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 .
Claims 1, 3-11, 13-14, 16, 18-21, 23-26, 36-54, 56-59, 61-64, 74-75, and 76-85 are under consideration.
Affidavits/Declarations
The Declaration under 37 CFR 1.132 filed 07/24/2026 is insufficient to overcome the rejection of claims 1, 3-11, 13-14, 16, 18-21, 23-26, 36-54, 56-59, 61-64, 74-75, and 76-85 is based upon 35 U.S.C. 103 as being unpatentable over Noguchi (Noguchi et al., US 2018/0147292 A1; Published 05/31/2018, of record), Albanese (Albanese, et al., CA 2895869 A1; Published 06/26/2014, of record) and Hu (Hu, et al., US 20180036423 A1; Published 02/08/2018, of record) as set forth in the last Office action because:
Declarant’s arguments use data to make the argument that the instant claimed combination of pH 4.7-5.3 histidine and 0.4 to 0.6 wt% sodium chloride is a critical combination of parameters. All of these data are made with respect to the relative amounts of conjugate (“1”), free drug-linker (“2”), TCEP/maleimide complex (“3”) and n-acetylcysteine “capped” drug-linker (“4”) as well as aggregate. The data presented compare: 1) main and aggregate peaks for separations performed at pH 5.1-5.2 vs pH 5.8 (paragraph 7), 2) contaminant species concentration as a function of diafiltration volume (paragraph 9), 3) contaminant species concentration before/after purification of two distinct ADCs (paragraph 11).
The data presented in paragraph 7 are unsuitable for analysis due to the data presented not showing the variance amongst the groups. The data presented in paragraph 7 compare main and aggregate peak % before and after purification for two entries performed at pH 5.1-5.2 and one entry performed at pH 5.8. The data presented are also very, very close (e.g. an average of 0.75% aggregation at pH 5.1-5.2 vs 1.1% at one point at pH 5.8) and it is impossible to make determinations with respect to differences between groups if the intragroup variance is not also known (cannot even be calculated as variance requires at least 3 points).
The data presented in paragraph 9 compare concentrations of contaminant species “3” and “4” as a function of diafiltration volume comparing histidine buffer vs histidine buffer + 0.5% sodium chloride. These data do appear to show more efficient removal of contaminant species “3” when the sodium chloride is added, however the data presented do not demonstrate that histidine at pH 5.1-5.2 and with 0.5% NaCl is a critical process parameter combination. All the data presented demonstrate is that the addition of an ionic species (sodium chloride) appears to increase the removal rate of contaminant species “3”, however these results are not unexpected at all, as adding salts to diafiltration buffers to increase removal efficiency by preventing electrostatic interactions between charged species (such as contaminant species “3”) and surface of the diafiltration membrane.
The data presented in paragraph 11 compare the relative amounts of contaminant species “3” and “4” for two distinct ADC separation processes (one for an anti-CDH6 ADC and a second for an anti-TA MUC1 antibody ADC, wherein separation takes place in pH 5 histidine with 0.5wt% NaCl. The data presented in paragraph 11 do not demonstrate anything unexpected, as it would be expected that the ultrafiltration/TFF steps described would reduce the relative concentrations of contaminant species “3” and 4”. Additionally, the data presented in paragraph 11are incapable of demonstrating that the alleged “critical” combination of parameter levels (histidine buffer at pH 4.7-5.1 combined with 0.5wt% NaCl ) because the data do not present any other combination of parameter levels other than the alleged “critical” combination. This makes the data incapable of establishing the criticality of the claimed “critical combination” of histidine at pH 4.7-5.1 + 0.5 wt% NaCl).
As such, when taken together, neither the data presented by Declarant nor Declarant’s arguments are insufficient to demonstrate that the combination of histidine at pH 4.7-5.1 + 0.5 wt% NaCl is a nonobvious and critical parameter combination for the instant claimed process.
New Rejections Necessitated by Amendment/Rejections Maintained
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.
Claim(s) 1, 3-11, 13-14, 16, 18-21, 23-26, 36-54, 56-59, 61-64, 74-75, and 76-85 is/are rejected under 35 U.S.C. 103 as being unpatentable over Noguchi (Noguchi et al., US 2018/0147292 A1; Published 05/31/2018, of record), Albanese (Albanese, et al., CA 2895869 A1; Published 06/26/2014, of record) and Hu (Hu, et al., US 20180036423 A1; Published 02/08/2018, of record).
