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 .
Detailed Action
The Amendments and Remarks filed 7/31/26 in response to the Office Action of 2/5/26 are acknowledged and have been entered.
Claims 1, 3, 5-10, 12, 13, 15-22, and 24 are pending.
Claims 1, 3, 5-10, 12, 13, 17, 18, and 21 have been amended by Applicant.
Claims 1, 3, 5-10, 12, 13, 15-22, and 24 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Objections Withdrawn
Objection to the specification is withdrawn.
Rejections Withdrawn
The rejection of claim 10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn.
The rejection of claims under 35 U.S.C. 103 as being unpatentable over Urbanska et al (Journal of Translational Medicine, 2014, 12(347): 1-12; 1/31/23 IDS) is withdrawn.
The rejection of claims under 35 U.S.C. 103 as being unpatentable over Urbanska et al (Journal of Translational Medicine, 2014, 12(347): 1-12; 1/31/23 IDS) in view of Chang et al (Nature Protocols, 2020, 15: 1507-1524), and Houot et al (Lymphoid Neoplasia, 2009, 114(16): 3431-3438; 1/31/23 IDS) is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 102
Claim(s) 13, 15, 17-22, and 24 remain rejected and claim 16 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Urbanska et al (Journal of Translational Medicine, 2014, 12(347): 1-12; 1/31/23 IDS).
Urbanska et al teaches T cells expressing BsAb-28z IR and BsAb-z IR, which are chimeric receptors that each comprise an extracellular domain of an immunoreceptor Folate Receptor alpha (FR alpha) and an intracellular signaling domain of CD28 and/or CD3 zeta, wherein the immunoreceptor functions as a costimulatory molecule and delivers simultaneous T cell receptor CD3 activation and CD28 costimulating signals in a target dependent manner, resulting in activation, proliferation and anti-tumor activity (Figure 1 and right column on page 2, in particular). Urbanska et al further teaches the T cells express the chimeric receptors by transducing the T cells with viral vectors comprising nucleic acids encoding the chimeric receptors (right column on page 4, in particular).
FR alpha of the BsAb-28z IR and BsAb-z constructs comprise extracellular “variants” of human CD137 extracellular domain lacking cysteine-rich domain 3 and cysteine-rich domain 4 of human CD137.
While Urbanska et al does not explicitly state extracellular domains of BsAb-28z IR or BsAb-z IR have attenuated binding to a ligand for a recited endogenous immunoreceptor (such as endogenous CD137), the constructs clearly would not predictably bind ligands for recited endogenous immunoreceptors that are not bound by FR alpha (such as endogenous CD137). Therefore, absent a showing otherwise, the BsAb-28z IR and BsAb-z IR constructs of Urbanska et al could be described as having attenuated binding to a ligand for a recited endogenous immunoreceptor.
Urbanska et al further teaches previous bispecific antibodies (BsAbs) have been used to kill cancer cells by coupling cytotoxic T cells (though CD3 T-cell receptor) with target cancer cells (left column on page 2, in particular). Urbanska et al further teaches a challenge with BsAbs that couple cytotoxic T cells using the CD3 T-cell receptor is that CD3 is found on T-cells other than cytotoxic T cells (left column on page 2, in particular). Urbanska et al further teaches a challenge with BsAbs that couple cytotoxic T cells using the CD3 T-cell receptor is that sustained stimulation via T-cell receptor CD3 without parallel costimulatory signals, such as those provided by CD28 receptor, results in impaired T-cell activation with induction of anergy or apoptosis (left column on page 2, in particular). Urbanska et al further teaches a combination of (a) T cells expressing BsAb-28z IR and BsAb-z IR; and (b) frBsAb antibody has numerous benefits over conventional BsAbs (Figure 2, in particular). frBsAb is a bispecific construct that binds (i) the extracellular domain of FR alpha of T cells expressing BsAb-28z IR and BsAb-z IR and (ii) a cancer cell antigen (TAA). Urbanska et al teaches benefits of the combination include (i) the ability to redirect preselected T-cells to tumor and (ii) the ability to use parallel costimulatory signaling to overcome impaired T-cell activation with induction of anergy or apoptosis (Figure 2, in particular).
