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 .
Information Disclosure Statement
The information disclosure statement filed on April 25, 2024 is acknowledged and has been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 1, 14, and 15 are objected to because of the following informalities:
Claim 1 ends with the phrase “an efficient dose of ionizing radiations.” The examiner suggests that the last noun should be in the singular tense and be corrected to “radiation.”
Claim 14 requires the subject is “selected from” something but only provides a single option. The examiner suggests amending the claim to read either as “The method of claim 1, wherein said subject has positive methylated O-6-methylguanine-DNA methyltransferase promoter status” or “The method of claim 1, wherein said subject is selected from subjects with positive methylated O-6-methylguanine-DNA methyltransferase promoter status.”
Claim 15 recites “…even more preferably of around…” which appears to be grammatically incorrect with the structure of the provided list of options. The examiner suggests amending to either “…even more preferably around…” or “…even more preferably a dose of around….”
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 3-13, 15-19, and 22-25 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 3 recites the limitation “…wherein M is…” in line 1. There is insufficient antecedent basis for this limitation in the claim, as “M” is not a feature of claim 1, from which claim 3 depends. For the purpose of examination, the examiner will interpret claim 3 to instead depend from claim 2, which recites the formula M-C-S-P.
Claim 4 recites the limitation “…wherein C is…” in line 1. There is insufficient antecedent basis for this limitation in the claim, as “C” is not a feature of claim 1, from which claim 4 depends. For the purpose of examination, the examiner will interpret claim 4 to instead depend from claim 2, which recites the formula M-C-S-P.
Claim 4 recites the phrase “e.g.,” which is interpreted to be equivalent to the phrase “for example.” This phrase renders the claim indefinite because it is unclear whether the limitation following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purpose of examination, the examiner will not interpret the phrase following “e.g.” to be required by the claim.
Claim 5 recites the limitation “…wherein P is…” in line 1. There is insufficient antecedent basis for this limitation in the claim, as “P” is not a feature of claim 1, from which claim 5 depends. For the purpose of examination, the examiner will interpret claim 5 to instead depend from claim 2, which recites the formula M-C-S-P.
Claim 6 lists a series of names of compounds as options for the identity of the radiopharmaceutical compound. However, the examiner notes that none of these compounds themselves are radiopharmaceutical compounds. The applicant defines on page 20 of the spec that a radiopharmaceutical “refers to a pharmaceutical compound which is labelled with a radionuclide element.” The molecules provided in the list of claim 6, as they are currently stated, are not labelled with a radionuclide and are therefore not radiopharmaceutical compounds. Therefore, it is not clear how these listed molecules are intended to relate to or limit the term radiopharmaceutical in this claim, rendering the claim indefinite. It is not clear whether these compounds are meant to be precursors to the radiopharmaceutical compounds of claim 1 or if the radiopharmaceutical compound of claim 1 is to comprise the listed molecules. For the purpose of examination, the examiner will interpret that claim 6 requires the radiopharmaceutical compound of claim 1 to comprise one of the listed molecules.
Claim 9 recites the limitation “said alkylating agent” in line 1. There is insufficient antecedent basis for this limitation in the claim, as an alkylating agent is not a feature of claim 1, from which claim 9 depends. For the purpose of examination, the examiner will interpret claim 9 to instead depend from claim 8, which includes a limitation of administering an alkylating agent.
Claim 10 recites the limitation “alkylating agent” in line 1. There is insufficient antecedent basis for this limitation in the claim, as an alkylating agent is not a feature of claim 1, from which claim 10 depends. For the purpose of examination, the examiner will interpret claim 10 to instead depend from claim 8, which includes a limitation of administering an alkylating agent.
Claim 11 recites the limitation “said alkylating agent” in line 1. There is insufficient antecedent basis for this limitation in the claim, as an alkylating agent is not a feature of claim 1, from which claim 11 depends. For the purpose of examination, the examiner will interpret claim 11 to instead depend from claim 8, which includes a limitation of administering an alkylating agent.
Claim 12 recites the limitation “said alkylating agent” in line 1. There is insufficient antecedent basis for this limitation in the claim, as an alkylating agent is not a feature of claim 1, from which claim 12 depends. For the purpose of examination, the examiner will interpret claim 12 to instead depend from claim 8, which includes a limitation of administering an alkylating agent.
Regarding claim 12, the phrase "for example" in lines 2-3 and 4 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purpose of examination, the examiner will interpret the scope of claim 12 to not include the limitations following the exemplary language. Thus, the scope is understood to include any time period of dosing the alkylating agent at a first dose and any time period of dosing the alkylating agent at a second dose.
Claim 13 recites the limitation “said alkylating agent” in line 1. There is insufficient antecedent basis for this limitation in the claim, as an alkylating agent is not a feature of claim 1, from which claim 13 depends. For the purpose of examination, the examiner will interpret claim 13 to instead depend from claim 12, which further depends on claim 8, which includes a limitation of administering an alkylating agent.
Claim 13 recites the limitation “the maintenance phase” in line 2. There is insufficient antecedent basis for this limitation in the claim, as a maintenance phase is not a feature of claim 1, from which claim 13 depends. For the purpose of examination, the examiner will interpret claim 13 to instead depend from claim 12, which includes a limitation relating to a maintenance phase.
Claim 16 recites the limitation “the induction phase” in line 2. There is insufficient antecedent basis for this limitation in the claim, as an induction phase is not a feature of claim 1, from which claim 16 depends. For the purpose of examination, the examiner will interpret claim 16 to instead depend from claim 9, which includes a limitation relating to an induction phase.
Claim 17 recites “wherein said radiopharmaceutical compound comprises a treatment interval of 2 weeks…” This phrase is unclear because a compound itself does not comprise a treatment interval. It is unclear how the concept of treatment interval is meant to relate to the radiopharmaceutical compound, rendering the claim indefinite in scope. For the purpose of examination, the examiner will interpret the claim to describe that the administration of the radiopharmaceutical occurs at an interval of 2 weeks, etc.
Claim 19 recites the limitation “said irradiation induction” in line 1. There is insufficient antecedent basis for this limitation in the claim, as irradiation induction is not a feature of claim 1, from which claim 19 depends. For the purpose of examination, the examiner will interpret claim 19 to instead depend from claim 9, which includes a limitation relating to an induction phase.
