DETAILED ACTION
Applicant’s amendment to the claims in the Response filed on 12/03/2025 is acknowledged.
The objection to the drawings is withdrawn in view of the replacement sheets filed on 12/03/2025.
The rejections of record under 35 U.S.C. § 112(b) are withdrawn in view of Applicant’s amendment to the claims in the Response filed on 12/03/2025.
The rejections of record under 35 U.S.C. § 103 are maintained and modified in view of Applicant’s amendment to the claims in the Response filed on 12/03/2025 as set forth below.
Claim Interpretation
For purposes of compact prosecution and applying prior art, the recitation of “measuring a level of expression of PTGRI, PTPN14, and ASPH or a combination thereof in the biological sample” in claim 1, as amended, was interpreted herein to require measuring expression levels of: 1) PTGRI, PTPN14, and ASPH; 2) any combination of PTGRI, PTPN14, and ASPH.
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 1-4, 6-8, 10, 17-19, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Knudsen (US 9,725,769, prior art of record) in view of McMorris et al. (US 2008/0306147, IDS-US, hereinafter “McMorris”) as evidenced by Stone et al. (WO 2017/008117, prior art of record, hereinafter “Stone”) and Fan et al. (Cancer Res., 66(24):11954-11966 (2006), prior art of record, hereinafter “Fan”).
Knudsen teaches a method of treating a solid tumor cancer, e.g., prostate cancer or breast cancer, in a subject with an illudin-based anti-cancer agent (Abstract; column 4, lines 31-36). Knudsen teaches that the method comprises extracting a biological sample, e.g., a tissue biopsy, from the subject (column 13, lines 44-60; column 21, lines 39-49).
Knudsen teaches that the method further comprises measuring expression levels of PTGR1, PTPN14, ASPH, or combination thereof in the biological sample (Abstract; columns 1-4; column 6, line 52; column 31, lines 34-50; Table 1, Affymetrix Probe 9; Table 3, Affymetrix Probes 228, 270) to identify the subject’s sensitivity to treatment with irofulven (an illudin-based anti-cancer agent); i.e., “[i]f the expression level of the biomarker(s) in the sample from the cancer patient is substantially similar (e.g., identical to or has the same trend of expression level) to the expression level of the biomarker(s) in the cell or tissue known to be sensitive to irofulven, then the cancer patient is predicted to be responsive to treatment with irofulven” (column 11, lines 39-40; column 25, lines 53-58).
Knudsen further teaches that the “biomarker PTGRl (SEQ ID NO: 203 or 210) may be used alone to predict cancer patient responsiveness to treatment with irofulven or in combination with one or more additional biomarkers” (column 31, lines 46-49). Knudsen teaches administering irofulven to a subject identified to be sensitive to irofulven treatment (Abstract; column 1, lines 47-53).
Knudsen teaches administration of a second therapeutic agent, including chemotherapeutic agents such as docetaxel, cabazitaxel, paclitaxel, etc. (column 5, line 66 to column 6, line 30). Knudsen also teaches the method is useful for prognosing and monitoring, e.g., prostate cancer (column 20, line 63-65).
While Knudsen teaches identifying a subject’s sensitivity to irofulven, an illudin-based anti-cancer agent, having the following structure:
PNG
media_image1.png
270
326
media_image1.png
Greyscale
,
the reference does not explicitly teach the illudin-based anti-cancer agent (hydroxyureamethyl-acylfulvene) as claimed:
PNG
media_image2.png
200
400
media_image2.png
Greyscale
However, McMorris teaches that the claimed illudin-based anti-cancer agent (hereinafter “claimed agent”) is an irofulven derivative “effective to treat cancer with reduced toxicity compared to treatment with a substantially equally effective dose of irofulven (6-hydroxymethylacylfulvene)” (¶¶ 0031, 0111 (I-6). McMorris further teaches that the agent can be formulated in pharmaceutically acceptable carrier (¶¶ 0023, 0049). McMorris teaches that the agent can be administered to treat solid tumor cancers such as prostate cancer or breast cancer (¶ 0043). McMorris further teaches that the agent is administered in combination with a second therapeutic agent such as a chemotherapeutic agent (¶¶ 0026, 0032, 0149).
