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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 18 May 2026 has been entered.
Response to Amendment
The amendment filed 18 May 2026 is acknowledged. Claim 16 is newly canceled. Claims 1 and 4 are amended.
Claim Status
Claims 1, 4, 6, and 8-13 are pending. Claims 10-13 are withdrawn as previously noted in the Non-Final Office action dated 19 November 2025. Claims 1, 4, 6, 8, and 9 are under examination in the instant office action.
Withdrawal of Rejections
The rejection of claims 1, 6, 8-9, and 16 under 35 U.S.C. 103 as being unpatentable over by US 2019/0324000 A1 to Randolph (herein after Randolph, Of record, PTO-892 dated 7/28/2025), published 24 October 2019 in view of Yan et. al. Structure Based Prediction of Asparagine Deamidation Propensity in Monoclonal Antibodies, mAbs, 10:6 901-912, DOI: 10.1080/19420862.2018.1478646 (Of record, cited in IDS dated 10/29/224 NPL No. 38) and Gervais, D. Protein deamidation in biopharmaceutical manufacture: understanding, control and impact, J. Chem. Technol. Biotechnol., 2015, 91 , 569 —575 published 17 November 2015 (Of record, PTO-892 dated 3/31/2025) is withdrawn in view of the amendments to the claims.
The rejection of claim 4 of under 35 U.S.C. 103 as being unpatentable over by US 2019/0324000 A1 to Randolph (herein after Randolph, Of record, PTO-892 dated 7/28/2025), published 24 October 2019 in view of Yan et. al. Structure Based Prediction of Asparagine Deamidation Propensity in Monoclonal Antibodies, mAbs, 10:6 901-912, DOI: 10.1080/19420862.2018.1478646 (Of record, cited in IDS dated 10/29/224 NPL No. 38) and Gervais, D. Protein deamidation in biopharmaceutical manufacture: understanding, control and impact, J. Chem. Technol. Biotechnol., 2015, 91 , 569 —575 (Of record, PTO-892 dated 3/31/2025) as applied to claims 1, 6, and 8-9 above, and further in view of WO2017/033121 A1 Monck et. al (hereinafter Monck et. al) published 2 March 2017 (Of record, PTO-892 dated 7/28/2025) is withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112- New
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.
Claims 1, 4, 6, 8, and 9 are 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.
Claim 1 is indefinite for the recitation of “detecting that the electropherogram of the DS or DP comprises four major peaks corresponding to peaks identified as C, 1, 2, and 3 and a minor cIEF peak corresponding to a peak identified as B”. As stated in MPEP §2173.05(s), “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim”. The peaks designated as C, 1, 2, 3, and B are internal referential designations referring to specific peaks in the exemplary cIEF electropherogram profile as shown in Figure 34. Further, it would not be clear to a person of ordinary skill in the art what characteristics the peaks must have to “correspond” to those peaks in the exemplary electropherogram and therefore the metes and bounds of the claim are unclear.
Dependent claims are rejected for failing to resolve the indefiniteness as described.
Claim Rejections - 35 USC § 103 – New/Modified, changes necessitated by amendment
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.
Claims 1, 4, 6, and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over by US 2019/0324000 A1 to Randolph (herein after Randolph, Of record, PTO-892 dated 7/28/2025), published 24 October 2019 in view of Yan et. al. Structure Based Prediction of Asparagine Deamidation Propensity in Monoclonal Antibodies, mAbs, 10:6 901-912, DOI: 10.1080/19420862.2018.1478646 (Of record, cited in IDS dated 10/29/224 NPL No. 38) and Gervais, D. Protein deamidation in biopharmaceutical manufacture: understanding, control and impact, J. Chem. Technol. Biotechnol., 2015, 91 , 569 —575 published 17 November 2015 (Of record, PTO-892 dated 3/31/2025) and WO2017/033121 A1 Monck et. al (hereinafter Monck et. al) published 2 March 2017 (Of record, PTO-892 dated 7/28/2025).