Claim 22 recites the limitation “instead of 177Lu” in lines 3-4. There is insufficient antecedent basis for this limitation in the claim, as 177Lu is not a feature of claim 1, from which claim 22 depends. The examiner notes that the “instead of 177Lu” phrase can be removed without changing the scope of the claim as the examiner understands it. The examiner suggests amending the claim to instead recite “…but with a radiometal suitable for imaging by evaluating said radiopharmaceutical compound suitable for imaging uptake in said subject.”
Claims 23-25 include a limitation that the subject is newly diagnosed with glioblastoma. The examiner interprets the term “newly” to be a relative term which renders the claim indefinite. The term “newly” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and on of ordinary skill in the art would not be reasonably of the scope of the invention. It is not clear what is required for a subject diagnosed with glioblastoma to no longer be considered “newly diagnosed.”
Regarding claim 25, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purpose of examination, the examiner will interpret the claim to not require the limitation following the exemplary language. Thus, the scope of the claim is understood to relate to any chemotherapeutic agent.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance:
Claim 3 recites the broad limitation that M may be selected from one of 44 listed radionuclides, and the claim also recites that M is preferably 177Lu, which is the narrower statement of the limitation.
Claim 4 recites the broad limitation that C may be one of 13 listed radionuclides, and the claim also recites that C is preferably DOTA, NOTA, or DTPA, and additionally recites that C is more preferably DOTA, which are narrower statements of the limitation.
Claim 5 recites the broad limitation that P may be one of 5 listed somatostatin receptor binding peptides, and the claim also recites that P is preferably selected from octreotide and octreotate, which is a narrower statement of the limitation.
Claim 6 recites the broad limitation that the radiopharmaceutical compound is one of 7 listed options, and the claim also recites that the compound is preferably DOTA-TOC or DOTA-TATE, additionally reciting that the compound is more preferably DOTA-TATE, which are narrower statements of the limitation.
Claim 7 recites the broad limitation that the compound is one of [177Lu]Lu-DOTA-TOC or [177Lu]Lu-DOTA-TATE, and the claim also recites that the compound is more preferably [177Lu]Lu-DOTA-TATE, which is a narrower statement of the limitation.
Claim 8 recites the broad limitation alkylating agent, and the claim also recites preferably temozolomide, which is a narrower statement of the limitation.
Claim 9 recites the broad limitation alkylating agent, and the claim also recites preferably temozolomide, which is a narrower statement of the limitation.
Claim 9 recites the broad limitation 50 to 100 mg/m2/day, and the claim also recites preferably around 75 mg/m2/day, which is a narrower statement of the limitation.
Claim 9 recites the broad limitation 4 to 8 weeks, and the claim also recites preferably 6 weeks, which is a narrower statement of the limitation.
Claim 10 recites the broad limitation alkylating agent, and the claim also recites preferably temozolomide, which is a narrower statement of the limitation.
Claim 11 recites the broad limitation alkylating agent, and the claim also recites preferably temozolomide, which is a narrower statement of the limitation.
Claim 12 recites the broad limitation alkylating agent, and the claim also recites preferably temozolomide, which is a narrower statement of the limitation.
Claim 13 recites the broad limitation alkylating agent, and the claim also recites preferably temozolomide, which is a narrower statement of the limitation.
Claim 13 recites the broad limitation of 50 to 400 mg/m2/day, and the claim also recites preferably between 75 to 300 mg/m2/day and additionally recites more preferably between 150 to 200 mg/m2/day, which are narrower statements of the limitation.
Claim 13 recites the broad limitation 20 to 28 weeks, and the claim also recites preferably 24 weeks, which is a narrower statement of the limitation.
Claim 15 recites the broad limitation of 0.925 GBq to 29.6 GBq; and the claim also recites preferably between 1.48 GBq to 18.5 GBq, preferably between 1.85 GBq to 14.8 GBq, more preferably between 3.7 GBq to 11.1 GBq, even more preferably of around 3.7 GBq, 5.55 GBq, 7.4 GBq, or 9.25 GBq; which are narrower statements of the limitation.
Claim 16 recites the broad limitation of 1 to 8 times per treatment, and the claim also recites preferably 2 to 7 times and more preferably 4 to 6 times, which are narrower statements of the limitation.
Claim 17 recites the broad limitation that a treatment interval is 2, 3, 4, 5, or 6 weeks; and the claim also recites that the interval is preferably 3 or 4 weeks, and further recites that it is more preferably 3 weeks; which are narrower statements of the limitation.
Claim 18 recites the broad limitation that the first dose of a radiopharmaceutical compound is administered 1 to 20 days prior to initiation of irradiation, and the claim also recites that the dose is preferably 3 to 15 or more preferably 7 to 10 days prior to initiation of irradiation, which are narrower statements of the limitation.
Claim 19 recites the broad limitation that irradiation induction is conducted at a dose between 1 Gy to 4 Gy/day, and the claim also recites that the dose is preferably around 2 Gy/day, which is a narrower statement of the limitation.
Claim 19 recites the broad limitation that irradiation is dosed during a period between 3 to 7 days per week, and the claim also recites that the dose is preferably around 5 days per week, which is a narrower statement of the limitation
Claim 19 recites the limitation that irradiation is dosed during a period of 4-8 weeks, and the claim also recites preferably 6 weeks, which is a narrower statement of the limitation.
Claim 22 recites the broad limitation “a radiometal suitable for imaging;” and the claim further recites preferably 68Ga, 67Ga, or 64Cu; and further recites more preferably 68Ga; which are narrower statements of the limitation.
Claim 24 recites the broad limitation alkylating agent, and the claim also recites preferably temozolomide, which is a narrower statement of the limitation.
Claim 24 recites the broad limitation that the radiopharmaceutical compound is administered prior to initiation of radiotherapy, and the claim also recites that the compound is administered preferably 7 to 10 days prior to initiation of radiotherapy, which is a narrower statement of the limitation.
Claim 25 recites the broad limitation that the radiopharmaceutical compound is administered prior to initiation of radiotherapy, and the claim also recites that the compound is administered preferably 7 to 10 days prior to initiation of radiotherapy, which is a narrower statement of the limitation.
The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. For the purpose of examination, the examiner will interpret the scope of each of these claims to be commensurate with the aforementioned broad limitations in each instance.
Claim Rejections - 35 USC § 102
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, 8-9, 12, 14, 16, and 23-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Laack (Laack, N. N.; et al., Int. J. Radiation Oncol. Biol. Phys., 2021).
