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 .
The response dated 7/14/2026 is acknowledged. Claims 1, 3-13 and 15-27 are pending. Claims 2, 14, and 28-29 are cancelled. Claims 1, 3-13 and 15-27 are considered on the merits below.
Information Disclosure Statement
The Information Disclosure Statements filed on 5/19/2026 and 7/14/2026 are in compliance with the provisions of 37 CFR 1.97 and have been considered. An initialed copy of the Form 1449 is enclosed herewith.
Response to Amendment
Applicant's amendments, filed 7/14/2026, with respect to the objection to the drawings have been fully satisfied and withdrawn.
In response to the applicant's amendments, the grounds of rejection for claims 1, 3-13 and 15-27 are new compared to the previous action due to the amendment, however rely on the same prior art.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3-13 and 15-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Regarding claim 1:
Step 2A, Prong 1: identify the abstract ideas. The monitoring (step f) is an observation or evaluation, therefore a mental step and abstract idea
Step 2A, Prong 2: has the abstract idea been integrated into a particular practical application?
Once the abstract idea is completed there is nothing particular about the molecule sample that is detected. Therefore the application of treating the detecting a molecule is at most generically linking the use of the abstract idea to a field of endeavor. MPEP 2106.05(h)
Step 2B: does the claim recite any elements which are significantly more than the abstract idea? Here, we are looking for elements in addition to the abstract idea which are not routine and conventional. Outside of the abstract idea, the claim is drawn to preparing the sample for monitoring including steps of obtaining, contacting, and eluting. These are well known routine and conventional steps and thus not “significantly more”.
Regarding claim 13, Step 2A, Prong 1: identify the abstract ideas. The monitoring (step f) is an observation or evaluation, therefore a mental step and abstract idea
Step 2A, Prong 2: has the abstract idea been integrated into a particular practical application?
Once the abstract idea is completed there is nothing particular about the molecule sample that is detected. Therefore the application of treating the detecting a molecule is at most generically linking the use of the abstract idea to a field of endeavor. MPEP 2106.05(h)
Step 2B: does the claim recite any elements which are significantly more than the abstract idea? Here, we are looking for elements in addition to the abstract idea which are not routine and conventional. Outside of the abstract idea, the claim is drawn to preparing the sample for monitoring including steps of manufacturing, contacting, injecting, and eluting. These are well known routine and conventional steps and thus not “significantly more”.
Regarding claim 27:
Step 2A, Prong 1: identify the abstract ideas. The monitoring (step f) is an observation or evaluation, therefore a mental step and abstract idea
Step 2A, Prong 2: has the abstract idea been integrated into a particular practical application?
Once the abstract idea is completed there is nothing particular about the molecule sample that is detected. Therefore the application of treating the detecting a molecule is at most generically linking the use of the abstract idea to a field of endeavor. MPEP 2106.05(h)
Step 2B: does the claim recite any elements which are significantly more than the abstract idea? Here, we are looking for elements in addition to the abstract idea which are not routine and conventional. Outside of the abstract idea, the claim is drawn to preparing the sample for monitoring including steps of a chemical exchange, injecting, and eluting. These are well known routine and conventional steps and thus not “significantly more”.
Dependent claims only further refine the abstract idea without adding significantly more.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3-13 and 15-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dimasi et al. (MABS, Vol. 9, No. 3, pp. 438-454, 2017, provided on the IDS on 3/10/2025) in view of Dillon et al. (US 2005/0161399 A1, provided on the IDS on 3/10/2025).
Regarding claim 1, Dimasi describes a method of detecting formation of a multi-specific molecule (abstract), the method comprising:
a. obtaining a multi-specific molecule sample (page 450 “10 mg of antibodies” (antibodies of the Dimasi (page 439 “iMAB”) are multi-specific molecules);
b. obtaining a reversed-phase high performance liquid chromatography (RP-HPLC) column (page 450 “rRP-HPLC was performed”);
c. contacting the multi-specific molecule sample in a polar aqueous mobile phase A with the RP-HPLC column, wherein the polar aqueous mobile phase comprises an ion-pairing agent (page 450 “The mobile phase A used was 0.1% trifluoroacetic acid in water”);
d. contacting an organic non-polar mobile phase B with the RP-HPLC column, wherein the organic non-polar phase comprises an ion-pairing agent (page 450 “the mobile phase B was 0.1% trifluoroacetic acid in acetonitrile”);
e. eluting the multi-specific molecule sample (page 450 “The antibodies were [eluted and] analyzed using an isocratic gradient from 20% to 50% mobile phase B for 20 min”); and
f. monitoring the amount of multi-specific molecule formation in the eluted multi- specific molecule sample (page 450 “The antibodies were monitored using an absorbance of 280 nm.”)
