Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/13/2025 has been entered.
Response to Amendment
3. This action is responsive to the amendments filed 8/13/2025. Claims 9, 11, and 20 have been amended. Claims 12-14 and 21 were canceled.
Response to Arguments
Claim Rejections – 35 U.S.C. 112(a)4. Applicant’s argument filed on 8/13/2025 with respect to the written description requirement has been fully considered. In substance, applicant argues that A) There is sufficient written description as well as enablement for amended claim 9 as well as its dependent claims for both in vitro and in vivo use (see remarks pg. 5-6).
5. In response to A), the examiner respectfully concurs with applicant’s arguments in part.
Specifically, the disclosure of paragraph 0007 of the specification and amending the limitation to only recite glioblastoma (GBM) as the cancer is sufficient to overcome the rejection and demonstrates sufficient written description and enablement. Thus, the rejection for insufficient written description as well as failing to comply with the enablement requirement under 35 U.S.C. 112(a) are withdrawn.
Claim Rejections – 35 U.S.C. 103
6. Applicant’s arguments filed on 8/13/2025 with respect to the art rejections have been fully considered but they are not persuasive. In substance, applicant argues that A) The claimed method provides unexpected results, specifically, synergy in the administration of mannose and alternating electric fields (AEF) (i.e. TTFields) to treat cancer and thus establishes non-obviousness (see remarks pg. 15) and B) The rejection is based on impermissible hindsight because none of the references are combinable (see remarks pg. 10)
7. In response to A), the examiner respectfully disagrees.At the onset, any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (differences in sedative and anticholinergic effects between prior art and claimed antidepressants were not unexpected) (see MPEP 716.02 – Section I). Merely alleging “synergy” as well as reciting the term “synergistic” in the claim (i.e. claim 20) does not in and of itself make the effects of a treatment greater than expected. Evidence of a greater than expected result may be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). Applicant has provided insufficient evidence of non-obviousness. In an attempt to provide evidence of unexpected results the Applicant refers to Figs. 10-11 of the disclosure. Figs. 10-11 illustrates, through the use of line graphs, sensitivity to mannose with and without tumor treat fields (TTFields). In Figs. 10-11, both line graphs are shown to be decreasing linearly with the line graph referencing the use of TTFields showing a greater effect on mannose uptake compared to the line graph referencing the absence of TTFields. Examiner notes that neither Fig. 10 nor Fig. 11 demonstrate the effect of TTFields alone (i.e. without mannose) and thus fails to at least demonstrate “an effect which is greater than the sum of each of the effects taken separately". However, even if this requirement was met, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.) (See MPEP 716.02 – Section I). The Examiner notes that the additive effect of two efficacious cancer treatments is not unexpected. For example, Patel, the primary reference, describes that chemotherapy, radiotherapy, surgery, and alternating electrical fields (TTFields) are all cancer treatment used to effectively treat glioblastoma. Thus, one of ordinary skill in the art would expect that combining the two cancer treatments, both of which are known to be efficacious, would yield greater efficacious results. Additionally, as evidenced by Chang et al. (“Tumor treating fields increases membrane permeability in glioblastoma cells”, published 12/5/2018), TTFields are known to increase transiently tumor cell membrane permeability, allowing for a synergistic effect with other chemotherapies (see abstract). Finally, it is also clear from Applicant’s arguments as well as reconsideration of the claims that the claimed method does not even require the unexpected result that the applicant is alleging. Therefore, the combination of the prior art still meets the scope of the limitations as currently claimed.
8. In response to B), the examiner respectfully disagrees.
At the onset, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Nevertheless, the Examiner has indicated a reason to combine along with an advantage for combining each of the teachings of the references. The Examiner has explicitly provided the rationale in the rejection below and directs Applicant to those rationales. Therefore, the Examiner maintains the rejections below do not rely upon impermissible hindsight.
Claim Rejections - 35 USC § 101
9. 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.
