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 1-7, 9-10, 14-22, and 24-28 are pending.
Claims 8, 11-13, 23, and 29-50 are cancelled.
Applicant’s election without traverse of the species of claim 27 having CDRs1-6 of SEQ ID NOs:1-6, respectively, in the reply filed on 12/19/2024 is reacknowledged.
Claim 28 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/19/2024.
Claims 1, 3, 6, 9-10, and 14 are amended.
Claims 1-7, 9-10, 14-22, and 24-27 are under examination on the merits.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/26/2026 has been entered.
Withdrawn Claim Rejections
The rejection of the claims under 35 USC §112(a) regarding lack of written is withdrawn in light of the 02/26/2026 claim amendments which sufficiently narrow the scope of what is claimed.
Maintained-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) 1-5, 14-15, 17-22, and 24-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merck (US 20170097333 A1) in view of Al-Aghbar et al (High-Affinity Ligands Can Trigger T Cell Receptor Signaling Without CD45 Segregation. Front Immunol. 2018 Apr 9;9:713. doi: 10.3389/fimmu.2018.00713).
Regarding claims 1 and 25, Merck teaches a (presumably in vitro) assay comprising effector T cells, i.e., Jurkat T cells, which express LAG3, TCR, CD3 (see for example paragraphs 0078 and 0104, abstract, and reference in its entirety); wherein the test substance being assayed may be a LAG3 agonist (see for example paragraph 0024). Although Merck does not explicitly state that the LAG-3, TCR, and CD3 are surface expressed, this embodiment is inherent to Merck as it is well established in the art that these receptors are surface expressed on T-cells. See the instant specification at page 2, lines 26-29. Merck goes on to teach that T-cell activation can also be determined based upon the level of activation of an NFAT (Nuclear Factor of Activated T cells) responsive element or IL-2 promoter or a fragment thereof, e.g., which is operably linked to a reporter gene; e.g., a promoter that comprises one or more NFAT responsive elements, which is in the T-cell. The level of reporter production in the T-cells indicates the extent to which such cells are activated (see for example paragraph 0100-0102).
Merck does not explicitly teach antigen and MHC class II-independent T cell (TCR) activation/agonism.
However, Al-Aghbar et al teach that anti-CD-3 antibodies (OKT3) are capable of activating T cells through a showing of calcium fluctuations as the readout (in contrast to the luminescent/fluorescent readout of Merck; see for example pages 2 and 5 of Al-Aghbar et al; see also Figure 2 and its caption at page 6 and Figure 3 and its caption at page 7). Note that the methods show that T cells were activated using scFvs (such as scFvs against CD-3 as discussed throughout Al-Aghbar et al with column 2 of page 4 being exemplary) in the absence of antigen presenting cells (APCs), thus in the absence of MHC class-II (being expressed on APCs) (see for example, pages 2-3).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Merck and Al-Aghbar et al. The artisan would have been motivated to make and use the invention as claimed because one of ordinary skill in the art would have found it obvious that stimulating the T cell(s) of Merck with an anti-CD3 antibody, such as that taught by Al-Aghbar et al, (instead of stimulating with Raji cells/SEE/SEB; noting that where the components perform the same function of activating T-cells through the TCR, it is prima facie obvious to swap known equivalents (see MPEP sections 2143(I)(B) and 2144.06 (II))) would be expected to predictably activate the T cells so that the T cell(s) can then be contacted with LAG3 agonist or candidate LAG3 agonist whereupon the molecule is considered a LAG3 agonist if it decreased reported expression by decreasing T cell activation which can successfully be measured according to the method of Merck as a visual signal (change in fluorescence/luminescence). This obvious substitution would modify the assay of Merck to be carried out in the absence of MHC class-II by removal of the raji cells comprising the natural ligand MHC class II. Note that Merck further teaches that, in an embodiment of the invention, expression of a reporter gene that is operably associated with a nuclear factor of activated T-cells response element (NFAT-RE) is measured to determine whether the T-cells are activated; wherein the T-cells are determined to be activated if expression of the reporter gene increases in the presence of the test substance relative to in the absence of the test substance. The artisan would have bene motivated to use the anti-CD3 antibody of Al-Aghbar et al instead of the raji cells and SEB of Merck in order to simplify the assay by reducing the number of components. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 2, Merck further teaches that this Jurkat LAG3 bioassay will have utility for CMC potency release, antibody screening, quality control and bioactivity testing (see paragraph 0022, for example). Merck also teaches that the LAG3 bioassay delivered high signal to noise ratios, a dynamic range of approximately 10-fold, and reproducible EC50 values to support potency comparisons for non-clinical pharmacology studies and CMC analytical potency release testing. LAG3 expression on primary cells isolated from PBMCs from human and non-human primates was very low, which presented challenges in demonstrating bioactivity and potency for anti-LAG3 antibodies (see paragraphs 0119-0121 and 0124, for example).
