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 .
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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/24/2025 has been entered.
Priority
This application is a U.S. National Stage (371) application of PCT/CN2017/116889 filed on 12/18/2017 which claims priority to Foreign Application No. CN201611180971.4 filed on 12/19/2016.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/24/2025 has been received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner and all references are considered except where they were lined through.
Claim Status
The Applicant did not further amend the claim set that was examined in the Office action of 04/24/2025. In the Office action of 04/24/2025, the following was noted: Claims 1 and 10-12 are currently amended and the Applicant notes that no new matter is added. Claims 4-8, 13 and 25-27 are previously presented. Claims 2-3 and 20-24 are cancelled. Claims 9 and 14-19 are withdrawn as they are directed to a non-elected invention.
Thus, claims 1, 4-8, 10-13 and 25-27 are pending and are under examination.
Maintained Rejections
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 (PHOSITA) 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.
Claims 1, 4-6, 8 and 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Fougeray et al. (Vaccine 24 (2006) 5426–5433) in view of Liang et al. (WO 2016/028672 A1).
Regarding claim 1, Fougeray teaches a method for determining MHC class II binding activity of a preparation comprising recombinant soluble human LAG-3 Ig fusion protein IMP321 (Abstract; page 5429, right column, third paragraph, “Sera were also analyzed for neutralising activity. Sera were incubated with IMP321 for 30 min and then the mixture was incubated with MHC class II+ positive B cells. Binding activity was assessed by FACS analysis.”).
Fougeray teaches testing a GMP-grade sLAG-3 (hLAG-3Ig or IMP321) protein in phase I clinical trials for vaccine development (Page 5427, left column, third paragraph, “Overall, these results gave us the rationale for testing a GMP-grade sLAG-3 (hLAG-3Ig or IMP321) protein in phase I clinical trials.”). Fougeray further tested the binding of GMP-grade sLAG-3 to MHC class II murine APC and the safety of repeated injections in a subject such as in a mouse (Page 5427, left column, third paragraph, “In the present study, we report on the nonclinical biological effects and safety evaluation of IMP321. In
vivo studies in mice have been made possible by first showing that this human LAG-3 protein binds to murine MHC class II+ APC”).
Fougeray teaches that the MHC class II-expressing cells are in solution such as a human MHC class II B- cell line or a murine lymphoma cell line (Page 5427, right column, second paragraph, “MHC class II+ human (LAZ-509, an EBV-transformed B-cell line) or murine (the A20 lymphoma cell
line) cells were incubated at 2×106 cells/ml with indicated concentrations of Alexa 488-conjugated IMP321”).
Regarding claim 1, Fougeray does not teach that the rate of binding of the IMP321 to MHC class II present on MHC class II-expressing cells is determined by a bio-layer interferometry (BLI) method.
Fougeray does not teach that the IMP321 or LAG-3Ig is immobilized to a reagent layer of a BLI probe.
Regarding claim 1, Liang specifically teaches how the rate of binding of LAG3 to MHC II is affected by using inhibitory anti-LAG3 antibodies with a BLI method (Page 26, lines 27-34, “For example, in an embodiment of the invention, when using BLI, the tip of a fiber-optic probe is coated with ligand (e.g., LAG3) and acts as the biosensor wherein binding of anti-LAG3 antibody or antigen-binding fragment to the LAG3 alters the interference pattern of white light reflected from the probe layer bound to LAG3 and an internal reference layer. The shift is indicative of LAG3/anti-LAG3 binding. In an embodiment of the invention, the LAG3 coated tip is immersed in a solution of analyte containing antibody or antigen-binding fragment, e.g., in the well of either a 96- or 384-well plate”; page 47, lines 20-30, “following functional properties: • Inhibits LAG3 binding to MHC class II molecules, e.g., on Daudi cells; for example inhibits human LAG3/MHC class II binding on Daudi cells…”; page 47, lines 4-8). Liang teaches calculating the rate constant of association and dissociation (ka and kd) as well as the equilibrium dissociation constant (Kd) to determine the rate of binding of mouse anti-human LAG3 antibodies to recombinant human LAG3 (Page 181, second paragraph, “Background subtraction binding sensorgrams were used for analyzing the rate constant of association (ka) and dissociation (kd), and the equilibrium dissociation constant KD”). A skilled artisan would further study the binding activity and rate of a LAG-3 analog such as with IMP321 to MHC class II to further assess the antibodies.
