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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114 was filed in this application after appeal to the Patent Trial and Appeal Board, but prior to a decision on the appeal. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on 02/04/2026 has been entered.
Rejections withdrawn
All rejections/objections of all cancelled claims are mooted.
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 on the subject of 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-acetylcystamine 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 02/04/2026 have been fully considered but they are not persuasive.
Applicant begins by suggesting that the cited references (Noguchi, Hu and Albanese) do not teach the ultrafiltration buffer, which comprises histidine buffer with sodium chloride between 0.4-0.6 wt % that is between pH 4.7-5.3. This assertation incorrect as both Hu and Noguchi’s ultrafiltration buffer comprising a millimolar-level buffer (histidine or chloride), whereas Hu’s ultrafiltration buffer additionally had 3 wt% NaCl and levels of high common electrolytes are routinely used to prevent ionic interactions with membranes during ultrafiltration. Hence, one of ordinary skill in the art would be motivated to include the sodium chloride of Hu with the histidine of Noguchi.
Applicant makes several arguments regarding how the Noguchi reference teaches DAR ratios that are 3.5-4.5, well below the claimed range of 7.5-8. Applicant was reminded that the Noguchi refence Rence was chosen as primary art due to that it was determined to encompass the most limitations of the claims and that, that the Noguchi reference purposefully slowed down the maleimide to cysteine conjugation to generate, low DAR ADCs, that one of ordinary skill in the art would expect this from reading the Abstract of Noguchi, which says the reaction is cooled deliberately to slow conjugation and all of this was explained in the Final Rejection of 02/11/2025.
Applicant also alleges the Office uses conclusory and unsupported taking note of the use of Office’s Assertion that maleimide-based conjugation of drug-linker moieties is a very well-developed field. Applicant’s claimed methods are routine in view of Noguchi and Hu, both of which contain a TRIS activation step, followed by conjugation of a linker-drug to an antibody followed by N-acetylcysteine capping followed by diafiltration of the small molecule drug-linker components. All of these are analogous unit operations shared amongst two prior art references and the instant claim set. The instant claimed method is little more than an application well-known analogous unit operations. The Albanese refence simply illustrates how inclusion of surfactants and sugars are also common in ADC production. Applicant also counts Office’s statement that achieving DAR of 8 is routine in the common art as “unsupported”. The Hu reference claims in Claim 15 that the method of Hu is capable of producing an ADC via maleimide chemistry with a DAR of 8. Examples maleimide-produced ADCs with DARs of 8 are not uncommon or unique.
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.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643