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 .
Claim for Domestic Benefit
This application claims the benefit of and priority to U.S. Provisional Application No. 63/385234, filed Nov. 29, 2022, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/15/2023 was filed prior to the mailing of the instant first Office action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. A copy of Forms PTO/SB/08 is attached to the instant Office action.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 6-8, 10-14, 16, 19-20 and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pal et al., A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma, bioRxiv, June 13, 2022, doi: 10.111101./2021.11.30.470644.
Regarding Claim 1, the reference Pal et al (pp3) anticipates as a method, the use of dihydroorotate dehydrogenase (DHODH) to be administered to a subject for the treatment of brain cancer. The art clearly identifies within the summary, as the provision of methods of treating conditions, such as cancer, using combination therapies that include in inhibitor of DHODH to disrupt pyrimidine synthesis which is critical for the growth of cancer cells.
Regarding claims 2-3 and 6-8, whereas the reference Pal et al (p30, “Methods Details”) anticipates the administration of at least one small molecule drug synergistic with a DHODH inhibitor as listed in claim 3. The DHODH inhibitor to be administered as identified as compound 1 (BAY2402234) in claim 6 to a subject where the brain cancer is a malignant glioma and where the malignant glioma is a glioblastoma as identified in claim 8. Accordingly, Pal et al discusses under the section Method Details (pp33), where the DHODH inhibitor (BAY2402234) is tested in combination with multiple compounds to include gemcitabine from the list in claim 3 with further description and results of the testing in fig.2 (pp21). Additionally, the art makes reference as to Diffuse Midline Glioma (DMG) which is a specific type of malignant glioma throughout the reference art as a primary topic of review. While this is common in younger populations with occurrences in younger adults, the genomics and proliferation remain the same in adult glioblastomas (aGBM).
Regarding claims 10-14, Pal et al. anticipates a method for decreasing the proliferation of malignant glioma tumor cells, comprising: contacting the glioma tumor cells, inclusion of small molecule drugs that inhibit an activity of dihydroorotate dehydrogenase or an associated activity, and where the contacting step is in vivo. Additionally, where the small molecule drug is compound 1 (BAY2402234) and is combined with at least one other small molecule drug as listed in claim 14. The combination of DHODH inhibitors with other anti-cancer drugs as an approach for the inhibition of tumor cell proliferation and further the combination of drugs as an approach for various tumor therapies that inhibit tumor proliferation has been identified and tested through multiple pathways associated with metabolism and DNA damage repair (pp5-6, “Results”). Additionally, the author further provides through figures or graphs where compound 1 (BAY2402234) inhibits pyrimidine biosynthesis and demonstrates decreased proliferation within DMGs and aGBM (pp21, Fig2 (C), Fig1E, S1B and S1C). Furthermore, Pal et al. further states that compound 1 (claim 12) and gemcitabine (claim 14) have been combined for testing (pp30, Methods Details) and where compound 1 (BAY2402234) has demonstrated through multiple testing processes, and where contact with glioma cells has been both in vitro and in vivo (claim 11) environments as initially identified in the reference art summary (pp3).
Regarding claim 16, whereas the reference Pal et al (pp17, ¶2 “Discussion”) anticipates the contacting step to be in vitro, where the malignant glioma tumors cells come into contact with compound 1 (BAY2402234) and at least one of the drugs listed from claim 3. Accordingly, the reference art states that compound 1 (BAY2402234) is administered and contacted with malignant tumor cells in vitro (pp13, Inhibition of de novo pyrimidine biosynthesis by BAY2402234 prolongs survival of mice harboring DBG orthotopic tumors). As also previously identified, that testing of efficacy of multiple combinations of small molecule drugs including gemcitabine have been conducted as outlined in Fig. 2 (pp22) and as described under Method Details (pp30).