Instant claim 1 recites a method for controlling the deamidation of heavy chain (HC) asparagine 43 (HC Asn43) and LC asparagine 93 (LC Asn93) during the production of a drug substance (DS) or drug product (DP) comprising a mammalian anti-TNF antibody having a heavy chain (HC) comprising SEQ ID NO: 36 and a light chain (LC) comprising SEQ ID NO: 37 wherein the method comprises: performing three consecutive stages of manufacture and detecting that the total deamidation is < 79% for HC Asn43, with <30% isoAsp43, and <5.8% for LC Asn93 at release, wherein the deamidation is measured by mass spectrometric peptide mapping using endoproteinase Lys-C digestion. Instant claim 16 teaches a method comprising producing a drug substance (DS) or drug product (DP) comprising a mammalian anti-TNF antibody comprising SEQ ID NO: 36 and light chain comprising SEQ ID NO: 37, wherein producing comprises performing three consecutive stages of manufacture and detecting that total deamidation is < 79% for HC Asn43, with <30% isoAsp43, and < 5.8% for LC Asn93 at release, wherein deamidation is measured by mass spectrometric peptide mapping using endoproteinase Lys-C digestion and comprising detecting and further comprising a step of performing four major cIEF peaks corresponding to the peaks identified as C, 1, 2, 3, and a minor cIEF peak corresponding to a peak identified as B. Claim 4 recites wherein at release wherein at release the sum of the percent area of the 4 major peaks is >91%, the area % of peak 3 = 12-33%, the area % of peak 2 = 34-43%, the area % of peak 1 = 17-33%, the area % of peak C = 5- 15%, and the area % of peak B is <6%. Claim 6 teaches wherein the three consecutive stages are performed under conditions comprising “a manufacturing operating range (MOR) of 70-90 hours, a maximum time limit of less than 115 hours combined, a pH 7.6 - 8.0, and a controlled room temperature of 15-25 °C”. Claim 8 teaches the method comprises “a maximum hold time for harvested cells of 21 days at 2-8 °C”. Claim 9 teaches the method of claim 8 wherein “3 consecutive stages comprise a cation exchange chromatography stage with a SO3- cation exchange resin column, an anion exchange chromatography stage with a (QXL) quaternary ammonium cross-linked agarose column, and a virus retentive filtering stage with polyvinylidene fluoride filters”.
Claim Interpretation: Regarding the particular deamidation profile and cIEF profiles of the anti-TNF antibody, the examiner would like to note that the active steps required by claims 1 only encompass 1) performing 3 consecutive stages of manufacture (claim 1 and 14); 2) and measuring the deamidation by mass spectrometric peptide mapping using endoproteinase Lys-C digestion and by cIEF electropherogram. The deamidation levels as detected by the method are measurements taken to determine the result of the manufacturing steps, as in quality control, and therefore the measurement steps themselves have no effect on the outcome of the profile of the antibody. MPEP §2111.04 states, “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. For example, assume a method claim requires step A if a first condition happens and step B if a second condition happens. If the claimed invention may be practiced without either the first or second condition happening, then neither step A or B is required by the broadest reasonable interpretation of the claim. If the claimed invention requires the first condition to occur, then the broadest reasonable interpretation of the claim requires step A. If the claimed invention requires both the first and second conditions to occur, then the broadest reasonable interpretation of the claim requires both steps A and B”. In the instant case, the particular claimed cIEF peaks do not add patentable weight to the scope of the claim because there is no difference to the active method steps conveyed by the particular cIEF profile; rather, it is the intended result of performing the active method steps.
Randolph teaches “methods of manufacture for producing anti-TNF antibodies, e.g., the anti-TNF antibody SIMPONI™ (golimumab) which comprises 9 processing stages (Fig. 39) including three consecutive stages of cation exchange chromatography (CEX), anion exchange chromatography (AEX), and virus removal filtration (Fig. 39). The anti-TNF antibody golimumab comprises a heavy chain and light chain of SEQ ID NO: 1 and 2 which are identical to instant SEQ ID NO: 36 and 37 (instant claim 1). Randolph further teaches that three consecutive CEX, AEX, and virus removal stages are completed at pH 7.6-8.0 (CEX column [0275-0276]; AEX column [282]; virus filtering [0285]) with less than 115 hours with a MOR of 70-90 hours at controlled room temperature 15-25 °C ([0279]) (instant claim 6). Stage 8 material is filtered through NFP™ virus retentive filters ([0287]). Randolph also teaches that prior to purification, “The harvest is stored in bioprocess containers (BPCs) in a 2-8° C. environment for a maximum period of 21 days after disconnection from the bioreactor” ([0259]) (instant claim 8).