However Dimasi is silent to wherein the polar aqueous mobile phase A is a solution comprising about 1% to about 5% isopropanol.
Dillon describes RP-HPLC for antibody analysis (abstract) and isopropanol as a mobile phase solvent ([0019] and [0021] “the mobile phase comprises a gradient of isopropanol from 5% isopropanol to 90% isopropanol,”). Additionally Dillon suggests motivation to used isopropanol in the mobile phases as it is not only facilitates separation, but helps spectra resolution ([0074] “It is of note that isopropanol facilitates Separation of the proteins components on the HPLC, but it is also advantageous in that it enhances ESI-MS spectra. It is likely that it reduces surface tension of the ES droplets and assists in ion formation (Apfell et al., J. Chromat., 712:177-190, 1995).”).
Therefore it would have been obvious to one skilled in the art at the time the invention was filed to incorporate isopropanol as a mobile phase solvent comprising about 1% to about 5% isopropanol into the method of Dimasi as suggested by Dillon as this would not only facilitates separation, but helps spectra resolution.
Regarding claim 3, the combination described above describes the method of claim 1, wherein the solution comprises about 2% isopropanol (Dillon: [0021] “the mobile phase comprises a gradient of isopropanol from 5% isopropanol (this is about 2%)).
Regarding claim 4, the combination described above describes the method of claim 1, wherein the ion-pairing agent in the polar aqueous mobile phase A is selected from the group consisting of trifluoroacetic acid (TFA), difluoroacetic acid (DFA), and formic acid (FA) (Dimasi: page 450 “trifluoroacetic acid in water”).
Regarding claim 5, the combination described above describes the method of claim 4, wherein the TFA is present in the polar aqueous mobile phase A at about 0.10% to about 2% (Dimasi: page 450 “0.1% trifluoroacetic acid in water”).
Regarding claim 6, the combination described above describes the method of claim 5, wherein the TFA is present in the polar aqueous mobile phase A at about 0.1% (Dimasi: page 450 “0.1% trifluoroacetic acid in water”).
Regarding claims 7, 8, and 9, the combination described above describes the method of claim 1, and wherein the organic non-polar mobile phase B is a solution comprising about 60% to about 80% isopropanol and about 15% to about 25% acetonitrile, about 70% isopropanol and 20% acetonitrile (Dillon: [0019] and [0021] “the mobile phase comprises a gradient of isopropanol from 5% isopropanol to 90% isopropanol,” and [0074] “solvent B has a pH of 2.0 and comprises 70% isopropanol, 20% acetonitrile”).
Regarding claim 10, the combination described above describes the method of claim 1, wherein the ion-pairing agent in the organic non- polar mobile phase B is selected from the group consisting of trifluoroacetic acid (TFA), difluoroacetic acid (DFA), and formic acid (FA) (Dimasi: page 450 “the mobile phase B was 0.1% trifluoroacetic acid in acetonitrile”).
Regarding claim 11, the combination described above describes the method of claim 10, wherein the TFA is present in the organic non- polar aqueous mobile phase B at about 0.1% to about 2% (Dimasi: page 450 “the mobile phase B was 0.1% trifluoroacetic acid in acetonitrile”).
Regarding claim 12, the combination described above describes the method of claim 11, wherein the TFA is present in the organic non- polar aqueous mobile phase B at about 0.1% (Dimasi: page 450 “the mobile phase B was 0.1% trifluoroacetic acid in acetonitrile”).
Regarding claim 13, Dimasi describes a method of detecting formation of a multi-specific antibody while performing a manufacturing process to produce a multi-specific antibody (abstract and figure 1), the method comprising:
a. performing a manufacturing process to produce a multi-specific antibody, wherein the manufacturing process results in a multi-specific antibody sample comprising an amount of a multi-specific antibody (figure 1);
b. setting up a reversed-phase high performance liquid chromatography (RP-HPLC) column (page 450 “rRP-HPLC);
c. injecting the multi-specific antibody sample in a polar aqueous mobile phase A in the RP-HPLC column, wherein the polar aqueous mobile phase comprises an ion- pairing agent (page 450 “10 mg of antibodies in PBS pH 7.2 were reduced with 42 mM dithiothreitol at 37_C for 20 min. rRP-HPLC was performed at 80_C, 1 mL/minute flow rate. The mobile phase A used was 0.1% trifluoroacetic acid in water (J.T. Baker);”);
d. applying an organic non-polar mobile phase B to the RP-HPLC column to form a gradient elution, wherein the organic non-polar mobile phase comprises an ion- pairing agent (page 450 “while the mobile phase B was 0.1% trifluoroacetic acid in acetonitrile (J.T. Baker).”);
e. eluting the multi-specific antibody sample (page 450 “The antibodies were [eluted and] analyzed using an isocratic gradient from 20% to 50% mobile phase B for 20 min”); and
f. monitoring the amount of multi-specific antibody formation in the eluted sample (page 450 “The antibodies were monitored using an absorbance of 280 nm.”).
