DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 1-15 are pending.
Claims 1-15 are examined on the merits.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
3. 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.
4. The rejection of claim(s) 1-8 and 12-14 under 35 U.S.C. 103 as being unpatentable over Michel et al., US 2017/0189445 A1 (published July 6, 2017/ IDS reference #2 submitted January 10, 2024), and further in view of Trikha et al., WO 2017/210463 A1 (published 07 December 2017) is maintained.
Initially, Applicant summarizes the teachings presented in the first action of merits (FAOM) mailed January 6, 2026, see Remarks submitted April 3, 2023, page 2, 2nd paragraph (para.).
Applicant follows with their point of view of what primary reference, Michel teaches, see para. bridging pages 2 and 4 of the Remarks. Applicant states, “[t]here is no disclosure in Michel et al. of radiotherapy as the first treatment step, no disclosure of radiosensitization, no disclosure of post-irradiation administration of xenon, and no disclosure of interference with radiation-induced DNA repair. Michel et al. therefore teaches an antiproliferative xenon/NMDA-antagonist combination, not a post-radiation xenon radiosensitizer.”, see sentence bridging pages 2 and 3 of the Remarks.
Applicant states secondary reference, Trikha does not cure the alleged deficiency of Michel and Trikha teaches “…synergistic combinations of marizomib with additional therapeutic agents…” for the treatment of CNS cancers, see para. bridging pages 3 and 4 of the Remarks. Applicant also points out paragraphs (paras.) of Trikha suggesting these teachings read on technically different aspects juxtaposed to the claimed invention. Applicant notes the importance of the claimed order/ timing of administration of treatment is not arbitrary, see page 4 of Remarks, 1st para.
Applicant concludes arguments, referencing the Federal Circuit reading on hindsight and criteria for establishing a proper case of obviousness, see para. bridging pages 4 and 5 of the Remarks submitted April 3, 2026.
Applicant’s arguments and points of view have been carefully considered, however fail to persuade.
The combination of references teaches the claimed invention. Additional teachings and components within the prior art references do not preclude the instant rejection as the claims include the transitional term, comprising, which reads on open language.
Other than the order of the combination of the therapeutic agents to be administered Applicant has not pointed to any teachings in the prior art references that “criticize, discredit, or otherwise discourage the solution claimed…”, see In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). Moreover, the “expectation of success need only be reasonable, not absolute.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007).
And while Applicant argues the particular order of administration of each of these agents is not taught by the prior art references, one of ordinary skill in the art has been provided the general guidance and motivation to modify the combination of previously successful anti-cancer agents in light of the targeted treatment taught in all the references as the prior art leads a person of ordinary skill in the art (POSA) to the parameters set forth in the claims. Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome.
One of ordinary skill in the art would have been motivated to
administer the therapeutic agents within the particular administration
order cited in the claims with a reasonable expectation of success by
teachings well known and noted herein that dosages of any pharmaceutical
composition may be adjusted and optimized especially in light of Michel wherein it is cited “it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the appended claims. The present invention may suitably comprise, consist or consist essentially of the elements disclosed and may be practiced in the absence of an element not disclosed. Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense.”, see page 6, section 0141. As well as Trikha states “[w]hile the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fail within the spirit and scope of the present invention.”, see Trikha, page 196, section 00778.
Addressing Applicant’s concerns regarding hindsight, rather than using hindsight, the Examiner points to specific disclosures in the prior art that describe the limitations of Applicants’ claimed invention. The Examiner’s obviousness conclusion is based on sufficiently articulated reasoning that overcomes any concerns about hindsight bias. See KSR, 550 U.S. at 418.
Moreover, 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).
The modification of the primary reference, Michel in light of the secondary reference, Trikha is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. The Examiner recognizes that obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988) and In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Michel teaches treating tumor proliferation of glial cells with xenon gas as an inhalable drug in combination with an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, in particular, memantine or nitromemantine, see page 1, sections 0002, 0009, 0018-0020, 0022, 0023, 0025, and 0029. Chemotherapy was not administered to the patient, see entire document.
