DETAILED ACTION
All rejections and objections not mentioned below have been withdrawn.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Acknowledgment is made of applicant’s claim for priority in parent Application No. 62/195,243, filed on 7/21/2015.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/31/2025 and 08/20/2025 are being considered by the examiner.
Claim Rejections - 35 USC § 103- Modified due to Amendments
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 67-69 and 79-86 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kwak et al., “Selective inhibition of MDR1 (ABCB1) by HM30181 increase oral bioavailability and therapeutic efficacy of paclitaxel,” European Journal of Pharmacology 627 (2010) 92-98 (IDS) (previously provide) in view of Lee et al., “A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer,” Cancer Res Treat 2014;46(3):234-242 (previously provide) in view of FDA, US Label. Taxol® (paclitaxel) injection (patient information included), Reference ID: 2939751. Bristol-Myers-Squibb Company. 2011 (previously provide) further in view of Ten Tije( Ten Tije et al European Journal of Cancer 40 (2004) 352–357) (previously provide) further in view of Martín (Breast Cancer Research (06/12/2015) 17:81) (previously provide) further in view of Broder (Broder et al., US 5968972 A, 1999) (previously provide) further in view of Kim (Kim et al., Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers, Br J Clin Pharmacol / 78:3 / 556–564, 2014).
Kwak teaches: “Multi-drug resistance 1 (MDR1, ABCB1), also known as P-glycoprotein (P-gp), restricts intestinal uptake of many drugs, and contributes to cellular resistance to cancer chemotherapy. In this study, we examined the pharmacologic characteristics of HM30181, a newly developed MDR1 inhibitor, and tested its capacity to ; increase the oral bioavailability and efficacy of paclitaxel, an anti-cancer drug usually given by intravenous injection” and “Treatment with HM30181 significantly increased the oral bioavailability of paclitaxel.” Compared to the control wherein 3.4% was absorbed, co-administration resulted in bioavailability of 41.3%; Cmax increased from 127.2 to 1253. Further, combination therapy yielded remission in mice until day 47, a result superior to that of paclitaxel monotherapy. The co-administration of 20 mg/kg paclitaxel and 10 mg/kg HM30181 given orally suppressed tumor growth by about 75%. Further, 40 mg/kg and 20 mg/kg, respectively, inhibited tumor growth 94% and induced remission. See p97, 2nd full par. Paclitaxel is widely used to treat breast, lung, head and neck, and ovarian cancers. However, multi-drug resistant cancer cells are difficult to treat because cells pump the drug out of the cells (p92). This helps to teach claims 67-69 and 79-86.
The reference Kwak also teaches “Treatment with HM30181 significantly increased the oral bioavailability of paclitaxel. The AUC for control i.v. paclitaxel (6 mg/kg) was 2728.1± 281.7 ng h/mL. The AUC value for oral paclitaxel-alone (20 mg/kg) was 308.5±160.6 ng h/mL, indicating that only 3.4% of orally administered paclitaxel was absorbed. Co-administration of HM30181 (10 mg/kg) increased the AUC of oral paclitaxel (20 mg/kg) to 3756.5± 865.9 ng h/mL, which corresponds to an oral bioavailability of 41.3%. In addition, the Cmax value increased from 127.2± 72.9 ng/mL to 1253.7±269.8 with HM30181, while Tmax and t1/2 did not change significantly) (page 95). This helps to teach claims 68, 69, 79-81, 83.
The reference Kwak does not specifically teach the amount of paclitaxel (all claims) or the time frame of dosing (all claims) or hypersensitivity (claim 69) and neurotoxicity (claim 68).