Laack teaches a method of treating glioblastoma wherein 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) is administered and radiation therapy is performed (pg. 1383-1384, Abstract). This method was performed on subjects newly diagnosed with glioblastoma (pg. 1384, Study population). In this method, subjects were administered with 18F-DOPA and a PET scan was performed (pg. 1385, Pretreatment imaging). Afterwards, target tumor volumes were irradiated with 51, 60, or 76 Gy of radiation therapy in 30 fractions (pg. 1385, Targeted delineation, treatment planning, and delivery). This combination of 18F-DOPA administration followed by radiation therapy resulted in an increase in median progression free survival among MGMT unmethylated glioblastoma subjects compared to historical controls (pg. 1390, PFS results).
Regarding claim 1, Laack teaches a method of treating glioblastoma in subjects newly diagnosed with glioblastoma (and therefore in need thereof) (pg. 1383, Abstract; and pg. 1384, Study population). This method includes the administration of 18F-DOPA (pg. 1385, Pretreatment imaging), which the examiner interprets to read on the administration of a radiopharmaceutical compound, as the compound comprises a radionuclide. The examiner also interprets this administration to read on administering “an efficient amount,” as this phrase is defined on pg. 19 of the instant specification to refer to an amount “that will elicit the biological or medical response of a subject” and the examiner interprets the generation of tumor imaging data to be a biological or medical response. Additionally, the method of Laack involves irradiating the subject with an effective amount of radiation therapy (pg. 1385, Target delineation, treatment planning, and delivery). As this method involves the administration of a radiopharmaceutical compound and irradiation of the subject in the aforementioned ways, it anticipates claim 1.
Regarding claim 8, Laack also teaches the co-administration of temozolomide concomitantly with radiation therapy (pg. 1385, Target delineation, treatment planning, and delivery).
Regarding claim 9, Laack teaches administering temozolomide at a dose of 75 mg/m2/day for an initial period of 6 weeks (pg. 1385, Target delineation, treatment planning, and delivery).
Regarding claim 12, Laack teaches administering temozolomide at one dose value (75 mg/m2/day) for a period of 6 weeks concomitant with radiotherapy followed by adjuvant dosing at 150-200 mg/m2/day (which is at least twice the first dose) in a second time period (pg. 1385, Target delineation, treatment planning, and delivery).
Regarding claim 14, Laack teaches that subjects treated with the method included those with methylated MGMT status (pg. 1384-1385, Study population), which the examiner interprets to read on a subject with positive methylated O-6-methylguanine-DNA methyltransferase promoter status.
Regarding claim 16, Laack teaches administration of the 18F-DOPA radiopharmaceutical once during the method (pg. 1385, Pretreatment imaging). One administration is within the claimed range of 1 to 8 times, therefore anticipating this limitation.
Regarding claim 23, Laack teaches that the subjects were newly diagnosed with glioblastoma (pg. 1384, Study population).
Regarding claim 24, Laack teaches a method of treating newly diagnosed glioblastoma patients, including those with positive methylated MGMT promoter status (pg. 1384-1385, Study population). Laack teaches that this method includes administering a radiopharmaceutical compound (18F-DOPA) prior to radiation therapy (pg. 1385, Pretreatment imaging). Laack teaches that subjects received radiation therapy concomitant with temozolomide (pg. 1385, Target delineation, treatment planning, and delivery). As the scope of the claim includes administering the radiopharmaceutical at any time period prior to the initiation of radiotherapy (see interpretation associated with 112(b) rejection), this method reads as a combination therapy that anticipates this claim.
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.
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.
Claims 1-19 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Stupp 2009 (Stupp, R.; et al., Lancet Oncol, 2009) in view of Nemati (Nemati, R.; et al., Clin. Nucl. Med., 2021 – provided by applicant in IDS filed April 25, 2024), Bison (Bison, S. M.; et al., EJNMMI Res., 2015), and Hartrampf (Hartrampf, P. E.; et al., Clin. Transl. Radiat. Oncol., 2020).
Stupp 2009 teaches a method of treating glioblastoma (pg. 459, Summary). The method of Stupp 2009 involves the treatment of both MGMT promoter methylation positive and negative subjects (pg. 459-460, Patients; pg. 462, Table 2; pg. 461, right column, last paragraph). Stupp 2009 teaches treating glioblastoma by two different methods: one being standard focal radiotherapy dosed in 30 daily 2 Gy doses and the other being standard radiotherapy plus concomitant daily temozolomide followed by adjuvant temozolomide (pg. 460, Study design and procedures). Stupp 2009 states that temozolomide is classified as an alkylating agent (pg. 464, right column, third paragraph, 7 lines from the bottom of the page). Stupp 2009 teaches that the combination of radiotherapy and temozolomide increases survival in general (pg. 461, Figure 2) but further specifies that for MGMT promoter methylation negative subjects, the survival benefit of adding temozolomide to radiotherapy was negligible (pg. 462, Table 2, Median column) or significantly less than the benefit achieved in MGMT promoter methylation positive subjects (pg. 463, Figure 4).
Stupp 2009 does not teach a method of treating glioblastoma including further administration of a radiopharmaceutical compound, nor the radiopharmaceutical compound comprising a somatostatin receptor binding peptide.
Nemati teaches a method of treating high-grade glioma using the radiopharmaceutical compound 177Lu-DOTATATE (pg. 389, Abstract). Nemati states that high-grade glioma cancers are a class that includes glioblastoma (pg. 389, right column, first paragraph). Nemati teaches first performing PET/CT using 68Lu-DOTATATE to confirm the presence of the somatostatin receptor in the tumors, which was a requirement of the inclusion criteria for the 177Lu-DOTATATE treatment (pg. 389, Study Design and Participants, first paragraph). Nemati teaches later administering 177Lu-DOTATATE by IV infusion over 30 minutes, administering 3.7-29.6 GBq of the radiopharmaceutical 1 to 4 times at intervals of 1 to 2 months (pg. 390, Treatment Delivery). Nemati observed complete remission in 12.5% of subjects, partial remission in 31.25% of subjects, and disease stability in 18.7% of subjects (pg. 391, Response to Therapy). Nemati also teaches that the 177Lu-DOTATATE therapy was well-tolerated and did not lead to notable toxicity (pg. 392, Safety Assessment).