The xenon is in a gas mixture with nitrogen and oxygen, see page 1, sections 0026-0028. “The gas containing xenon is administered to the patient by inhalation”, see page 2, sections 0041 and 0048. “[T]he xenon gas is administered to the patient for an inhalation time of a few minutes to a few hours, typically between 15 minutes and 6 hours, preferentially less than 4 hours”, see page 2, section 0075.
Michel does not teach the patient’s glioma cells (cancerous glial cells) were initially treated with radiation therapy (RT) and the xenon gas is administered:
-after RT at the latest 360 minutes (6 hours) after the completion of the RT (claim 3);
-immediately after completion of the RT (claim 4); and/ or
-continues for at least 30 minutes or for about 360 (6 hours) minutes (claims 5 and 6).
However, Michel does teach spans of time xenon gas is inhaled that overlap with the time points set forth in claims 3-6, see page 2, section 0075.
Furthermore, Trikha teaches treating malignant glioma with a combination of therapeutic agents including radiotherapy, see abstract; page 1, section 0004; and page 3, section 0012. In some embodiments, the glioma has a “…promoter of the subject's gene encoding O6-methylguanine- DNA methyltransferase is unmethylated.”, see page 2, section 0010; and section 00220 bridging pages 29 and 30.
Chemotherapy was not administered to the patient at the same time as RT, nor inhalation of xenon gas, see entire document.
Trikha teaches concomitant treatment including focal radiotherapy (RT), see section 00282 bridging pages 46 and 47. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer the focal RT prior to the xenon gas treatment because both documents teach combinatorial therapy, as well as “it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art…Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense.”, see Michel, page 6, section 0141; and Trikha, page 196, section 00778.
One of ordinary skill in the art would have been motivated to administer the therapeutic agents in the manner set forth to arrive at a successful and effective treatment for the purpose of achieving the desired treatment outcome. Further, one of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings well known in the art, the manner at which any pharmaceutical composition is administered may be adjusted and optimized.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235(CCPA 1955).
5. The rejection of claim(s) 15 under 35 U.S.C. 103 as being unpatentable over Michel et al., US 2017/0189445 A1 (published July 6, 2017/ IDS reference #2 submitted January 10, 2024), and further in view of Trikha et al., WO 2017/210463 A1 (published 07 December 2017) is maintained.
Applicant restates the instant rejection and avers “[f]or the same reasons as recited [previously], the rejection of claim 15 is likewise unpersuasive.”, see Remarks submitted April 3, 2023, page 5, last full paragraph (para.); 3rd line from bottom of page 5; and arguments presented in segment 4 beginning on page 2, herein.
Applicant concludes the arguments noting the teachings of Michel and Trikha, stating “[t]heir combination does not disclose, nor render obvious, the specific in vitro sequence of radiation first and xenon therafter for sensitization of MGMT unmethylated glioma cells.”, see para. bridging pages 5 and 6.
Applicant’s arguments and points of view have been carefully considered, however fail to persuade.
The combination of references teaches the claimed invention. Additional teachings and components within the prior art references do not preclude the instant rejection as the claims include the transitional term, comprising, which reads on open language.
Other than the order of the combination of the therapeutic agents to be administered Applicant has not pointed to any teachings in the prior art references that “criticize, discredit, or otherwise discourage the solution claimed…”, see In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). Moreover, the “expectation of success need only be reasonable, not absolute.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007).
And while Applicant argues the particular order of administration of each of these agents is not taught by the prior art references, one of ordinary skill in the art has been provided the general guidance and motivation to modify the combination of previously successful anti-cancer agents in light of the targeted treatment taught in all the references as the prior art leads a person of ordinary skill in the art (POSA) to the parameters set forth in the claims. Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome.