As discussed above the binding of LAG-3 to an antibody indirectly teaches the rate or activity of binding between LAG-3 and MHC class II in a competitive assay. Liang taught the rate of binding between LAG-3 and the competing antibody (Page 181, lines 4-8, “Background subtraction binding sensorgrams were used for analyzing the rate constant of association (ka) and dissociation (kd), and the equilibrium dissociation constant KD. The resulting data sets were fitted with a 1: 1 Langmuir Binding Model using the Biacore T200 evaluation software (version 2.0). Table 4 summarizes the affinities for the mouse anti-human LAG3 antibodies to recombinant human LAG3” and Table 4, “ka1”, “kd1”, “KD”).
Liang teaches that LAG-3 or a derivative is immobilized to a reagent layer of a BLI probe (Page 26, lines 27-29).
As the BLI assay teaches the immersion of the probe into a solution comprising a ligand, a skilled artisan would immerse a probe with immobilized LAG-3 into a solution comprising Daudi cells that express MHC Class II molecules to determine the binding of LAG-3 to MHC Class II molecules.
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the competitive assay of Liang with the GMP-grade preparation of an MHC II binding agent of Fougeray to further improve the specificity of the method for determining MHC II binding activity of a preparation of a GMP-grade product because Liang taught how to use an antibody that competes with the binding of LAG-3 to MHC class II for possible therapeutic use (Page 47, lines 20-25) and Fougeray teaches how to use a GMP-grade preparation of an MHC II binding agent such as LAG-3 in vaccine development (Page 5427, left column, third paragraph). Fougeray further suggested using the preparation as an immunopotentiator for therapeutic vaccines (Page 5432, last paragraph). An artisan is motivated to combine the above methods to develop a specific therapeutic method based on the binding of a ligand such LAG-3 to its receptor such as MHC class II. A PHOSITA would have a reasonable expectation of success in combining the methods of Fougeray and Liang because the methods are directed to detecting protein-protein interactions.
It would have been obvious for a PHOSITA to combine the binding method of Liang with the GMP-product of Fougeray because it assures that the product comes with guaranteed quality for therapeutic purposes.
Regarding claim 4, Fougeray teaches that wherein the MHC class II- expressing cells or dendritic cells are present at a density of at least 1E6/mL in complete culture medium (Page 5427, right column, last paragraph).
Regarding claim 6, Fougeray teaches that wherein the blocking reagent comprises albumin (Page 5428, left column, second paragraph).
Regarding claims 25-26, Fougeray teaches that wherein the MHC class II-expressing cells or dendritic cells are present at a density of at least 1E6/mL in complete culture medium (Page 5427, right column, last paragraph).
Regarding claim 27, Fougeray teaches that herein the blocking reagent comprises bovine serum albumin (BSA) (Page 5428, left column, second paragraph).
Regarding claim 5, Liang teaches that wherein the reagent layer has been pre-treated with a blocking reagent to minimize non-specific binding of the MHC class II- expressing cells to the reagent layer (Page 182, lines 22-27).
Regarding claim 8, An artisan would know that wherein the MHC class II- expressing Daudi cells of Liang are thawed, ready-to-use cells obtained from a frozen stock solution from ATCC (ATCC product sheet retrieved from https://www.atcc.org/products/ccl-213?matchtype=&network=g&device=c&adposition=&keyword=&gad=1&gclid=CjwKCAjwh8mlBhB_EiwAsztdBO2sRiRBnZbdLKjbj2nCYe8Wzi9WQLxCzMZrLRUXNXBoWSHNhLgJEhoCnzEQAvD_BwE).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Fougeray et al. (Vaccine 24 (2006) 5426–5433) and Liang et al. (WO 2016/028672 A1) as applied to claim 1 above, and further in view of Ombra et al. (Nucleic Acids Research, 1993, Vol. 21, No. 3, 381-386).