Bison teaches a method of treating neuroendocrine tumors using a combination of temozolomide and peptide receptor radiotherapy (pg. 1, Abstract). Bison teaches using the somatostatin receptor-targeting radiopharmaceutical compound 177Lu-DOTA,Tyr3-octreotate (pg. 2, Background, second paragraph; and pg. 2, Experimental setup), which is the same molecule as 177Lu-DOTATATE. Bison teaches several dosing regimens to compare different combinations of temozolomide and 177Lu-DOTATATE (pg. 3, combination of PRRT and TMZ and Fig. 1).Bison teaches that for all groups in which temozolomide and 177Lu-DOTATATE were provided in combination, survival was increased and tumor volume decreased compared to all single therapeutic agent groups (pg. 7, right column, second paragraph; and pg. 8, Fig. 5). Bison notes that no signs of severe toxicity were observed in the combination therapy (pg. 10, left column, second paragraph).
Hartrampf teaches combination therapy of a somatostatin receptor directed peptide receptor radionuclide therapy (PRRT) and external beam radiotherapy in meningioma (pg. 29, Abstract). More specifically, Hartrampf teaches first performing PET imaging to assess somatostatin receptor expression in the tumor, then performing PRRT in the subjects by intravenously administering about 7.4 GBq of 177Lu-DOTATATE or 177LuDOTATOC, and then 1-9 days later performing external beam radiotherapy in the subjects (pg. 30, Sections 2.2-2.3). Hartrampf teaches that no severe toxicities were observed in the subjects, indicating good safety for this combination therapy (pg. 31, Adverse events). Hartrampf teaches that 7 of the 10 subjects who received this treatment achieved disease stabilization (pg. 31, Section 3.3, first paragraph). Hartrampf concludes that the combination of somatostatin receptor directed peptide receptor radionuclide therapy and external beam radiotherapy is feasible and safe in meningioma patients (pg. 29, Abstract, Conclusions).
A person of ordinary skill in the art would have recognized that Stupp 2009, Nemati, Bison, and Hartrampf all teach methods of treating cancer. More specifically, Stupp 2009, Nemati, and Hartrampf teach methods of treating brain tumors, with Stupp 2009 and Nemati specifically teaching methods of treating glioblastoma. It would be recognized that Stupp 2009 teaches radiation therapy and radiation therapy in combination with temozolomide are effective methods at treating glioblastoma and that Nemati teaches that 177Lu-DOTATATE can be used to treat glioblastoma. It would also be recognized that Bison teaches that 177Lu-DOTATATE can be used in combination with temozolomide for cancer treatment and that Hartrampf teaches that 177Lu-DOTATATE can be used in combination with brain irradiation therapy for cancer treatment, which suggests applying such combinations in other cancers for which those therapies can be used (as is described by Stupp 2009 and Nemati) or at least suggests such a combination is feasible.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating glioblastoma taught by Stupp 2009 to further include 177Lu-DOTATATE treatment as taught by Nemati because Bison and Hartrampf suggest that combination of 177Lu-DOTATATE with temozolomide or radiation therapy is a safe and viable cancer treatment method (MPEP § 2143(I)(G)). This would have yielded the predictable outcome of a method of treating glioblastoma comprising a combination of radiation therapy and a radiopharmaceutical (177Lu-DOTATATE) with or without an alkylating agent (temozolomide).
A person of ordinary skill in the art would have had a reasonable expectation of success in adding the 177Lu-DOTATATE component to the treatment regimens of Stupp 2009 because Nemati teaches that 177Lu-DOTATATE is safe and effective for the treatment of glioblastoma. This is evidence that administration of these therapies can be performed in glioblastoma patients. Furthermore, Hartrampf teaches that 177Lu-DOTATATE is safe and feasible to use in combination with radiation in meningioma. As Hartrampf teaches IV-administration of 177Lu-DOTATATE and brain-targeting external beam radiation therapy, the lack of toxicity taught by Hartrampf would likely translate to glioblastoma subjects as the same therapies are applied in the same way. Additionally, Bison teaches 177Lu-DOTATATE is safe and effective in combination with TMZ in treating neuroendocrine tumors, which suggests the potential for similar results in other cancers for which TMZ and 177Lu-DOTATATE are already taught as treatments.
The skilled artisan would have been motivated to add the 177Lu-DOTATATE component to the treatment regimens of Stupp 2009 because Nemati teaches that 177Lu-DOTATATE is effective for the treatment of glioblastoma. Additionally, Bison teaches that combination of 177Lu-DOTATATE with temozolomide results in a better treatment of neuroendocrine tumors. The skilled artisan would be motivated to attempt to improve glioblastoma treatment methods to increase the survival and improve the wellbeing of patients.
Regarding claim 1, Stupp 2009 teaches a method of treating glioblastoma in subjects in need thereof (pg. 459, Summary). The method of Stupp 2009 includes irradiating the subject with 60 Gy of fractionated radiotherapy (pg. 460, Study design and procedures). This reads on the limitation of irradiating the subject with ionizing radiations. Additionally, Nemati teaches a method of treating high-grade gliomas with 177Lu-DOTATATE (pg. 389, Abstract; and pg. 390, Treatment Delivery). Furthermore, Hartrampf teaches combination therapy of a somatostatin receptor-directed peptide receptor radionuclide therapy and external beam radiotherapy in meningioma (pg. 29, Abstract). Hartrampf concludes that the combination of somatostatin receptor directed peptide receptor radionuclide therapy and external beam radiotherapy is feasible and safe in meningioma patients (pg. 29, Abstract, Conclusions). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 1 obvious.
Regarding claims 2-7, Nemati teaches a method of treating high-grade gliomas using 177Lu-DOTATATE (pg. 390, Treatment Delivery). This compound can be described by the formula of claim 2 wherein M is a radionuclide (177Lu), C is a chelating agent capable of chelating the radionuclide (DOTA), S is not present (which is within the scope of optional), and P is a somatostatin receptor binding peptide (octreotate) covalently linked to the DOTA moiety. Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claims 2-7 obvious.
Regarding claim 8, the method of Stupp 2009 further includes the administration of temozolomide (pg. 460, Study design and procedures). Stupp 2009 states that temozolomide is classified as an alkylating agent (pg. 464, right column, third paragraph, 7 lines from the bottom of the page). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 8 obvious.
Regarding claim 9, Stupp 2009 teaches administration of temozolomide at 75 mg/m2/day for a period of up to 49 days (pg. 460, Study design and procedures). As the range of up to 49 days significantly overlaps with the claimed range of 4 to 8 weeks (28-56 days), this renders the claimed range obvious (MPEP § 2144.05(I)). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 9 obvious.