One of ordinary skill in the art would have been motivated to
administer the therapeutic agents within the particular administration
order cited in the claims with a reasonable expectation of success by
teachings well known and noted herein that dosages of any pharmaceutical
composition may be adjusted and optimized especially in light of Michel wherein it is cited “it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the appended claims. The present invention may suitably comprise, consist or consist essentially of the elements disclosed and may be practiced in the absence of an element not disclosed. Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense.”, see page 6, section 0141. As well as Trikha states “[w]hile the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fail within the spirit and scope of the present invention.”, see Trikha, page 196, section 00778.
The modification of the primary reference, Michel in light of the secondary reference, Trikha is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. The Examiner recognizes that obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988) and In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Michel teaches treating tumor proliferation of glial cells with xenon gas as an inhalable drug in combination with another anti-cancer therapeutic agent, see page 1, sections 0002, 0009, 0018-0020, 0022, 0023, 0025, and 0029. “[T]he xenon gas is administered to the patient for an inhalation time of a few minutes to a few hours, typically between 15 minutes and 6 hours, preferentially less than 4 hours”, see page 2, section 0075.
Michel does not teach the in vitro study of sensitizing glioma cells for radiation in vitro, wherein glioma cells were initially treated with radiation therapy (RT), and the xenon gas is administered thereafter.
However, Trikha teaches treating malignant glioma with a combination of therapeutic agents including radiotherapy, see abstract; page 1, section 0004; page 3, section 0012. In some embodiments, the glioma has a “…promoter of the subject's gene encoding O6-methylguanine- DNA methyltransferase is unmethylated.”, see page 2, section 0010; and section 00220 bridging pages 29 and 30.
Trikha teaches concomitant treatment including focal radiotherapy (RT), see section 00282 bridging pages 46 and 47. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer the RT prior to the xenon gas treatment because both documents teach combinatorial therapy, as well as “it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art…Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense.”, see Michel, page 6, section 0141; and Trikha, page 196, section 00778.
Trikha also teaching in vitro studies utilizing multiple glioma cell lines, see page 108, section 00391.
One of ordinary skill in the art would have been motivated to adapt the in vivo assays, to in vitro assays, wherein the therapeutic agents would be administered in the manner set forth to arrive at a successful and effective treatment for the purpose of validating the desired treatment outcome. Further, one of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings presented in Trikha and also it is well known in the art, the manner at which any pharmaceutical composition is administered may be adjusted and optimized.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235(CCPA 1955).
6. The rejection of claim(s) 1-14 under 35 U.S.C. 103 as being unpatentable over Michel et al., US 2017/0189445 A1 (published July 6, 2017/ IDS reference #2 submitted January 10, 2024), and further in view of Trikha et al., WO 2017/210463 A1 (published 07 December 2017) and Schulz-Ertner et al. (J. Clin. Oncol. 25(8): 953-964, March 10, 2007) is maintained.
Applicant restates the instant rejection and avers “[f]or the reasons recited [previously], the combination of Michel and Trikha does not render obvious the claimed invention. Schutlz-Ertner does not provide the missing evidence needed for the obviousness [rejection]…”, see page 6 of the Remarks submitted April 3, 2026. Applicant points out claims 9 to 11, noting Schulz-Ertner reads on general radiotherapy, “adds no missing inventive concept”, thus “cannot remedy the deficiencies of Michel… and Trikha…”, see para. bridging pages 6 and 7 of the Remarks.
Applicant’s arguments and points of view have been carefully considered, however fail to persuade.
Applicant points out particulars of what the individual references do and do not teach, these assertions do not obviate the instant rejection.
The combination of references teaches the claimed invention. Additional teachings and components within the prior art references do not preclude the instant rejection as the claims include the transitional term, comprising, which reads on open language.
Other than the order of the combination of the therapeutic agents to be administered Applicant has not pointed to any teachings in the prior art references that “criticize, discredit, or otherwise discourage the solution claimed…”, see In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). Moreover, the “expectation of success need only be reasonable, not absolute.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007).