Regarding claim 9, Randolph teaches “In Stage 7, the Stage 6 material is purified using a Q Sepharose™ XL (GE Healthcare Bio-Sciences, Pittsburgh, Pa., USA) anion exchange chromatography column and an automated chromatography skid. Golimumab flows through the resin while DNA, other impurities, and viruses (if present) are retained” [0280]; “For the Stage 6, using a UNOsphere S™ cation exchange chromatography column, the analyzed transition fronts included, e.g., the front generated during loading of solvent/detergent (S/D) treated material” [0303]; and “In Stage 8, the Stage 7 material, purified by anion exchange chromatography, is filtered through NFP™ virus retentive filters. This step targets the removal of both small and large viruses potentially present” [0287]. As evidenced by the instant specification, an UNOsphere S™ column is a tradename of a SO3- cation exchange resin chromatography column (p. 121-122, para [00398]); Q Sepharose XL™ is a tradename of a quaternary ammonium cross-linked agarose column (p. 123, para [00406]); and NFP™ virus retentive filter is a tradename for polyvinylidene fluoride virus retentive filters (p. 124, [00413]).
Randolph does not teach a method for controlling the deamidation HC Asn43 and LC Asn93 of the anti-TNF antibody or a method comprising producing of a DS or DP comprising three consecutive stages of manufacture followed by detecting, wherein deamidation of are determined by mass spectrometric peptide mapping using mass spectrometric peptide mapping using endoproteinase Lys-C digestion of the anti-TNF antibody. Yan et. al. and Gervais resolve this deficiency.
Yan et. al. teaches “identification of asparagine sites (Asn) that are prone to deamidation is critical to the development of therapeutic monoclonal antibodies” (Abstract). Yan et. al. teaches specifically: “deamidation of asparagine (Asn) residues to aspartate (Asp) or isoaspartate (isoAsp) is a common degradation pathway that occurs during the manufacturing and storage of monoclonal antibodies (mAbs)” (p 901 paragraph 1). Further, “the ratio of Asp to isoAsp varies depending on the reaction buffer and local structure environment” (p 901 paragraph 2, emphasis the examiner’s). In particular, Yan evidences that “6 of the 29 Asn residues in the fragment variable region of the unstressed mAbs had deamidation levels >0.5%”: HC Asn57, LC Asn93, HC Asn43, LC Asn28, LC Asn53, and HC Asn55. “HC Asn43 was the most sensitive site, with >70% deamidation under normal, unstressed storage conditions. The levels of deamidation at the other 5 sites were <5%” (p 902 paragraph 3). Therefore, deamidation of monoclonal antibodies such as SEQ ID NO: 36 and 37 at HC Asn43 and LC Asn93 is an inherent characteristic of the product that is determined by the antibody sequence and by the methods of manufacturing such as buffer pH. The instant anti-TNF antibody and antibody produced by the method of Randolph, with identical sequences and produced with the same manufacturing technique, would be expected to comprise the same <79% HC Asn43, <5.8% LC Asn93 and <30% isoAsp43 at release as defined by the instant claims.
Yan et. al. teaches a method of determining deamidation of monoclonal antibodies at the HC Asn43 and LC Asn93 (p 902 Results, Deamidation of IgG1 mAbs under normal and stressed conditions section) by Lys-C peptide mapping with digestion of Lys-C followed by reverse-phase HPLC and liquid chromatography-tandem mass spectrometry (LC-MS/MS) (p 910 Materials and Methods, Lyc-C peptide mapping section). Yan also teaches that “HC Asn57, LC Asn93, HC Asn43, LC Asn28, LC Asn53 and HC Asn55 were identified as deamidation “hot spots” in the Fv region” (p 902 Results, Deamidation of IgG1 mAbs under normal and stressed conditions section) and that identification of Asn sites that are prone to deamidation is critical for the development of therapeutic monoclonal antibodies because the rates of Asn deamidation can vary dramatically among different sites” (Abstract).