Regarding claim 10, Stupp 2009 teaches that concomitant administration of temozolomide started on the first day of radiotherapy (pg. 460, Study design and procedures). The examiner interprets this language to mean that radiation and temozolomide were initiated on the same day. Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 10 obvious.
Regarding claim 11, Stupp 2009 teaches that temozolomide is administered concomitantly with radiation therapy from the first to the last day of radiotherapy (pg. 460, Study design and procedures). The examiner interprets this language to mean that the alkylating agent was administered concomitantly with the irradiation without interruption. Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 11 obvious.
Regarding claim 12, Stupp 2009 teaches that temozolomide is administered at a dose of 75 mg/m2/day daily during concomitant dosing with radiotherapy and that after radiotherapy, temozolomide is administered after the period of radiotherapy at a dose of 150-200 mg/m2/day for 5 days every 28 days for a period of six such cycles (pg. 460, Study design and procedures). While Stupp 2009 does not directly define these phases as an “induction phase” or “maintenance phase,” these periods of time include the required structural components of the claim and these phrases are not interpreted to distinguish the claimed method over the art. Furthermore, the dosing at 150-200 mg/m2/day in the second phase is at least twice the dose of 75 mg/m2/day from the first phase. Additionally, Stupp 2009 teaches that the second phase involved up to six 28-day cycles, which is equivalent to a period of up to 24 weeks. Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 12 obvious.
Regarding claim 13, during the second phase of temozolomide administration in the method of Stupp 2009 (which as described above reads on the claimed maintenance phase), the alkylating agent is administered at a dose of 150-200 mg/m2/day for 5 consecutive days every 28 days for a period of up to six 28-day cycles (pg. 460, Study design and procedures). The period of up to six 28-day cycles is equivalent to a period of up to 24 weeks. Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 13 obvious.
Regarding claim 14, the method of Stupp 2009 included 46 subjects with glioblastoma with positive methylated O-6-methylguanine-DNA methyltransferase promoter status (pg. 459-460, Patients; pg. 462, Table 2; pg. 461, right column, last paragraph). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 14 obvious.
Regarding claim 15, Nemati teaches administration of 177Lu-DOTATATE radiopharmaceutical compound at 3.7 to 29.6 GBq (pg. 390, Treatment Delivery). This is within and significantly overlaps the claimed range of 0.925 to 29.6 GBq (see claim interpretation with associated 112(b) rejection), rendering the claimed range obvious (MPEP § 2144.05(I)). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 15 obvious.
Regarding claim 16, Nemati teaches administration of the 177Lu-DOTATATE radiopharmaceutical compound 1 to 4 times during the treatment period (pg. 390, Treatment Delivery). This is within and overlaps with the claimed range of 1 to 8 times, therefore rendering the claimed range obvious (MPEP § 2144.05(I)). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 16 obvious.
Regarding claim 17, Nemati teaches administration of the 177Lu-DOTATATE radiopharmaceutical compound in intervals of 1 to 2 months (pg. 390, Treatment Delivery). The examiner interprets this range to be equivalent to about 4 to 8 weeks, which overlaps the claimed range of 2-6 weeks, rendering it obvious (MPEP § 2144.05(I)). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 17 obvious.
Regarding claim 18, Hartrampf teaches a method combining administering a somatostatin receptor targeting radiopharmaceutical compound followed by initiation of radiation therapy 1 to 9 days later (pg. 30, Section 2.3). This range is within the claimed range of 1-20 days, rendering the claimed range obvious (MPEP § 2144.05(I)). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 18 obvious.
Regarding claim 19, Stupp 2009 teaches performing radiation therapy at a dose of 2 Gy per day (pg. 460, Study design and procedures). This is within the claimed range of 1-4 Gy/day, rendering the claimed dose range obvious. Furthermore, Stupp 2009 teaches that this dose was daily for 30 days (pg. 460, Study design and procedures). The examiner interprets this teaching to read on irradiation 7 days per week for 30 days. The 7 days per week is within the claimed range of 3-7 days per week, rendering this limitation obvious. Additionally, the 30 day period is with the range of 4-8 weeks (28-56 days), also rendering that limitation obvious. Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 19 obvious.
Regarding claim 22, Nemati teaches administering subjects with 68Ga-DOTATATE, performing PET/CT, and evaluating the imaging to determine somatostatin receptor expression in the tumor tissue (pg. 389, Study Design and Participants). This was part of the inclusion criteria to determine if a subject was selected to later receive 177Lu-DOTATATE (pg. 389, Study Design and Participants; and pg. 390, Treatment Delivery). This imaging assessment being part of the inclusion criteria reads on the “selected for the treatment” claim limitation. Furthermore, this method uses a 68Ga radiometal for imaging instead of the 177Lu radiometal used for treatment within the same radiopharmaceutical precursor DOTA-TATE. Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 22 obvious.
Regarding claim 23, Stupp 2009 teaches treatment of subjects newly diagnosed with glioblastoma (pg. 459-460, Patients). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 23 obvious.
Regarding claim 24, Stupp 2009 teaches the treatment of subjects newly diagnosed with glioblastoma (pg. 459-460, Patients) and subjects who have positive MGMT promoter methylation status (pg. 459-460, Patients; pg. 462, Table 2; pg. 461, right column, last paragraph). Stupp 2009 teaches treatment of glioblastoma using a combination of radiotherapy and the alkylating agent temozolomide (pg. 460, Study design and procedures). Nemati teaches the treatment of high-grade gliomas with the 177Lu-DOTATATE radiopharmaceutical compound (pg. 390, Treatment Delivery). Hartrampf teaches the combination of a somatostatin receptor targeted radiopharmaceutical and radiotherapy (pg. 30, Sections 2.2-2.3). Bison teaches the combination of 177Lu-DOTATATE with temozolomide (pg. 3, Combination therapy of PRRT and TMZ; and pg. 3, Fig. 1). As described above, the combination of the teachings of these references results in a combination therapy including the radiopharmaceutical 177Lu-DOTA-TATE, radiation therapy, and temozolomide. Furthermore, Nemati teaches administration of the radiopharmaceutical compound 68Ga-DOTATATE prior to initiation of radiotherapy (pg. 389, Study Design and Participants). Additionally, Hartrampf teaches administration of 177Lu-DOTATATE/-TOC 1-9 days before initiation of radiotherapy (pg. 30, Sections 2.2-2.3). Therefore, the combination of Stupp 2009, Nemati, Bison, and Hartrampf renders claim 24 obvious.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Stupp 2009, Nemati, Bison, and Hartrampf, as applied to claims 1-19 and 22-24 above, and further in view of Stupp 2005 (Stupp, R; et al., N. Engl. J. Med., 2005).
