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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/26/2026 has been entered.
Priority
The application claims domestic benefit to US provision application 63/108,194, filed 10/30/2020.
Claim Status
The Amendment, filed on 01/26/2026, is acknowledged in which:
Claims 1-40, 42-44, 46-48, 50, 53, 55-56, and 61-106 are canceled.
Claims 41, 45, 49, 52, and 57-60 are currently amended.
Claims 51 and 54 were previously presented.
Claims 107-111 are new.
Claims 41, 45, 49, 51-52, 54, 57-60, and 107-111 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/26/2026 has been considered by the examiner.
Withdrawn Objections and Rejections
In the office action dated 07/25/2025,
All previous rejections of claims 1, 6, 8-9, 29, 35, 61-62, 64-66, 69, 71, 83, 86, 89, and 99-106 are rendered moot in view of claim cancellations.
Claim 57 was rejected under 35 USC 112(b) for reciting unclear abbreviations. Applicant’s amendment to the claim has overcome the rejection and the rejection is withdrawn.
Claim 41 was rejected under 35 USC 103 as being unpatentable over WO’110 in view of Bak. Applicant’s amendment to the claim (i.e. narrowing the claim scope for just depth filtration) has overcome the rejection as previously stated and the rejection is withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Rajendran and Carta discussed below.
Claims 49 and 51 were rejected under 35 USC 103 as being unpatentable over Follman and Bak; claims 52 and 54 were rejected under 35 USC 103 as being unpatentable over Follman and Bak, and in further view of Liu; and claims 57-60 were rejected under 35 USC 103 as being unpatentable over Follman, Bak, and Liu, and in further view of Nguyen, Althouse, or 3M. Applicants amendment to change the dependency of the claims to base claim 41 has overcome the rejections as previously stated and the rejections are withdrawn. However, upon further consideration, a modified ground(s) of rejection are made in view of Rajendran and Carta discussed below.
Claims 49, 51, 52, 54, and 57-58 were provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over copending Application No. 17/517,531. Applicant’s amendment to change the dependency of the claims to base claim 41 has overcome the rejections and the rejections are withdrawn.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
New and Modified Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 41, 45, 49, 51-52, 54, and 110 are rejected under 35 U.S.C. 103 as being unpatentable over US 2016/0176921 A1 (herein Rajendran) and Carta (Bulletin 7000. Bio-Rad Laboratories. 2017), and as evidenced by the Zeta PlusTM datasheet (3M. 2016).
Rajendran teaches purification of antibodies from cells may exhibit slow flow rates and/or fouling due to plugging of one or more filters in the process with soluble protein aggregates, which can then result in recombinant protein loss and/or negatively impact the safety of the resulting antibody product. Rajendran discloses that depth filtration can be performed after (a) capture and (b) one or more unit operations (claims 1 and 21), including ion exchange chromatography (claims 4 and 24). Rajendran teaches that introducing depth filtration downstream within a purification platform (i.e. after polishing chromatography) can improve yields of final viral filtration step (Fig 1; ¶ [0127]-[0128]; Fig 3), and that early use of depth filtration in antibody purification (i.e. between chromatography steps) can significantly decrease soluble protein aggregates (¶ [0124]). Rajendran further teaches a recombinant antibody purification platform comprising the following in order: a capture step (MabSelectTM SuReTM; Protein A affinity chromatography), depth filtration (Zeta PlusTM DELI cellulose fiber-based depth filter as evidenced by the product datasheet), CEX chromatography (POROSTM 50HS), and MM-HIC/IEX chromatography (CaptoTM adhere ImpRes) (Example 4; Fig 5 (shown below) and Fig 6). While Rajendran demonstrates that early depth filtration can significantly reduce protein aggregates, Rajendran also observed the amount of aggregates can again increase with performance of additional steps (¶ [0125]).
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Rajendran does not explicitly teach depth filtration between CEX and MM-HIC/IEX steps.
Carta teaches the formation of aggregates can occur on-column during monoclonal antibody (mAb) purification using CEX resins, the degree of which may be resin- and mAb specific (Abstract, Fig 1) (e.g. double peaks observed using various CEX resins including POROS 50HS at pH 4.8).
It has been held that selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); See MPEP 2144.04(IV)(C)). In the instant case, the primary reference Rajendran teaches that depth filtration can be employed between various steps of a purification platform and that regardless of placement would have a reasonable expectation of reducing protein aggregation and/or HCP contaminants. Carta further teaches that CEX can reintroduce aggregates downstream, therefore routine optimization well within the skill of an ordinary artisan could lead to modifying the order of operations as taught by Rajendran to place a depth filtration step between CEX and MM-IEX/HIC steps within scope of the instant claims.
Claims 57 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Rajendran and Carta as applied to claim 54 above, and further in view of Nguyen (Biotechnol J. 2019;14(1):e1700771).
The combined teachings of Rajendran and Carta are as discussed above.
While Rajendran teaches a depth filter comprising cellulose and perlite, they do not teach a depth filter composition within full scope of the recited groups (i)-(iv).