Gervais teaches that “deamidation is a common post-translational modification occurring in biopharmaceutical proteins, affecting L-asparagine (Asn) […] The rate of deamidation reactions are influenced by factors including protein structure (primary, secondary and higher structure), temperature and pH. In the vast majority of cases, deamidation is undesirable in biopharmaceuticals, and may lead to potential changes in protein structure, function, stability and immunogenicity” (Abstract). Gervais teach that “In this regard, it is important to characterise, understand and control PTMs during an early stage of biopharmaceutical product development” (Introduction, para. 2, emphasis is the examiner’s). Further, Gervais teaches that “regulatory bodies usually insist that the deamidation profile of a biopharmaceutical product be measured, tracked and controlled throughout manufacture” (Introduction, para. 3). Regarding the downstream process steps such as those of the instant claims, Gervais teaches “upstream processes are generally performed at physiological or near-physiological temperatures while downstream processes are carried out at ambient or refrigerated temperatures. Nevertheless, process designers should try to ensure that buffers used in downstream processes are of sufficiently low pH (<7.0–7.5) such that deamidation reactions are minimised, especially if the product contains sequence motifs with predicted lability” (“Deamidation during downstream processing and storage” section, para. 1); “Carta and co-workers 63-65 have studied the performance of two commercially available cation-exchange resins (Capto S and Unosphere-S) in detail with respect to deamidated and non-deamidated mAb purification. They found that adsorptive displacement occurs during chromatography of more weakly bound protein forms (e.g. deamidated variants) by more strongly bound forms such as the main species” (“Deamidation during downstream processing and storage” section, para. 2).
It would have been obvious for a person having ordinary skill in the art, before the effective filing date, to add the method of determining deamidation status by Lys-C digestion and mass spectrometry at release to the manufacturing method of Randolph in order to benefit from detecting and controlling deamidating during manufacturing as taught by Gervais and detecting the level deamidation at “hot spots” LC Asn93 and HC Asn43 as taught by Yan, because Yan in view of Gervais would motivate control of the highly labile “hot spots” LC Asn93 and HC Asn43 as taught by Yan. This would result in a method comprising the three consecutive stages of manufacture of the anti-TNF antibody comprising SEQ ID NO: 36 and 37, which have residues LC Asn93 and HC Asn43 as taught by Randolph that are identical in composition to the stages of manufacture of the instant claims, followed by a step of detecting or measuring deamidation by mass spectrometric peptide mapping using endoproteinase Lys-C digestion. In regards to the limitation that under such conditions, total deamidation is controlled to the specific levels, this is an intended result of the active method steps as taught, and therefore the level of deamidation would be inherent to a method comprising the identical steps as taught by Randolph (an identical protein structure, subject to exactly the same time, temperature, and pH conditions would be expected to produce the exact deamidation profile of the instant antibody). Using manufacturing steps to control the deamidation profile, followed by a measurement step, would have a predictable effect because an artisan would expect that Asn deamidation is likely to affect antibody function, stability, and immunogenicity, or at the very least regulatory approval, as taught by Gervais. Adding the step of Lys-C digestion would have a predictable result when applied to the anti-TNF manufacturing technique of Randolph because Yan teaches the technique for use with therapeutic monoclonal antibodies in general and specifically teaches LC Asn93 and HC Asn43 which are comprised by the antibody of Randolph.
Randolph in view of Yan et. al. and Gervais does not teach the method of controlling the anti-TNF antibody deamidation further comprising a step of detecting that the antibody drug product are determined by the specific peaks corresponding to the 4 major peaks as described in claim 4. Monck et. al. resolves this deficiency.