As described above, the combination of Stupp 2009, Nemati, Bison, and Hartrampf teaches a method of treating glioblastoma comprising a combination of radiation therapy and a radiopharmaceutical (177Lu-DOTATATE) with or without an alkylating agent (temozolomide). More specifically, Stupp 2009 teaches treating glioblastoma by two different methods: one being standard focal radiotherapy dosed in 30 daily 2 Gy doses (60 Gy total) and the other being standard radiotherapy plus concomitant daily temozolomide followed by adjuvant temozolomide (pg. 460, Study design and procedures). Additionally, Nemati teaches a method including first performing PET/CT using 68Lu-DOTATATE to confirm the presence of the somatostatin receptor in the tumors, which was a requirement of the inclusion criteria for the 177Lu-DOTATATE treatment (pg. 389, Study Design and Participants, first paragraph). Nemati teaches later administering 177Lu-DOTATATE by IV infusion over 30 minutes, administering 3.7-29.6 GBq of the radiopharmaceutical 1 to 4 times at intervals of 1 to 2 months (pg. 390, Treatment Delivery). Furthermore, Bison teaches a method using a combination of 177Lu-DOTATATE and temozolomide (pg. 3, combination of PRRT and TMZ and Fig. 1). Bison teaches the combination resulted in increased survival and decreased tumor volume compared to all single therapeutic agent groups (pg. 7, right column, second paragraph; and pg. 8, Fig. 5) and that the combination did not result in severe toxicity (pg. 10, left column, second paragraph). Lastly, Hartrampf teaches that the combination of 177Lu-DOTATATE and external beam radiotherapy is feasible and safe in meningioma patients (pg. 29, Abstract, Conclusions; and pg. 31, Section 3.3, first paragraph).
The combination of Stupp 2009, Nemati, Bison, and Hartrampf does not teach administering irradiation for 5 consecutive days followed by 2 days of rest for 6 consecutive weeks.
Stupp 2005 teaches a method of treating glioblastoma (pg. 987, Abstract). More specifically, Stupp 2005 teaches using either standard focal radiotherapy alone or standard radiotherapy plus concomitant daily temozolomide followed by adjuvant temozolomide (pg. 988, Study Design and Treatment, first paragraph). Stupp 2005 teaches that the radiotherapy consisted of irradiation at a dose of 2 Gy per fraction given once daily five days per week (Monday through Friday) over a period of six weeks, for a total of 60 Gy (pg. 988, Study Design and Treatment). Stupp teaches that these regimens were safe and effective means for treating glioblastoma (pg. 992, Safety; pg. 992, Figure 1; and pg. 993, right column, second paragraph).
A person of ordinary skill in the art would recognize that Stupp 2009 and Stupp 2005 teach very similar methods for treating glioblastoma. It would be recognized that in both references, in both the radiotherapy alone and radiotherapy in combination with temozolomide regimens, a total of 60 Gy irradiation is given to the subjects. It would be recognized that both radiotherapy regimens were performed in combination with concomitant temozolomide followed by adjuvant temozolomide.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the radiotherapy dosing regimen of the combination of Stupp 2009, Nemati, Bison, and Hartrampf with the radiotherapy dosing regimen of Stupp 2005 because this is a simple substitution of methods known in the prior art that serve the same purpose and one of skill in the art could have substituted one method for another resulting in the predictable outcome of a glioblastoma treatment method in combination with temozolomide and 177Lu-DOTATATE wherein irradiation is performed for 5 consecutive days followed by 2 days without irradiation (MPEP § 2143(I)(B)).
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the radiotherapy method of Stupp 2009 with that of Stupp 2005 because these are very similar methods with the same amount of total radiation. Stupp 2005 demonstrates that this irradiation method is safe and effective alone and safe and in combination with temozolomide.
The skilled artisan would have been motivated to make this substitution to further optimize dose timing. Additionally, specifically administering radiation on Monday through Friday would be beneficial to a practitioner of the art because such dosing would then occur on typical business days, potentially allowing for better staffing and resource availability on these days of the week.
Regarding claim 20, Stupp 2005 teaches administration of irradiation at a dose of 2 Gy per day five consecutive days per week (Monday through Friday) over a period of six weeks (pg. 988, Study Design and Treatment, second paragraph). Therefore, the combination of Stupp 2009, Nemati, Bison, Hartrampf, and Stupp 2005 renders claim 20 obvious.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Stupp 2009, Nemati, Bison, and Hartrampf, as applied to claims 1-19 and 22-24 above, and further in view of Lahmi (Lahmi, L; et al., J. Clin. Neurosci., 2019).
As described above, the combination of Stupp 2009, Nemati, Bison, and Hartrampf teaches a method of treating glioblastoma comprising a combination of radiation therapy and a radiopharmaceutical (177Lu-DOTATATE) with or without an alkylating agent (temozolomide). More specifically, Stupp 2009 teaches treating glioblastoma by two different methods: one being standard focal radiotherapy dosed in 30 daily 2 Gy doses (60 Gy total) and the other being standard radiotherapy plus concomitant daily temozolomide followed by adjuvant temozolomide (pg. 460, Study design and procedures). Additionally, Nemati teaches a method including first performing PET/CT using 68Lu-DOTATATE to confirm the presence of the somatostatin receptor in the tumors, which was a requirement of the inclusion criteria for the 177Lu-DOTATATE treatment (pg. 389, Study Design and Participants, first paragraph). Nemati teaches later administering 177Lu-DOTATATE by IV infusion over 30 minutes, administering 3.7-29.6 GBq of the radiopharmaceutical 1 to 4 times at intervals of 1 to 2 months (pg. 390, Treatment Delivery). Furthermore, Bison teaches a method using a combination of 177Lu-DOTATATE and temozolomide (pg. 3, combination of PRRT and TMZ and Fig. 1). Bison teaches the combination resulted in increased survival and decreased tumor volume compared to all single therapeutic agent groups (pg. 7, right column, second paragraph; and pg. 8, Fig. 5). Lastly, Hartrampf teaches that the combination of 177Lu-DOTATATE and external beam radiotherapy is feasible and safe in meningioma patients (pg. 29, Abstract, Conclusions; and pg. 31, Section 3.3, first paragraph).
The combination of Stupp 2009, Nemati, Bison, and Hartrampf does not teach irradiation of the subject using whole-brain irradiation.
