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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10-13-2025 has been entered.
Status of the Claims
Claims 1,5-6,9,13-14,19-26,30-31 and 36-40 are currently pending in the Application with claims 1,5-6,13,25 and 30 currently withdrawn as directed to non-elected species and inventions. Therefore claims 9, 14, 19-24, 26, 31 and 36-40 are examined on the merits below.
Response to Arguments-Claim Rejections - 35 USC § 112a Written Description
In the instantly claim set Applicant has amended claim 9 to incorporate the fully defined heavy and light chain of the “G4723A” antibody previously claimed in now cancelled claims 45 and 46. Because the heavy and light chain sequences of the antibody portion of the ADC is now fully defined including the heavy and light chain CDR 1-3 regions the previously applied rejection under 112a written description is removed.
Response to Arguments-Claim Rejections - 35 USC § 103
In reply to previously applied rejections and as applied below, Applicant traverses. Applicant describes that the rejection over the combined references of Hilderbrand, Kovtun, Smith and Portwood does not allow one to arrive at the claimed invention with a reasonable expectation of success. Applicant further describes that the instantly claimed molecule provides “unexpended” (unexpected) results and synergies when combined with a PARP inhibitor such as olaparib or talazoparib describing that the DNA-damaging effects of the IMGN632 are thereby enhanced in such a combination.
Regarding the reasonable expectation of success, as previously described the disclosure of Kovtun and Hilderbrand disclose a base device/method of IMGN-632 as a CD123 directed ADC for the treatment of AML for example. This molecule is identical to the molecule which is instantly claimed in the method of claim 9, and it is described it may be utilized in combination methods with other agents.
The further disclosure of Portwood for instance provides a similar device as a CD33 directed ADC of which the ADC component is a DNA alkylating agent similar to that incorporated into the IMGN-632 ADC molecule.
The disclosure of Smith provides clear evidence that PARP inhibition through utilization of Talazoparib in combination with DNA damaging agents provide synergistic effects. Particularly the disclosure describes that “PARP1 inhibitors were initially developed as potentiators of anticancer DNA damaging agents”.
Regarding the indication that the claimed method provides unexpected synergistic effects, it is found that the unexpected results must in fact be unexpected. In the instant case as described above an artisan of ordinary skill considering the preponderance of the evidence provided by the disclosure of the cited references would find that it would reasonably be expected that combining a previously disclosed effective DNA-damaging ADC (IMGN-632) with a PARP inhibitor, a class of drugs which is known to provide synergistic effects when combined with DNA-damaging therapeutics would result in a beneficial synergistic effect. "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) MPEP 716.02(c) II.
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.
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.
Claims 9, 14, 19-24, 26, 31 and 36-40 are rejected under 35 U.S.C. 103 as being unpatentable over Kovtun (Blood Advances, 24 April 2018, Volume 2, Number 8, pp 849-858 and further in view of Hilderbrand (US10287256B2 ), Portwood (Blood (2016) 128 (22) : 1645) and Smith (Clin Cancer Res; 21(4) February 15, 2015) .
Instant claims 9 and 26 describe method of treating cancer in a subject or alternatively inducing cancer cell death in a population of cancer cells through administration of an anti-CD123 ADC comprising an anti-CD123 antibody linked to an “indolinobenzodiazepine pseudodimer” with designated antibody antigen binding domains, in combination with a PARP inhibitor, such as elected Talazoparib or (non-elected Olaparib). The molecule of claims 9 and 26 appears significantly to be comprised of the previously disclosed/described IMGN632.
With regards to the instant claimed 9 and 26 for example the disclosure of Kovtun (Blood) describes utilization of IMGN632 ADC designed for the purposes of treating AML cancer. The disclosure describes that the IMGN632 molecule exhibits potent anti-AML activity while at the same time sparing normal bone marrow progenitors, thus potentially exhibiting an improved safety profile compared to a X-ADC wherein the drug conjugate is a DNA crosslinking IGN payload (abstract). IMGN632 appears to be the same ADC as presented in claims 51 and 52 and therefore the CDR are inherently present as combined/ indicated in claim 1. The antibody of the disclosure of Kovtun is the antiCD123 “G4723A” antibody which is described as the instant figure 1 the identical ADC when conjugated to the sulfonated-DGN549-C DNA alkylating agent. Additionally with regards to the instantly claimed characterized antibody molecule (CD123 targeting moiety) the disclosure of Hilderbrand describes ADC comprising indolinobenzodiazepine drug conjugate wherein the antibody (SEQ ID NO 25, 26 ; HC, LC respectively which are directed to the CD123 cell surface molecules identical to the instantly claimed SEQ ID NO: 10 and 11 (HC, LC respectively).