Nguyen teaches depth filter Milistak+ HC Pro X0SP, which is defined in the instant specification as a depth filter with (i) a silica filter aid and a polyacrylic fiber pulp (¶ [0104]), tested at pH 5 and 8 with Protein A eluates and shows comparable yields to cellulose- and diatomaceous earth-based depth filters for mAb purification (Table 4).
One of ordinary skill in the art would recognize that various depth filters can be employed based on sample characteristics. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that routine optimization of a purification platform as taught by the combined teachings of Rajendran and Carta could prompt the use of a depth filter as taught by Nguyen for mAb purification.
Claims 57 and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Rajendran and Carta as applied to claim 54 above, and further in view of US 2016/0272674 A1 (herein Althouse).
The combined teachings of Rajendran and Carta are as discussed above.
While Rajendran teaches a depth filter comprising cellulose and perlite, they do not teach a depth filter composition within full scope of the recited groups (i)-(iv).
Althouse teaches various purification platforms with in-process depth filtration (i.e. between chromatography steps). Specifically, Althouse teaches an X0HC filtration step (Table 2) and an EmphazeTM AEX synthetic depth filter step (performed at pH 7.8; Table 6). This depth filtration was performed as a load filter for MM HIC/IEX chromatography (CaptoTM adhere) (Figure 5). The EmphazeTM depth filter is defined in the instant specification as a depth filter with (ii) a hydrogel Q (quaternary amine)-functionalized non-woven media and a multi-zone microporous membrane (¶ [0107]).
One of ordinary skill in the art would recognize that various depth filters can be employed based on sample characteristics. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that routine optimization of a purification platform as taught by the combined teachings of Rajendran and Carta could prompt the use of a depth filter as taught by Althouse (e.g. EmphazeTM depth filter at pH 7.8) for mAb purification.
Claims 57 and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Rajendran and Carta as applied to claim 54 above, and further in view of the Polisher ST installation and operation instructions (3M Purification Inc., “Polisher ST scale-up capsules: scale-up capsules installation and operation instruction,” 34‑8726‑1126‑3 datasheet, Oct 22 2020; herein 3M-Ref).
The combined teachings of Rajendran and Carta are as discussed above.
While Rajendran teaches a depth filter comprising cellulose and perlite, they do not teach a depth filter composition within full scope of the recited groups (i)-(iv).
3M-Ref teaches Polisher ST filters, defined in the instant specification as a depth filter with (iv) a Q-functionalized non-woven material and a Gu-functionalized membrane (¶ [0110]), can be used and substituted in place of other depth filters based on purification needs (i.e. stronger filtration). 3M-Ref also teaches the recommended pH range for use with Polisher ST products is pH 5 to 9 (Page 2, bullet 10).
It would be obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that routine optimization of depth filters within a purification platform as taught by the combined teachings of Rajendran and Carta would lead to use of a Polisher ST depth filter as taught by 3M-Ref within, especially to remove negatively charged impurities. Moreover, it would have been prima facie obvious to optimize and use any pH within the taught range. See MPEP § 2144.05.
Claims 107-108 are rejected under 35 U.S.C. 103 as being unpatentable over Rajendran and Carta as applied to claim 41 above, and further in view of Dwivedi (Int J Pharm. 2018;552(1-2):422-436).
The combined teachings of Rajendran and Carta are discussed above.
Rajendran further teaches formulation can include adding a pharmaceutically acceptable excipient to the purified recombinant protein (e.g. antibody), examples of which are “well known in the art.” Rajendran does not specifically teach polysorbates (e.g. PS20 or PS80).
Dwivedi teaches that mAbs have surface characteristics that can lead to strong surface adhesion and interfacial stress increasing the propensity of unfolding, forming particles, and reducing biotherapeutic activity (pg 422, left column). Non-ionic detergent excipients, most often polysorbates (specifically PS20 and PS80), are widely used to stabilize mAbs from the aforementioned stress conditions due to biocompatibility and low toxicity.
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine a polysorbate (e.g. PS20 or PS80) into a composition comprising a mAb after purification (i.e. as taught by the combined teachings of Rajendran and Carta) to improve the stability and long term therapeutic activity of isolated mAbs.
Claim 109 is rejected under 35 U.S.C. 103 as being unpatentable over Rajendran, Carta, and Dwivedi as applied to claim 107 above, and further in view of US 10,525,137 B2 (herein Connolly).
The combined teachings of Rajendran, Carta, and Dwivedi are discussed above
However, while Dwivedi teaches polysorbates within pharmaceutical compositions are known to degrade over time (Figure 2), none of the aforementioned references discuss formulation to prevent polysorbate degradation.
Connolly teaches enzymatic degradation of polysorbate in monoclonal antibodies can occur and remains a significant challenge in biopharmaceutical development (column 2, ¶ 4). Connolly teaches a method of reducing polysorbate hydrolysis in an aqueous formulation comprising polysorbate, the method comprising adding cyclodextrin to the formulation (claim 1), wherein the formulation is stable (defined as retaining physical stability and/or chemical stability and/or biological activity; column 7, ¶ 4) for at least about 6-24 months (claim 11).