Regarding claim 3, Merck teaches a (presumably in vitro) assay comprising (presumptively, a plurality in light of the use of plural T cells) effector T cells, i.e., Jurkat T cells, which express LAG3, TCR, CD3 (see for example paragraphs 0078 and 0104, abstract, and reference in its entirety); wherein the test substance being assayed may be a LAG3 agonist (see for example paragraph 0024). Although Merck does not explicitly state that the LAG-3, TCR, and CD3 are surface expressed, this embodiment is inherent to Merck as it is well established in the art that these receptors are surface expressed on T-cells. See the instant specification at p.2, lines 26-29. In an embodiment of the invention, the reporter construct comprises the reporter gene (e.g., luciferase (meeting the limitations of instant claim 20) or green fluorescent protein; note that this is held to read upon claim 17’s recitation of a heterologous nucleic acid reporter in light of the instant specification’s definition of this term (see p. 12) operably linked to a minimal (m)CMV promoter and tandem repeats of the NFAT consensus sequence (see for example paragraph 0100-0102) (meeting the limitations of instant claims 18-19). Merck additionally teaches that in an embodiment of the invention, expression of a reporter gene that is operably associated with a nuclear factor of activated T-cells response element (NFAT-RE) is measured to determine whether the T-cells are activated (see for example paragraph 0006-meeting the limitations of instant claim 18). Moreover, Merck teaches that the LAG3 bioassay represented the first in vitro human cell line assay that recapitulated the optimal balance of components of an immune synapse required to observe LAG3-mediated repression of the MHC class II and TCR interaction and anti-LAG3 mediated relief of that repression (FIG. 9 and paragraph 0119, for example).
Merck does not teach that the assay is carried out in the absence of MHC class-II.
However, as noted above, Al-Aghbar et al teach a method of using an anti-CD3 antibody to agonize/activate T cells such that APCs expressing MHC class-II (such as the raji cells of Merck and SEB) are not needed (see the rejection of claim 1 above).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Merck and Al-Aghbar et al. The artisan would have been motivated to make and use the invention as claimed because one of ordinary skill in the art would glean that TCR signaling increases reporter gene expression (such as luminescence), TCR signaling is modulated by LAG3 wherein LAG3 agonism inhibits TCR signalling and thereby effects a measurable decrease in reporter expression (such as a decrease in luminescence where the reporter is luciferase) (bolstered by Merck’s further teaching that in an embodiment of the invention, a cytotoxic anti-LAG3 antibody or antigen-binding fragment thereof that depletes T-cells may be considered a LAG3 agonist since it leads to reduced T-cell activity (see for example paragraph 0025)). The artisan would have been further motivated because Merck teaches that the assay and this means of interpretation are successful in screening for LAG3 agonists, where substitution of the raji cells for the anti-CD3 antibody of Al-Aghbar et al is desirable and predictable for simplifying the assay of Merck by reducing the number of reagents/components required for the assay, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 4, Merck and Al-Aghbar et al teach the assays of instant claims 1 and 3 and further teaches that, in an embodiment of the invention, expression of a reporter gene that is operably associated with an nuclear factor of activated T-cells response element (NFAT-RE) is measured to determine whether the T-cells are activated; wherein the T-cells are determined to be activated if expression of the reporter gene increases in the presence of the test substance relative to in the absence of the test substance. The level of reporter expression indicates the extent to which the T-cells are activated.
