DETAILED ACTION
This Office action details a first action on the merits for the above referenced application No. Claims 1-4, 6, 9, 12-15, 20-25, 27, 29, 31-33, and 43 are pending in this application.
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 .
Priority
This application is a 35 USC 371 National Stage filing of international application No. PCT/US21/51338 filed on 21 Sep. 2021, which claims benefit under 35 USC 119(e) to US provisional application No. 63/081,217 filed on 21 Sep. 2020.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 12 Jun. 2023, 3 Nov. 2023, 3 Nov. 2023, 26 Jun. 2024, 26 Jun. 2024, 27 Sep. 2024, 27 Sep. 2024, 31 Oct. 2024, 31 Oct. 2024, 13 Dec. 2024, 5 Feb. 2025, and 25 Aug. 2025 have been considered by the examiner.
Claim Objections
Claim 6 is objected to because of the following informalities: in claim 6, “the substrate” should be “the detectably labeled substrate”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 3 and 29 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. In claim 3, the recitation of “such as” renders the claim as indefinite because it is not clear if the recitation and the limitations that follow are merely examples or required limitations.
In claim 29, the recitations of “(ABT-199)” and “(ABT-263)” are indefinite because it is not clear if the recitations are merely examples or required limitations. The Examiner suggests removing those recitations from the claim.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 33 is rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea without significantly more. The claim(s) recite(s) comparing the sizes or volumes of the glioblastoma tumor at the first time point and at the at least one subsequent time point, wherein a decrease in tumor size or volume at a subsequent time point relative to the further time point indicates therapy is effective. This limitation relates to a mental process. MPEP 2106.04(a)(2)(III). This judicial exception is not integrated into a practical application because nothing is done as a result of the comparing. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the following steps relate extra-solution data gathering that are themselves mental processes and are well known routine and conventional steps: (i) assessing the size or volume the glioblastoma tumor at a first time point, and (ii) assessing the size or volume of the glioblastoma tumor at least one subsequent time point. Those limitations are construed as mental processes because those limitations can be done by looking at conventional imaging data. The claim further requires that patient has received a dose of the therapy between the first and the at least one subsequent time point; however, the administration of EGFR TKI therapy is routine and conventional cancer treatments as described by the references cited herein.
Patent eligibility under 35 USC 101 requires analysis of the following two-step Alice/Mayo test.
Step 1 asks if the claim is directed to a process, machine, manufacture or compositions of matter. In the instant case, the answer is yes because instant claim 33 is directed to a process having steps for assessing the size or volume of a glioblastoma tumor at a first time point and at least one subsequent time point.
Step 2A asks if the claim is directed to a law of nature, a natural phenomenon (product of nature), or an abstract idea. Step 2A is a two-prong inquiry. Prong-one asks if the claim recites an abstract idea, law of nature, or natural phenomenon. In this case, the answer is yes since the claim requires the step of comparing the sizes or volumes of the glioblastoma tumor at the first time point and at the at least one subsequent time point, wherein a decrease in tumor size or volume at a subsequent time point relative to the further time point indicates therapy is effective. This is an abstract idea requiring a mental comparison and an inference based on the comparison. See MPEP 2106.04(a)(2)(IIII). Prong-two asks if the claim recites an additional element that integrates the judicial exception into a practical application. In this case, the answer is no since nothing in claim 33 is done as a result of the recited abstract idea.
Step 2B asks if the claim recites additional elements that amount to significantly more than the judicial exception. In this case, the answer is no as the claim does not add significantly more that the judicial exception. The claim is not eligible subject matter under 35 USC 101. There are no additional steps beyond the judicial exceptions recited in the claim that are not routine and customary in the art. Note 2106.05, second paragraph:
An inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." … Instead, an "inventive concept" is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself. Alice Corp., 573 U.S. at 27-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).
Limitations the courts have found not to be enough to qualify as significantly more when recited in a claim with a judicial exception include: (i) simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality to the judicial exception, and (ii) adding insignificant extra-solution activity to the judicial exception, e.g., mere data gathering in conjunction with an abstract idea such as a step of obtaining information so that the information can be analyzed by an abstract mental process. The additional steps of assessing the size and volume of the glioblastoma tumor at a first and at least one subsequent time point relate to routine and convention data gathering activity recited at a high level of generality. Treating a patient who has a glioblastoma tumor with EGFR TKI therapy is routine and conventional cancer therapy as noted by references cited herein
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-4, 6, 9, 12-15, 20-21, 23-25, 27, 29, 31-33, and 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nathanson et al. (WO 2019/067543 A1; published 4 Apr. 2019; see IDS filed on 12 Jun. 2023).