Regarding claim 7, Fougeray and Liang teach all of the limitations of the claim as discussed above but Fougeray fails to teach that wherein the MHC class II- expressing cells are Raji cells.
Regarding claim 7, Ombra teaches that wherein the MHC class II- expressing cells are Raji cells (Page 382, left column, second paragraph; page 382, right column, third paragraph).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the class-II MHC expressing cell line of Ombra with the method of Fougeray and Liang to further improve the specificity of the method for determining MHC II binding activity of a preparation of a GMP-grade product because Ombra used a cell line in which the expression of a class II MHC is studied (Page 382, right column, third paragraph). A skilled artisan is motivated to combine the above methods to develop a specific therapeutic method based on the binding of a ligand such LAG-3 to its receptor such as MHC class II. A PHOSITA would have a reasonable expectation of success in combining the methods of Fougeray, Liang and Ombra because the methods are in the field of detecting protein-protein interactions and expression.
It would have been obvious for a PHOSITA to combine the expression system of Ombra with the binding method of Liang and the GMP-product of Fougeray to make a product that overcomes many technicalities and comes with guaranteed quality for therapeutic purposes.
Claims 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Fougeray et al. (Vaccine 24 (2006) 5426–5433) and Liang et al. (WO 2016/028672 A1) as applied to claim 1 above, and further in view of Sultana et al. (Current Protocols in Protein Science 19.25.1-19.25.26, February 2015).
Regarding claims 10-13, Fougeray and Liang teaches many of the limitations of the claims, but Fougeray fails to teach the parameters of the BLI assay.
Regarding claims 10-13, Sultana teaches optimizing conditions and critical parameters to minimize experimental errors prior to performing BLI assays, wherein such parameters include, positive and negative controls, buffer and concentrations of analyte (19.25.20), wherein the positive control is a previously characterized interacting molecule and the negative control is a biologically non-relevant molecule. Therefore, it would have been obvious for an artisan to determine the MHC binding activity of a reference sample of IMP321 to compare to the binding activity of a reference preparation i.e., positive IMP321 controls as for example having a binding activity set at 100% and negative IMP321 controls as for example denatured proteins preparations i.e., by alkali or acids to lose biological activity as in the method of Liang et al. An artisan is motivated to do so, as these controls are important for validation and for checking non-specific binding to a bait with a non-relevant biological activity or reduced biological activity.
It would have been obvious for a PHOSITA before the effective filing date of the application to combine BLI assay optimization of Sultana with the methods of Liang and Fougeray to improve the specificity of the method for determining MHC II binding activity of a preparation of a GMP-grade product because Sultana taught how to optimize a BLI assay with its different parameters (19.25.20) and further taught how to measure different affinities of the assay to properly study binding assays (Abstract). A skilled artisan is motivated to combine the above methods to develop a specific therapeutic method based on the binding of a ligand such LAG-3 to its receptor such as MHC class II. A PHOSITA would have a reasonable expectation of success in combining the methods of Fougeray, Liang and Sultana based on the methods being in the field of detecting protein-protein interactions.
It would have been obvious for a PHOSITA to combine the optimization protocols of Sultana with the binding method of Liang and the GMP-product of Fougeray to make a product that overcomes many technicalities and comes with guaranteed quality for therapeutic purposes.
Response to Arguments
Applicant's arguments filed on 10/24/2025 have been fully considered but they are not persuasive.
The Applicant alleged that the combination of the cited prior art of Fougeray and Liang does not teach or suggest each and every limitation of amended claim 1.
Per MPEP 2143.03, all the limitations of a claim must be considered when weighing differences between the claimed invention and the prior art in determining the obviousness of a process or method claim. In the instant case, claim 1 recites the following limitations to consider:
A method for determining MHC class II binding activity of a preparation.