Regarding claim 5, as discussed above, one of ordinary skill in the art would glean that TCR signaling increases reporter gene expression (such as luminescence), TCR signaling is modulated by LAG3 wherein LAG3 agonism inhibits TCR signalling and thereby effects a measurable decrease in reporter expression (such as a decrease in luminescence where the reporter is luciferase) (bolstered by Merck’s further teaching that in an embodiment of the invention, a cytotoxic anti-LAG3 antibody or antigen-binding fragment thereof that depletes T-cells may be considered a LAG3 agonist since it leads to reduced T-cell activity (see for example paragraph 0025)).
Regarding claim 6, Merck further teaches TCR activation via the antigen-dependent (using raji cells), MHC class-II-dependent (using staphylococcal enterotoxin, Staphylococcal enterotoxin B (e.g., which is not Staphylococcal enterotoxin B (SEB) if the T-cell is a Jurkat cell), Staphylococcal enterotoxin A (SEA), Staphylococcal enterotoxin D (SED) or Staphylococcal enterotoxin E (SEE)) (see reference in its entirety).
Merck does not explicitly teach antigen and MHC class-II-independent T cell (TCR)activation.
However, Al-Aghbar et al teach anti-CD-3 antibodies (such as OKT3) which are capable of activating T-cells through a showing of calcium fluctuations as the readout (in contrast to the luminescent/fluorescent readout of Merck).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Merck and Al-Aghbar et al. The artisan would have been motivated to make and use the invention as claimed because one of ordinary skill in the art would understand that stimulating the T cell of Merck with an anti-CD3 antibody, such as that taught by Al-Aghbar et al, (instead of stimulating with Raji cells/SEE/SEB; noting that where they components perform the same function of activating T-cells through the TCR, it is prima facie obvious to swap known equivalents (see MPEP sections 2143(I)(B) and 2144.06 (II)) would be expected to predictably activate the T cells so that the cell can then be contacted with LAG3 agonist or candidate LAG3 agonist whereupon the molecule is considered a LAG3 agonist if it decreased reported expression by decreasing T cell activation which can successfully be measured according to the method of Merck as a visual signal (change in fluorescence/luminescence). Note that Merck further teaches that, in an embodiment of the invention, expression of a reporter gene that is operably associated with a nuclear factor of activated T-cells response element (NFAT-RE) is measured to determine whether the T-cells are activated; wherein the T-cells are determined to be activated if expression of the reporter gene increases in the presence of the test substance relative to in the absence of the test substance. Further, because the active steps and claimed components of the instant method and that of Merck as modified by Al-Aghbar et al are identical, it is presumed that the activation and conditions therefore are antigen-independent, MHC class II-independent, and TCR-mediated, absent evidence to the contrary upon which it would appear that the claims as drafted may suffer from one or more deficiencies with respect to 35 USC §112(a). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 7, as noted above, Merck in view of Al-Aghbar et al teaches that increased reporter expression is indicative of T cell activation (presumably through the TCR; particularly where the method of Merck is modified by Al-Aghbar et al as discussed above). Merck goes on to teach that in an embodiment of the invention, a cytotoxic anti-LAG3 antibody or antigen-binding fragment thereof that depletes T-cells may be considered a LAG3 agonist since it leads to reduced T-cell activity. An example of such an antibody is IMP731 (see for example paragraphs 0025, 0073, 0078-0079 of Merck). From this teaching, one of ordinary skill in the art would have understood that a LAG3 agonist decreases T cell activation and would thereby be expected to decrease reporter expression (luminescence) as compared to expression in the absence of the agonist, such that a test substance that decreases reporter expression may be identified as an agonist of LAG3.