The reference Lee teaches “The purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers”(Purpose Section). Lee teaches administration of HM30181A 1 hour prior to paclitaxel treatment. See p235, 4th full par. Lee et al. teaches: an effective plasma concentration of paclitaxel was achieved at 120 mg/m2 and absorption appeared to be limited at dosages above 300 mg/m2. Lee explains that an effective concentration of paclitaxel was achieved with a dose of 120 mg/m2. A major obstacle to efficacy of paclitaxel is P-gp. However, HM30181A with paclitaxel is shown to be efficacious increased the oral bioavailability of paclitaxel. Dose levels shown in Table 2 administer combinations ranging from 30-210 mg/m2 HM30181A and 60 up to 180 mg/m2 paclitaxel with almost no hematologic toxicities. See Tables 2-4. The claimed dosage of 200 mg/m2 ± 20 % paclitaxel is above a dosage taught to be efficacious and below the MTD for paclitaxel and includes 180 mg/m2. This helps to teach claim 84.
The reference Lee teaches “Recently, efforts have been focused on developing an oral formulation of paclitaxel. The potential advantages of oral formulation include the following: lack of
hypersensitivity, convenience for patients, and potential continuous exposure to paclitaxel”(p.234) and “The common toxicities of conventional paclitaxel include hypersensitivity, neutropenia, and neuropathy [1]. CrEL is a well-documented risk factor of hypersensitivity reactions, and CrEL-free formulations do not cause hypersensitivity reactions [3,21,22]. Oral paclitaxel and HM30181A did not induce hypersensitivity reactions without premedication, similar to the other CrEL-free paclitaxel formulations. The major determinant of neutropenia could be the length of time in which the upper limit of the paclitaxel therapeutic level (0.1 μM) is exceeded [1]. In this study, the duration of time for which the upper limit of the paclitaxel therapeutic level was exceeded was much shorter than that for which the lower limit of the therapeutic level (0.01 μM) was exceeded. Such property may have contributed to the low incidence of neutropenia in our study”(p.240). Additionally, since the active step of the method is obvious over the art, e.g. administering the composition to a cancer subject the claim has been taught even if what the method has been suggest for was not present the method has still been made obvious. This helps to teach claim 69 and 68.
Further, peak plasma concentrations occur rapidly including within 0.5-1 hr based on the rapid absorption. See p238, par. 1st. Pharmacokinetic parameters for paclitaxel by dose are shown in Table 5. Table 2 shows that combination therapy with HM30181A and paclitaxel are well tolerated and Cmax and AUC exhibit dose linearity below a dosage of 300 mg/m2 paclitaxel. This provides a predictability for routine dosage optimization. Additionally one would have a reasonable expectation that increasing bioavailability though HM30181A would increase plasma concentrations of paclitaxel which would be expected to increase AUC. Additionally, table 5 teaches AUC within the ranges of claim 81. This helps to teach claims 68-69 and 79-81 and 83.
Administration was studied for cycles of 1, 8, 15, and 28 day cycles of administration. See abstract. HM30181 was escalated from 30-210 mg/m2. Table 2 below shows that dosage combinations and those that had a dose limited toxicity.
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Overall, co-administration of 120 mg/m2 paclitaxel was achieved with HM30181A without significant toxicity. Several studies report that weekly paclitaxel is highly active and better tolerate than a three-weekly schedule. Both regimens should remain in consideration. (p.240) Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). This helps to teach claims 67-69 and 79-85.
The reference Broder teaches “Method For Increasing The Oral Bioactivity Of Pharmaceutical Agents”(title) and “Dosing schedules for the treatment method of the present invention, for example, the treatment of paclitaxel-responsive diseases with oral paclitaxel dosage forms co-administered with enhancing agents, can likewise be adjusted to account for the patient's characteristics and disease status. Preferred dosing schedules for administration of oral paclitaxel are (a) the daily administration to a patient in need thereof of 1-3 equally divided doses providing about 20-600 mg/m2 (based on body surface area), with said daily administration being continued for 1-4 consecutive days each 2-3 weeks, or (b) administration for about one day each week. The former schedule is comparable to use of a 96-hour paclitaxel infusion every 2-3 weeks, which is considered by some a preferred IV treatment regimen. A preferred dosing schedule for oral administration of etoposide co-administered with enhancing agents is the daily administration to a patient in need thereof of 1-3 equally divided doses providing about 50-100 mg/m.sup.2 (based on body surface area) in the treatment of patients with testicular cancer and about 35-50 mg/m.sup.2 as a daily dose in the treatment of small cell lung cancer, with the daily administration being continued for 5-21 days in each case and with a period of about 2-3 weeks in between each course of treatment”(column 12-13). This helps to teach claims 82 and 85.