Therefore in summary the disclosure of Kovtun and Hilderbrand account for the antibody full length HC and LC molecules as SEQ ID NO 25, 26 of Hilderbrand, or as indicated by the disclosure of Kovtun as IMGN632.
With regards to the claimed method and the treatment of (elected) AML which may be relapsed or refractory for example (19-22 and 36-39) the disclosure of Kovtun specifically describes that the IMGN632 ADC was highly effective in eliciting cytotoxicity inducing cell death in primary AML derived from a variety of patient types including those suffering from relapsed and or/relapsed refractory AML. It would therefore be obvious as one element of treatment to utilize the said anti-CD123 ADC in a simple monotherapy in the indicated disease states.
The utilization of the mono-therapeutic IMGN632 ADC in which a DNA alkylating agent is thereby preferentially delivered to a CD123+ AML cell, thereby inducing cell death is thereby established as at least obvious as described above. The disclosure of Kovtun does not suggest additional therapeutic agent such as PARP inhibitor talazoparib in addition to IMGN632 ADC for the treatment of/induction of cell death in AML cells for example. However the disclosure of Hilderbrand does indicate that the ADC of the invention may be utilized in combination of second therapeutic agents (115) for treatment of AML for example.
The further disclosure of Portwood however for example describes the utilization of a CD33 directed indolinobenzodiazepine ADC for the treatment of AML in combination with a PARP inhibitor (olaparib) for the purposes of synergistic enhanced anti-tumor activity in CD33+ AML cells. The disclosure thereby indicates that combination treatment of AML with the indicated ADC and a PARP inhibitor provided synergistic effects in “chemo-resistant” disease (relapse/refractory) as well as in systemic human AML xenograft models. Thus the usefulness of combination therapy of AML with ADC and PARP inhibitor is established. In support of the combination therapy of a DNA alkylating agent, such as the instantly claimed ADC disclosed by Kovtun and Hilderbrand, the disclosure of Smith tested the ability of the selective PARP inhibitor talazoparib (instantly elected) to synergistically augment/potentiate the in-vitro cytotoxic effects of DNA alkylating agents , in this case temozolomide for instance (abstract). Thus toxic DNA damage induced by the DNA-alkylating agent may thereby be maintained/potentiated through simultaneous inhibition of PARP, a molecule involved in DNA repair. The table 1 of Smith for example indicates the potentiation effect of said DNA-alkylating agent/ PARP inhibitor talazoparib ( as elected and claims 14, 31) for example in a number of hematological cell lines including those derived from AML samples (Kasumi-1) (table 1).
It would therefore be obvious to combine a CD123-ADC (as instantly claimed ) which delivers an alkylating drug compound to AML cells for example with a potentiating agent of talazoparib for example to arrive a therapy that has improved therapeutic index and synergistic effects compared to either monotherapy alone
With regards to the instant claim 23 , all the references describe treatment method, reagents and modalities with regards to a human subject or human cell lines in pre-clinical models and it would therefore be obvious to provide said treatment to a human subject.
With respect to instant claim 24 , the disclosure of Portwood and Smith for example indicate method in which the PARP inhibitor and the additional treatment method are administered at the same time so that DNA damage induced by the alkylating agent is sufficiently potentiated by the simultaneous presence of the PARP DNA-repair complex.
With respect to claim 40 and the limitation that the administering is carried out “in vivo” all the references describe treatment method, reagents and modalities with regards to a human subject or human cell lines in pre-clinical models and it would therefore be obvious to provide said treatment to a human subject in-vivo for the beneficial purposes of treating a relapsed/refractory AML for example.
Conclusion
Summary: No claims are allowed
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/BRIAN HARTNETT/ Examiner, Art Unit 1644
/JANET L ANDRES/ Supervisory Patent Examiner, Art Unit 1671