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Merck and Al-Aghbar et al. The artisan would have been motivated to make and use the invention as claimed because one of ordinary skill in the art would have found it obvious as of the filing date to use a CD3 antibody as taught by Al-Aghbar in lieu of the Raji cells of Merck as functional equivalents (see MPEP §2143(I)(B) and 2144.06(II)) in the method of Merck which teaches the use of an activated jurkat T-cell with LAG3 and a reporter (luciferase for example) to screen for LAG3 agonists be looking for a decrease in reporter relative to the observed reporter expression in an activated state in the absence of the LAG3 agonist/candidate agonist in order to screen for LAG3 agonists such that agonists are compounds which decrease the expression of the reporter. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 14, as discussed above, Merck in view of Al-Aghbar et al make obvious the use of an anti-CD3 antibody, OKT3, as the T cell activator in the assay of Merck as a functional equivalent. The artisan, being motivated for reasons discussed above, to practice the assay of Merck in view of Al-Aghbar et al, would have understood that activation of the T cell using OKT3 would be cell-free, antigen-independent, MHC class II-independent, TCR-mediated activation. Therefore, the teachings of Merck as modified by Al-Aghbar et al are deemed to make obvious the claim limitations.
Regarding claim 15, Merck teaches contacting the cells with multiple concentrations of LAG3 agonist/candidate agonist in 10 fold increments (see for example paragraph 0088) as an embodiment of using the cell-based assay to screen for LAG3 agonists.
Regarding claims 17-20, Merck further teaches that in an embodiment of the invention, the reporter construct comprises the reporter gene (e.g., luciferase (meeting the limitations of instant claim 20) or green fluorescent protein; note that this is held to read upon claim 17’s recitation of a heterologous nucleic acid reporter in light of the instant specification’s definition of this term (see p. 12) operably linked to a minimal (m)CMV promoter and tandem repeats of the NFAT consensus sequence (see for example paragraph 0100-0102) (meeting the limitations of instant claims 18-19).
Regarding claim 21, Merck further teaches a method for making a T-cell of the assay comprising introducing a polynucleotide encoding LAG3 into one or more T-cells (e.g., Jurkat cells) (see for example, paragraph 0007, 0070, 0075) which, in light of the definition at page 12 of the instant specification, is deemed to meet the limitation of a heterologous nucleic acid encoding a LAG3.
Regarding claim 22, Merck further teaches that, where the test substance (agonist/antagonist) is an anti-human LAG3, a matched IgG4 isotype anti-human antibody against PCSK9 was used as a negative control (see for example, paragraphs 0132).
Regarding claim 24, Merck further teaches that the test substance can be a LAG3 inhibitor or a LAG3 agonist such as an anti-LAG3 antibody or antigen-binding fragment thereof, wherein a LAG3 agonist may agonize a LAG3 activity (see for example paragraphs 0024-0025).
Regarding claim 26, As further discussed above, Merck teaches the use of Jurkat T cells which express LAG3 (LAG+) and may have a reporter which is luciferase operably linked to an NFAT-RE (see for example, paragraphs 0100-0102; where the luciferase may be renilla, Photinus pyralis, or firefly luciferase), where the test substance may be a LAG3 agonist which retains LAG3 agonistic function/activity (see for example, the abstract and paragraphs 0024-0025).
Claim(s) 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merck and Al-Aghbar et al, as applied to claims 1-5, 14-15, 17-22, and 24-26 above, in further view of Chang et al (Does OKT3 monoclonal antibody react with an antigen-recognition structure on human T cells? Proc Natl Acad Sci U S A. 1981 Mar;78(3):1805-8. doi: 10.1073/pnas.78.3.1805).
