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 1-6 2 are pending and currently under consideration. Claim Objections Claim 60 is objected to because of an apparent typographical error. The word “at” appears to be missing between “conditions” and “a” at the last line of claim 60. Proper correction is required. Claim Rejections - 35 USC § 112 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 appl icant regards as his invention. Claim s 12, 39, 40, 45-49 , and 62 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. Claims 12, 40, 43, 48, and 49 are rejected because claims 12, 40, 43, and 48 recite “…to one of the two antibody heavy chains of the anti-PD-1 antibody.”. There is insufficient antecedent basis for “the two antibody heavy chains of the anti-PD-1 antibody” in the claims. Claim 39 is rejected for reciting “The method of claim 29, wherein the cell culture temperature regime may be further….” Claim 29 recites two different temperature regimes. There is insufficient antecedent basis for “the cell culture temperature regime” in claim 39. Claims 45-49 are rejected because claim 45 recites “…e) selecting the cell culture that modulated production of the product related impurity; f)….” There is insufficient antecedent basis for “the cell culture that modulated production of the product related impurity” in the claims. Claim 62 recites “…wherein the protein secretion profiles measured before and after the temperature shift….” There is insufficient antecedent basis for “the protein secretion profiles measured before and after the temperature shift” in the claim. Claim Rejections - 35 USC § 102 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale , or otherwise available to the public before the effective filing date of the claimed invention. Claim(s) 1-10 and 45-47 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Gomez et al (Biotechnology and Bioengineering, 20 18 , 115(12): 2930-2940 ; 9/28/23 IDS ) . Gomez et al teaches a method comprising establishing at least two cell cultures each inoculated with a CHO cell line expressing an asymmetric multispecific antibody (“B-Ab A ”), culturing at least once cell culture at a first regime at 36 °C for seven days and then cultured at a second regime at 32.5 °C for seven days, comparing amounts of secreted antibody products (including proper heterodimers and improper homodimers where identical long heavy chains are mis- paired) , and selecting 36 °C as having reduced expression of mis-paired identical long heavy chains (Table 1, Table 2, Figure 4, and Material and Methods, in particular). Gomez et al further teaches said method wherein a biphasic cell culture process was selected that uses a first regime inoculating stably transformed CHO host cells expressing the asymmetric multispecific antibody into a vessel (same as “bioreactor”) comprising culture medium at 36 °C to maximize cell growth first for 3 days and then shifting to culturing the cells for 10 more days with a second regime at 32.5 °C for production and harvesting of the asymmetric multispecific antibody , followed by protein-A or CEX purification of the asymmetric multispecific antibody, led to improve quality and purification yield ( see 2.1 Cell culture at right column on page 2931, Table 4 , and left column on page 2939, in particular). Asymmetric multispecific antibody produced by the method of Gomez et al is equivalent to an asymmetric multispecific antibody produced by the method of instant claim 45. Claim Rejections - 35 USC § 103 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- 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gomez et al (Biotechnology and Bioengineering , 2018 , 115(12): 2930-2940 ; 9/28/23 IDS ) as applied to claim s 1-10 and 45-47 and further in view of Ali et al (WO 2019/140196 A1; 7/18/2019 ; 9/28/23 IDS ) . The biphasic cell culture process of Gomez et al for generating asymmetric multispecific antibodies is discussed above . Gomez et al does not specifically teach generating an asymmetric multispecific antibody comprising an IL-21 mutein . However, these deficiencies are made up in the teachings of Ali et al . Ali et al teaches an asymmetric multispecific antibody comprising a PD-1 targeting antibody fused to an IL-21 mutein that overcomes significant barriers associated with cytokine therapeutics and allows for antibody-like dosing and selectively delivery of the IL-21 mutein in a PD-1 targeted manner wherein the IL-21 mutein can selectively activate and expand PD-1 expressing T cells in vivo ([0089], in particular). The asymmetric multispecific antibody of Ali et al has the following general structure: Ali et al further teaches the multispecific antibody comprising VH and VL domains of SEQ ID NOs: 382-384 and 385-387 , which comprise instant SEQ ID NOs: 382-384 and 385-38 9 ( [00227], in particular ). Ali et al further teaches the multispecific antibody comprising VH and VL domains of SEQ ID NOs: 362-364 and 365-369 , which comprise instant SEQ ID NOs: 362-364 and 365-369 ( [00237], in particular ). Ali et al further teaches the multispecific antibody comprising VL domain of SEQ ID NOs: SEQ ID NO:391 (which comprise instant SEQ ID NO: 391), a heavy chain comprising SEQ ID NO: SEQ ID NO:556 (which comprises instant SEQ ID NO:556), and a heavy chain attached to IL-21 mutein comprising SEQ ID NO:501 (which comprises instant SEQ ID NO:501) ( [00227], in particular ). Ali et al further teaches the multispecific antibody comprising VL domain of SEQ ID NO: 371 (which comprise instant SEQ ID NO: 371), a heavy chain comprising SEQ ID NO: 559 (which comprises instant SEQ ID NO:559), and a heavy chain attached to IL-21 mutein comprising SEQ ID NO: 513 (which comprises instant SEQ ID NO:513 and instant SEQ ID NO:244 ) ( [ 0 0237], in particular ). One of ordinary skill in the art would have been motivated, with a reasonable expectation of succes s, to