Recombinant soluble human LAG-3 IG fusion protein IMP321.
Use as a quality control assay in good manufacturing practices (GMP)-grade production.
Determining a rate of binding of the IMP321 to MHC class II molecules present on MHC class II-expressing cells using bio-layer inferometry (BLI).
IMP321 is immobilized to a reagent layer of a BLI probe.
MHC class II-expressing cells are in solution.
Regarding the first limitation of claim 1 pertaining to a method for determining MHC class II binding activity of a preparation, Fougeray teaches a method for determining MHC class II binding activity of a preparation comprising recombinant soluble human LAG-3 Ig fusion protein IMP321 (Abstract; page 5429, right column, third paragraph, “Sera were also analyzed for neutralising activity. Sera were incubated with IMP321 for 30 min and then the mixture was incubated with MHC class II+ positive B cells. Binding activity was assessed by FACS analysis.”).
Regarding the second limitation of claim 1 pertaining to recombinant soluble human LAG-3 IG fusion protein IMP321, Fougeray teaches testing a GMP-grade sLAG-3 (hLAG-3Ig or IMP321) protein in phase I clinical trials for vaccine development (Page 5427, left column, third paragraph, “Overall, these results gave us the rationale for testing a GMP-grade sLAG-3 (hLAG-3Ig or IMP321) protein in phase I clinical trials.”). Fougeray further tested the binding of GMP-grade sLAG-3 to MHC class II murine APC and the safety of repeated injections in a subject such as in a mouse (Page 5427, left column, third paragraph, “In the present study, we report on the nonclinical biological effects and safety evaluation of IMP321. In vivo studies in mice have been made possible by first showing that this human LAG-3 protein binds to murine MHC class II+ APC”).
Regarding the third limitation of claim 1 pertaining to use as a quality control assay in good manufacturing practices (GMP)-grade production, the physical and chemical characteristics of a product are not necessarily directed to the intended use of the product. In the instant case, Fougeray teaches testing a GMP-grade sLAG-3 (hLAG-3Ig or IMP321) protein in phase I clinical trials for vaccine development (Page 5427, left column, third paragraph).
Regarding the fourth limitation of claim 1 pertaining to determining a rate of binding of the IMP321 to MHC class II molecules present on MHC class II-expressing cells using bio-layer inferometry (BLI), Liang specifically teaches how the rate of binding of LAG3 to MHC II is affected by using inhibitory anti-LAG3 antibodies with a BLI method (Page 26, lines 27-34, “For example, in an embodiment of the invention, when using BLI, the tip of a fiber-optic probe is coated with ligand (e.g., LAG3) and acts as the biosensor wherein binding of anti-LAG3 antibody or antigen-binding fragment to the LAG3 alters the interference pattern of white light reflected from the probe layer bound to LAG3 and an internal reference layer. The shift is indicative of LAG3/anti-LAG3 binding. In an embodiment of the invention, the LAG3 coated tip is immersed in a solution of analyte containing antibody or antigen-binding fragment, e.g., in the well of either a 96- or 384-well plate”; page 47, lines 20-30, “following functional properties: • Inhibits LAG3 binding to MHC class II molecules, e.g., on Daudi cells; for example inhibits human LAG3/MHC class II binding on Daudi cells…”; page 47, lines 4-8). Liang teaches calculating the rate constant of association and dissociation (ka and kd) as well as the equilibrium dissociation constant (Kd) to determine the rate of binding of mouse anti-human LAG3 antibodies to recombinant human LAG3 (Page 181, second paragraph, “Background subtraction binding sensorgrams were used for analyzing the rate constant of association (ka) and dissociation (kd), and the equilibrium dissociation constant KD”). A skilled artisan would further study the binding activity and rate of a LAG-3 analog such as with IMP321 to MHC class II to further assess the antibodies.