10. Claims 9-11 and 20 are rejected under 35 U.S.C 101 because the claimed invention is directed to an abstract idea (i.e. mental process) without significantly more.
Step 1:
The claimed invention in claims 9-11 and 20 are directed to statutory subject matter as the claims recite a method (i.e. a process). Thus, they are directed to statutory categories of invention (See MPEP 2106.03).
Step 2A – (Prong 1): Independent claim 9 recites a judicial exception by reciting the contingent limitations of “if the first level is lower than the second level by at least 20%, determining that the patient is susceptible to treatment using alternating electric fields”. These limitations, as drafted, is a process that, under its broadest reasonable interpretation covers performance of the limitation that can be performed by a human mind (including an observation, evaluation, judgment, opinion) or by a person using a pen and paper. For example, these limitations are nothing more than a clinician administering a compound (i.e. mannose) labelled with an imaging probe to a patient with glioblastoma, applying alternating electrical fields (i.e. electrical stimulation therapy), measuring uptake of the compound over time and the clinician then looking at the response to the therapy. The clinician can look at the data and make a determination if a patient is susceptible to the treatment. Specifically, if the first level of mannose uptake is lower than the second level of mannose uptake by at least 20%, a clinician can make a determination that a patient with glioblastoma is susceptible to treatment using alternating electric fields. Therefore, the claims are directed to a judicial exception (see MPEP 2106.04(a)(2)).
Step 2A – (Prong 2):
Regarding claim 9, the judicial exception is not integrated into a practical
application. Claim 9 recites the steps of “administering mannose labelled with an imaging probe” and “measuring a first level of uptake of the mannose” which amounts to nothing more than pre-solution activity. Furthermore, the steps of “treating the GBM cells with alternating electric fields” and “measuring a second level of uptake of the mannose” are also the pre-solution of data-gathering.
Step 2B:
The claims do not include additional elements that are sufficient to amount to
significantly more than the judicial exception. As discussed above with respect to integration of the abstract idea into a practical application, the additional element of administering a compound labelled with an imaging probe and measuring uptake of the compound over time is nothing more than mere pre-solution activity of data gathering, which does not amount to an inventive concept. Moreover, administering a compound labelled with an imaging probe and measuring uptake over time is well-understood, routine, and conventional as shown in at least (Furumoto, NPL reference, “In Vitro and In Vivo Characterization of 2-Deoxy-2-18F-Fluoro-D-Mannose as a Tumor-Imaging Agent for PET”, published 8/1/2013), (Gonzalez, NPL reference, “Mannose impairs tumour growth and enhances chemotherapy”, 11/21/2018), Yamamichi et al. (Japanese Publication: JPH09176179A – Applicant Cited) and (Fukuda, NPL reference, “Study for Cancer Diagnosis…[18F]-2-Fluoro-2-Deoxy-D-Mannose: A new Tracer for Cancer Detection”, published 1982). Additionally, the additional element of applying alternating electric fields followed by taking measurements is also nothing more than mere pre-solution activity of data gathering, which does not amount to an inventive concept. Moreover, applying alternating electric fields followed by taking measurements is well-understood, routine, and conventional as shown in at least Schmidt et al. (US Pub.: 2020/0330757 A, – Previously Cited), (Chang, NPL reference, “Tumor treating fields increases membrane permeability in glioblastoma cells”, published 12/5/2018) and (Mittal, NPL reference, “Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies”, published February, 2018).
11. Regarding dependent claims 10-11 and 20, the limitations of claim 9 further define the limitations already indicated as being directed to the abstract idea. While the dependent claims further define the abstract idea, it does not set forth any additional elements that integrate the claims into a practical application or add any additional elements that amount to significantly more than the abstract idea.
Thus, when considered as a whole and in combination, claims 9-11 and 20 are directed to an abstracted idea and are therefore rejected.