It would have been prima facie obvious at the time of filing to modify the method taught by Knudsen, which identifies a subject’s sensitivity to irofulven, to identify a subject’s sensitivity to the claimed agent, which is a derivative of irofulven with reduced toxicity, with a reasonable expectation of success. Both irofulven and the claimed agent are illudin-based anti-cancer agents used to treat identical solid tumor cancers, and one of ordinary skill in the art would have been motivated to modify Knudsen in view of McMorris in order to identify a subject’s sensitivity to the claimed agent, which advantageously exhibits reduced toxicity compared to irofulven, with a reasonable expectation of success.
Instant claim 4 recites that ASPH is methylated. As discussed above, instant claim 4 was interpreted consistent with the Specification to mean methylation of the protein or gene. In this regard, ASPH methylation is not an active method step to be performed, selected, assayed, or even appreciated, but, rather, a characteristic of a subject being evaluated. In this regard, Stone evidences that estrogen receptor 1 (ESR1) positive breast cancer subjects exhibit aberrant ASPH gene methylation (Abstract; Table 1, Row 56; Table 3, Row 17). Similarly, Fan evidences that ASPH exhibits aberrant gene methylation and overexpression in MCF-7 breast cancer cells (Abstract; Table 2). As discussed above, Knudsen and McMorris both teach treatment of breast cancer and, therefore, reasonably encompass subjects having ASPH methylation.
Regarding instant claim 10, Knudsen teaches administration of irofulven or a different therapy based upon expression of the markers as well as treatment of patients who have experienced a recurrence following a treatment with a cancer therapy other than irofulven, surgery, or radiation (column 48, lines 44-63). This reasonably encompasses “modifying a targeted drug therapy based on expression of a gene,” as claimed.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Knudsen and McMorris as applied to claims 1-4, 6-8, 10, 17-19, and 23-25 above, and further in view of Chemotherapy Preparation | Harold Leever Regional Cancer Center (https://web.archive.org/web/20161001000000*/https://www.leevercancercenter.org/care-services/cancer-treatment-services/preparing-for-chemotherapy/, prior art of record, available online August 28, 2016, access September 11, 2024, hereinafter “Leever”)
As discussed above, claims 1-4, 6-8, 10, 17-19, and 23-25 were rendered prima facie obvious by the teachings of Knudsen and McMorris. The references do not explicitly teach assessing the subject’s overall health and treatment history before initiating the illudin-based
anti-cancer therapy. However, Leever teaches it was routine at the time of filing for subjects to under to blood tests, medical exams, dental exams, etc. prior to starting chemotherapy (page 1). One of ordinary skill in the art would have been motivated to modify Knudsen and McMorris in view of Leever in order to gauge the subject’s overall health and treatment history to advantageously reduce the risk of complications, e.g., infection, during treatment with a reasonable expectation of success.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Knudsen and McMorris as applied to claims 1-4, 6-8, 10, 17-19, and 23-25 above, and further in view of Bardin et al. (Eur. J. Cancer, 50:2005-2009 (2014), prior art of record, hereinafter “Bardin”).
As discussed above, claims 1-4, 6-8, 10, 17-19, and 23-25 were rendered prima facie obvious by the teachings of Knudsen and McMorris. The references do not explicitly teach the limitations of instant claims 21-22. However, Bardin teaches that “[t]herapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individuali[z]e treatment by adapting drug dose to improve efficacy and/or reduce toxicity,” and that “cytotoxic drugs are characteri[z]ed by steep dose–response relationships and narrow therapeutic windows.” (Abstract).
It would have prima facie obvious at the time of filing to modify Knudsen and McMorris in view of Bardin to include, inter alia, monitoring the subject for adverse reactions during the treatment period and the adjusting the treatment duration based on the subject’s response to the claimed agent based on its efficacy. One of ordinary skill in the art would have been motivated to modify Knudsen and McMorris in view of Bardin in order to advantageously monitor the subject for adverse reactions and minimize the treatment duration with a reasonable expectation of success.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
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, 17-19, 21, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18,759,622.
The conflicting claims are drawn to an overlapping method of treating a solid tumor cancer, i.e., lung cancer and non-small cell lung cancer (NSCLC), in a subject comprising administration of the claimed anti-cancer agent (hydroxyureamethyl-acylfulvene) as well as a second therapeutic agent such as radiation or a chemotherapeutic agent (paclitaxel) (claims 1-17).