Regarding the fifth limitation of claim 1 pertaining to immobilizing IMP321 to a reagent layer of a BLI probe, Liang teaches that LAG-3 or a derivative is immobilized to a reagent layer of a BLI probe (Page 26, lines 27-29, “For example, in an embodiment of the invention, when using BLI, the tip of a fiber-optic probe is coated with ligand (e.g., LAG3) and acts as the biosensor”).
Regarding the sixth limitation of claim 1 pertaining to the presence of MHC class II-expressing cells in solution, Fougeray teaches that the MHC class II-expressing cells are in solution such as a human MHC class II B- cell line or a murine lymphoma cell line (Page 5427, right column, second paragraph, “MHC class II+ human (LAZ-509, an EBV-transformed B-cell line) or murine (the A20 lymphoma cell
line) cells were incubated at 2×106 cells/ml with indicated concentrations of Alexa 488-conjugated IMP321”).
The Applicant further alleged that there is no motivation for one of skill in the art to combine the cited art with a reasonable expectation of success.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, It would have been obvious for a PHOSITA before the effective filing date of the application to combine the competitive assay of Liang with the GMP-grade preparation of an MHC II binding agent of Fougeray to further improve the method for determining MHC II binding activity of a preparation of a GMP-grade product because Liang taught how to use an antibody that competes with the binding of LAG-3 to MHC class II for possible therapeutic use (Page 47, lines 20-25) and Fougeray teaches how to use a GMP-grade preparation of an MHC II binding agent such as LAG-3 in vaccine development (Page 5427, left column, third paragraph). Fougeray further suggested using the preparation as an immunopotentiator for therapeutic vaccines (Page 5432, last paragraph). A skilled artisan is motivated to combine the above methods to develop a specific therapeutic method based on the binding of a ligand such LAG-3 to its receptor such as MHC class II. A PHOSITA would have a reasonable expectation of success in combining the methods of Fougeray and Liang because the methods are directed to detecting protein-protein interactions.
It would have been obvious for a PHOSITA to combine the binding method of Liang with the GMP-product of Fougeray because it assures that the product comes with guaranteed quality for therapeutic purposes.
The Applicant alleged that the Office has made a leap to consider it obvious to substitute an antibody in a BLI assay (as allegedly taught in Liang) with a cell expressing MHC II molecules in order to arrive at the instantly claimed assay. The Applicant further alleged that a cell expressing (a plurality of) MHC II molecules is very different from an antibody.
This argument is not persuasive. Substituting an antibody for a cell that express the receptor for a ligand in solution is not a leap because the probe is still a biosensor that is coated with the same ligand in either case. The ligand-coated probe still acts as a bait for catching either an antibody or a cell with the receptor (MHC class II). Both scenarios are examples of affinity binding. Furthermore, unlike the binding of an antigen to an IgM antibody, there is no steric hinderance issue with a well-coated probe with the ligand, and thus it is used for probing an antibody or a cell. In the instant case, the probe is coated with IMP321 which allows the probe to fish for antibodies or for cells that express MHC class II.
The Applicant alleged that the Office is applying impermissible hindsight in combining selected passages from Fougeray and Liang to arrive at the claimed invention.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, 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). In the instant case, Liang taught how to use an antibody that competes with the binding of LAG-3 to MHC class II for possible therapeutic use (Page 47, lines 20-25) and Fougeray teaches how to use a GMP-grade preparation of an MHC II binding agent such as LAG-3 in vaccine development (Page 5427, left column, third paragraph). Fougeray further suggested using the preparation as an immunopotentiator for therapeutic vaccines (Page 5432, last paragraph). A skilled artisan is motivated to combine the above methods to develop a specific therapeutic method based on the binding of a ligand such LAG-3 to its receptor such as MHC class II.
Thus, the previous rejection of claim 1 and all its dependent claims (4-8, 10-13 and 25-27) under 35 U.S.C. 103, regarding obviousness, is still maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OMAR RAMADAN whose telephone number is (571)270-0754. The examiner can normally be reached Monday-Friday 8:30 am - 5:00 pm.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678