Merck and Al-Aghbar teach as set forth above.
Regarding claim 9, Merck and Al-Aghbar et al do not teach that the OKT3 is used at a concentration of ~6-30 X 10-12.
However, Chang et al teach that OKT3 antibody is mitogenic and this effect appears to require receptor activation in that it occurs at low concentration (10-12 M) of OKT3 antibody, requiring the intact IgG (see for example, the abstract at page 1805), where this concentration is deemed sufficient to activate the T cells (see for example the title and abstract at page 1805).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Merck, Al-Aghbar et al, and Chang et al. The artisan would have been motivated to make and use the invention as claimed because Chang et al teach a concentration of 10-12 of OKT3 is effective. The artisan would have understood this to teach a lower end of efficacy of 1X10-12 M, such that using a concentration of 6-30 X 10-12 M (a higher concentration than the art-taught lower end of the range of concentrations known to be effective) would have been mere routine optimization of the concentration of OKT3 used in the assay of Merck as modified by Al-Aghbar et al and Chang et al. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Routine optimization is not considered inventive and no evidence has been presented that arriving at the claimed concentration was anything other than routine, that the properties of the claimed concentration from the optimization has any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art. Optimization of parameters is a routine practice that would be obvious for the artisan to employ. See MPEP § 2144.05. Here, Chang et al teach that low concentrations of OKT3 (10-12) are sufficient to act upon T cells which would lead the artisan to optimize the method for using a lower concentration of OKT3 to minimize side effects and to be more cost effective. Additionally, the claim scope could easily encompass 1x1012 where the concentration is modified by the tilde (~) (see the rejection of claims 9-10 under 35 USC §112(b) above). The artisan would have had a reasonable expectation of success based on the cumulative disclosure of the combined prior art references.
Where the components of the assay of Merck as modified by Al-Aghbar et al are the same as those encompassed by the claims and where the concentration of the OKT3 as claimed is made obvious by Chang et al, the prior art references, in combination, are deemed to make obvious the effects of the claimed concentration (such as the concentration being that at which maximal inhibition of expression of reporter occurs in the presence of an agonist of LAG-3) because function flows from structure. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 10, Merck in view of Al-Aghbar et al teaches that increased reporter expression is indicative of T cell activation (presumably through the TCR; particularly where the method of Merck is modified by Al-Aghbar as discussed above). Merck goes on to teach that in an embodiment of the invention, a cytotoxic anti-LAG3 antibody or antigen-binding fragment thereof that depletes T-cells may be considered a LAG3 agonist since it leads to reduced T-cell activity. An example of such an antibody is IMP731 (see for example paragraphs 0025, 0073, 0078-0079 of Merck). Merck teaches that the T cells are contacted with an activator by teaching that they are contacted with the raji cells comprising SEE/SEA/SED (see for example, the abstract and paragraphs 0005 and 0072).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because one of ordinary skill in the art would have understood that a LAG3 agonist decreases T cell activation and would thereby be expected to decrease reporter expression (luminescence) as compared to expression in the absence of the agonist, such that a test substance that decreases reporter expression may be identified as an agonist of LAG3. Therefore, one of ordinary skill in the art would have found it obvious as of the filing date to use a CD3 antibody as taught by Al-Aghbar in lieu of the Raji cells of Merck as functional equivalents (see MPEP §2143(I)(B) and 2144.06(II)) in the method of Merck which teaches the use of an activated jurkat T-cell with LAG3 and a reporter (luciferase for example) to screen for LAG3 agonists be looking for a decrease in reporter relative to the observed reporter expression in an activated state in the absence of the LAG3 agonist/candidate agonist, with a reasonable expectation of success, in order to screen for LAG3 agonists such that agonists are compounds which decrease the expression of the reporter. The artisan would have found it obvious to use the recited concentration because Chang et al teach that 1012 is a low-end of a concentration of anti-CD3 antibody known to be effective for activating T cells such that a concentration higher than 1012 would be expected to function to activate T cells. Note that the claims may well encompass a concentration of 1X1012 in light of the current drafting (see the rejection of claims 9-15 under 35 USC §112(b) above as well as the rejection of claim 9 under 35 US C§103 above for additional discuss/detail). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merck and Al-Aghbar et al, as applied to claims 1-5, 14-15, 17-22, and 24-26 above, in further view of Li et al (ICECAP: An Integrated, General-Purpose, Automation-Assisted IC50/EC50 Assay Platform. Journal of Laboratory Automation. 2014;20(1):32-45. doi:10.1177/2211068214562449).