Lahmi teaches a method of treating glioblastoma using whole-brain irradiation (pg. 39, Abstract). More specifically, Lahmi teaches performing radiotherapy at a dose of 45 Gy in 25 fractions of 1.8 Gy each over a period of 5 weeks using a target volume that was the whole brain (pg. 40, Section 2.2, first paragraph). Additionally, Lahmi teaches concurrent temozolomide administration during the whole brain irradiation regimen followed by adjuvant temozolomide administration (pg. 40, Section 2.2). Lahmi demonstrates that the whole brain irradiation method produced similar results to other glioblastoma treatment methods (pg. 41, section 3.2; and pg. 42, Section 5). Lahmi concludes that whole brain irradiation is feasible, efficacious, and safe for a treatment of glioblastoma (pg. 44, Section 6).
A person of ordinary skill in the art would have recognized that both Lahmi and Stupp 2009 teach methods of treating glioblastoma using a combination of radiotherapy and temozolomide. It would be recognized that the total dose amounts, fractional dose amounts, and total treatment time are similar between these two methods.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of radiotherapy of the combination of Stupp 2009, Nemati, Bison, and Hartrampf with the radiotherapy method of Lahmi because these claim elements were known in the art to serve the same purpose and one of skill in the art could have modified the irradiation method of Stupp 2009 to make it whole brain irradiation without changing the function of the radiation therapy resulting in the predictable outcome of a glioblastoma treatment method in combination with temozolomide and 177Lu-DOTATATE wherein radiotherapy is performed using whole brain irradiation (MPEP § 2143(I)(A)).
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the radiotherapy method of Stupp 2009 to use whole brain irradiation as taught by Lahmi because these are very similar methods using radiation to target brain tissue. Furthermore, Lahmi demonstrates that this irradiation method is safe and effective in combination with temozolomide.
The skilled artisan would have been motivated to make this substitution to further optimize the means of dosing radiotherapy. Additionally, Lahmi refers to literature demonstrating that glioblastoma patients may present with multiple lesions (pg. 39, right column, first paragraph). In these situations, whole brain irradiation would be easier, and likely safer, than performing multiple focal radiotherapy treatments.
Regarding claim 21, Lahmi teaches a method of treating glioblastoma in which whole brain radiotherapy was administered with concurrent temozolomide treatment (pg. 40, Section 2.2). Therefore, the combination of Stupp 2009, Nemati, Bison, Hartrampf, and Lahmi renders claim 21 obvious.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Stupp 2009 in view of Nemati, Hartrampf, and McCann (US 11,129,912 B1).
As described above, Stupp 2009 teaches a method of treating glioblastoma involving the treatment of both MGMT promoter methylation positive and negative subjects (pg. 459-460, Patients; pg. 462, Table 2; pg. 461, right column, last paragraph). Stupp 2009 teaches treating glioblastoma by two different methods: one being standard focal radiotherapy dosed in 30 daily 2 Gy doses and the other being standard radiotherapy plus concomitant daily temozolomide followed by adjuvant temozolomide (pg. 460, Study design and procedures). Stupp 2009 teaches that the combination of radiotherapy and temozolomide increases survival in general (pg. 461, Figure 2) but further specifies that for MGMT promoter methylation negative subjects, the survival benefit of adding temozolomide to radiotherapy was negligible (pg. 462, Table 2, Median column) or significantly less than the benefit achieved in MGMT promoter methylation positive subjects (pg. 463, Figure 4).
Stupp 2009 does not teach a method of treating glioblastoma including further administration of a radiopharmaceutical compound, nor administering the radiopharmaceutical compound at intervals of 4 weeks for the first two intervals followed by 3 week intervals for the third and any following intervals.
As described above, Nemati teaches a method of treating high-grade glioma using the radiopharmaceutical compound 177Lu-DOTATATE (pg. 389, Abstract). Nemati teaches first performing PET/CT using 68Lu-DOTATATE to confirm the presence of the somatostatin receptor in the tumors, which was a requirement of the inclusion criteria for the 177Lu-DOTATATE treatment (pg. 389, Study Design and Participants, first paragraph). Nemati teaches later administering 177Lu-DOTATATE by IV infusion over 30 minutes, administering 3.7-29.6 GBq of the radiopharmaceutical 1 to 4 times at intervals of 1 to 2 months (pg. 390, Treatment Delivery). Nemati observed complete remission in 12.5% of subjects, partial remission in 31.25% of subjects, and disease stability in 18.7% of subjects (pg. 391, Response to Therapy). Nemati also teaches that the 177Lu-DOTATATE therapy was well-tolerated and did not lead to notable toxicity (pg. 392, Safety Assessment).
As described above, Hartrampf teaches combination therapy of a somatostatin receptor directed peptide receptor radionuclide therapy (PRRT) and external beam radiotherapy in meningioma (pg. 29, Abstract). More specifically, Hartrampf teaches performing PRRT in the subjects by administering 177Lu-DOTATATE or 177LuDOTATOC, and then 1-9 days later performing external beam radiotherapy in the subjects (pg. 30, Sections 2.2-2.3). Hartrampf teaches that 7 of the 10 subjects who received this treatment achieved disease stabilization (pg. 31, Section 3.3, first paragraph). Hartrampf concludes that the combination of somatostatin receptor directed peptide receptor radionuclide therapy and external beam radiotherapy is feasible and safe in meningioma patients (pg. 29, Abstract, Conclusions).
McCann teaches a 177Lu-containing radiopharmaceutical compound 177Lu-PSMA I&T (column 1, lines 36-40). McCann teaches that this radiopharmaceutical compound can be used to treat cancers (column 23, lines 24-30) and that it can be used in combination with other therapeutic agents (column 24, lines 30-34). In such a method of use, McCann teaches that the administration of a 177Lu-containing radiopharmaceutical compound may be occur at intervals of 1-10 weeks (column 24, lines 25-29).