The conflicting claims further teach: extracting a biological sample (e.g., a tumor biopsy) from the subject; measuring the expression level of, inter alia, PTGR1, in the biological sample from the subject; identifying the subject having cancer sensitive to treatment with hydroxyureamethyl-acylfulvene; and treating the subject with the hydroxyureamethyl-acylfulvene if, inter alia, on the expression level in the subject of PTGR1 is greater than the level in subjects without the solid tumor cancer (claims 1-17).
The conflicting claims teach that the efficacy of the treatment is assessed through imaging techniques such as MRI or CT scans after the administration of each therapeutic agent (claim 17), which would reasonably allow for adjusting treatment duration based upon the subject’s response to hydroxyureamethyl-acylfulvene. Regarding instant claim 23, identifying sensitivity to hydroxyureamethyl-acylfulvene based on PTGRl expression would reasonably encompasses predicting the subject’s prognosis since it would indicate a subject’s response to therapy.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4, 6-8, 10, 17-19, 21, and 23-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18,759,622 in view of Knudsen as evidenced by Lakshminarasimhan et al., Adv. Exp. Med. Biol., 945:151-172 (2016), prior art of record, hereinafter “Lakshminarasimhan”)
The rejection of claims 1, 17-19, 21, and 23 is set forth above. The conflicting claims do not explicitly teach the limitations of instant claims 4, 6-8, 10, and 24-25. However, Knudsen teaches a method of treating a solid tumor cancer, lung cancer (e.g., non-small cell lung carcinoma, large cell carcinoma, bronchogenic carcinoma, and papillary adenocarcinoma, in a subject with an illudin-based anti-cancer agent (Abstract; column 2, lines 14-17; column 4, lines 31-36). Knudsen teaches that the method further comprises measuring expression levels of PTGR1, PTPN14, ASPH, or combination thereof in the biological sample (Abstract; columns 1-4; column 6, line 52; column 31, lines 34-50; Table 1, Affymetrix Probe 9; Table 3, Affymetrix Probes 228, 270) to identify the subject’s sensitivity to treatment with irofulven (an illudin-based anti-cancer agent like the one of the conflicting claims); i.e., “[i]f the expression level of the biomarker(s) in the sample from the cancer patient is substantially similar (e.g., identical to or has the same trend of expression level) to the expression level of the biomarker(s) in the cell or tissue known to be sensitive to irofulven, then the cancer patient is predicted to be responsive to treatment with irofulven” (column 11, lines 39-40; column 25, lines 53-58).
Knudsen further teaches that the “biomarker PTGRl (SEQ ID NO: 203 or 210) may be used alone to predict cancer patient responsiveness to treatment with irofulven or in combination with one or more additional biomarkers” (column 31, lines 46-49). Knudsen teaches administering irofulven in a pharmaceutically acceptable carrier to a subject identified to be sensitive to irofulven treatment (Abstract; column 1, lines 47-53; column 50, lines 1-17). Knudsen also teaches the method is useful for prognosing and monitoring cancer (column 20, line 63-65).
One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Knudsen in order to advantageously measure expression of other markers known in the prior art to indicate sensitivity to illudin-based anti-cancer agents in order to advantageously predict a subject’s response to hydroxyureamethyl-acylfulvene with a reasonable expectation of success.
Instant claim 4 recites that ASPH is methylated. As discussed above, instant claim 4 was interpreted consistent with the Specification to mean methylation of the protein or gene. In this regard, ASPH methylation is not an active method step to be performed, selected, assayed, or even appreciated, but, rather, a characteristic of a subject being evaluated. As evidenced by Lakshminarasimhan, regulation of DNA methylation is a critical epigenetic mechanism of cancer initiation, maintenance, and progression (Abstract). As such, absent evidence to the contrary, the conflicting claims and Knudsen, reasonably encompass subjects having ASPH methylation. Regarding instant claim 10, Knudsen teaches administration of irofulven or a different therapy based upon expression of the markers as well as treatment of patients who have experienced a recurrence following a treatment with a cancer therapy other than irofulven, surgery, or radiation (column 48, lines 44-63). This reasonably encompasses “modifying a targeted drug therapy based on expression of a gene,” as claimed.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 17-21, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18,759,622 in view of Leever.