Noguchi teaches a method of manufacturing antibody-drug conjugates (Noguchi, Abstract). Regarding the structural limitations of claims 1 and 45, Noguchi teaches identical structures for both the intermediate drug-linker compound (Noguchi, ¶ 0294) as well as the final antibody-drug-linker compound (Noguchi, ¶ 0269). Regarding the limitations of steps (i) and (ii) of claim 1, the limitations of steps (i) and (ii) of claim 45, Noguchi teaches that the method of Noguchi comprises first reducing an antibody interchain disulfides and then reacting the drug-linker intermediate of Noguchi with the antibody (Noguchi, Claim 1). Regarding claims 2-3 and step (i) of claim 45, Noguchi teaches that the antibody is reduced with TRIS (Noguchi, claim 8). Regarding the limitations of step (iii) of claim 1, step (iii) of claim 45 as well as claim 12, Noguchi teaches that the reaction is terminated by adding a capping agent that is N-acetyl cysteine (Noguchi, ¶ 0224-0226). Regarding claims 4-8, 45-50 Noguchi teaches that the reaction is performed in a phosphate or acetate buffer with a pH between 6 and 8 and in the presence of EDTA (Noguchi, ¶ 0215-0218). Regarding claim 5 specifically, the pH of a buffered solution depends on the component concentrations and as such the pH of the phosphate buffer of Noguchi was adjusted when the disodium hydrogen phosphate was added. Regarding claims 9-10 and 51-52, Noguchi teaches that the reduction buffer contains polysorbate-20 (Noguchi, ¶ 0295). Regarding claims Regarding step (iv) of claim 1, claim 36, claim 74 as well as claims 13-14, Noguchi teaches that the ADC is ultrafiltered into a histidine buffer following conjugation (Noguchi, ¶ 0295). Regarding step (iv) of claim 1, claim 36, claim 74, 13-14 claims 15-16, 18-21 and 54-59 Noguchi teaches that the conjugation reaction, which contains the salt sodium phosphate at 0.3 M disodium hydrogen phosphate (same as about 0.5 wt%), was removed via a concentration/ultrafiltration step using a Pellicon ultrafilter, wherein the ADC was ultrafiltered into pH 10 mM 5 histidine (Noguchi, ¶ 0295-0297). Regarding claims 38-39 and 42, Noguchi teaches that the ADC of Noguchi is present in a pharmaceutical composition that also contains dextrose (an excipient) and an emulsifier (same as surfactant) (Noguchi, ¶ 0279) and adding this excipient and emulsifier forms a method that satisfies the limitations of claims 76-77 and 80 as well when taken together with Noguchi.
Noguchi does not teach that the excipient added in the final step of the product of the method of Noguchi comprises an excipient that is sucrose or trehalose and a surfactant that is polysorbate 20 or polysorbate 80. Noguchi does not teach that the immunoconjugate comprises an anti-HER2 antibody having a HC of instant SEQ ID NO: 1 and a LC of instant SEQ ID NO: 2. Noguchi does not teach the ultrafiltration buffer used to remove the residual drug-linker moieties following N-acetylcysteine addition is a histidine buffer with a pH from 4.7-5.3 and a NaCL from 0.4-0.6 wt%. Noguchi does not teach that the drug to antibody ratio of the ADC to be produced is between 7.5 and 8.
Albanese teaches that stabilizers are added to the formulation including a stabilizer (including sucrose and trehalose) and a surfactant (including polysorbate 20 and polysorbate 80). Albanese teaches that the composition of Albanese comprises an anti-HER2 antibody having HC of Albanese’s SEQ ID NO: 10 (same as instant SEQ ID NO: 1) and LC of Albanese’s SEQ ID NO: 11 (same as instant SEQ ID NO: 2).
Hu teaches that the ADCs of Hu comprises anywhere between 1 and 8 drug-linker moieties bound to an antibody (Hu, Claim 15). Hu teaches an ultrafiltration method for method of removing leftover maleimide-comprising drug-linker moieties following addition maleimide-based conjugation to an antibody followed by N-acetyl cystine capping, wherein the ultrafiltration buffer comprises 0.3% wt% NaCl, 20 mM sodium citrate, and at a pH of 6.0 (Hu, ¶ 0158-0152).