The FDA reference teaches “Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of TAXOL at dose levels of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table” (page 2, table 1) and “The recommended regimen is TAXOL 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks”(page 45). The reference Ten Tije teaches “Paclitaxel is a cytotoxic agent with proven antitumour activity in metastatic breast cancer. Weekly administration of paclitaxel has demonstrated sustained efficacy together with a more favourable toxicity profile (e.g. less myelotoxicity) than the 3-weekly administration. This study evaluates the activity and toxicity of weekly paclitaxel (Taxol1) as first-line chemotherapy in elderly patients (>70 years of age) with hormone-refractory metastatic breast cancer. Patients with metastatic breast cancer received 80 mg/m2 paclitaxel administered weekly on days 1, 8 and 15 of a 28-day cycle”(abstract) and “Paclitaxel (Taxol1, Bristol-Myers Squibb, Woerden, The Netherlands) was infused intravenously (i.v.) over 1 h, at a dose of 80 mg/m2 , and given on days 1, 8 and 15 of a 28 day cycle”(Section 2.2). The reference Martín teaches “The recommended starting dose of nab-paclitaxel for the treatment of MBC is 260 mg/m2 administered intravenously over 30 min q3w[every 3 weeks]”(page 1-2). It would have been prima facie obvious to a person of ordinary skill in the art prior to filing the instant application to combine the teachings of the FDA , Martin or Ten Tije references because they were previously known and approved treatment method for TAXOL alone with the combinations taught by Lee or Kwak since one would want to compare the oral administration to a well known i.v. method. One would expect the AUC of the combination of the two compounds to be higher because Kwak teaches that the AUC of a comparison was higher than the control i.v. paclitaxel. Additionally one would have a reasonable expectation that increasing bioavailability though HM30181A would increase plasma concentrations of paclitaxel which would be expected to increase AUC. One would have been motivated to do so to remove some of the disadvantages of the i.v. method as discussed above. It would have been obvious to have a significantly higher oral dose (and/or with more dosages) than intravenous to achieve a similar result as Kwak; a much higher AUC for the combination versus the control this would help teach the instant claims since the ratio of dose and dosages of oral versus intravenous has also not been specified in the instant claims. Additionally, since the active step of the instant claim has been rendered obvious, the therapeutic effect would necessarily follow via conducting the method. This helps to teach claims 68 and 79-80 and 83.
The reference Kim teaches “The present study also showed that HM30181 had a rather flat dose–response profile over the range of 15 to 180 mg (Tables 1 and 2; Figures 2 and 3). This finding may suggest that the P-gp inhibition effect of HM30181 was saturated at doses lower than or equal to 15 mg. Further studies are warranted to investigate adequately the dose– response relationship profile of HM30181, particularly at doses <15 mg”(page 562) and “Collectively, the moderate inhibition of P-gp by HM30181, thought to be primarily in the intestine, may be construed as beneficial because it enables more specific P-gp inhibition, leading to fewer adverse events” (page 562). This helps to teach claims 67-69 and 79-86.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill might reasonably infer from the teachings. See In re opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA 1976). A reference is not limited to working examples. See In re Fracalossi 215 USPQ 569 (CCPA 1982).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing date of the instant application to combine the teachings of Kwak and Lee to arrive at the claimed methods because they both teach on the combination of paclitaxel and HM30181. One would be motivated to do so because the combination of paclitaxel and HM30181 are taught to be co-administered to treat cancers because HM30181 potently and selectively inhibits MDR1, which pumps paclitaxel out of cells. Thus, the combination has a synergistic effect in enhancing the bioavailability of paclitaxel. Further, the combination has an effective concentration that is safe and effective when in the range of 120 to 300 mg/m2. The claimed concentration of paclitaxel all fall within this range.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing date of the instant application to combine the teachings of Kwak and Lee with Kim because Kim teaches the compound HM30181 and so it would have been obvious to use concentrations in the range of 15 mg doses because Kim teaches the compound HM30181 was saturated at doses lower than or equal to 15 mg. One would have been motivated to use doses in this range to limit any undesirable side effects from unnecessarily high doses. One would have a reasonable expectation of success because HM30181 and paclitaxel have already been shown to work in combination with each other and HM30181 has been shown to saturate at 15 mg or less.
