further indicating that “after a suitable period of time, the outflow is directed to the next adsorbent in series whereby essential loss of target compound is avoided” (c7/2-5). One of ordinary skill in the art immediately recognizes that BRYNTESSON discloses that the breakthrough point and time of a sample can be optimized. 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). Thus, the claimed q10% value at the various residence times would have been obvious to optimize to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Regarding Claim 12, modified BRYNTESSON makes obvious the method of Claim 5. BRYNTESSON further discloses a cleaning-in-place (CIP) step after elution of a column wherein an alkaline solution such as sodium hydroxide is used (i.e., steps e), e’), and e’’), after steps c), c’), and c’’), respectively, comprising conveying a cleaning liquid through said first, second, and third chromatography columns; c8/26-35).
Regarding Claim 13¸ modified BRYNTESSON makes obvious the method of Claim 12. BRYNTESSON is deficient in explicitly disclosing a concentration of the alkali wash solution, much less being at least 0.1 M alkali. However, JOHANSSON recognizes that conventional practice in affinity chromatography requires the use of 0.1 to 1 M NaOH solution for cleaning and sanitizing (p0005). Thus, the claimed range of at least 0.1 M alkali would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Regarding Claim 14, modified BRYNTESSON makes obvious the method of Claim 13. BRYNTESSON further discloses sodium hydroxide as the alkaline solution (i.e., wherein the alkali comprises NaOH; c8/26-35).
Regarding Claim 16, modified BRYNTESSON makes obvious the method of Claim 1. RAJENDRAN the feed medium includes between about 0.5 mg/mL to about 15 mg/mL recombinant protein (p0087), which overlaps with the claimed range of said process feed comprises 4-15 mg/mL antibodies and therefore, establishes a case of prima facie obviousness (MPEP 2144.05).
Regarding Claim 17, modified BRYNTESSON makes obvious the method of Claim 1. JOHANSSON further discloses polypeptide density of 7-15 mg/mL (p0025), which reads upon the claimed range of 5 to 25 mg/mL.
Regarding Claim 18, modified BRYNTESSON makes obvious the method of Claim 1. JOHANSSON further discloses the solid support is a cross-linked polysaccharide (i.e., wherein said porous particles comprise a crosslinked polysaccharide; p0026-0027). Such cross-linking advantageously provides high rigidity suitable for high flow rates and high back pressures (p0027).
Regarding Claim 19, as described in the rejections of Claims 1 and 3, modified BRYNTESSON makes obvious the claimed method f separation of antibodies by affinity chromatography.
Response to Amendments/Arguments
Applicant’s arguments filed 14 October 2025 have been fully considered.
Regarding the rejections of Claims 1-14 and 16-19 under 35 U.S.C. 103 as being unpatentable over BRYNTESSON et al. (US Patent 7,901,581) in view of JOHANSSON et al. (US PGPub 2014/0329995 A1) and RAJENDRAN et al. (US 2016/0176921 A1), Applicant’s amendments are persuasive; these rejections have been withdrawn. However, upon further search and consideration, new grounds of rejection are made for Claims 1-14 and 16-19 under 35 U.S.C. 103 as being unpatentable over BRYNTESSON et al. (US Patent 7,901,581) in view of JOHANSSON et al. (US PGPub 2014/0329995 A1), RAJENDRAN et al. (US 2016/0176921 A1), and BIOPHARMACEUTICAL PURIFICATION STRATEGIES (Genetic Engineering & Biotechnology News, Vol. 27, No. 11, 01 June 2007; https://www.genengnews.com/insights/biopharmaceutical-purification-strategies/).
Applicant’s arguments have been considered but are not persuasive because they are directed to prior art rejections that have been withdrawn. Therefore, the arguments are not commensurate in scope with the present prior art rejections.
In particular, Applicant’s argument regarding RAJENDRAN disclosing bed heights of at least 20 cm as evidenced by Tables 7 and 8 is noted (pg. 6-7). Applicant is apparently arguing that such disclosures teaches away from the as-amended limitation of requiring bed heights of no more than 10 cm. However, such disclosed bed heights by RAJENDRAN are merely preferred embodiments. Disclosed examples and preferred embodiments do not constitute a teaching away from a 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). The newly cited prior art BRS discloses that bed heights are optimizable and even further discloses bed heights less than 10 cm are preferred for the types of adsorbents disclosed by BRYNTESSON and JOHANSSON.
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.
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