Merck and Al-Aghbar teach as set forth above.
The combined references do not explicitly teach that the IC50 value is determined.
However, Li et al teach that IC50 and EC50 values are commonly used to evaluate drug
potency (see abstract). Li et al further teach that determining the IC50/EC50 values is a straightforward process: Obtain a dose–response curve for the drug, then calculate the IC50 or EC50 value. To obtain the dose–response curve, the typical IC50/EC50 assay process usually involves the following: first, design a preparation scheme for the spiking solutions and the final matrix solutions; then, decreasing concentration levels of the drug-spiking solutions are prepared in neat solvent such as DMSO and then spiked into blank matrix. Afterward, aliquots of the matrix solutions are incubated at specific temperatures for a specific amount of time. At the end of incubation, samples are processed and/or extracted, then followed by analytical measurement of the response. Dose and response data are plugged into software such as GraphPad Prism (GraphPad Software, San Diego, CA) to calculate the IC50/EC50 values one compound at a time. To increase throughput in dedicated high-throughput screening (HTS) labs, these assays usually follow certain very specific procedures and sometimes even use specific hardware (see for example paragraphs 1-2 of the introduction).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Li et al document, through teaching how to determine the IC50 and that IC50 is commonly used, that such determination would have been obvious to use to understand certain pharmacologic parameters and that such determination would have been obvious to one of ordinary skill in the art as of the filing date. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merck and Al-Aghbar et al, as applied to claims 1-5, 14-15, 17-22, and 24-26, above, in further view of Immutep (WO2017037203A1; as cited on the 04/06/2022 IDS).
Merck and Al-Aghbar et al teach as set forth above.
Regarding claim 27,. Merck further teaches that test agonists may be anti-LAG3 antibodies.
Merck and Al-Aghbar et al do not appear to teach an antibody comprising the instantly recited sequences.
However, Immutep teaches an anti-LAG3 antibody comprising said sequences (SEQ ID NO: 7 of Immutep comprises sequences identical to instant SEQ ID NOs: 1-3 and SEQ ID NO: 8 of Immutep comprises sequences identical to instant SEQ ID NOs: 4-6 (see for example fig. 22 and page 10 of Immutep).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Merck, Al-Aghbar et al, and Immutep. The artisan would have been motivated to make and use the invention as claimed because, where Merck teaches the use of an anti-LAG3 antibody as the agonist for LAG3, one of ordinary skill in the art would have found it obvious to use the antibody of Immutep as a functional equivalent of the anti-LAG3 antibody agonists of Merck given that they are taught to perform the requisite function of agonizing LAG3. Note that the MPEP provides that it is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to swap one known anti-LAG3 agonistic antibody for another (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses:
A. Applicant argues that the concentration of fragment is described because molarity is the number of moles/liter of solute (see page 1 of the 02/26/2026 remarks).
Response: This is unpersuasive. The number of moles per solute (n) is mass dependent (see for example, Molekula as cited in the rejection under 35 USC §112(a) for lack of written description of claims 9-10 above).
B. Applicant argues for withdrawal of the rejections under 35 USC §103 because modifying Merck according to Al-Aghbar et al, per Applicant’s argument, is not prima facie obvious because the modification allegedly changes the principle of operation of the assay of MERCK which requires APCs (MHC class-II expressing raji cells), citing to MPEP §2143.01(VI) (see pages 12-17 of the 02/26/2026 remarks).
