DETAILED ACTION
The amendment filed on 03/02/2026 has been entered and fully considered. Claims 1-5, 7, 10-11, 13-14, 17-18, 20, 23, 30, 32-33, 35-36 and 39 are pending. Claims 18, 20, 23, 32-33, 35-36 and 39 have been withdrawn from consideration. Claims 1-5, 7, 10-11, 13-14, 17 and 30 are considered on merits, of which claim 23 is amended.
Response to Amendment
In response to amendment, the examiner maintains rejection over the prior art established in the previous Office 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 .
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-2, 5, 7 and 10-11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mills et al. (Methods, 2015) (Mills).
Regarding claim 1, Mills teaches a method for immunoglobulin repertoire profiling (the presence of M-protein) (abstract), the method comprising:
reducing a mixture of immunoglobulins in a sample, the sample optionally further comprising a standard immunoglobulin, thereby obtaining a second sample comprising a mixture of light chains (LCs) and heavy chains (HCs) or light chains and Fd domains (Fig. 2, page 60, par 1);
ionizing the second sample with an ionizer (ESI) (Fig. 2, page 60, par 1);
detecting a multiplicity of ions generated by the ionization of the second sample with a current detector (TOF) (Fig. 3, page 60, par 7);
determining ion masses for each of the multiplicity of ions detected with the current detector with a mass analyzer (Fig. 2, page 60, par 8);
generating a mass-domain spectrum from the ion masses with the mass analyzer (Fig. 3, page 60, par 8); and
determining one or more metrics capturing the heterogeneity or relative abundance of individual immunoglobulins (page 58, par 0, page 63, par 0, page 64, pr 0).
Mills teaches exactly that the immunoglobulins are purified and reduced so as to release light chains from heavy chains, thereby producing a reduced sample that contains dissociated light chains and heavy chains before any optional downstream chromatographic separation. The fact that Mills then subjects the reduced material to reversed-phase chromatography prior to TOF-MS does not negate that the reduced sample itself comprises the claimed mixture. A reference is not limited to only the final fraction entering the detector when it expressly discloses preparation of the reduced sample containing dissociated HCs and LCs.
Mills analyzes immunoglobulins in human serum in the presence of polyclonal background, generates mass-domain spectra from reduced immunoglobulin chains, and determines abundance-related information from those spectra. Thus, even if Mills emphasizes monoclonal species detection, Mills still teaches analysis of immunoglobulins within a heterogeneous serum repertoire and therefore meets or at least suggests the broad “repertoire profiling” language as claimed.
Mills’ discussion that light chains are smaller and ionize more readily than intact immunoglobulins merely explains an analytical advantage of examining reduced chain species; it does not criticize, discredit, or otherwise discourage consideration of heavy chain information, nor does it state that heavy-chain-containing reduced mixtures should not be used. At most, Mills identifies a sensitivity benefit for LC detection. That is not a teaching away from a reduced sample containing both LC and HC species, particularly where Mills itself acknowledges dissociation of immunoglobulins into heavy and light chains.
Regarding claim 2, Mills teaches that wherein an Ion Titer (IT), a degree of clonality (DoC), a spectral correlation coefficient, or any combination thereof is determined (relative abondance of the polyclonal kappa and lambda populations) (page 63, par 0).
Regarding claim 5, Mills teaches that the method further comprising fractionating the sample prior to reduction (Fig. 2, page 58, par 3).
Regarding claim 7, Mills teaches that wherein the mixture of different immunoglobulins in the sample are chemically modified prior to ionization (disulfide bonds are reduced) (Fig. 2, page 60, par 1).
Regarding claim 10, Mills teaches a method of identifying a donor comprising the method claim 1, wherein the sample has been collected from a candidate donor and wherein the donor is identified from the one or more metrics capturing the heterogeneity or relative abundance of individual immunoglobulins (page 57, par 1).
Regarding claim 11, Mills teaches a method for obtaining a target immunoglobulin comprising the method according to claim 10 and further comprising obtaining a target immunoglobulin from the donor (page 57, par 1).
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mills et al. (Methods, 2015) (Mills) in view of Lee et al. (US 2012/0245857) (Lee).
Regarding claim 3, Mills does not specifically teach that wherein the Ion Titer (IT) is determined by a ratio between (i) a sum of mass-domain peak intensities across a light chain region and mass-domain peak intensities across a heavy chain region or Fd region and (ii) a sum of mass-domain peak intensities across a standard region divided by the value of the standard immunoglobulin.
However, Lee teaches that wherein the Ion Titer (IT) is determined by a ratio between (i) a sum of mass-domain peak intensities across a light chain region and mass-domain peak intensities across a heavy chain region or Fd region and (ii) a sum of mass-domain peak intensities across a standard region divided by the value of the standard immunoglobulin (par [0052][0119-[0121]). It would have been obvious to one of ordinary skill in the art to modify the method of Mills by determining the ratio of mass-domain peak intensities of light chains to heavy chains as taught by Lee. The motivation being to determine the ion titers in a sample for determining the presence and quantities of antibodies in a sample.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mills et al. (Methods, 2015) (Mills) in view of Murray et al. (US 2020/0003784) (Murray).
Regarding claim 4, Mills does not specifically teach that wherein the degree of clonality (DoC) is determined by a ratio between a sum of mass-domain peak intensities across a light chain region and a sum of mass-domain peak intensities across a peak window.