Regarding claims 19-20 and 22, whereas the reference Pal et al. (pp22-23) anticipates the increased sensitivity of compound 1 (BAY2402234) as in claim 19, in combination with a small molecule drug from claim 20 and where a malignant glioma is a glioblastoma as identified in claim 22. The author makes reference to the testing and sensitivity of compound 1 when combined with various secondary agents such as gemcitabine (pp8, first complete ¶) and further results can be seen in Fig 2G-1. As previously identified, where glioblastomas (identified as aGBM) and diffuse midline gliomas (DMG) were both included in the testing to determine sensitivity as visualized in the description of Fig2 (pp21-22) in reference to Fig S2 and Table S3.
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 4 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Pal et al. as applied to 1-3, 6-8, 10-14, 16, 19-20 and 22, and further in view of Kumar WO 2020/219423 Al, Combination Therapies Including Inhibitors of Dihydroorotate Dehydrogenase (2020).
The teachings of Pal et al. are set forth above in the 102 rejections and are incorporated herein. While Pal et al. teaches a method for the treating of a brain cancer where the subject is administered an inhibitor of dihydroorotate dehydrogenase and where the DHODH is compound 1 (BAY2402234) and where the subject is administered a second agent of small molecule drugs listed in claim 3 synergistic with the inhibitor. In addition, Pal et al. further teaches where the method increases sensitivity of a malignant glioma to the administration of compound 1 (BAY2402234) and a second small molecule drug. However, Pal et al does not teach where at least one small molecule drug is co-administered or is administered sequentially with the inhibitor.
Regarding claims 4 and 21, where a combination consisting of compound 1 (BAY2402234) and a small molecule drug is co-administered or administered sequentially. The methodology provided by Kumar WO 2020/219423 Al as a multi-stage therapy where DHODH inhibitors are administered to a patient in one stage and a second therapeutic agent is administered in another stage. Within the methodology, it is noted that the stages can occur concurrently, overlap partially or fully, or overlap completely. It is further noted that there may also be gaps within the stages of varying amounts of time for the treatment regimen and treatment cycles because as further discussed in the section “Determining a Dosing Regimen for the Second Therapeutic Agent”, Kumar identifies that the different stages of multistage treatment may be sequential, where the staging and gaps between the cycles will be dependent on the response of the subject (page 2, ¶33-34).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention for claims 4 and 21, where at least 1 small molecule drug is co-administered with the inhibitor or administered sequentially, with a reasonable expectation of success in view of the prior art for the following reasons:
Per MEPE §2143 (I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious and well-within the ordinary skill in the art, to co-administer or administer sequentially the DHODH inhibitor and/or a second small molecule drug. The testing and methodologies established by Pal et al. and Kumar clearly demonstrate when combining multiple drugs for treatment, that one skilled in the art would administer the treatments according to the established protocols or treatment plans. Furthermore, if a treatment regimen is not co-administered in combination of a DHODH and with at least one small molecule drug listed in claims 3 and 20, then the combination would have to be administered sequentially because as Kumar previously noted that the intervals can be overlapping or have intervals that could include days, weeks or months between treatments based on the needs and response of the subject.
Claims 5 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Pal et al. as applied to 1-3, 6-8, 10-14, 16, 19-20 and 22, and further in view of Sulman et al., "Radiation Therapy for Glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline", Journal of Clinical Oncology, vol. 35:3, January 20, 2017.
The teachings of Pal et al. are set forth above in the 102 rejections and are incorporated herein. While Pal et al. teaches a method for the treating of a brain cancer where the subject is administered an inhibitor of dihydroorotate dehydrogenase and where the DHODH is compound 1 (BAY2402234) and where the subject is administered a second agent of small molecule drugs listed in claim 3 synergistic with the inhibitor. However, Pal et al does not teach where the treatment regimen includes the administration of chemoradiation at least once to the subject.