Response: This is unpersuasive. The T cells in the assay are not acting differently. Unlike in In re Ratti, where the claims were directed to an oil seal requiring resiliency and the prior art oil seal required rigidity, the instant claims require a T cell expressing LAG3 which can be activated by an agonist in an assay and the prior art (Merck) teaches a T cell expressing LAG3 which can be activated by an agonist in an assay. The claimed portion of the assay (the T cell) is not changed with respect to its principle of operation. Instead, as pointed out in the rejection s of the claims under Merck as the primary reference, the fact patter of modifying Merck in view of Al-Aghbar et al more closely resembles basic KSR rationale which supplies that swapping one prior element for a known functional equivalent is prima facie obvious. Here, Merck teaches that the T cell(s) in the assay are activated by raji cells and SEB. Al-Aghbar et al teach an anti-CD3 antibody can activate T cells. The raji cells and SEB of Merck are a functional equivalent of the anti-CD3 antibody of Al-Aghbar et al serving the same purpose of activating T cells (see MPEP sections 2143(I)(B) and 2144.06 (II))). Regarding the motivation to modify the assay of Merck et al to use an anti-CD3 antibody to activate/agonize the T cells rather than the raji cells and SEB in order to simplify the assay by reducing the number of reagents/components as discussed in the rejection under35 USC §103 as presented in this Office Action. Therefore, the rejections are maintained at this time. Applicant relies upon these arguments (for withdrawal of the independent claims) to support the request withdrawal of the rejections of claims 9-10, 16, and 27, which are found unpersuasive and maintained for the same reasons as iterated herein.
Remarks for Applicant’s Consideration
Regarding the rejection of the claims for lack of written description of the genus of T cell activator/agonist (used interchangeably throughout the disclosure) acting in an MHC class-II independent manner, amendment of the claims to limit to the full length OKT3 or UCHT1 (such that all 6 CDRs required for binding are clearly defined) would be responsive to provide description for this genus. Regarding the rejection of the claims for lack of written description of the concentration of the fragment of OKT3 or UCHT1, evidence that the concentration is truly independent or/accounts for the different mass of different sized fragments/different potential valencies to provide a concentration of the fragment(s) that would function as required in the claimed method would be responsive to the noted concern. Alternatively, amendment to eliminate reference to the fragment would be responsive. Regarding the rejection under 35 USC 112(b), amendment of the claim to clarify the metes and bounds of the encompassed concentration would be responsive. Regarding the rejections of the claims for obviousness of Merck and Al-Aghbar et al, an evidenced argument for why the T cells in the assay or the ability of the assay to screen for LAG3 (candidate) agonists would be substantially, unpredictably altered or would yield a surprising/critical result would be responsive. For the rejections of the claims for obviousness of Merck, Al-Aghbar et al, and Chang et al, an evidenced argument showing something unpredictable, surprising, and/or critical about the claimed concentration (as well as amendment to clarify the metes and bounds of the recited concentration) would be responsive.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Smith (WO2014047231A1) teaches that antibodies against CD3 have been shown to cluster CD3 on T cells, thereby causing T cell activation in a manner similar to the engagement of the TCR by peptide-loaded MHC molecules (see for example, paragraph 0002).
Any inquiry concerning this communication or earlier communications from the
examiner should be directed to ASHLEY GAO whose telephone number is (571) 272-5695. The
examiner can normally be reached on M-F 9:00 am - 6:00 pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
supervisor, Gregory Emch can be reached on (571) 272-8149. The fax phone number for the
organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent
Application Information Retrieval (PAIR) system. Status information for published applications
may be obtained from either Private PAIR or Public PAIR. Status information for unpublished
applications is available through Private PAIR only. For more information about the PAIR
system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR
system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would
like assistance from a USPTO Customer Service Representative or access to the automated
information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights