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 11/25/25 in response to the Office Action of 6/25/25 are acknowledged and have been entered.
Claims 1-8, 12, and 21-26 are pending.
Claims 1, 3, 4, 12, 21, and 24-26 have been amended by Applicant.
Claims 1-8, 12, and 21-26 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.
The following Office Action contains NEW GROUNDS of rejections Necessitated by Amendments.
Rejections Withdrawn
The rejection of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn.
The rejection of claims 1-8 and 12 under 35 U.S.C. 103 as obvious over Banerjee et al (Mol Cancer Res, 2016, 14(4_Supp):A25), as evidenced by Gerard et al (Cancer Drug Resis, 2024, 7(29): 1-23) is withdrawn.
The rejection of claims 1 and 2 under 35 U.S.C. 103(a) as being unpatentable over Frank et al (US 2011/0165149 A1; 7/7/11) in view of Banerjee et al (Mol Cancer Res, 2016, 14(4_Supp):A25) and Nitta et al (Cancer Medicine, 2016, (5)(3): 486-499) is withdrawn.
The rejection of claims under 35 U.S.C. 103 as being unpatentable over Banerjee et al (Mol Cancer Res, 2016, 14(4_Supp):A25) in view of Cheung et al (WO 2011/140828 A1; 11/17/11) and Kim et al (Nucleic acid Research, 2018, 46(3): 1424-1440) is withdrawn.
The rejection under 35 U.S.C. 101 is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claim(s) 21 remains rejected under 35 U.S.C. 103 as obvious over Banerjee et al (Mol Cancer Res, 2016, 14(4_Supp):A25), as evidenced by Gerard et al (Cancer Drug Resis, 2024, 7(29): 1-23).
Banerjee et al teaches ABCB5 is a molecular marker of a subset of chemoresistant tumor-initiating cells populations in numerous cancers and that inhibiting the function of ABCB5 with an anti-ABCB monoclonal antibody sensitizes temozolomide resistant glioblastoma cells to temozolomide-induced cell killing and apoptosis (Abstract). Banerjee et al further teaches a method comprising in vivo systemic administration of the anti-ABCB function-blocking monoclonal antibody (clone 3C2-1D12) to subjects with glioblastoma (GBM) results in a significant reduction in tumor growth and sensitization of the GBM to TMZ therapy (Abstract). Banerjee et al further teaches the anti-ABCB function-blocking monoclonal antibody sensitizes GBM to TMZ therapy by revoking G2/M arrest (Abstract).
Banerjee et al does not explicitly state “administering” TMZ to the GBM subjects that were sensitized to TMZ therapy by administration of anti-ABCB function-blocking monoclonal antibody. However, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to treat subjects with GBM tumors comprising cancer cells expressing ABCB5 that are resistant to TMZ by performing a method comprising administering an effective amount of an inhibitor of ABCB5, such as the anti-ABCB monoclonal antibody of Banerjee et al, to the subjects followed by administering TMZ to the subjects to resensitize the GBM cells to TMZ in an effort to promote GBM cell death because Banerjee et al teaches ABCB5 is a molecular marker of a subset of chemoresistant tumor-initiating cells populations in numerous cancers and that inhibiting the function of ABCB5 with an anti-ABCB monoclonal antibody sensitizes temozolomide resistant GBM to TMZ-induced cell killing and apoptosis in cell culture and administration of the anti-ABCB function-blocking monoclonal antibody to subjects with GBM results in a significant reduction in tumor growth and sensitization of the GBM to TMZ therapy in vivo.
Further one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said method wherein the subjects are identified as having a chemoresistant GBM with G2/M arrest in the GBM cells and the administered ABCB5 inhibitor reverses G2/M cell cycle arrest in the cells because Banerjee et al teaches the anti-ABCB function-blocking monoclonal antibody sensitizes GBM to TMZ therapy by revoking G2/M arrest.
Further, in an effort to ensure the target of the administered inhibitor is present on GBM cells of a subject to be treated by the method, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said method wherein GBM cancer cells from the subject are determined to express ABCB5 by isolating GBM cancer cells from the subject and detecting expression of ABCB5 by the GBM cancer cells, wherein expression of ABCB5 is indicative of resistance to TMZ because Banerjee et al teaches ABCB5 is a molecular marker of a subset of chemoresistant tumor-initiating cells populations in numerous cancers and the inhibitor of ABCB5 therapeutically functions by targeting ABCB5 on GBM cells.
As evidenced by Gerard et al, the anti-ABCB function-blocking monoclonal antibody (clone 3C2-1D12) of Banerjee et al binds the fifth extracellular loop of ABCB5 at amino acids 493-508 of ABCB5 (Table 2 and page 7, in particular). Such an antibody “has specificity for a cyclical form or a linear form of an extracellular” portion of ABCB.
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 6/25/25, Applicant argues the skilled artisan would not have had a reasonable expectation of success in achieving the claimed method in the absence of teaching found in the instant application. Applicant further argues no reasonable expectation of success in achieving a significant decrease in tumor volume relative to either the ABCB5 antibody or fragment thereof or Temozolomide alone following the combined administration of ABCB5 antibody or fragment thereof and Temozolomide. Applicant further argues a lack of suggestion in the cited art to link an agent to an antibody.
The amendments to the claims and the arguments found in the Reply of 6/25/25 have been carefully considered, but are not deemed persuasive. In regards to the arguments that the skilled artisan would not have had a reasonable expectation of success in achieving the claimed method in the absence of teaching found in the instant application and there is no reasonable expectation of success in achieving a significant decrease in tumor volume relative to either the ABCB5 antibody or fragment thereof or Temozolomide alone following the combined administration of ABCB5 antibody or fragment thereof and Temozolomide, one would be motivated, with an expectation of success (including success of achieving a significant decrease in tumor volume relative to either the ABCB5 antibody or fragment thereof or Temozolomide alone), to administer an effective amount of the ABCB antibody of Banerjee et al to reverse the chemoresistance of a subject with GBM cells expressing ABCB5 and further administer temozolomide to the subject to treat cancer (as claimed) for the reasons stated above and because Banerjee et al teaches ABCB5 is a molecular marker of a subset of chemoresistant tumor-initiating cells populations in numerous cancers and that inhibiting the function of ABCB5 with an anti-ABCB monoclonal antibody sensitizes temozolomide resistant glioblastoma cells to temozolomide-induced cell killing and apoptosis (Abstract).
In regards to the argument of a lack of suggestion in the cited art to link an agent to an antibody, the rejected claim does not recite an agent linked to an antibody.
Claim Rejections - 35 USC § 103
Claims 22-23 remain rejected and claims 24-26 are rejected under 35 U.S.C. 103(a) as being unpatentable over Frank et al (US 2011/0165149 A1; 7/7/11) in view of Banerjee et al (Mol Cancer Res, 2016, 14(4_Supp):A25) and Nitta et al (Cancer Medicine, 2016, (5)(3): 486-499).
Frank et al teaches treating cancer by using ABCB5 binding molecules (Abstract, in particular). Frank et al further teaches said method wherein the binding molecules are antibodies that bind ABCB5 ([0006], in particular). Frank et al further teaches monoclonal antibody “3C2-1D12” is an antibody that binds ABCB5 ([0009], in particular). Frank et al further teaches antibodies that bind ABCB5 include bispecific antibodies ([0020], in particular). Frank et al further teaches bispecific antibodies may be formed from two intact antibodies, antibody fragments, and antibody molecules such as scFv ([0057], in particular). Frank et al further teaches scFv are made by linking light and/or heavy chain variable regions of an antibody ([0138]-[0140], in particular).
Frank et al does not specifically teach a method of treating GBM or a bispecific antibody that binds both ABCB5 and a receptor tyrosine kinase. However, these deficiencies are made up in the teachings of Banerjee et al and Nitta et al.
Banerjee et al teaches administering the monoclonal anti-ABCB5 antibody “3C2-1D12” of Frank et al to subjects with GBM reduces tumor growth and sensitizes GBMs to TMZ therapy (Abstract, in particular).
Nitta et al teaches administering the monoclonal antibody nimotuzumab that binds the receptor tyrosine kinase EGFR to subjects with GBM enhances TMZ-induced growth suppression of GBM cells (Figure 3, in particular). Nitta et al further teaches nimotuzumab inhibits EGFR signaling (paragraph spanning pages 490-491) and inhibits phosphorylation at threonine 308 and appears to preferentially affect EGFRvIII signaling compared with wt EGFR (right column on page 490, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating GBM comprising administering an effective amount of a bispecific antibody comprising an “3C2-1D12” anti-ABCB5 binding domain and a nimotuzumab anti-EGFR to subjects with GBMs and administering TMZ to the subjects with GBM because Frank et al teaches treating cancer by using ABCB5 binding molecules such as bispecific antibodies that bind ABCB5 and bispecific antibodies comprising the binding domains of “3C2-1D12” and nimotuzumab would predictably provide therapeutic benefit when administered with to GBM patients with TMZ because monoclonal anti-ABCB5 antibody “3C2-1D12” is known to reduce tumor GBM tumor growth and sensitize GBMs to TMZ therapy and nimotuzumab is known to enhance TMZ-induced growth suppression of GBM cells. This is an example of some teaching, suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art references or combine prior art reference teachings to arrive at the claimed invention.
In particular regards to amended claim 24, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method wherein the binding domains of the bispecific antibody comprise scFv because Frank et al teaches bispecific antibodies may be formed from antibody molecules such as scFv ([0057], in particular) and that scFv are made by linking light and/or heavy chain variable regions of an antibody ([0138]-[0140], in particular).