However Dimasi is silent to wherein the polar aqueous mobile phase A is a solution comprising about 1% to about 5% isopropanol.
Dillon describes RP-HPLC for antibody analysis (abstract) and isopropanol as a mobile phase solvent ([0019] and [0021] “the mobile phase comprises a gradient of isopropanol from 5% isopropanol to 90% isopropanol,”). Additionally Dillon suggests motivation to used isopropanol in the mobile phases as it is not only facilitates separation, but helps spectra resolution ([0074] “It is of note that isopropanol facilitates Separation of the proteins components on the HPLC, but it is also advantageous in that it enhances ESI-MS spectra. It is likely that it reduces surface tension of the ES droplets and assists in ion formation (Apfell et al., J. Chromat., 712:177-190, 1995).”).
Therefore it would have been obvious to one skilled in the art at the time the invention was filed to incorporate isopropanol as a mobile phase solvent comprising about 1% to about 5% isopropanol into the method of Dimasi as suggested by Dillon as this would not only facilitates separation, but helps spectra resolution.
Regarding claim 15, the combination described above describes the method of claim 13, wherein the solution comprises about 2% isopropanol (Dillon: [0021] “the mobile phase comprises a gradient of isopropanol from 5% isopropanol (this is about 2%)).
Regarding claim 16, the combination described above describes the method of claim 13, wherein the ion-pairing agent in the polar aqueous mobile phase A is selected from the group consisting of trifluoroacetic acid (TFA), difluoroacetic acid (DFA), and formic acid (FA) (Dimasi: page 450 “The mobile phase A used was 0.1% trifluoroacetic acid in water”).
Regarding claim 17, the combination described above describes the method of claim 16, wherein the TFA is present in the polar aqueous mobile phase A at about 0.10% to about 2% (Dimasi: page 450 “The mobile phase A used was 0.1% trifluoroacetic acid in water”).
Regarding claim 18, Dimasi describes The method of claim 17, wherein the TFA is present in the polar aqueous mobile phase A at about 0.1% (Dimasi: page 450 “The mobile phase A used was 0.1% trifluoroacetic acid in water”).
Regarding claim 19, the combination described above describes the method of claim 13, wherein the organic non-polar mobile phase B is a solution comprising about 60% to about 80% isopropanol and about 15% to about 25% acetonitrile (Dillon: [0074] “solvent B has a pH of 2.0 and comprises 70% isopropanol, 20% acetonitrile”).
Regarding claim 20, the combination described above describes the method of claim 19, wherein the solution comprises about 70% isopropanol (Dillon: [0074] “solvent B has a pH of 2.0 and comprises 70% isopropanol, 20% acetonitrile”)
Regarding claim 21, the combination described above describes the method of claim 19, wherein the solution comprises about 20% acetonitrile (Dillon: [0074] “solvent B has a pH of 2.0 and comprises 70% isopropanol, 20% acetonitrile”).
Regarding claim 22, the combination described above describes the method of claim 19, wherein the ion-pairing agent in the organic non- polar mobile phase B is selected from the group consisting of trifluoroacetic acid (TFA), difluoroacetic acid (DFA), and formic acid (FA) (Dillon: [0074] “0.1% TFA.”).
Regarding claim 23, the combination described above describes the method of claim 22, wherein the TFA is present in the organic non- polar aqueous mobile phase B at about 0.1% to about 2% (Dillon: [0074] “0.1% TFA.”)..
Regarding claim 24, the combination described above describes the method of claim 23, wherein the TFA is present in the organic non- polar aqueous mobile phase B at about 0.1% (Dillon: [0074] “0.1% TFA.”).
Regarding claim 25, the combination described above describes the method of claim 13, wherein the manufacturing process to produce a multi-specific antibody is selected from the group consisting of a knob in hole process, a strand exchange engineered domain process, a chemical linked bispecific antibody (BsAb) process, an immunoglobulin domain crossover process, and a controlled Fab arm exchange (cFAE) and dual variable domain process (Dimasi: page 448 “The iMab-EI DNA sequence, which consisted of the variable domains from the 2 parental antibodies, the light and heavy chain constant domains, and the linkers, was assembled using synthetic oligonucleotides (Thermo Fisher Scientific).”).
Regarding claim 26, the combination described above describes the method of claim 13, wherein the multi-specific antibody is a bispecific antibody (Dimasi: abstract “bispecific monovalent antibodies in IgG1 format”).