Monck et. al. teaches a method of measuring acidic and basic forms corresponding to the deamidation levels of a therapeutic monoclonal antibody by capillary isoelectric focusing (cIEF) (Example 2, p 80 lines 14-35). Monck et. al. teaches using the acidic peaks other than the main peak (Figure 2 and Table 7) to determine acidic variant which “comprise deamidated antibody variants”. Further, Monck et. al. teaches the use of the characterization studies such as cIEF in order to determine “that particular deamidated antibody variants […] can impact the function of the composition of mepolizumab. Therefore, specific levels of these variants should be maintained to ensure appropriate function/efficacy” (p 96 lines 3-7).
It would have been obvious for a person having ordinary skill in the art, before the effective filing date, to apply a step of deamidation products using cIEF and by setting release criteria to the method of producing the anti-TNF antibody of Randolph. Although the different peaks are different because these are different antibodies, it would be obvious to one of ordinary skill in the art to perform routine optimization by calculating the predicted isoelectric points of the known anti-TNF antibody and to look for peaks at the pHs corresponding to predicted deamidated antibody derivatives (See MPEP 2144.05.II.A). Additionally, it would be obvious to a person of ordinary skill in the art to apply a release standard based on the deamidated peaks because Monck teaches that the deamidated variants can impact antibody function. This would result in the application of the cIEF profile with the particular peaks of claim 1 with the characteristics of the peaks of claim 4. Applying the known method of cIEF would have a predictable effect because these are both known therapeutic monoclonal antibodies.
Response to arguments
Applicant’s remarks filed 15 May 2026 have been fully considered but are not persuasive.
Applicant argues that Randolph, Yan, and Gervais, alone or in combination, do not teach or suggest every element of the present claims because of the amendment to claim 1 to require the step of determining the cIEF peaks as previously recited in claim 4 (Remarks p. 7 ¶2). This is moot in view of the new 103 rejection, necessitated by amendment, of claims 1, 4, 6, and 8-9 in view of Randolph, Yan, Gervais, and Monck.
Applicant states that the deamidation profile of the instant antibody is not inherently present because the instant method would not necessarily result in the specific deamidation profile recited by the claims as required by MPEP 2112 (Remarks 5/18/2026 p. 8 ¶s 1-5). This is not persuasive. As described in the 103 rejection above, the result of measuring the particular peaks of the deamidation profile is an intended result that stems from the active manufacturing steps that would result in the controlled deamidation. MPEP 2112 states “"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999)”. As described in the 103 rejection above Randolph, Yan, and Gervais make obvious all of the active method steps of the method of controlling deamidation or the method comprising producing a DP or DS as recited in the claims. Yan et. al. and Gervais et. al. describe how the conditions of these active manufacturing steps (e.g. pH, temperature) would result in a particular deamidation state. Therefore, as described in the 103 rejection above, the particular deamidation profile of the instant antibody would inherently and necessarily be the result of performing identical active manufacturing steps. The deamidation which is a structural property of the antibody produced by the method is inherent to 1) the amino acid structure of the antibody and 2) the particular process steps used to produce the antibody. If the process used to control deamidation is identical to the process used to manufacture the antibody, including all relevant factors that determine deamidation levels including antibody structure and manufacturing steps (and the particulars of those manufacturing steps including pH, temperature, time, etc.) the resulting antibody must have the same deamidation profile, and therefore a person of ordinary skill in the art by performing the steps as taught by Randolph and then adding the obvious measurement step as taught by Yan and Gervais would necessarily obtain the same deamidation measurement profile. Additionally, the instant claims do not recite any active methods steps that would result in control of deamidation to restrict the deamidation profile as claimed, for instance particular times, temperatures, and pHs of the active manufacturing steps that would result in control of deamidation in the antibody. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., control of active methods step which would result in a deamidation profile different than the identical active method steps taught by the prior art) are not recited in the rejected claim(s). 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). The Examiner further notes that MPEP 2145 states “However, arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984)”. Therefore, the Examiner has shown evidence based on Gervais et. al. and Yan et. al. that because primary sequence and the characteristics of manufacturing steps (e.g. pH, temperature) and the Applicant has not presented any evidence that this is not the case (see MPEP §2112).