Regarding claims 5 and 15, where the method comprises administering at least once to the subject chemoradiation therapy. As previously identified, Pal et al. makes reference to the use and impact of DHODH inhibitors, specifically compound 1 (BAY2402234) for the various types of brain cancers and does not teach the administering of chemoradiation to a subject. Sulman teaches that partial-brain fractionated radiotherapy with concurrent and adjuvant temozolomide is the standard of care after biopsy or resection of newly diagnosed glioblastoma (Abstract: Recommendations and Table:1). Additionally, Sulman further notes that Radiation should be initiated as soon as safely permissible and generally initiated within 3-6 weeks after surgery (The Bottom Line, Key Recommendations for Radiation Therapy for Glioblastoma, #2).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention for claims 5 and 15, where the subject is administered at least once chemoradiation, with a reasonable expectation of success in view of the prior art for at least the following reasons:
Per MPEP §2143 (I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious and well-within the ordinary skill in art, to administer chemoradiation therapy to the subject at least once as a method because the administration of chemoradiation has been published as current guidance for clinical providers by the American Society of Clinical Oncology. Additionally, the use of radiotherapy with the inclusion of temozolomide (alkylating agent) is a current modality, which allows for focal radiation treatments, increasing the potential for penetrating the blood brain barrier, and increasing sensitivity to DHODH or other small molecule drug activities.
Claims 9, 18, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Pal et al. as applied to 1-3, 6-8, 10-14, 16, 19-20 and 22, and further in view of Padfield, Ellis and Kurian “Current therapeutic advances targeting EGFR and EGFRvIII in glioblastoma”, Front Oncol, Jan 29:5:5 (2015).
The teachings of Pal et al. are set forth above in the 102 rejections and are incorporated herein. Pal et al. teaches within the art, that the brain cancer is a malignant glioma and where the malignant glioma is a glioblastoma. However, Pal et al. does not teach where the glioblastoma overexpresses EGFR or mutant EGFRviii.
Regarding claims 9, 18 and 23 where the instant application states that the glioblastoma overexpresses EGFR or mutant EGFRviii. As previously referenced, Pal et al. teaches the use and impact of DHODH inhibitors, specifically compound 1 (BAY2402234) for the various types of brain cancers which includes gliomas and glioblastomas, however the reference art does not teach that the glioblastoma overexpresses EGFR or mutant EGFRviii. Padfield, Ellis and Kurian teach that glioblastoma formations are referred to as Primary Glioblastoma (GBM). Where as noted in the reference art, Primary GBMs are frequently associated with EGFR amplifications where approximately half of patients have the specific mutation of EGFRviii (pp.1, Introduction). The overexpression of EGFR and the co-expressed EGFRviii complicates signaling pathways, proliferation and tumorigenesis. This has led to the identification of four modes of EFGR targeted therapies. Tyrosine kinase inhibitors are a noted targeted mode of therapy which includes the named drugs in claim 3,14 and 20 (pp2, “EGFR Targeted Therapies”).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention for claims 9, 18, 23 where the glioblastoma overexpresses EGFR or mutant EGFRviii, with a reasonable expectation of success in view of the prior art for at least the following reasons:
Per MPEP § 2143(I)(G), a prima facie case of obviousness exists where some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. It would have been obvious and well within the ordinary skill in the art that a malignant glioma would comprise a glioblastoma and present with an overexpression of EGFR and/or EGFRviii. Glioblastomas are a Grade IV classification under the World Health Organization grading system and are known to be the most aggressive and malignant form of this tumor type. As previously referenced, growth factors and their correlating receptors are primary controllers of cellular proliferation; therefore, it is consistent with the prior art to utilize small molecule drugs to target secondary metabolic pathways. One of ordinary skill in the art would have concluded that DHODH inhibitors, such as compound 1 (BAY2402234) which target primary metabolic pathways and the use of a second small-molecule drug (as listed in claims 3, 14, and 20) targeting a secondary metabolic pathway with the inclusion of chemoradiation would be used to treat glioblastomas presenting with an overexpression of EGFR or mutant EGFRviii. Additionally, one in the art would also reasonably conclude—as demonstrated by Padfield, Ellis, and Kurian, where EGFR overexpression and mutant EGFRviii expression account for approximately 57% and 50% of glioblastoma presentations respectively—that because the second small molecule drugs target secondary pathways of proliferation, that this method would be used to further encompass and include the treatment for all glioblastoma subjects.
Summary of the Claims
Claims 1-23 are pending.
Claims 1-23 are rejected.
No claim is in condition for allowance.
Conclusion
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/S.H.D./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627