perform a combined method comprising the method of Gomez et al of establishing at least two cell cultures each inoculated with a CHO cell line expressing an asymmetric multispecific antibody Ali et al, culturing at least once cell culture at a first regime at 36 °C for seven days and then cultured at a second regime at 32.5 °C for seven days, comparing amounts of secreted antibody products (including proper heterodimers and improper homodimers where identical long heavy chains are mis-paired), and selecting a temperature as having reduced expression of mis-paired identical long heavy chains in order to optimize proper pairing because Gomez et al teaches asymmetric mmlultispecific antibodies pair differently at different temperatures (Table 1, Table 2, Figure 4, and Material and Methods, in particular). This is an example of a simple substitution of one known element for another to obtain predictable result s. This is further an example of use of known technique to improve similar methods or products in the same way . This is further an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. One of ordinary skill in the art would have been motivated, with a reasonable expectation of succes s, to further perform the method using using the biphasic cell culture process of Gomez et al in order to further optimize generation of the asymmetric multispecific antibody of Ali et al because Gomez et al teaches the biphasic cell culture process comprising culture medium at 36 °C maximizes cell growth first for 3 days and then shifting to culturing the cells for 10 more days with a second regime at 32.5 °C for production and harvesting of the asymmetric multispecific antibody, followed by protein-A or CEX purification of the asymmetric multispecific antibody, improves quality and purification yield (see 2.1 Cell culture at right column on page 2931, Table 4, and left column on page 2939, in particular). This is an example of a simple substitution of one known element for another to obtain predictable result s. This is further an example of use of known technique to improve similar methods or products in the same way . This is further an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. T herefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results. Claim Rejections - 35 USC § 103 Claim(s) 1-10, 45-47, and 50 -62 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gomez et al (Biotechnology and Bioengineering , 2018 , 115(12): 2930-2940 ; 9/28/23 IDS ) as applied to claim s 1- 10 and 45-47 above, and further in view of Lio n berger et al (WO 2019/075476 A2; 4/18/19 ) . Teachings of Gomez et al are discussed above. Gomez et al does not specifically teach methods involving a nanofluidic chip. However, these deficiencies are made up in the teachings of Li n oberger et al . Lio n berger et al teaches developing a new antibody production line can take many months of work and cost millions of dollars ([00219], in particular). Lio n berger et al further teaches a microfluidic device (same as “chip”; see [00060 ]) that is able to screen and identify promising clones days after seeding individual clones that would offers significant time and cost advantages ([00219], in particular) . Lio n berger et further teaches the microfluidic devices comprising many (including 3,500) chambers ([00059] and [00510], in particular) in which analytes can be produced and measured ([0002], in particular). Lio n berger et al further teaches analytes that are antibodies can be measured bound to a reporter that is a peptide epitope that binds the antibody ([00251], in particular). Lio n berger et further teaches top analyte producers can be selected and exported from the microfluidic devices in order to expand the cells (“micro-objects”) ([0008], in particular). Lio n berger et further teaches cells expressing analytes can be exported into well plates those well s can then be introduced to shaker flasks and then scaled-up ([00500], in particular). Lio n berger et further teaches the temperature of the microfluidic device can be regulated ([00217], in particular). One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to rapidly develop an optimized clone that generates an asymmetric multispecific antibody of Gomez et al by performing a combined method comprising placing a single cell clone expressing an asymmetric multispecific antibody into each chamber of a microfluidic device of Lioberger et al, culturing the cell in medium at the temperatures and time points of the biphasic cell culture process of Gomez et al, determine the amount of asymmetric multispecific antibody produced by each clone, and export (as taught by Lio n berger et al) those clones producing elevated amounts of the asymmetric multispecific antibody any time after day 6 (after the three days at lower temperature of Gomez et al) into multi- wells of plates (such as those described on right column on page 2931 of Gomez et al) , shaker flasks, and then scaled-up because the microfluidic device of Lio n berger et al has the ability to culture antibody-producing cells at optimized temperatures taught by Gomez et al and has the benefit of analyzing thousands of clones at a time for optimal antibody production. Further, the number of cells per chamber at export is predictably lower compared to a single cell cultured solely at 36 °C because Gomez et al identifies 36 °C as a temperature to maximize cell growth. This is an example of prior art elements according to known methods to yield predictable results . This is further an example of use of known technique to improve similar methods in the same wa y. This is further drawn to some t eaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention . Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT SEAN E AEDER whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-8787 . 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