Applicant argues that “the deamidation levels of the recited antibodies generated during manufacturing further define the methods of controlling deamidation of the recited antibody and therefore hold patentable weight” (p. 8 ¶6) and that “Applicant submits that the present claims are not directed to generic monitoring of deamidation, but require controlling deamidation of the specific residues, HC Asn43 and LC Asn93 within the specific recited anti-TNF antibodies defined by SEQ ID NO:36 and SEQ ID NO:37 comprising the specific quantitative release limitations defined by the specific recited deamidation profile, measured by the specific analytical methods of mass spectrometric peptide mapping using endoproteinase Lys-C digestion, and further comprising the specific cIEF electropherogram profile as defined by comprising four major peaks (C, 1, 2, 3) and a minor peak (B). Thus, the claimed method of controlling deamidation is not merely a generic quality attribute, but rather the claimed method is directed to a tightly defined and antibody-specific control strategy that integrates specific peptide mapping limitations with a specific cIEF peak distribution” (p. 9 ¶2). Further, Applicant specifies that the “claimed method recites detecting a defined level or pattern of deamidation events at one or more particular residues”. This is not persuasive. As described in the 103 rejection and arguments above, the active steps recited by applicant are generic as claimed (e.g. “performing three consecutive stages of manufacture” reads on any 3 stages). A person of ordinary skill in the art would combine the method of manufacturing as taught by Randolph (which is identical to the instant method of manufacturing, including all of the active methods step not recited in the claims but described by the specification) and the method of controlling deamidation as made obvious by Yan, Gervais, and Monck as described above and as taught by Yan, Gervais, and Monck it was common in the art to 1) measure the deamidation of particular residues (including known HC Asn43 and known LC Asn93 as taught by Yan, described in the 103 above). Because the measuring step would not result in any changes to the deamidation profile, the result of the determining (e.g. the particular cIEF peaks of the electropherogram) is a mental process and a person of ordinary skill in the art would determine the exact same profile for the exact same antibody because, once the antibody which inherently has the same deamidation profile because it is manufactured by the exact same method, then the same measurements would be determined once the active step of measuring is performed. Absent additional active method steps, there is no method of controlling deamidation that is distinguished from the prior art. As described above, a person of ordinary skill in the art would apply control of deamidation, which is a form of quality control, to any antibody because, as taught by Gervais, regulatory bodies insist that these characteristics of antibodies are controlled during manufacture.
Applicant argues that “the deamidation profile and electropherogram profile are structural features of the recited antibody that can impact its properties and differentiate it from other antibodies, including antibodies having the same heavy and light chain amino acid sequences […] Thus, the deamidation levels as detected by the present method are not merely results for determining quality control but instead are measurable, structural features of the recited antibodies produced. This is not persuasive because the instant prior art teaches and suggests every active method step of the recited claims. MPEP states “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.” As described in the 103 and arguments above, the antibody of Randolph must have an identical deamidation profile because it comprises the identical primary sequence and is made by exactly the same method of manufacturing. There are no differences in active methods steps that would result in a person of ordinary skill in the art detecting a different deamidation profile because all of the features of the method (e.g. time, pH) are taught by the prior art and do not result in any structural change to the claimed method.