It would be prima facie obvious to add the 0.3 wt% NaCl present in the ultrafiltration buffer of Hu to the 10 mM histidine buffer of Noguchi. One of ordinary skill in the art would be motivated to do this to improve the ultrafiltration buffer of Noguchi by the 0.3wt% NaCl art element of Hu. One of ordinary skill in the art would have a reasonable expectation of success forming the modified ultrafiltration buffer collectively taught by Hu and Noguchi, said buffer comprising 10 mm, pH 5 histidine and 0.3 wt% NaCl because Hu teaches that 0.3wt% NaCl is a known ultrafiltration buffer component for the purposes of removing unreacted ADC reactant.
It would be prima facie obvious to one of ordinary skill in the art to further modify the modified method of Noguchi and Hu discussed above to include the polysorbate 20 or polysorbate 80 surfactants of Albanese, the sucrose or trehalose excipients of Albanese and the anti HER2 antibody of Albanese as well the 8 ADC DAR of Hu. The net result of this modification would be a production processes for producing an anti-HER2 ADC with a DAR between 7.5-8, wherein pH. 5.0 10 mM histidine and 0.3 wt% NaCl are present in the ultrafiltration step of the process and the final product is formulated with sucrose or trehalose as an excipient and polysorbate 20 or polysorbate 80 as surfactants. One of ordinary skill in the art would be motivated to make these modifications in order to produce an anti-HER2 ADC with a DAR from 7.5-8 using production processes that are standard in the art. One of ordinary skill in the art would have a reasonable expectation of success performing these modifications because: 1) Noguchi teaches that excipients are added to the final products and Albanese teaches sucrose and trehalose are acceptable excipients, 2) Noguchi teaches that emulsifiers are present in the final product and Albanese teaches that polysorbate 20 and polysorbate 80 are acceptable surfactants (same as emulsifiers) and 3) Hu teaches the presence of 0.3wt% % sodium chloride in ultrafiltration buffers.
Regarding the DAR limitations of the instant claims, Hu teaches DAR values ranging from 1 to 8. “[W]here 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
Regarding the 0.4wt% limitation, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties.") (See MPEP § 2144.05). As such, one of ordinary skill in the art would expect the difference between a 0.4wt% NaCl Histidine ultrafiltration buffer and the same buffer a 0.3wt% NaCl histidine ultrafiltration buffer would be negligible with respect to pertinent properties.
Response to Arguments
Applicant's arguments filed 7/24/2026 have been fully considered but they are not persuasive.
Applicant presents three main arguments, with two of them (Remarks of 07/24/2026, p 17, ¶ 6- p 19, ¶ 1; as well as Remarks of 07/24/2026, p 20, ¶ 4 – p 24, ¶ 2) rely on the alleged criticality of combination of parameters as articulated in the Sakuratani Declaration, which has been addressed above and, as such, will not be addressed again here.
Applicant also argues that Hu and Albanese do not provide any motivation to combine or reasonable expectation of success. Applicant argues that the Hu document teaches the production of a different ADC (emphasis added by Applicant) with a different average number of drug-linker moieties and a buffer pH of 6.0, which Applicant argues is expressly outside the scope of the claims (0.4-0.6 wt% NaCl; histidine, pH 4.7-5.3). Regarding the differing number of drug-linker moieties argument, as articulated in both the Nonfinal Rejection of 02/26/2026 as well as the Final Rejection of 02/11/2025, the lower DAR of Hu was accomplished by intentionally lowering the reaction temperature of the conjugation reaction to slow the conjugation process and anyone of skill in the art with a working knowledge of chemical kinetics would instantly recognize this relationship between reaction rate and temperature. The fact that Hu’s pH was 6.0, which is outside of the claimed range of 4.7-5.1 pH, is not relevant as the combined method of Noguchi, Hu and Albanese articulated above uses the pH of 5.0 taught by Noguchi and not the pH 6.0 of Hu, with the Hu reference was included for its teaching of 0.3 wt% NaCl of Hu and not the pH of Hu.
Regarding the “different ADC” argument, this is not relevant as conjugation between a drug-linker moiety comprising a maleimide crosslinker and an antibody involves reaction between maleimide groups on the drug-linker and the thiols of the antibody should not be affected by the type of antibody, provided the antibody’s thiols remain intact. Additionally, Applicant demonstrates knowledge that the instant claimed process should be capable of attaching the instant claimed drug-linker moiety to a wide range of antibodies by virtue of presentation of the table found at paragraph 11 of the Sakuratani Declaration of 7/24/2026, which compares conjugation and subsequent separation of an anti-CDH6 ADC as well as an anti-TA MUC1 ADC.
Conclusion
Claims 1, 3-11, 13-14, 16, 18-21, 23-26, 36-54, 56-59, 61-64, 74-75, and 76-85 are rejected
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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