The rejection of claims 1, 17-19, 21, and 23 is forth above. The conflicting claims do not explicitly teach assessing the subject’s overall health and treatment history before initiating the illudin-based anti-cancer therapy. However, Leever teaches it was routine at the time of filing for subjects to under to blood tests, medical exams, dental exams, etc. prior to starting chemotherapy (page 1). One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Leever in order to gauge the subject’s overall health and treatment history to advantageously reduce the risk of complications, e.g., infection, during treatment with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 17-19, and 21-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18,759,622 in view of Bardin.
The rejection of claims 1, 17-19, 21, and 23 are set forth above. The conflicting claims do not explicitly teach the limitations of instant claim 22. However, Bardin teaches that “[t]herapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individuali[z]e treatment by adapting drug dose to improve efficacy and/or reduce toxicity,” and that “cytotoxic drugs are characteri[z]ed by steep dose–response relationships and narrow therapeutic windows.” (Abstract).
It would have prima facie obvious at the time of filing to modify the conflicting claims in view of Bardin to include, inter alia, monitoring the subject for adverse reactions during the treatment period and the adjusting the treatment duration based on the subject’s response to the claimed agent based on its efficacy. One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Bardin in order to advantageously monitor the subject for adverse reactions and minimize the treatment duration with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-7, 14-15, 18-21, 28-29, 31-34, and 41 of copending Application No. 18/319,919.
The conflicting claims are drawn to an overlapping methods to treating and determining sensitivity of a cancer, e.g., a solid breast or prostate tumor, to an anti-cancer agent, comprising determining an expression level of at least one biomarker, an expression level of at least one gene associated with DNA repair, a transcription level of at least one thereof, or any combination thereof, wherein the anti-cancer agent comprises illudin or an illudin analog such as hydroxyureamethyl-acylfulvene or irofulven (claims 1-3, 5-7, 15, 18-21, 29, 31-34). The conflicting claim teach that the biomarker comprises expression of PTGR1 (claims 14, 28, and 41). Regarding instant claim 23, identifying sensitivity to hydroxyureamethyl-acylfulvene based on PTGRl expression would reasonably encompasses predicting the subject’s prognosis since it would indicate a subject’s response to therapy
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6-8, 10, 17-19, and 23-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-7, 14-15, 18-21, 28-29, 31-34, and 41 of copending Application No. 18/319,919 in view of Knudsen as evidenced by Stone and Fan.
The rejection of instant claims 1-3 and 23 is set forth above. The conflicting claims do not explicitly teach the limitation of instant claims 4, 6-8, 10, 17-19, and 24-25. However, Knudsen teaches a method of treating solid tumor cancer, e.g., prostate cancer or breast, in a subject with an illudin-based anti-cancer agent, i.e., irofulven (Abstract; column 4, lines 31-36). Knudsen teaches that the method comprises extracting a biological sample, e.g., a tissue biopsy, from the subject (column 13, lines 44-60; column 21, lines 39-49).
Knudsen teaches that the method further comprises measuring expression levels of PTGR1, PTPN14, ASPH, or combination thereof in the biological sample (Abstract; columns 1-4; column 6, line 52; column 31, lines 34-50; Table 1, Affymetrix Probe 9; Table 3, Affymetrix Probes 228, 270) to identify the subject’s sensitivity to treatment with irofulven (an illudin-based anti-cancer agent); i.e., “[i]f the expression level of the biomarker(s) in the sample from the cancer patient is substantially similar (e.g., identical to or has the same trend of expression level) to the expression level of the biomarker(s) in the cell or tissue known to be sensitive to irofulven, then the cancer patient is predicted to be responsive to treatment with irofulven” (column 11, lines 39-40; column 25, lines 53-58).
Knudsen further teaches that the “biomarker PTGRl (SEQ ID NO: 203 or 210) may be used alone to predict cancer patient responsiveness to treatment with irofulven or in combination with one or more additional biomarkers” (column 31, lines 46-49). Knudsen teaches administering irofulven to a subject identified to be sensitive to irofulven treatment (Abstract; column 1, lines 47-53).
