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
Restriction/Election of Species and Status of the Claims
Applicant’s election with traverse of Group I, comprising claims 1-15, 17-18, and 20-21 in the response filed on February 3rd 2026 is acknowledged. Applicant’s election of ‘acute myeloid leukemia’ as the single hematologic neoplasm, ‘allogeneic HCT’ as the single hemotopoietic cell transplant, and ‘siremadlin (HDM-201)’ as the single MDM2 inhibitor in the response filed on February 3rd 2026 is acknowledged. Applicant traverses the restriction/election of species requirement on the grounds that “the patent office has not established that it would pose an undue burden to examine the full scope of the invention.” This is not found persuasive because:
The species of MDM2 inhibitors do not share a common structural moiety and thus would require a divergent search strategy to constitute a complete search.
The species of hemotological neoplasms after hematological cell transplantation differ in their pathologies and treatment.
The patient populations of “patients who have received a hematological cell transplant” and “patients who have not received a hematological cell transplant” are distinct and separate.
Furthermore, applicant has not argued the art provided demonstrating that the “shared technical feature” of the invention does not make a contribution over the prior art (see the restriction/election of species requirement filed on October 3rd 2025). Thus, the restriction/election of species requirement is deemed proper and therefore made FINAL.
Claims 1-15 and 17-21 are pending. Claim 19 has been withdrawn from consideration as being directed towards a nonelected invention. Claims 1-15, 17-18, and 20-21 are examined on their merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statement filed on October 17th 2023 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of references cited from the IDS is included with this Office Action.
Minor Informalities
It is noted that spelling errors are present in multiple claims. For example, allogeneic is frequently misspelled as “allogenic.” Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10, 15 and 21 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.
Claim 10 is indefinite for the phrase, “wherein administration of the MDM2 inhibitor leads to upregulation…” because one of ordinary skill in the art could not reasonably determine how the phrase further limits the method of claim 1.
The phrase appears to limit the specific MDM2 inhibitor administered. However, there is no guidance in the specification as to how the inhibitor must be limited in order achieve such activity, but only evidence that the embodied inhibitors do so (see Figure 4). Furthermore, the activity described would be an intended result of the administration that would occur when certain MDM2 inhibitors are administered, but applicant does not give guidance as to which particular MDM2 inhibitors, or which moieties on such inhibitors achieve such activity, and there is no comparison to inhibitors which do not achieve such activity. As one of ordinary skill in the art could not reasonably determine how the phrase, “wherein administration of the MDM2 inhibitor leads to upregulation…” further limits the method of claim 1, claim 10 is indefinite.
Claim 15 and its dependent claim 21 are indefinite for the phrase “wherein administration of the MDM2 inhibitor increases…” because one of ordinary skill in the art could not reasonably determine how the phrase further limits the method of claim 1. The phrase does not appear to limit the MDM2 inhibitor administered, the amount administered, the patient population receiving administration, the method of administration, or any other aspect of the method other than the results of the administration. The claim language is repeated in the specification (specification, pg. 5), but no guidance is provided as to how the method of claim 1 must be further limited in order to achieve the results described in claim 15. As one of ordinary skill in the art could not reasonably determine which aspects of claim 1 must be further limited in order to achieve the results described in claim 15, claim 15 and its dependent claim 21 are indefinite.
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 to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4, 6-8, 10, 15, 17, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Ball (Ball et al., Which are the most promising targets for minimal residual disease-directed therapy in acute myeloid leukemia prior to allogeneic stem cell transplant? Haematologica. 2019 Aug; 104(8):1521-1531).
Claim 1 is directed towards a method of treating and/or preventing a hematological neoplasm relapse after hematopoietic cell transplantation via administration of a mouse double minute 2 (MDM2) inhibitor. The MDM2 protein is known to One such inhibitor is idasanutlin.
Ball teaches administration of idasanutlin to an acute myeloid leukemia patient population at high risk of relapse (Ball, pg. 1523, TP53). Ball does not explicitly teach the treatment of a patient population that has previously received hematopoietic cell transplantation (HCT). However, one of ordinary skill in the art would have a reasonable expectation of success in administering idasanutlin to a patient population at high risk of relapse after HCT, because:
Idasanutlin (and other MDM2 inhibitors) are known to trigger apoptosis in cancer cells in a P53-dependent manner.