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 9-11 are rejected under 35 U.S.C 103 as being unpatentable over Patel et al. (NPL reference, “CBMT-03. A NOVEL METABOLIC PET TRACER STRATEGY TO DETERMINE EARLY EFFECTS OF TUMOR TREATING FIELDS (TTFIELDS), published 11/5/2018 – Previously Cited) and further in view of Krex et al. (US Pub.: 2019/0307781 A1, – Previously Cited) and further in view of Gonzalez et al. (NPL reference, “Mannose impairs tumour growth and enhances chemotherapy”, published 11/21/2018, – Previously Cited) and further in view of Fukuda et al. (NPL reference, “Study for Cancer Diagnosis…[18F]-2-Fluoro-2-Deoxy-D-Mannose: A new Tracer for Cancer Detection”, published 1982 – Previously Cited).
Regarding claim 9, Patel teaches a method of determining susceptibility of
cells to treatment of glioblastoma (GBM) using alternating electric fields, comprising:
administering a compound to GBM cells (e.g. CBMT-03 Heading, – using a radiotracer to take measurements in glioblastoma cells); measuring a first level of uptake of the compound in the GBM cells (e.g. CBMT-03 Heading, – uptake of the compound (i.e. PKM2) is measured several times including 3 or 6 day treatments as well as before and after application of electric fields); treating the GBM cells with alternating electric fields at a frequency between 100 and 500 kHz for a first interval of time after measuring the first level (e.g. CBMT-03 Heading, – compound (i.e. PKM2) is measured several times including 3 or 6 day treatments as well as before and after application of electric fields at 100–300 kHz); measuring a second level of uptake of the compound in the GBM cells after the first interval of time (e.g. CBMT-03 Heading, – compound (i.e. PKM2) is measured several times including 3 or 6 day treatments as well as before and after application of electric fields).
However, Patel does not explicitly teach that the treatment is done in a patient and that the administered compound is mannose labelled with an imaging probe.
Krex, in a similar field of endeavor of cancer treatment, discloses treating cancer (i.e. glioblastoma) in a patient using alternating electric fields (e.g. abstract; paragraph 0002). Additionally, Krex discloses that the cancer treatment studies done in vitro can be extended to the in vivo context through the use of the Optune system (e.g. paragraph 0079).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Patel to do the treatment in a patient, as taught and suggested by Krex, because the purpose of in vitro research is to first demonstrate the efficacy of the treatment method so it can be applied to a patient and it also allows clinicians to study biological processes within a living organism, providing a more accurate representation of how treatments manifest in a complex physiological environment.
However, Patel in view of Krex does not explicitly teach that the administered compound is mannose labelled with an imaging probe.
Gonzalez, in a similar field of endeavor of cancer therapy, discloses administering mannose to treat cancer (e.g. pg. 719, – administering mannose to treat cancer; pg. 721 and Fig. 3C – continuously (before, during, after) measuring tumor volume when mannose is administered as well as measuring tumor volume when mannose is used together with another form of treatment).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combination of Patel and Krex to include administering mannose, as taught and suggested by Gonzalez, because the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death (Gonzalez, pg. 719).
However, Patel in view of Krex in view of Gonzalez does not teach administering mannose labelled with an imaging probe.
Fukuda, in a similar field of endeavor of cancer diagnosis methods, discloses administering mannose labelled with an imaging probe (e.g. pg. 1, – 18F-FDM).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combination of Patel, Krex, and Gonzalez to include administering mannose labelled with an imaging probe to cells of the patient having cancer, as taught and suggested by Fukuda, for the purpose of being able to non-invasively monitor mannose levels in tumors using positron emission tomography (PET) imaging and determine whether treatment is effective (Fukuda, pg. 1).