Knudsen teaches administration of a second therapeutic agent, including chemotherapeutic agents such as docetaxel, cabazitaxel, paclitaxel, etc. (column 5, line 66 to column 6, line 30). Knudsen also teaches the method is useful for prognosing and monitoring, e.g., prostate cancer (column 20, line 63-65).
Knudsen teaches administering irofulven in a pharmaceutically acceptable carrier to a subject identified to be sensitive to irofulven treatment (Abstract; column 1, lines 47-53; column 50, lines 1-17). Knudsen also teaches the method is useful for prognosing and monitoring cancer (column 20, line 63-65).
One of ordinary skill in the art would have been motivated to modify the conflicting claims in order to advantageously measure expression of other markers known in the prior art to indicate sensitivity to illudin-based anti-cancer agents in order to advantageously predict a subject’s response to hydroxyureamethyl-acylfulvene with a reasonable expectation of success.
Instant claim 4 recites that ASPH is methylated. As discussed above, instant claim 4 was interpreted consistent with the Specification to mean methylation of the protein or gene. In this regard, ASPH methylation is not an active method step to be performed, selected, assayed, or even appreciated, but, rather, a characteristic of a subject being evaluated. In this regard, Stone evidences that estrogen receptor 1 (ESR1) positive breast cancer subjects exhibit aberrant ASPH gene methylation (Abstract; Table 1, Row 56; Table 3, Row 17). Similarly, Fan evidences that ASPH exhibits aberrant gene methylation and overexpression in MCF-7 breast cancer cells (Abstract; Table 2). As discussed above, Knudsen teaches treatment of breast cancer and, therefore, reasonably encompass subjects having ASPH methylation.
Regarding instant claim 10, Knudsen teaches administration of irofulven or a different therapy based upon expression of the markers as well as treatment of patients who have experienced a recurrence following a treatment with a cancer therapy other than irofulven, surgery, or radiation (column 48, lines 44-63). This reasonably encompasses “modifying a targeted drug therapy based on expression of a gene,” as claimed.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 20, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-7, 14-15, 18-21, 28-29, 31-34, and 41 of copending Application No. 18/319,919 in view Leever.
The rejection of instant claims 1-3 and 23 is set forth above. The conflicting claims do not explicitly teach the assessing the subject's overall health and treatment history before initiating the illudin-based anti-cancer therapy. However, Leever teaches it was routine at the time of filing for subjects to under to blood tests, medical exams, dental exams, etc. prior to starting chemotherapy (page 1). One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Leever in order to gauge the subject’s overall health and treatment history to advantageously reduce the risk of complications, e.g., infection, during treatment with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3 and 21-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-7, 14-15, 18-21, 28-29, 31-34, and 41 of copending Application No. 18/319,919 in view of Bardin.
The rejection of instant claims 1-3 and 23 is set forth above. The conflicting claims do not explicitly teach the limitations of instant claims 21-22. However, Bardin teaches that “[t]herapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individuali[z]e treatment by adapting drug dose to improve efficacy and/or reduce toxicity,” and that “cytotoxic drugs are characteri[z]ed by steep dose–response relationships and narrow therapeutic windows.” (Abstract).
It would have prima facie obvious at the time of filing to modify the conflicting claims in view of Bardin to include, inter alia, monitoring the subject for adverse reactions during the treatment period and the adjusting the treatment duration based on the subject’s response to the claimed agent based on its efficacy. One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Bardin in order to advantageously monitor the subject for adverse reactions and minimize the treatment duration with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 10, 17-18, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 9,15-17, and 19 of copending Application No. 17/998,117 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to an overlapping method of treating pancreatic cancer, i.e., a solid tumor cancer, in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of hydroxyureamethyl acylfulvene and a chemotherapeutic agent (e.g., cisplatin or paclitaxel), wherein the subject has a high level of PTGR1 (claims 1, 4, 9, 15-17, and 19).
The conflicting claims are further drawn to method of treating pancreatic cancer in a subject, comprising: (a) obtaining or having obtained an expression level in a sample from a subject for a plurality of targets, wherein the plurality of targets comprises includes PTRG1; (b) determining that the subject is sensitive to a treatment with a hydroxyureamethyl acylfulvene; and (c) administering a cancer treatment including a hydroxyureamethyl acylfulvene (claim 18).
