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 applicant's election of Group I, claims 1-27, in their reply dated 1/9/2026 is acknowledged. Claims 28 and 29 were cancelled.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-27 are pending and considered on the merits below.
Information Disclosure Statement
The Information Disclosure Statements filed on 3/10/2025 and 6/30/2025 are in compliance with the provisions of 37 CFR 1.97 and has been considered. An initialed copy of the Form 1449 is enclosed herewith.
Response to Amendment
Regarding canceled claims 28 and 29, canceled and not entered claims must be listed by only the claim number and status identifier, without presenting the text of the claims. (MPEP 714(II)C).
Drawings
The drawings are objected to because
The drawings (see Figures 4, 5, 6, and 9) have legibly text. Lettering style having capital letters which should be at least 0.3175 cm. (0.125 inch) high, but may be no smaller than 0.21 cm. (0.08 inch) high (e.g., a font size of 6) in portrait orientation and presented in a form having sufficient clarity and contrast between the paper and the writing thereon to permit the direct reproduction of readily legible copies in any number by use of photographic, electrostatic, photo-offset, and microfilming processes and electronic capture by use of digital imaging and optical character recognition; and only a single column of text. See 37 CFR 1.52(a) and (b).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 1-27 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 is 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 is 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 is 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 § 102
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 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, 4-6, 10-13, 16-18, and 25-27 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dimasi et al. (MABS, Vol. 9, No. 3, pp. 438-454, 2017, 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.”)
Regarding claim 4, Dimasi 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) (page 450 “trifluoroacetic acid in water”).
Regarding claim 5, Dimasi 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% (page 450 “0.1% trifluoroacetic acid in water”).
Regarding claim 6, Dimasi describes The method of claim 5, wherein the TFA is present in the polar aqueous mobile phase A at about 0.1% (page 450 “0.1% trifluoroacetic acid in water”).
Regarding claim 10, Dimasi 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) (page 450 “the mobile phase B was 0.1% trifluoroacetic acid in acetonitrile”).
Regarding claim 11, Dimasi 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% (page 450 “the mobile phase B was 0.1% trifluoroacetic acid in acetonitrile”).
Regarding claim 12, Dimasi describes the method of claim 11, wherein the TFA is present in the organic non- polar aqueous mobile phase B at about 0.1% (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.”).
Regarding claim 16, Dimasi 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) (page 450 “The mobile phase A used was 0.1% trifluoroacetic acid in water”).
Regarding claim 17, Dimasi 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% (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% page 450 “The mobile phase A used was 0.1% trifluoroacetic acid in water”.
Regarding claim 25, Dimasi 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 (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, Dimasi describes the method of claim 13, wherein the multi-specific antibody is a bispecific antibody (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.”).
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) 2, 3, 7-9, 14-15 and 19-24 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 2, Dimasi describes the method of claim 1, however 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 2, 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 claims 7, 8, and 9, Dimasi the method of claim 1, and the organic non-polar mobile phase B is a solution comprising acetonitrile (page 450).
However Dimasi is silent to 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 (specifically about 70% isopropanol and 20% acetonitrile in claims 8 and 9 respectively).
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,” and [0074] “solvent B has a pH of 2.0 and comprises 70% isopropanol, 20% acetonitrile”). 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 60% to about 80% isopropanol and about 15% to about 25% acetonitrile into the method of Dimasi as suggested by Dillon as this would not only facilitates separation, but helps spectra resolution. In combination this would also result in the percentages of acetonitrile described.
Regarding claim 14, Dimasi describes the method of claim 13, however 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 14, 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 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.”).
Conclusion
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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/EMILY R. BERKELEY/
Examiner
Art Unit 1796
/LYLE ALEXANDER/ Supervisory Patent Examiner, Art Unit 1797