The instant claim uses inclusive or open-ended language to define the scope of the claim. Specifically, the term “comprising” is inclusive and does not exclude additional, unrecited elements or method steps (see MPEP 2111.03). Therefore, by broadest reasonable interpretation, the “formulating an output” and final “composition” as recited in the instant claim can include additional elements, such as cyclodextrin to prevent polysorbate degradation as taught by Connolly. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine the teachings of Rajendran, Carta, Dwivedi, and Connolly (i.e. purifying an antibody composition according to the methods as taught by the combined methods of Rajendran and Carta with a final formulation comprising a polysorbate as taught by Dwivedi and a cyclodextrin as taught by Connolly) with a reasonable expectation of success in generating a composition with polysorbate degradation of about 50% or less per year.
Claim 111 is rejected under 35 U.S.C. 103 as being unpatentable over Rajendran and Carta as applied to claim 41 above, and further in view of Liu (MAbs. 2010;2(5):480-499).
The combined teachings of Rajendran, Carta, and Dwivedi are discussed above.
However, while Rajendran teaches the general use of viral filtration and UF/DF after polishing chromatography (Figure 3). Rajendran does not teach the order of operation as recited in the instant claim (i.e. DF/UF after virus filtration).
Liu teaches a typical antibody recovery process involves virus filtration after polishing chromatography followed by UF/DF.
As discussed above, selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); See MPEP 2144.04(IV)(C)). In the instant case, Liu suggests that typical antibody processing utilizes UF/DF after virus filtration. Therefore routine optimization well within the skill of an ordinary artisan could lead to modifying the order of operations as taught by the combined teachings of Rajendran and Carta (i.e. capture > CEX > depth filtration > MM-HIC/IEX > virus filtration) to place a UF/DF step after virus filtration as taught by Liu to be a typical protocol for mAb purification generating an order of operations in scope with the instant claim.
Response to Arguments - 35 USC § 103
Applicant's arguments, filed 01/26/2026, have been fully considered in so far as they apply to the new/modified rejections above (necessitated by applicant’s amendments), but they are not persuasive.
Applicant states:
“Amended independent claim 41 is based, at least in part, on the unexpected finding disclosed in the application that the specifically claimed purification platform removes hydrolytic HCPs responsible for polysorbate degradation, thus producing purified compositions having significantly decreased rates of polysorbate degradation. For instance, Example 7 demonstrates a comparison between two purification platforms: (1) a control purification platform comprising a capture step, a CEX step, and a MM-HIC/AEX chromatography step; (2) the control purification platform with the addition of a depth filtration step between the CEX step and the MMHIC/ AEX chromatography step. Each purification platform was assessed for its ability to reduce hydrolytic activity in the resulting purified compositions using a free fatty acid and mass spectrometry (FAMS) assay, which measures the content of free fatty acid after polysorbate 20 (PS20) degradation. As shown in FIG. 7, the addition of a depth filtration step within the specific claimed sequence of steps decreased the hydrolytic activity remarkably and unexpectedly better than the control purification platform without the additional depth filter step.
None of the cited references [WO’110 and Bak] teach or suggest that a purification platform comprising, in the following order: a capture step; a CEX chromatography step; a depth filtration step, and a MM-HIC/IEX chromatography step…” (Remarks, pg 11-12)
Applicant’s argument, with respect to a purification platform using specific depth filtration, are not persuasive because the scope of independent claim 41 has narrowed to include limitations not previously rejected (i.e. depth filtration, instead of depth filtration or HIC). New grounds of rejection are made in view of newly found prior art references Rajendran and Carta. Briefly, Rajendran teaches in-process depth filtration between various steps of the purification platform can improve purity of mAb yields (i.e. reduce aggregates). Carta teaches that CEX can introduce aggregates into mAb preparations. Therefore routine optimization well within the skill of an ordinary artisan could lead to modifying the order of operations as taught by Rajendran to place a depth filtration step between CEX and MM-IEX/HIC steps within scope of the instant claims. Moreover, it has been held that selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); See MPEP 2144.04(IV)(C)).
Regarding unexpected results, applicant argues that the addition of a depth filtration step adds an unexpected benefit (i.e. decreases hydrolytic activity) in the purified composition in comparison to a purification platform without depth filtration. However, the new grounds of rejection necessitated by applicant’s amendments now includes reference to purification platforms with depth filtration, which was shown to improve the properties of resulting purified compositions containing mAbs. Therefore, in order to establish unexpected results, applicant should demonstrate specific placement of the depth filtration step and/or composition of depth filters offers significant benefits beyond general use of a depth filtration step. MPEP 716.02(b)(I) dictates that evidence relied upon to establish results are unexpected and significant should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance" (Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)). Further, mere conclusions that results are unexpected "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration." (Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992). While the lack of objective evidence of nonobviousness does not weigh in favor of obviousness, (Miles Labs. Inc. v. Shandon Inc., 997 F.2d 870, 878, 27 USPQ2d 1123, 1129 (Fed. Cir. 1993), cert. denied,127 L. Ed. 232 (1994)), where a prima facie case of obviousness is established (i.e. selection of any order of performing process steps is prima facie obvious), the failure to provide rebuttal evidence is dispositive.
Conclusion
No claims are currently allowed.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647