It would have been prima facie obvious to a person of ordinary skill in the art prior to filing the instant application to combine the teachings of Kwak and Lee with the teachings of Broder because all three teach on combining paclitaxel with an agent to enhance bioavailability. Thus it would be obvious to use the suggest amounts and time frame of Broder for paclitaxel in combination with HM30181 as the enhancing agent because it is just substituting known compound for the same purpose of enhancing the bioavailability of paclitaxel. One would have a reasonable expectation of success because all three teaches are for paclitaxel bioavailability enhancement and thus it has a reason expectation to work. One would be motivated to do so to enhance bioavailability of paclitaxel for cancer treatment.
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 67 and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 11, 14-16 and 19-20 of copending Application No. 17/963,504 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claim being examined is generic to a species or sub-genus claimed in a conflicting patent application.
The application ‘504 claims:
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This anticipates claims 67 and 69.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 67-69 and 79-86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 11, 14-16 and 19-20 of copending Application No. 17/963,504 in view of Kwak et al., “Selective inhibition of MDR1 (ABCB1) by HM30181 increase oral bioavailability and therapeutic efficacy of paclitaxel,” European Journal of Pharmacology 627 (2010) 92-98 (IDS) in view of Lee et al., “A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer,” Cancer Res Treat 2014;46(3):234-242 in view of FDA, US Label. Taxol® (paclitaxel) injection (patient information included), Reference ID: 2939751. Bristol-Myers-Squibb Company. 2011 further in view of Ten Tije( Ten Tije et al European Journal of Cancer 40 (2004) 352–357) further in view of Martín (Breast Cancer Research (06/12/2015) 17:81) further in view of Broder (Broder et al., US 5968972 A, 1999) .
The application ‘504 claims:
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This helps to teach claim 67-69 and 79-85.
The application ‘504 does not specifically teach the amount of paclitaxel or AUC(68, 79, 81, 80, 82-84) or the time frame of dosing (85) or hypersensitivity (claim 69) and neurotoxicity (claim 68).
The secondary references further teach that all needed changes would be obvious as outlined in the 103 rejection (which is incorporated herein by reference).
It would have been prima facie obvious to a person of ordinary skill in the art to combine the teachings of application ’504 with Kwak and Lee to arrive at the claimed methods because they all teach on the combination of paclitaxel and HM30181. One would be motivated to do so because the combination of paclitaxel and HM30181 are taught to be co-administered to treat cancers because HM30181 potently and selectively inhibits MDR1, which pumps paclitaxel out of cells. Thus, the combination has a synergistic effect in enhancing the bioavailability of paclitaxel. Further, the combination has an effective concentration that is safe and effective when in the range of 120 to 300 mg/m2. The claimed concentration of paclitaxel all fall within this range. Absent evidence to the contrary, the claimed dosage regimens are optimizable result-effective variables in view of the teachings of the prior art. Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing date of the instant application to combine the teachings of application ’504 and Kwak and Lee with Kim because Kim teaches the compound HM30181 and so it would have been obvious to use concentrations in the range of 15 mg doses because Kim teaches the compound HM30181 was saturated at doses lower than or equal to 15 mg. One would have been motivated to use doses in this range to limit any undesirable side effects from unnecessarily high doses. One would have a reasonable expectation of success because HM30181 and paclitaxel have already been shown to work in combination with each other and HM30181 has been shown to saturate at 15 mg or less.