Regarding instant claim 10, the conflicting claims teach that the subject has undergone radiation therapy, surgery, chemotherapy prior to identifying sensitivity and potential treatment with hydroxyureamethyl-acylfulvene (claims 15-17 and 19), which would reasonably encompass modifying a targeted drug therapy based on expression of PTRGl.
Regarding instant claim 23, identified sensitivity to hydroxyureamethyl-acylfulvene based on PTGRl expression would reasonably encompasses predicting the subject’s prognosis since it would indicate a subject’s response to therapy
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1-3, 10, 17-18, and 23-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 9,15-17, and 19 of copending Application No. 17/998,117 in view of Knudsen as evidenced by Lakshminarasimhan.
The rejection of claims 1-3, 10, 17-18, and 23 are set forth above. The conflicting claims do not explicitly teach the limitations of instant claims 4, 6-8, 19, and 24-25. However, Knudsen teaches a method of treating solid tumor cancer, e.g., pancreatic cancer, with an illudin-based anti-cancer agent (Abstract; column 2, lines 4-7; column 4, lines 31-36). Knudsen teaches that the method comprises extracting a biological sample, e.g., a tissue biopsy, from the subject (column 13, lines 44-60; column 21, lines 39-49).
Knudsen teaches that the method further comprises measuring expression levels of PTGR1, PTPN14, ASPH, or combination thereof in the biological sample (Abstract; columns 1-4; column 6, line 52; column 31, lines 34-50; Table 1, Affymetrix Probe 9; Table 3, Affymetrix Probes 228, 270) to identify the subject’s sensitivity to treatment with irofulven (an illudin-based anti-cancer agent like the one of the conflicting claims); i.e., “[i]f the expression level of the biomarker(s) in the sample from the cancer patient is substantially similar (e.g., identical to or has the same trend of expression level) to the expression level of the biomarker(s) in the cell or tissue known to be sensitive to irofulven, then the cancer patient is predicted to be responsive to treatment with irofulven” (column 11, lines 39-40; column 25, lines 53-58).
Knudsen further teaches that the “biomarker PTGRl (SEQ ID NO: 203 or 210) may be used alone to predict cancer patient responsiveness to treatment with irofulven or in combination with one or more additional biomarkers” (column 31, lines 46-49). Knudsen teaches administering irofulven in a pharmaceutically acceptable carrier to a subject identified to be sensitive to irofulven treatment (Abstract; column 1, lines 47-53; column 50, lines 1-17). Knudsen also teaches the method is useful for prognosing and monitoring cancer (column 20, line 63-65).
One of ordinary skill in the art would have been motivated to modify the conflicting claims in order to advantageously measure expression of other markers known in the prior art to indicate sensitivity to illudin-based anti-cancer agents in order to advantageously predict a subject’s response to hydroxyureamethyl-acylfulvene with a reasonable expectation of success.
Instant claim 4 recites that ASPH is methylated. As discussed above, instant claim 4 was interpreted consistent with the Specification to mean methylation of the protein or gene. In this regard, ASPH methylation is not an active method step to be performed, selected, assayed, or even appreciated, but, rather, a characteristic of a subject being evaluated. As evidenced by Lakshminarasimhan, regulation of DNA methylation is a critical epigenetic mechanism of cancer initiation, maintenance, and progression (Abstract). As such, absent evidence to the contrary, the conflicting claims and Knudsen, reasonably encompass subjects having ASPH methylation. Regarding instant claim 10, Knudsen teaches administration of irofulven or a different therapy based upon expression of the markers as well as treatment of patients who have experienced a recurrence following a treatment with a cancer therapy other than irofulven, surgery, or radiation (column 48, lines 44-63). This reasonably encompasses “modifying a targeted drug therapy based on expression of a gene,” as claimed.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 10, 17-18, 20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 9, 15-17, and 19 of copending Application No. 17/998,117 in view Leever.
The rejection of claims 1-3, 10, 17-18, and 23 is set forth above. The conflicting claims do not explicitly teach the assessing the subject's overall health and treatment history before initiating the illudin-based anti-cancer therapy. However, Leever teaches it was routine at the time of filing for subjects to under to blood tests, medical exams, dental exams, etc. prior to starting chemotherapy (page 1). One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Leever in order to gauge the subject’s overall health and treatment history to advantageously reduce the risk of complications, e.g., infection, during treatment with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 10, 17-18, and 21-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 9, 15-17, and 19 of copending Application No. 17/998,117 in view of Bardin.