A person of ordinary skill in the art would have recognized that Stupp 2009, Nemati, Hartrampf, and McCann all relate to cancer treatment. More specifically, Stupp 2009, Nemati, and Hartrampf teach methods of treating brain tumors, with Stupp 2009 and Nemati specifically teaching methods of treating glioblastoma. It would be recognized that Stupp 2009 teaches radiation therapy alone is similarly effective to radiation therapy in combination with temozolomide in subjects negative for MGMT promoter methylation and that Nemati teaches that 177Lu-DOTATATE can be used to treat glioblastoma. It would also be recognized that Hartrampf teaches that 177Lu-DOTATATE can be used in combination with radiation therapy for cancer treatment and that McCann teaches that 177Lu-containing radiopharmaceutical compounds can be dosed in a range of intervals.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating glioblastoma taught by Stupp 2009 to further include 177Lu-DOTATATE treatment as taught by Nemati because Hartrampf suggests that combination of 177Lu-DOTATATE with temozolomide or radiation therapy is a safe and effective cancer treatment method (MPEP § 2143(I)(G)). Additionally, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the 177Lu-DOTATATE treatment interval of Nemati with the interval of McCann, as this is an alternative dosing interval known in the art that serves a similar function, allowing for incorporation in the radiopharmaceutical administration element without altering the other features (MPEP § 2143(I)(A)). This would have yielded the predictable outcome of a method of treating glioblastoma comprising a combination of radiation therapy and a radiopharmaceutical (177Lu-DOTATATE) without an alkylating agent (temozolomide).
A person of ordinary skill in the art would have had a reasonable expectation of success in adding the 177Lu-DOTATATE component to the treatment regimens of Stupp 2009 because Nemati teaches that 177Lu-DOTATATE is safe and effective for the treatment of glioblastoma. Additionally, Hartrampf teaches that 177Lu-DOTATATE is safe and feasible to use in combination with radiation in meningioma. As Hartrampf teaches IV-administration of 177Lu-DOTATATE and brain-targeting external beam radiation therapy, the lack of toxicity taught by Hartrampf would likely translate to glioblastoma subjects as the same therapies are applied in the same way. There would also be a reasonable expectation of success at the interval as taught by McCann because this amounts to changing the frequency with which a step is performed.
The skilled artisan would have been motivated to add the 177Lu-DOTATATE component to the treatment regimens of Stupp 2009 because Nemati teaches that 177Lu-DOTATATE is effective for the treatment of glioblastoma. The skilled artisan would be motivated to improve glioblastoma treatment methods to increase the survival and improve the wellbeing of patients. Additionally, the skilled artisan would be motivated to apply the radiopharmaceutical dosing intervals of McCann to optimize dosage for improved patient outcomes.
Regarding claim 25, Stupp 2009 teaches the treatment of subjects newly diagnosed with glioblastoma (pg. 459-460, Patients) and subjects who have unmethylated MGMT promoter status (pg. 459-460, Patients; pg. 462, Table 2; pg. 461, right column, last paragraph). Stupp 2009 teaches treatment of glioblastoma using radiotherapy without the presence of additional chemotherapeutic agents (pg. 460, Study design and procedures). Nemati teaches the treatment of high-grade gliomas with the 177Lu-DOTATATE radiopharmaceutical compound (pg. 390, Treatment Delivery). Hartrampf teaches the combination of a somatostatin receptor targeted radiopharmaceutical and radiotherapy (pg. 30, Sections 2.2-2.3). As described above, the combination of the teachings of these references results in a combination therapy including the radiopharmaceutical 177Lu-DOTA-TATE and radiation therapy. Additionally, Nemati teaches a treatment interval between administrations of 177Lu-DOTA-TATE of 1-2 months (pg. 390, Treatment Delivery), which the examiner interprets to be equivalent to 4-8 weeks. This dosing interval of 4-8 weeks includes the scope of the claimed 4 week interval for the first two intervals and the 4-8 week range approaches the scope of the claimed 3 week interval for the later cycles, rendering that interval obvious (MPEP § 2144.05(I)). Additionally, McCann teaches that the administration of a 177Lu-containing radiopharmaceutical compound may be occur at intervals of 1-10 weeks (column 24, lines 25-29), rendering both claimed dosing intervals obvious. Furthermore, Nemati teaches administration of the radiopharmaceutical compound 68Ga-DOTATATE prior to initiation of radiotherapy (pg. 389, Study Design and Participants). Additionally, Hartrampf teaches administration of 177Lu-DOTATATE/-TOC 1-9 days before initiation of radiotherapy (pg. 30, Sections 2.2-2.3). Therefore, the combination of Stupp 2009, Nemati, Hartrampf, and McCann renders claim 25 obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8-9, 11-17, 19, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8-17, 20-22, 24-25, 29, and 31-32 of copending Application No. 19/150,647 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claim 1, conflicting claim 1 of copending application 19/150,647 is drawn to a method of treating glioblastoma comprising administering a radiopharmaceutical compound in combination with radiotherapy.
Regarding instant claim 8, conflicting claim 2 of copending application 19/150,647 includes further administering an alkylating agent.
Regarding instant claim 9, conflicting claim 4 of copending application 19/150,647 includes administering temozolomide at an induction phase at a dose from 50-100 mg/m2/day for a period of 4-8 weeks.
Regarding instant claim 11, conflicting claim 4 of copending application 19/150,647 includes administering temozolomide concomitantly with radiotherapy.
Regarding instant claim 12, conflicting claim 5 of copending application 19/150,647 includes administering temozolomide concomitantly with radiotherapy at a dose of 50-100 mg/m2/day for a period of 4-8 weeks (through dependence on conflicting claim 4) and administration during a maintenance phase at a dose of 50-400 mg/m2/day for a period of 20-28 weeks.
Regarding instant claim 13, conflicting claim 5 of copending application 19/150,647 includes administering temozolomide at a dose of 50-400 mg/m2/day for a period of 20-28 weeks.
Regarding instant claim 14, conflicting claim 25 of copending application 19/150,647 is drawn to a method of treating subjects with positive methylated O-6-methylguanine-DNA methyltransferase promoter status.
Regarding instant claim 15, conflicting claim 20 of copending application 19/150,647 includes the administration of the radiopharmaceutical compound at a dose of 3.7-11.1 GBq at each administration.
Regarding instant claim 16, conflicting claim 17 of copending application 19/150,647 is drawn to a method in which the radiopharmaceutical compound is administered 1-10 times per treatment.
Regarding instant claim 17, conflicting claim 17 of copending application 19/150,647 is drawn to a method in which the radiopharmaceutical compound is administered at an interval of 2-6 weeks.
Regarding instant claim 19, conflicting claim 22 of copending application 19/150,647 is drawn to a method in which radiotherapy is conducted at a dose of 1-4 Gy/day during a period of 4-8 weeks.
Regarding instant claim 23, conflicting claim 24 of copending application 19/150,647 is drawn to a method of treating subjects newly diagnosed with glioblastoma.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
Prosecution Insights