Applicant argues that the deamidation levels of the recited antibodies generated during manufacture are directed towards specific deamidation events and a specific peak patten and not an open-ended search for theoretical deamidation products (Remarks 5/18/2026 p. 10 ¶2) and that, the specific deamidation profiled of the recited antibodies provides meaningful limitations that should hold patentable weight (Remarks p. 10 ¶1 and 4). MPEP 2112 states “"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999)”. As described in the 103 rejection above Randolph, Yan, and Gervais make obvious all of the active method steps of the method of controlling deamidation or the method comprising producing a DP or DS as recited in the claims. Yan et. al. and Gervais et. al. describe how the conditions of these active manufacturing steps (e.g. pH, temperature) would result in a particular deamidation state. Therefore, as described in the 103 rejection above, the particular deamidation profile of the instant antibody would inherently and necessarily be the result of performing the active manufacturing steps described. Applicant further argues “the deamidation profile is a structural feature of the recited antibody that can impact its properties and differentiate it from other antibodies, including antibodies having the same heavy and light chain amino acid sequences […] Thus, the deamidation levels as detected by the present method are not merely results for determining quality control but instead are measurable, structural features of the recited antibodies produced” (Remarks 10/28/2025 p. 8). This is not persuasive because, as described above, the deamidation which is a structural property of the antibody produced by the method is inherent to 1) the amino acid structure of the antibody and 2) the particular process steps used to produce the antibody. If the process used to control deamidation is identical to the process used to manufacture the antibody, including all relevant factors that determine deamidation levels including antibody structure and manufacturing steps (and the particulars of those manufacturing steps including pH, temperature, time, etc.) the resulting antibody must have the same deamidation profile, and therefore a person of ordinary skill in the art by performing the steps as taught by Randolph and then adding the obvious measurement step as taught by Yan and Gervais would necessarily obtain the same deamidation measurement profile.
Lastly, applicant argues that the cited art does not provide any reasonable expectation of success because Yan and Gervais teach that antibody deamidation is unpredictable there is no reasonable expectation of success for controlling the deamidation of the specific instantly claimed antibody (Remarks 5/18/2026 p. 10-p. 12). Further, Applicant argues that because Yan and Gervais teach that deamidation is unpredictable and the degree of effect on antibody function is unpredictable, the references teach away from the instant invention (Remarks 5/18/2026 p. 12 ¶1). This is not persuasive because Randolph teaches all of the active manufacturing steps that are determinative of the deamidation profile as claimed and teaches that the resultant antibody is an active anti-TNF drug. An artisan would rightfully understand that without any alteration to the steps of the manufacturing process, an effective drug with the same properties would be made. Without any claims directed towards specific differences in the active steps taken to control the deamidation profile and evidence that an artisan could not reasonably produce the instantly claimed drug using the steps (which, as described above, must necessarily result in the instantly claimed deamidation profile because all of the factors which may influence deamidation are identical), an artisan has a reasonable expectation of success in making the effective drug product with the deamidation profile as claimed. As described in the arguments above, the particular deamidation profile is inherent to the method because the method includes the antibody structure and all of the particular conditions of the active methods steps that could determine the deamidation profile. There are no limitations recited in the claims that would alter the results of the deamidation from the prior art. There are no claimed steps that describe any differences in the method either before the deamidation measurement, which would result in a different deamidation profile, or after the deamidation measurement, resulting in an active difference in process because of the results of the deamidation profile. There is nothing in Randolph, Yan, Gervais, or Monck that would suggest that the method of Randolph results in a drug product with an unsuitable deamidation profile; and the fact that Yan and Gervais teach that the particular deamidation profile of a given antibody for a given method is unpredictable is not sufficient to teach away from the instant method because an artisan would be able to predict that, due to the success of the method of Randolph in manufacturing a suitable drug product, the resulting antibodies would have a deamidation profile within parameters that still allow for its effective function. Randolph teaches an identical process for manufacturing comprising all the limitations of the claims (and even additional aspects of the method that are not claimed) that could alter the antibody deamidation profile. As described the temperature, timing, and pH steps of the manufacturing process are identical for an identical drug product. Thus, no matter how unpredictable a given antibody deamidation profile may be, performing the manufacturing method of Randolph followed by the determining deamidation profile steps as taught by Yan and Gervais must necessarily result in the claimed profile. In regards to sequence context, formulation, storage conditions, and structural conformation, these are all features that could change antibody deamidation but are not recited in the claims as active steps. The examiner encourages the applicant that, if there are any differences in the instant method that result in the deamidation profile as claimed to distinguish it from the prior art method with identical manufacturing steps apart from a determining step (which would not result in any differences to the deamidation profile of the antibody), these limitations should be recited in the claims to distinguish from the prior art method which, as described above, would inherently result in the claimed method because two identical antibodies manufactured with identical processes would necessarily be expected to have the same deamidation profile.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, the examiner was considering only knowledge gleaned from Yan, Gervais, and Monck which, as described above, teach how and why a person of ordinary skill in the art would be motivated to add a step of measuring deamidation (by endopeptidase Lys-c digestion and mass spectrometry) in particular for an antibody with the hotspot residues LC Asn93 and HC Asn43, and additionally the factors such as antibody structure and manufacturing conditions of pH, temperature, and time at a particular stage that would determine the antibody deamidation profile. Thus, as described in the arguments above, the result of the deamidation profile both 1) does not further limit the claims because it is the intended result of the measurement step and 2) is taught by the art because an artisan would expect an antibody with identical structure made by an identical process as taught by Randolph would result in the same deamidation profile. Therefore, without hindsight, an artisan pursuing methods of manufacturing the instantly claimed anti-TNF antibody would, from Randoph, Yan, and Gervais, have arrived with a reasonable expectation of success at the instantly claimed method.