The rejection of instant claims 1-3, 10, 17-18, and 23 is set forth above. The conflicting claims do not explicitly teach the limitations of instant claims 21-22. However, Bardin teaches that “[t]herapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individuali[z]e treatment by adapting drug dose to improve efficacy and/or reduce toxicity,” and that “cytotoxic drugs are characteri[z]ed by steep dose–response relationships and narrow therapeutic windows.” (Abstract).
It would have prima facie obvious at the time of filing to modify the conflicting claims in view of Bardin to include, inter alia, monitoring the subject for adverse reactions during the treatment period and the adjusting the treatment duration based on the subject’s response to the claimed agent based on its efficacy. One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Bardin in order to advantageously monitor the subject for adverse reactions and minimize the treatment duration with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments filed 12/03/2025 have been fully considered but they are not persuasive. Applicant’s arguments are discussed to the extent they apply to the current grounds of rejection set forth above.
On pages 10-11 of the Response, Applicant urges that prior art of record fails to suggest “that the same biomarkers, used in the same way, will predict sensitivity to a structurally related but distinct illudin analog, nor do they suggest the particular comparative framework required by the present claims, namely comparison to expression levels in a subject without solid tumor cancer.”
As discussed above, in addition to being structurally related, the prior art teaches that both irofulven and (-)HydroxyUreaMethylAcylfulvene (hereinafter “HUMA”) are illudin-based anti-cancer agent useful for treating solid tumor cancers, e.g., prostate cancer or breast cancer. As further discussed above, McMorris teaches that HUMA is an irofulven derivative effective to treat cancer with reduced toxicity compared to treatment with a substantially equally effective dose of irofulven. As such, given that both compounds are structurally similar illudin-based anti-cancer agents used for treatment of the same cancers, one of ordinary skill in the art would have had a reasonable and predicable expectation of success when applying the expression levels profiles of PTGR1, PTPN14, and ASPH to predict prognosis taught by Knudsen for irofulven to the method taught by McMorris using HUMA for the same purpose.
On pages 11-12 of the Response, Applicant urges, with respect to claim 20, that the “prior art does not suggest [the claimed] integrated use of health and treatment history within the claimed biomarker-defined HUMAF treatment algorithm.” Claim 20 broadly requires “assessing the subject’s overall health and treatment history before initiating the illudin-based anti-cancer therapy.” As discussed above, Leever teaches that it was routine at the time of filing for subjects to under to blood tests, medical exams, dental exams, etc. prior to starting chemotherapy. As such, Leever provides a clear teaching, suggestion, and motivation to assess a subject’s overall health and treatment history prior to administration of HUMA.
On page 12 of the Response, Applicant urges that the instant claims “involve adjusting treatment duration, not drug plasma concentration, based on clinical response in subjects who have already been selected for [HUMA] treatment by virtue of their biomarker profile and the specified comparative threshold.” As discussed above, Bardin teaches that it was well-known to monitor drugs in subject to individuali[z]e treatment by adapting drug dose to improve efficacy and/or reduce toxicity,” and that “cytotoxic drugs are characteri[z]ed by steep dose–response relationships and narrow therapeutic windows.” (Abstract). As such, Bardin provides a clear teaching, suggestion, and motivation to monitor a subject’s progress with and sensitivity to HUMA using the expression levels profiles of PTGR1, PTPN14, and ASPH taught by Knudsen with a reasonable expectation of success.
On pages 12-13 of the Response, Applicant urges that “the conflicting claims in the referenced applications do not recite this same combination of specific agent, biomarker panel, comparative normal-subject reference, and clinical use of the biomarker information.” Applicant’s arguments were fully considered, but were not found persuasive for the reasons set forth above.
Conclusion
NO CLAIMS ARE ALLOWED
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THOMAS J VISONE whose telephone number is (571)270-0684. The examiner can normally be reached Monday-Thursday, 8:30 AM to 6:30 PM.
Examiner interviews are available via telephone 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, Patricia Mallari can be reached at 571-272-4729. 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.
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672