The patient population wherein MDM2 inhibitors would be especially useful, wherein there exists P53 mutations, is especially susceptible to relapse after allogeneic stem cell transplantation. See Ball:
“p53 is a transcription factor that is activated by cellular stress and promotes cell cycle arrest, senescence and apoptosis. Loss of p53 induces oncogenic self-renewal in mouse hematopoietic progenitor cells. In AML, inactivating mutations in the TP53 gene occur in 7-18% of patients with newly diagnosed AML and are enriched in patients with other poor prognostic features including complex karyotype and therapy-related disease. The co-occurrence of TP53 mutations and a complex karyotype is associated with an especially dismal prognosis and a high rate of relapse after allogeneic SCT. In AML, p53 inactivation more commonly results from overexpression of negative regulators. MDMX and MDM2 inhibit p53 transactivation and induce its ubiquitination with subsequent degradation. Idasanutlin is an oral selective MDM2 inhibitor capable of activating apoptosis in a p53-dependent manner.”
[Ball, pg. 1523, TP53]
One of ordinary skill in the art would thereby have a reasonable expectation of success in preventing acute myeloid leukemia (AML) relapse in a patient population that has received an allogeneic stem cell transplantation, and claim 1 is prima facie obvious.
Claim 2 further limits the hematological neoplasm of claim 1 to a leukemia and is prima facie obvious for the same reasons as claim 1.
Claim 3 further limits the hematological neoplasm of claim 1 to a leukemia and is prima facie obvious for the same reasons as claim 1.
Claim 4 limits the HCT of claim 1 to an allogeneic HCT and is prima facie obvious for the same reasons as claim 1.
Claim 6 requires that, in the method of claim 1, the MDM2 inhibitor is administered after the HCT and before the occurrence of a relapse (i.e. that the MDM2 inhibitor is used to prevent a relapse). Claim 6 is thereby prima facie obvious for the same reasons as claim 1.
Claim 7 requires that, in the method of claim 1, the inhibitor is administered to a leukemia patient after the occurrence of a relapse. Ball teaches administration of idasanutlin to a relapsed
AML patient population (Ball, pg. 1523, TP53), and claim 7 is thereby prima facie obvious.
Claim 8 limits the MDM2 of claim 1 to be selected from a group that includes idasanutlin. Claim 8 is thereby prima facie obvious for the same reasons as claim 1.
Claim 10 is directed towards the method of claim 1 wherein administration of the MDM2 inhibitor leads to upregulation of the TRAIL-R1/R2 receptors. As idasanutlin accomplishes this activity1, claim 10 is prima facie obvious for the same reasons as claim 1.
Claim 15 is directed towards the method of claim 1 wherein administration of the MDM2 inhibitor increases a graft-versus-leukemia effect. As idasanutlin accomplishes this activity1, claim 15 is prima facie obvious for the same reasons as claim 1.
Claim 17 is directed towards the method of claim 1 wherein administration of the MDM2 inhibitor increases production of perforin. As idasanutlin accomplishes this activity1, claim 17 is prima facie obvious for the same reasons as claim 1.
Claim 20 limits the leukemia of claim 3 to acute myeloid leukemia and is prima facie obvious for the same reasons as claim 3.
Claim 21 is directed towards the method of claim 15 wherein the graft-versus-leukemia effect is mediated by CD8+ allo-T cells and the cytotoxic (i.e. antiproliferative) activity of such cells is dependent on the TRAIL-R activity in such cells.
Claims 5 and 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Ball in view of Kennedy-Nasser (Kennedy-Nasser et al., T-cell therapy after hematopoietic stem cell transplantation. Current Opinion in Hematology 14(6):p 616-624, November 2007).
Claim 5 requires that, in the method of claim 1, the HCT comprises T cells.
For the teachings of Ball as they are relevant to claim 1 see the above 103 rejection for claim 1. Regarding the transplantation of T-cells, while this is not explicitly taught by Ball, one of ordinary skill in the art would have had a reasonable expectation of success in administering T cells in the HCT, because this is commonly done in order to avoid the complications that come with a regenerating immune system in allogeneic HSCT. See Kennedy-Nasser:
“The need for adoptive T-cell therapies after hematopoietic stem cell transplantation (HSCT) became clearly evident from the consequences of T-cell depletion. Allogeneic HSCT has always been associated with high rates of viral infection, and these problems often increased after T-cell depletion. Moreover, unacceptably high relapse rates from chronic myeloid and other leukemias were observed. These complications were associated with profound T-cell lymphopenia and spawned efforts to replace the missing T cells and restore viral-specific and tumor-specific immunity.”
[Kennedy-Nasser, pg. 616]
One of ordinary skill in the art would therefore have a reasonable expectation of success in administering T-cells with the allogeneic HSCT and claim 5 is prima facie obvious.
Claim 11 is directed towards the method of claim 1, wherein the treatment further comprises administration of an allogeneic (from a donor) T cell transplantation. For the teachings of Ball as they are relevant to claim 1 see the above 103 rejection for claim 1. Regarding the transplantation of donated T cells, such transplantation is prima facie obvious (see the above 103 rejection for claim 5). Claim 11 is thereby prima facie obvious.