Nathanson et al. teach compositions and methods for treating cancer (see title). Nathanson et al. teach methods of treating glioblastoma and other EDFR mediated cancers that have been determined to have altered glucose metabolism in the presence of inhibitors (see abstract). Nathanson et al. teach EGFR inhibitors of formula (I-a)
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and (I-b)
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such as JKG010
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(pg. 116). JKG010 reads on a compound of instant formula (I) wherein R2a=R2b= R3=H; Z=aryl; and R11 and R12 taken together complete a heterocyclic ring. Erlotinib reads on a compound of instant formula (I) wherein R2a=R2b= R3=H; Z=aryl; R11=OR7, R7=alkoxyalkyl; and R12=OR8, R8=alkoxyalkyl. Nathanson et al. teach that metabolic responders show significant decrease in 18F-FDG uptake whereas non-responders show no significant decrease (pg. 5). The glucose metabolism inhibitor is a EGFR inhibitor. Activation may be dues to an increase EGFR copy number (pg. 38).
Fig. 26A depicts the 18F FDG PET/CT imaging of GBM39 (glioblastoma) intracranial xenografts before (reference level determined by measuring the uptake of FDG in glioblastoma before administrating the EGFR TKI therapy; level representative of typical glucose uptake in a glioblastoma) and after 15 h (within 7 d after treating) erlotinib treatment. (Reads on a methods of treating a glioblastoma and identifying a metabolic process inhibitor as an effective treatment, the method comprising administering to a subject a subject a first dose of an epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib, EGFR TKI, metabolic process inhibitor wherein the metabolic process is glycolysis), administering to the subject 18F-FDG (a detectably labeled substrate for a metabolic process), measuring by PET the amount of 18F-FDG in the glioblastoma after administering the EGFR TKI wherein a decrease in the amount of 18F-FDG to reference level indicates that the glioblastoma is a metabolic responder to the inhibitor wherein the metabolic process is glycolysis wherein the reference level is determined by measuring the uptake of the 18F-FDG in the glioblastoma before administering the erlotinib wherein measuring the amount of labeled substrate in the glioblastoma comprises a PET scan, and wherein the reference level is a known level of typical glucose uptake in a glioblastoma, wherein the glioblastoma comprises a wild type EGFR.) The control can comprise a cancer with a wildtype ERGF expression and the control is taken from the patient before the subject is subjected to glucose metabolism inhibitors (pg. 36). The reference level is an average level of expression determined from a cohort of subjects with cancer or without cancer (pg. 80).
Fig. 27A
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depicts the percent change in 18F-FDG uptake at indicated times of erlotinib treatment relative to vehicle in two metabolic responders (HK301 and GBM39; glioblastomas). Fig. 27C depicts the percent change in 18F-FDG uptake in HK301 and HK217 following genetic knockdown of EGFR (see pg. 8). Nathanson et al. teach methods of treating malignant glioma and GBM in a subject, the method comprising administering to the subject after the subject has been determined to be susceptible to a glucose metabolism inhibitor and amount of the p53 stabilizer. The subject has been determined to be susceptible to a glucose metabolism inhibitor by a method comprising obtaining a tumor biopsy from the subject, measuring the level of glucose uptake by the tumor cells in the presence of any glucose metabolism inhibitor, comparing the level of glucose uptake by the tumor cells obtained to the level of glucose uptake by a control and determining that the subject is susceptible to the glucose metabolism inhibitor if the level of glucose uptake is attenuated compared to control. The glucose uptake is measured by the uptake of 18F-FDG and detecting 18F-FDG is by PET and the biopsy is taken from a GBM tumor (pgs. 46, 53). Nathanson et al. teach methods of assessing the sensitivity of cancer cells or tumor to treatment with glucose metabolism inhibitor and a cytoplasmic p53 stabilizer, the method comprising measuring or detecting the level of glucose uptake by cancer cells and comparing the level of glucose uptake with control wherein the glucose is 18F-FDG and the detecting is done by PET. The inhibitors include erlotinib. The cytoplasmic p53 stabilizer is MDM2 antagonist such as nutlin or a BCL-2 inhibitor such as antisense oligodeoxynucleotide G3139 or a Bcl-xL inhibitor such as WEHI 539 (pg. 48) The glucose uptake inhibitor and cytoplasmic p53 stabilizer are administered after determining that the subject susceptible to reduced glucose metabolism by EGFR inhibitor and are administering in the same composition (conjointly) or as separate compositions (pg. 49). The methods further comprise additional therapy (pgs. 50-51). Patients may be treated for 10 or more days (see pg. 66). Nathanson et al. teach EGFR polysomy (pg. 4). Fig. 29 B depicts fluorescence in situ hybridization for HK393 showing polysomy of EGFR and depicts copy number gain (CN gain polysomy). Treating includes a reduction of tumor size (pg. 81).