Regarding claim 27, Dimasi describes a method of detecting formation of a bispecific antibody while performing a controlled FAB arm exchange (cFAE) to produce a bispecific antibody (abstract and figure 1), the method comprising:
a. performing a controlled FAB arm exchange (cFAE) to produce a cFAE sample, wherein the cFAE sample comprises an amount of a bispecific antibody (page 438 “This approach involved the molecular exchange of heavy chain and light chain domains within the antigen-binding fragment (Fab),” and page 439 “a single-chain IgG design without any domain interface mutations (herein termed ‘innovative monoclonal antibody’ (iMab)) could overcome inefficiencies inherent with the use of 2 independent genes to form a full-length IgG-Bs molecule with monovalent antigen binding and with IgG1-like sequence and structure. The key design element of the iMab is based on the hypothesis that the light and heavy chains of different antigen specificity (i.e., 2 different light and heavy chains), if in close proximity (i.e., cotranscribed, co-translated, co-folded, co-secreted), will force the monovalent bispecific formation of the iMab.” And figure 1);
b. setting up a reversed-phase high performance liquid chromatography (RP-HPLC) column (page 450 “rRP-HPLC was performed”);
c. injecting the cFAE sample in a polar aqueous mobile phase A in the RP-HPLC column, wherein the polar aqueous mobile phase comprises an ion-pairing agent (page 450 “The mobile phase A used was 0.1% trifluoroacetic acid in water”);
d. applying an organic non-polar mobile phase B to the RP-HPLC column to form a gradient elution, wherein the organic non-polar mobile phase comprises an ion- pairing agent (page 450 “the mobile phase B was 0.1% trifluoroacetic acid in acetonitrile”);
e. eluting the cFAE sample (page 450 “The antibodies were [eluted and] analyzed using an isocratic gradient from 20% to 50% mobile phase B for 20 min”); and
f. monitoring the amount of bispecific antibody formation in the eluted sample (page 450 “The antibodies were monitored using an absorbance of 280 nm.”).
However Dimasi is silent to wherein the polar aqueous mobile phase A is a solution comprising about 1% to about 5% isopropanol.
Dillon describes RP-HPLC for antibody analysis (abstract) and isopropanol as a mobile phase solvent ([0019] and [0021] “the mobile phase comprises a gradient of isopropanol from 5% isopropanol to 90% isopropanol,”). Additionally Dillon suggests motivation to used isopropanol in the mobile phases as it is not only facilitates separation, but helps spectra resolution ([0074] “It is of note that isopropanol facilitates Separation of the proteins components on the HPLC, but it is also advantageous in that it enhances ESI-MS spectra. It is likely that it reduces surface tension of the ES droplets and assists in ion formation (Apfell et al., J. Chromat., 712:177-190, 1995).”).
Therefore it would have been obvious to one skilled in the art at the time the invention was filed to incorporate isopropanol as a mobile phase solvent comprising about 1% to about 5% isopropanol into the method of Dimasi as suggested by Dillon as this would not only facilitates separation, but helps spectra resolution.
Response to Arguments
Applicant's arguments filed 7/14/20026 have been fully considered but they are not persuasive.
The applicant argues that (1) the 101 is overcome because the claims provide technical improvements over what is routine in the art, particularly peak shape; (2) that the two prior art references are non-analogous art resulting in hindsight reasoning for the combination, (3) the claims provide unexpected results regarding the peak shape, and (4) the solvent ranges provided by the prior art do not overlap that required by the claim.
In response to the applicant’s argument that (1) the 101 is overcome because the claims provide technical improvements over what is routine in the art, particularly peak shape, it is noted that the features upon which applicant relies (i.e., peak shape) 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). Furthermore for reasoning in the above rejection, the 101 rejection is maintained.
In response to the applicant’s argument that (2) that the two prior art references are non-analogous art resulting in hindsight reasoning for the combination, 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). Additionally, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, both art references are drawn to detecting molecules using column chromatography.
In response to the applicant’s argument that (3) the claims provide unexpected results regarding the peak shape, it is noted that the features upon which applicant relies (i.e., peak shape) 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). Furthermore for reasoning in the above rejection, the 101 rejection is maintained.
In response to the applicant’s argument that (4) the solvent ranges provided by the prior art do not overlap that required by the claim, one cannot show nonobviousness by attacking only one teaching of a reference, when the prior describes more than one embodiment, as cited above. Furthermore, the instant claims modify the range with “about”, thus overlap in range with that cited in the prior art.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY R BERKELEY whose telephone number is (571)272-9831. The examiner can normally be reached M-Th 9-6.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lyle Alexander can be reached at (571) 272-1254. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LYLE ALEXANDER/Supervisory Patent Examiner, Art Unit 1797
/EMILY R. BERKELEY/
Examiner
Art Unit 1796
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