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Figure 2A:
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Response to Arguments
In the Reply of 7/31/26, Applicant argues Folate Receptor alpha of Urbanska et al is not a recited endogenous immunoreceptor of claim 13. Applicant further argues Urbanska et al does not teach substituting an immunoreceptor recited by claim 13 for Folate Receptor alpha of Urbanska et al. Applicant further argues there is no indication in Urbanska et al that the segment of Folate Receptor alpha includes in Urbanska et al’s chimeric receptor (amino acids 1-231 of Folate Receptor alpha) has attenuated binding to a ligand for Folate Receptor alpha.
The amendments to the claims and the arguments found in the Reply of 7/31/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that Folate Receptor alpha of Urbanska et al is not a recited endogenous immunoreceptor of claim 13, the examiner agrees. FR alpha of the BsAb-28z IR and BsAb-z constructs comprise extracellular “variants” of human CD137 extracellular domain lacking cysteine-rich domain 3 and cysteine-rich domain 4 of human CD137.
In regards to the argument Urbanska et al does not teach substituting an immunoreceptor recited by claim 13 for Folate Receptor alpha of Urbanska et al, the examiner agrees. However, the claims do not require a “substituting” step.
In regards to the argument that there is no indication in Urbanska et al that the segment of Folate Receptor alpha includes in Urbanska et al’s chimeric receptor (amino acids 1-231 of Folate Receptor alpha) has attenuated binding to a ligand for Folate Receptor alpha, the examiner agrees. The claims do not recite constructs that have attenuated binding to a ligand for Folate Receptor alpha. Further, while Urbanska et al does not explicitly state extracellular domains of BsAb-28z IR or BsAb-z IR have attenuated binding to a ligand for a recited endogenous immunoreceptor (such as endogenous CD137), the constructs clearly would not predictably bind ligands for recited endogenous immunoreceptors that are not bound by FR alpha (such as endogenous CD137). Therefore, absent a showing otherwise, the BsAb-28z IR and BsAb-z IR constructs of Urbanska et al could be described as having attenuated binding to a ligand for a recited endogenous immunoreceptor.
Claim Rejections - 35 USC § 103
Claim(s) 1, 3, 5-9, 12, 13, 15-22, and 24 remain rejected and claim 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Urbanska et al (Journal of Translational Medicine, 2014, 12(347): 1-12; 1/31/23 IDS) in view of Chang et al (Nature Protocols, 2020, 15: 1507-1524), Houot et al (Lymphoid Neoplasia, 2009, 114(16): 3431-3438; 1/31/23 IDS), and Yi et al (PLOS ONE, 2014, 9(1)(e86337): 1-10).
Teachings of Urbanska et al are discussed above.
Urbanska et al does not specifically teach a chimeric receptor comprising the extracellular domain of human CD137, a CD137 construct lacking all or part of a cysteine-rich domain 3 (CRDIII) and a cysteine-rich domain 4 (CRDIV) of a human CD137. However, these deficiencies are made up in the teachings of Chang et al, Houot et al, and Yi et al.
Chang et al teaches extracellular ligand-binding domains of chimeric receptors, such as chimeric antigen receptors, can be swapped for any given ligand of interest with little to no tuning of signaling domains required (see Advantages and limitations on page 1508, in particular).
Houot et al teaches human primary lymphoma tumors are infiltrated with CD137+ T cells and that anti-CD137 agonistic antibodies induce an antitumor effect that is mediated by CD8 T cells and induced long-lasting immunity (Abstract, in particular).