Claim 12 is directed towards the method of claim 11 wherein the allogeneic T cell transplantation is a donor lymphocyte infusion. Kennedy-Nasser teaches donor lymphocyte infusion after HSCT (Kennedy-Nasser, pg. 617, Table 1), and claim 12 is thereby prima facie obvious.
Claim 13 is directed towards the method of claim 11, wherein the donor of the allogeneic T cell transplantation is also the donor of the HCT. Neither Kennedy-Nasser nor Ball explicitly state the identity of the donors of each of the T cell transplantation and the HCT. However, one of ordinary skill in the art would have had a reasonable expectation of success in using the same donor for both transplantations, because doing so would minimize immune system complications. The allogeneic stem cell transplantation is performed in order to allow T-cells adapted to the cancer to develop in the patient. Prior to the production of new T-cells, there is a period where the patient is immunocompromised due to the lack of T-cells. T-cells are often donated to the patient in order to quickly restore immune activity. Receiving the T-cells from the same donor as the HCT decreases the likelihood that such T-cells will recognize the newly spawned T-cells as ‘foreign,’ and thereby allows for immune protection coinciding with an effective treatment. Thus, having one donor for both the allogeneic T cell transplantation and the HCT is prima facie obvious, and claim 13 is prima facie obvious.
Claim 14 is directed towards the method of claim 11 the MDM2 inhibitor is administered after the HCT and before, and/or the same day as, and/or after administration of the allogenic T cell transplantation. As administration of the MDM2 inhibitor after the HCT (see the above 103 rejection for claim 6) and alongside an allogeneic T cell transplantation (see the above 103 rejection for claim 11), claim 14 is prima facie obvious.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Ball in view of Pi (Pi et al., Evaluating dose-limiting toxicities of MDM2 inhibitors in patients with solid organ and hematologic malignancies: A systematic review of the literature, Leukemia Research, Volume 86, 2019, 106222, ISSN 0145-2126).
Claim 9 is directed towards the method of claim 8 wherein the MDM2 inhibitor is siremadlin (HDM-201). For the teachings of Ball as they are directed to claim 8, see the above 103 rejection of claim 8. While Ball does not explicitly teach the administration of siremadlin, one of ordinary skill in the art would have a reasonable expectation of success in substituting the idasanutlin of Ball’s method for siremadlin, because they are both known MDM2 inhibitors to be used in the treatment of acute myeloid leukemia (Pi, pg. 3, Table 1). See MPEP 2144.06(II). Claim 9 is thereby prima facie obvious.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Ball in view of Yoshimura (Yoshimura et al., Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma, Cancer Science Volume 105, Issue 7, p. 795-801).
Claim 18 is directed towards the method of claim 1 wherein the treatment further comprises administration of an exportin-1 (XPO-1) inhibitor. For the teachings of Ball as they relate to claim 1, see the above 103 rejection for claim 1. Regarding co-administration with an exportin-1 inhibitor, one of ordinary skill in the art would have a reasonable expectation of success in administering the two drugs together, because both drugs mediate the nuclear export of p53, through different mechanisms, and thus would work together synergistically for the treatment of the cancer. See Yoshimura:
“The nuclear export of p53 is cooperatively mediated by MDM2 and XPO1. MDM2 activates the nuclear export signal (NES) in p53 through its E3 ubiquitin ligase activity, leading a conformational change in p53 that exposes p53’s NES domain. Following ubiquitination, XPO1 recognizes p53’s NES and exports the protein from the nucleus to the cytoplasm, where it is unable to execute transcriptional activity to regulate cell fate. As we mentioned previously, XPO1 is highly expressed in MCL cells, which may limit p53-mediated transcriptional activity, and hence the ability of p53 to trigger apoptosis. It has been reported that wild-type p53 is abnormally sequestered in the cytoplasm in certain human tumor cells.”
[Yoshimura, pg. 796]
One of ordinary skill in the art would therefore have a reasonable expectation of success in administering an exportin-1 inhibitor in the described treatment, and claim 18 is thereby prima facie obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Anthony Seitz whose telephone number is (703)756-4657. The examiner can normally be reached 7:30 AM ET - 5:00 PM ET M-F.
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/A.J.S./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 For evidentiary support, see Brummer, who describes the antitumor activity of idasanutlin and the pathways affected by it (Brummer T, Zeiser R. The role of the MDM2/p53 axis in antitumor immune responses. Blood. 2024 Jun 27;143(26):2701-2709). Note that such activity would be inherent in the administration of the compound regardless of when such activity is discovered.
Prosecution Insights