With regards to the limitations of “if the first level is lower than the second level by at least 20%, determining that the patient is susceptible to treatment using alternating electric fields”, the Examiner notes that these are contingent limitations and thus the claim does not require that these criteria be met. The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met (see MPEP 2111.04 (II). The combination of Patel, Krex, Gonzalez, and Fukuda continues the treatment regardless of mannose uptake level and thus teaches the scope of the required limitations as currently claimed. However, the Examiner will preliminarily address the contingent limitations. While, Patel in view of Krex in view of Gonzalez in view of Fukuda does not explicitly disclose “if the first level is lower than the second level by at least 20%, determining that the patient is susceptible to treatment using alternating electric fields”, Patel does note that that there is an important need to assess early on whether a patient’s GBM is responding to a given therapy (see CBMT-03 Heading) and a clinician/skilled artisan would have a predetermined threshold to make a determination of whether or not a treatment is effective in a patient.
Regarding claim 10, Patel in view of Krex in view of Gonzalez in view of Fukuda teaches the method of claim 9 as discussed above, and Patel further teaches wherein the alternating electric fields have a frequency between 180 and 220 kHz (e.g. CBMT-03 Heading – applying alternating electric fields at 200 kHz).
Regarding claim 11, the Examiner notes that this claim is based on the contingent limitations of claim 9 and since the contingent limitations of claim 9 which recite “if the first level is lower than the second level by at least 20%, determining that the patient is susceptible to treatment using alternating electric fields” are not being considered as being required under the broadest reasonable interpretation, the limitations of claim 11 are also not required (see MPEP 2111.04 (II). However, the Examiner will preliminarily address claim 11. Patel in view of Krex in view of Gonzalez in view of Fukuda teaches the method of claim 9 as discussed above. With regards to the limitation of “after the determining step treating the patient for GBM using alternating electric fields and mannose or mannose labelled with an imaging probe”, the combination of Patel, Krex, Gonzalez, and Fukuda continues the treatment regardless of mannose uptake level.
Claims 20 is rejected under 35 U.S.C 103 as being unpatentable over Patel and further in view of Krex and further in view of Gonzalez and further in view of Fukuda as evidenced by Chang et al. (“Tumor treating fields increases membrane permeability in glioblastoma cells”, published 12/5/2018, – see abstract).
Regarding claim 20, the Examiner notes that this claim depends on claim 11 and claim 11 is based on the contingent limitations of claim 9 and since the contingent limitations of claim 9 which recites “if the first level is lower than the second level by at least 20%, determining that the patient is susceptible to treatment using alternating electric fields” are not being considered as being required under the broadest reasonable interpretation, the limitations of claim 20 are also not required (see MPEP 2111.04 (II). However, the Examiner will preliminarily address claim 20. Patel in view of Krex in view of Gonzalez in view of Fukuda teaches the method of claim 11 as preliminarily addressed above. The combination of Patel, Krex, Gonzalez, and Fukuda does not explicitly teach the limitation of wherein the treatment results in synergistic inhibition of the cancer cells. However, Patel discloses that chemotherapy, radiotherapy, surgery, and alternating electrical fields (TTFields) are all cancer treatment used to effectively treat glioblastoma (see CBMT-03 Heading). Additionally, Gonzalez teaches the use of mannose with another form of chemotherapy enhances tumor regression (see pg. 719 and 721). Thus, one of ordinary skill in the art when using these two known efficacious cancer treatments together would expect an additive/synergistic effect in tumor inhibition. Furthermore, as evidenced by Chang, the use of alternating electric fields (i.e. TTFields) is known to increase transiently tumor cell membrane permeability, allowing for a synergistic effect with other chemotherapies such as 5-aminolevulinic acid (see abstract). Therefore, knowing that the alternating electric fields increases permeability in glioblastoma cells and results in synergistic effect when used with other cancer treatments, one of ordinary skill would expect a similar synergy to occur when using alternating electric fields with another known cancer treating compound such as mannose. Finally, this limitation although not specifically present in the prior art is the natural result of the combination of the prior art elements (See MPEP 2112 – Section IV).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL TEHRANI whose telephone number is (571)270-0697. The examiner can normally be reached 9:00am-5:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Benjamin Klein can be reached at 571-270-5213. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/D.T./Examiner, Art Unit 3792
/Benjamin J Klein/Supervisory Patent Examiner, Art Unit 3792