In particular regards to amended claim 25, binding of the bispecific antibody to EGFR of a target cell using binding domains of the monoclonal antibody nimotuzumab of the bispecific antibody predictably results in downregulation of signaling of EGFR because Nitta et al teaches nimotuzumab inhibits EGFR signaling (paragraph spanning pages 490-491) and inhibits phosphorylation at threonine 308 and appears to preferentially affect EGFRvIII signaling compared with wt EGFR (right column on page 490, in particular).
In particular regards to amended claim 26, an IC50 value (measured by just any way) of the bispecific antibody is decreased at least 100-fold as compared to an IC50 value (measured by just any way) of an imaginable monospecific antibody to ABCB5 because the bispecific antibody (with the added advantage of having a binding domain of nimotuzumab -that is known to enhance TMZ-induced growth suppression of GBM cells) would more potently treat GBMs when administered with to GBM patients with TMZ (as compared to administering an antibody monospecific to ABCB5 alone) because (i) the binding domain of monoclonal anti-ABCB5 antibody “3C2-1D12” of the bispecific antibody is known to reduce tumor GBM tumor growth and sensitize GBMs to TMZ therapy and (ii) the binding domain of nimotuzumab of the bispeicifc antibody is known to enhance TMZ-induced growth suppression of GBM cells.
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 11/25/25, Applicant repeats arguments addressed above.
Claim Objections
Claim 25 is objected to because of an apparent typographical error. Claim 25 recites “…to the target cell results in….” Because the claim does not previously mention a target cell, it appears the claim should recite “to a target cell” in place of “to the target cell.” Proper correction is required.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 112
Claims 1-3, 6-8 and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-3, 6-8 and 12 are rejected because both claim 1 and claim 3 recite “…and wherein the combined administration of ABCB5 antibody or fragment thereof and Temozolomide results in….” There is insufficient antecedent basis for “the combined administration of ABCB5 antibody or fragment thereof and Temozolomide” in the claims.
Claim Rejections - 35 USC § 103
Claims 1-8 and 12 are rejected under 35 U.S.C. 103(a) as being unpatentable over Frank et al (US 2011/0165149 A1; 7/7/11) in view of Nitta et al (Cancer Medicine, 2016, (5)(3): 486-499).
Frank et al teaches treating cancer by using ABCB5 binding molecules (Abstract, in particular). Frank et al further teaches said method wherein the binding molecules are antibodies that bind ABCB5 ([0006], in particular). Frank et al further teaches monoclonal antibody “3C2-1D12” is an antibody that binds ABCB5 ([0009], in particular). Frank et al further teaches delivering therapeutic agents to a cell by contacting the cell with ABCB5 binding molecules conjugated to a therapeutic agent such as a chemotherapeutic or toxin to be delivered to a cancer cell ([0005], [0011], [0054], and [0168], in particular).
Frank et al does not specifically teach a method of treating GBM. However, these deficiencies are made up in the teachings of Banerjee et al and Nitta et al.
Banerjee et al teaches administering the monoclonal anti-ABCB5 antibody “3C2-1D12” of Frank et al to subjects with GBM reduces tumor growth and sensitizes GBMs to TMZ therapy (Abstract, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating GBM comprising administering an effective amount of an antibody comprising an “3C2-1D12” anti-ABCB5 conjugated to a chemotherapeutic and/or toxin to subjects with GBMs and administering TMZ to the subjects with GBM because Frank et al teaches treating cancer by using ABCB5 binding molecules such as antibodies that bind ABCB5 conjugated to a chemotherapeutic and/or toxin would predictably provide therapeutic benefit when administered with to GBM patients with TMZ because monoclonal anti-ABCB5 antibody “3C2-1D12” is known to reduce tumor GBM tumor growth and sensitize GBMs to TMZ therapy and Frank et al teaches delivering therapeutic agents to a cell by contacting the cell with ABCB5 binding molecules conjugated to a therapeutic agent such as a chemotherapeutic or toxin to be delivered to a cancer cell ([0005], [0011], [0054], and [0168], in particular). This is an example of some teaching, suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art references or combine prior art reference teachings to arrive at the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 112
Claims 1-8 and 12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
Claims 1 and 3 recite methods of administering to a subject having a cancer an ABCB5 antibody that is conjugated to a therapeutic agent and a chemotherapeutic agent to the subject. Descriptions of methods of administering to a subject having a cancer an ABCB5 antibody that “is conjugated to a therapeutic agent” and a chemotherapeutic agent to the subject are not found in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors, at the time the invention was filed, had possession of the claimed invention.
Claim 4 recites methods of administering to a subject having a cancer an ABCB5 antibody that is conjugated to a therapeutic agent. Descriptions of methods of administering to a subject having a cancer an ABCB5 antibody “that is conjugated to a therapeutic agent” are not found in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors, at the time the invention was filed, had possession of the claimed invention.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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