However, Murray teaches that wherein the degree of clonality (DoC) is determined by a ratio between a sum of mass-domain peak intensities across a light chain region and a sum of mass-domain peak intensities across a peak window (par [0034] [0097][0117]). It would have been obvious to one of ordinary skill in the art to modify the method of Mills by using light chain ratios to determine clonality as taught by Murray. The motivation being to use light chain mass spectra data to determine the degree of clonality in a sample.
Claim(s) 13-14 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mills et al. (Methods, 2015) (Mills) in view of FDA (FDA-approved IVIG labels and guidance, 2003).
Regarding claim 13, Mills teaches a method of preparing a proteome product (therapeutic monoclonal Igs) comprising the method according to 11 (page 57, par 2).
When preparing any immunoglobulin-containing product from donor material, it is routine practice to contact the Ig with pharmaceutically acceptable stabilizers/excipients in an aqueous carrier/diluent (e.g., glycine), and to use anticoagulants such as citrate during collection/processing of donor blood/plasma—practices documented in FDA-approved IVIG labels and guidance.
Incorporating these standard formulation/processing steps with Mills’ Ig profiling method would predictably stabilize the immunoglobulin and ensure safe handling/processing of donor samples, an expected outcome for a POSITA.
Regarding claim 14, Mills teaches a method of treating a subject in need of a proteome product, the method comprising administering an effective amount of the proteome product prepared by the method according to claim 13 to the subject (page 57, par 2, Fig. 6).
Regarding claim 17, Mills teaches a proteome product (therapeutic monoclonal Igs) prepared by the method according to claim 13 (page 57, par 2).
Claim(s) 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mills et al. (Methods, 2015) (Mills) in view of Lee et al. (Nature Medicine, 2016) (Lee2016)
Regarding claim 30, Mills does not specifically teach that wherein the method further comprises isolating one or more cells from the sample comprising the target proteoform or a complex thereof and sequencing a nucleic acid from the isolated cells, wherein the sequenced nucleic acid corresponds to the target proteoform or a complex thereof.
However, Lee2016 teaches that wherein the method further comprises isolating one or more cells from the sample comprising the target proteoform or a complex thereof and sequencing a nucleic acid from the isolated cells, wherein the sequenced nucleic acid corresponds to the target proteoform or a complex thereof (Fig. 1, page 1457, par 1). It would have been obvious to one of ordinary skill in the art to modify the method of Mills by isolating one or more cells from the sample comprising the target proteoform or a complex thereof and sequencing a nucleic acid from the isolated cells, wherein the sequenced nucleic acid corresponds to the target proteoform or a complex thereof, in order to find the sequence of the target proteoform.
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive.
Applicant argues that Mills does not teach analyzing “a mixture of light chains and heavy chains or light chains and Fd domains” because Mills separates the reduced heavy and light chains prior to MS analysis and measures the LC portion of intact monoclonal immunoglobulins. Applicant further argues that Mills is directed only to detection of monoclonal light chains above a normal polyclonal repertoire, and therefore neither anticipates nor renders obvious the presently claimed repertoire profiling method. Applicant also contends that Mills teaches away from use of heavy chains because light chains ionize more readily and are detected more sensitively.
These arguments are not persuasive.
First, the claims do not require simultaneous mass analysis of unreduced or unresolved heavy and light chains in a single undivided chromatographic band. Rather, claim 1 requires reducing a mixture of immunoglobulins in a sample, thereby obtaining a second sample comprising a mixture of light chains and heavy chains or light chains and Fd domains, followed by ionization, detection, mass analysis, and spectrum generation. Mills teaches exactly that the immunoglobulins are purified and reduced so as to release light chains from heavy chains, thereby producing a reduced sample that contains dissociated light chains and heavy chains before any optional downstream chromatographic separation. The fact that Mills then subjects the reduced material to reversed-phase chromatography prior to TOF-MS does not negate that the reduced sample itself comprises the claimed mixture. A reference is not limited to only the final fraction entering the detector when it expressly discloses preparation of the reduced sample containing dissociated HCs and LCs.
Second, Applicant’s attempt to distinguish Mills on the basis that Mills focuses on monoclonal immunoglobulin detection rather than “repertoire profiling” is not persuasive. The claimed method is broad. It recites reducing a mixture of immunoglobulins, generating a mass-domain spectrum, and determining one or more metrics capturing heterogeneity or relative abundance of individual immunoglobulins. Mills analyzes immunoglobulins in human serum in the presence of polyclonal background, generates mass-domain spectra from reduced immunoglobulin chains, and determines abundance-related information from those spectra. Thus, even if Mills emphasizes monoclonal species detection, Mills still teaches analysis of immunoglobulins within a heterogeneous serum repertoire and therefore meets or at least suggests the broad “repertoire profiling” language as claimed.
Third, Applicant’s argument that Mills teaches away is unpersuasive. A reference teaches away only when it discourages or criticizes the claimed approach. Mills’ discussion that light chains are smaller and ionize more readily than intact immunoglobulins merely explains an analytical advantage of examining reduced chain species; it does not criticize, discredit, or otherwise discourage consideration of heavy chain information, nor does it state that heavy-chain-containing reduced mixtures should not be used. At most, Mills identifies a sensitivity benefit for LC detection. That is not a teaching away from a reduced sample containing both LC and HC species, particularly where Mills itself acknowledges dissociation of immunoglobulins into heavy and light chains.
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 XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./Primary Examiner, Art Unit 1797