And while Applicant argues the particular order of administration of each of these agents is not taught by the prior art references, one of ordinary skill in the art has been provided the general guidance and motivation to modify the combination of previously successful anti-cancer agents in light of the targeted treatment taught in all the references as the prior art leads a person of ordinary skill in the art (POSA) to the parameters set forth in the claims. Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome.
One of ordinary skill in the art would have been motivated to
administer the therapeutic agents within the particular administration
order cited in the claims with a reasonable expectation of success by
teachings well known and noted herein that dosages of any pharmaceutical
composition may be adjusted and optimized especially in light of Michel wherein it is cited “it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the appended claims. The present invention may suitably comprise, consist or consist essentially of the elements disclosed and may be practiced in the absence of an element not disclosed. Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense.”, see page 6, section 0141. As well as Trikha states “[w]hile the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fail within the spirit and scope of the present invention.”, see Trikha, page 196, section 00778.
The modification of the primary reference, Michel in light of the secondary references, Trikha and Schulz-Ertner is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. The Examiner recognizes that obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988) and In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Michel teaches treating tumor proliferation of glial cells with xenon gas as an inhalable drug in combination with an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, in particular, memantine or nitromemantine, see page 1, sections 0002, 0009, 0018-0020, 0022, 0023, 0025, and 0029. Chemotherapy was not administered to the patient, see entire document.
The xenon is in a gas mixture with nitrogen and oxygen, see page 1, sections 0026-0028. “The gas containing xenon is administered to the patient by inhalation”, see page 2, sections 0041 and 0048. “[T]he xenon gas is administered to the patient for an inhalation time of a few minutes to a few hours, typically between 15 minutes and 6 hours, preferentially less than 4 hours”, see page 2, section 0075.
Michel does not teach the patient’s glioma cells (cancerous glial cells) were initially treated with radiation therapy (RT) and the xenon gas is administered:
-after RT at the latest 360 minutes (6 hours) after the completion of the RT (claim 3);
-immediately after completion of the RT (claim 4); and/ or
-continues for at least 30 minutes or for about 360 (6 hours) minutes (claims 5 and 6).
Michel does not teach explicitly teach the focal RT is ionizing radiation including photon beam radiation, proton beam radiation and heavy ion beam radiation.
However, Michel does teach spans of time xenon gas is inhaled that overlaps with the time points set forth in claims 3-6, see page 2, section 0075.
Furthermore, Trikha teaches treating malignant glioma with a combination of therapeutic agents including radiotherapy, see abstract; page 1, section 0004; and page 3, section 0012. In some embodiments, the glioma has a “…promoter of the subject's gene encoding O6-methylguanine- DNA methyltransferase is unmethylated.”, see page 2, section 0010; and section 00220 bridging pages 29 and 30.
Chemotherapy was not administered to the patient at the same as RT, nor inhalation of xenon gas, see entire document.
Trikha teaches concomitant treatment including focal RT, see section 00282 bridging pages 46 and 47. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer the RT prior the xenon gas treatment because both documents teach combinatorial therapy, as well as “it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art…Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense.”, see Michel, page 6, section 0141; and Trikha, page 196, section 00778.
Schulz-Ertner teaches particle RT using particle beams, protons, heavier ions and photon beams, see abstract; and entire document. These types of RT are ionizing radiation.
One of ordinary skill in the art would have been motivated to administer the therapeutic agents in combination and in the manner set forth to arrive at a successful and effective treatment for the purpose of achieving the desired treatment outcome as established in all references, see all three in their entireties. Further, one of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings well known in the art, the manner at which the administration of any pharmaceutical composition may be adjusted and optimized.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235(CCPA 1955).
Conclusion
7. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
8. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however can normally be reached between 8AM-8PM, Monday through Friday.
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, Julie Wu can be reached on 571-272-0859. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
17 June 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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