Nathanson et al. do not exemplify methods of treating a glioblastoma or identifying a metabolic process inhibitor such that if the amount is less than the reference level, the subject is treated with the EGFR TKI for a period of time and imaging the glioblastoma to assess a change in tumor volume over time, optionally wherein a decrease in tumor volume identifies the inhibitor as an effective treatment for the glioblastoma and optionally identifying a polysomy in the glioblastoma tumor. Nathanson et al. do not further exemplify a method wherein an altered copy number of EGFR is caused by an amplification of the EGFR. Nathanoson et al. do not exemplify a method further comprising administering additional therapy to the subject if the glioblastoma is identified as a metabolic responder optionally subsequent to identifying the glioblastoma as a metabolic responder and optionally wherein the additional therapy is a cytoplasmic p53 stabilizer selected from an MDM inhibitor such as nutlin, a BCL-2 inhibitor such as G3139, or Bcl-xL such as WEHI 539. Nathanoson et al. do not further exemplify a method comprising assessing the size of the glioblastoma tumor at a first time point, assessing the size of the glioblastoma tumor as at least one subsequent time point wherein the patient has received at least one dose of therapy between the first and the at least subsequent time point and comparing the sizes at those time points wherein a decrease in tumor size indicates the therapy is effective.
However, it would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Nathanson et al. (methods of treating a glioblastoma in a subject and identifying a metabolic process inhibitor as an effective treatment for glioblastoma that include administering to a subject having a glioblastoma tumor a first dose of EGFR TKI/metabolic process inhibitor/erlotinib; administering the 18F-FDG that is a substrate for the metabolic process that is glycolysis; and measuring by PET the amount of 18F-FDG in the glioblastoma after administering the EGFR/TKI therapy wherein a decrease in 18F-FDG relative to a reference level of FDG uptake obtained before administration of the EGFR TKI/metabolic process inhibitor and representative of typical glucose uptake in a glioblastoma and wherein the imaging comprises an imaging between 0 and 7 d after treating the subject with the EGFR TKI the wherein the glioblastoma comprises a wild type or mutant EGFR) so that if the measured amount of 18F-FDG is less than the reference level, the subject is treated with erlotinib, or other EGFR TKI or other metabolic process inhibitor for a period of time and imaging the glioblastoma to assess a change in tumor volume over the period of time optionally wherein a decrease in tumor volume identifies the inhibitor as an effective treatment of the glioblastoma as taught Nathanson et al. because the treating for a period of time would have been expected to provide effective treatment that advantageously increases survival rates. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Nathanson et al. so that the altered copy number of EGFR is cause by amplification of EGFR or by further identifying a polysomy in the glioblastoma as taught by Nathanson et al. because it would have been expected to enable non-invasively identifying GBMs having increased EGFR copy gains, which drive glucose uptake. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Nathanson et al. by further administering additional therapy to the subject if the glioblastoma is identified as a metabolic responder or if the glioblastoma does not decrease in volume over time optionally wherein the additional therapy is p53 stabilizer selected from an MDM inhibitor such as nutlin, an BCL-2 inhibitor such as antisense oligonucleotide G3139, and a Bcl-xL inhibitor such as WEHI 539 and optionally wherein the EGFR TKI and p53 inhibitor are administered conjointly as taught by Nathanson et al. because the additional therapy comprising further administration would have been expected to advantageously provide synergistically enhanced tumor suppression in vivo.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Nathanson et al. by monitoring a glioblastoma tumor in a subject receiving EGFR TKI therapy, the method comprising assessing the size of the glioblastoma tumor at a first time point, assessing the size of the glioblastoma tumor at a second time point where the subject has received a dose of EGFR TKI therapy between the first and subsequent time point and comparing the sizes of the glioblastoma tumor at the first time point and the subsequent time point wherein a decrease in tumor size at a subsequent time point relative to the first time point indicates the therapy is effective as taught and motivated by Nathanson et al. because the monitoring would have been expected to advantageously enable non-invasively assessing the effectiveness of treatment over a period of time wherein the effectiveness is based on a reduction of tumors size.
Claim(s) 1-4, 6, 9, 12-15, 20-25, 27, 29, 31-33, and 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nathanson et al. (WO 2019/067547 A1; published 4 Apr. 2019; see IDS filed on 12 Jun. 2023), in view of Tajima et al. (Med Mol Morphol; published 2016; see attached 892).
Nathanson et al. teach as discussed above.
Nathanson et al. do not further a teach a polysomy that is a trisomy 7.
Tajima et al. teach cystic apocrine ductal carcinoma in situ with increased EGFR expression, trisomy 7, and associate focal invasion (see title). Tajima et al. present a case of cystic ADCIS showing moderate EGFR expression and EGFR copy number gain as a result of trisomy 78 (see pg. 170). Increased expression of EGFR might result from EGFR copy number gain derived from polysomy 7 as demonstrated by FISH analysis. (see pg. 175).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Nathanson et al. so that the altered copy number of EGFR is caused by trisomy 7 as taught by Tajima et al. because the trisomy 7 would have been expected to advantageously enable identifying and treating EGFR expressing glioblastoma by administering an EGFR TKI.
Conclusion
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618