Figure 2 of Yi et al teaches human CD137 extracellular domain constructs “hE2” and “hE3”, which lack CRDIII and CRDIV, cannot bind to the ligand of human CD137 (hCD137L).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to therapeutically treat a subject with lymphoma using a “CD137-redirected” method of Urbanska et al by performing a combined method comprising administering to the subject a therapeutically effective amount of (a) T cells that have been transduced with a vector harboring a nucleic acid encoding and expressing BsAb-28z IR or BsAb-z IR and (b) frBsAb antibody used for redirection of the T cells wherein (i) the extracellular domain of human CD137 is substituted in place of the FR alpha extracellular domain of the BsAb-28z IR and (ii) an anti-CD137 agonist binding domain is swapped in place of the portion of frBsAb antibody that binds FR alpha because Urbanska et al recognizes the BsAb-28z IR and BsAb-z IR immunoreceptors functions as costimulatory molecules to deliver simultaneous T cell receptor CD3 activation and CD28 costimulating signals in a target dependent manner, resulting in activation, proliferation and anti-tumor activity (Figure 1 and right column on page 2, in particular), Chang et al teaches extracellular ligand-binding domains of chimeric receptors can be swapped for any given ligand of interest with little to no tuning of signaling domains required (see Advantages and limitations on page 1508, in particular), and Houot et al teaches human primary lymphoma tumors are infiltrated with CD137+ T cells and that anti-CD137 agonistic antibodies induce an antitumor effect that is mediated by CD8 T cells and induced long-lasting immunity (Abstract, in particular). By both (i) swapping the CD137 extracellular domain in place of the FR alpha extracellular domain in the BsAb-28z IR and BsAb-z IR and (ii) swapping the anti-CD137 agonist binding domain in place of the portion of frBsAb antibody that binds FR alpha, one would be able to activate both the recombinant T cells and endogenous infiltrated CD137+ T CD8 T cells with the anti-CD137 agonist in a manner analogous to the “redirected” method of Figure 2A of Urbanska et al.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the extracellular domain of human CD137 of the recombinant T cells consists of hE2 or hE3 (and which lack CRDIII and CRDIV) and wherein the agonist bispecific antibody of the combined method binds epitopes within hE2 or hE3 in an effort to prevent offsite activation of the recombinant T cells by endogenous hCD137L, just as the construct of Urbanska et al was touted as having the benefit of lacking offsite activation by endogenous ligand of FA alpha.
This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 7/31/26, Applicant argues Urbanska et al teaches away from substituting the extracellular domain of CD137 for that of FRa and altering the bispecific antibody so that it binds to the extracellular domain of CD137 instead of the extracellular domain of FRa because those changes would increase risk of offsite activation without any countervailing benefit taught by the art. Applicant further argues that using a portion of CD137 extracellular domain in the chimeric receptor would not reduce risk of offsite activation by a bispecific antibody since claim 1 specifies the bispecific antigen binding molecule is able to bind to and agonize the endogenous immunoreceptor.
The amendments to the claims and the arguments found in the Reply of 7/31/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that Applicant argues Urbanska et al teaches away from substituting the extracellular domain of CD137 for that of FRa and altering the bispecific antibody so that it binds to the extracellular domain of CD137 instead of the extracellular domain of FRa because those changes would increase risk of offsite activation without any countervailing benefit taught by the art, the examiner disagrees. The combined method reduces risk of offsite activation of the extracellular domain of CD137 by using a human extracellular domain of CD137 of the recombinant T cells that consists of hE2 or hE3 (and which lack CRDIII and CRDIV). Figure 2 of Yi et al teaches human CD137 extracellular domain constructs “hE2” and “hE3”, which lack CRDIII and CRDIV, cannot bind to the ligand of human CD137 (hCD137L).
In regards to the argument that using a portion of CD137 extracellular domain in the chimeric receptor would not reduce risk of offsite activation by a bispecific antibody since claim 1 specifies the bispecific antigen binding molecule is able to bind to and agonize the endogenous immunoreceptor, Applicant is arguing limitations not recited by the claims. The claims do not recite reducing risk of offsite activation by a bispecific antibody. However, a human extracellular domain of CD137 of the recombinant T cells of the combined method that consists of hE2 or hE3 (and which lack CRDIII and CRDIV) would exhibit attenuated binding to CD137 ligand compared to binding of the ligand by endogenous CD137 because Figure 2 of Yi et al teaches human CD137 extracellular domain constructs “hE2” and “hE3”, which lack CRDIII and CRDIV, cannot bind to the ligand of human CD137 (hCD137L).
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.
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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