Regarding the rejection of claims 4 in view of Randolph, Yan, Gervais, and Monck, Applicant argues that Monck does not resolve the deficiencies of Randolph, Yan, and Gervais because “Monck does not teach or suggest a method for controlling the deamidation of Asn43 and Asn93 during the production of an anti-TNF antibody having a heavy chain comprising SEQ ID NO: 36 and a light chain comprising SEQ ID NO: 37, wherein the method comprises performing three consecutive stages of manufacture, detecting that the total deamidation is <79% for HC Asn43, with <30% isoAsp43, and <5.8% for LC Asn93 at release, wherein deamidation is measured by mass spectrometric peptide mapping using endoproteinase Lyc-C digestion; and detecting that the electropherogram of the DS or DP comprises four major cIEF peaks corresponding to peaks identified as C, 1, 2, and 3 and a minor cIEF peak corresponding to a peak identified as B”. This is not persuasive because the standard is not that any particular prior art teach all of the limitations of the claims. In response to applicant's arguments against the references individually, 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). As described in the 103 rejection above, the claims are rejected in view of Randolph, Yan, Gervais, and Monck, which combined teach 1) all of the active methods steps comprising three consecutive steps of manufacturing the instant antibody with identical manufacturing conditions; 2) methods of measuring deamidation by mass-spec and endopeptidase C digestion and cIEF (Yan and Monck); and 3) motivation to combine the measurement step to the manufacturing step in order to control deamidation to maintain effectiveness of the drug product as taught by Yan and Gervais. This would have a reasonable expectation of success because Randolph teaches the exact manufacturing steps and Yan, Gervais, and Monck teach that a person of ordinary skill in the art would believe that the specifics of manufacturing steps (e.g. time, pH) would result in deamidation control and a specific deamidation profile, and a person of ordinary skill in the art would understand how to apply the method of measuring deamidation to different antibody drug products as taught by Gervais.
Applicant argues that the antibody of Monck is the deamidation of an entirely different antibody with a different primary sequence, structural context, and deamidation prone residues and that Monck does not teach that its findings are broadly transferable to unrelated antibodies (Remarks 5/18/2026 p. 14-p. 15). This is not persuasive, because as described in the 103 rejection and arguments above, a person of ordinary skill in the art would have a reasonable expectation in view of Yan et. al. and Gervais et. al. to apply a different method of deamidation across different antibodies. Once a person of ordinary skill in the art had motivation to combine 1) the active method steps of controlling during manufacturing as taught by Randolph and 2) the methods of detecting deamidation at release as taught by Yan, Gervais, and Monck, this would naturally results in detecting the deamidation profiles of the instant antibody because the steps of measuring do not result in any changes to the deamidation profile of the antibody of Randolph. A person of ordinary skill in the art would understand and be motivated to determine the particular release criteria for deamidation of any antibody because as taught by Gervais, Yan, and Monck, deamidation can effect antibody function and it is required by most regulatory agencies that it be controlled as described in the 103 above. As discussed in the arguments above, practicing the active steps of the method as taught by Randolph, Gervais, Yan, and Monck would result in exactly the instantly claimed method because there are no active steps that would change the particular deamidation profile, or active steps after the determination of the deamidation profile beyond that are outside of the scope of the prior art as described in the 103 rejection and arguments above.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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