It would have been prima facie obvious to a person of ordinary skill in the art prior to filing the instant application to combine the teachings of the FDA , Martin or Ten Tije references because they were previously known and approved treatment method for TAXOL alone with the combinations taught by Lee or Kwak since one would want to compare the oral administration to a well known i.v. method. One would expect the AUC of the combination of the two compounds to be higher because Kwak teaches that the AUC of a comparison was higher than the control i.v. paclitaxel. Additionally one would have a reasonable expectation that increasing bioavailability though HM30181A would increase plasma concentrations of paclitaxel which would be expected to increase AUC. One would have been motivated to do so to remove some of the disadvantages of the i.v. method as discussed above. It would have been obvious to have a significantly higher oral dose (and/or with more dosages) than intravenous to achieve a similar result as Kwak; a much higher AUC for the combination versus the control this would help teach the instant claims since the ratio of dose and dosages of oral versus intravenous has also not been specified in the instant claims. Additionally, since the active step of the instant claim has been rendered obvious, the therapeutic effect would necessarily follow via conducting the method. This helps to teach claims 68 and 79-80 and 83.
It would have been prima facie obvious to a person of ordinary skill in the art prior to filing the instant application to combine the teachings of Kwak and Lee with the teachings of Broder because all three teach on combining paclitaxel with an agent to enhance bioavailability. Thus it would be obvious to use the suggest amounts and time frame of Broder for paclitaxel in combination with HM30181 as the enhancing agent because it is just substituting known compound for the same purpose of enhancing the bioavailability of paclitaxel. One would have a reasonable expectation of success because all three teaches are for paclitaxel bioavailability enhancement and thus it has a reason expectation to work. One would be motivated to do so to enhance bioavailability of paclitaxel for cancer treatment.
This is a provisional nonstatutory double patenting rejection.
Claims 67 and 69 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-13 of copending Application No. 18/689,344 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claim being examined is generic to a species or sub-genus claimed in a conflicting patent application.
The application ‘344 claims:
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This anticipates instant claims 67 and 69.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 67-69 and 79-86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-13 of copending Application No. 18/689,344 in view of Kwak et al., “Selective inhibition of MDR1 (ABCB1) by HM30181 increase oral bioavailability and therapeutic efficacy of paclitaxel,” European Journal of Pharmacology 627 (2010) 92-98 (IDS) in view of Lee et al., “A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer,” Cancer Res Treat 2014;46(3):234-242 in view of FDA, US Label. Taxol® (paclitaxel) injection (patient information included), Reference ID: 2939751. Bristol-Myers-Squibb Company. 2011 further in view of Ten Tije( Ten Tije et al European Journal of Cancer 40 (2004) 352–357) further in view of Martín (Breast Cancer Research (06/12/2015) 17:81) further in view of Broder (Broder et al., US 5968972 A, 1999) .
The application ‘344 claims:
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This helps to teach claim 67-69 and 79-85.
The application ‘344 does not specifically teach the amount of paclitaxel or AUC(68, 79, 81, 80, 82-84) or the time frame of dosing (85) or hypersensitivity (claim 69) and neurotoxicity (claim 68).
The secondary references further teach that all needed changes would be obvious as outlined in the 103 rejection (which is incorporated herein by reference).
It would have been prima facie obvious to a person of ordinary skill in the art to combine the teachings of application ‘344 with Kwak and Lee to arrive at the claimed methods because they all teach on the combination of paclitaxel and HM30181. One would be motivated to do so because the combination of paclitaxel and HM30181 are taught to be co-administered to treat cancers because HM30181 potently and selectively inhibits MDR1, which pumps paclitaxel out of cells. Thus, the combination has a synergistic effect in enhancing the bioavailability of paclitaxel. Further, the combination has an effective concentration that is safe and effective when in the range of 120 to 300 mg/m2. The claimed concentration of paclitaxel all fall within this range. Absent evidence to the contrary, the claimed dosage regimens are optimizable result-effective variables in view of the teachings of the prior art. Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing date of the instant application to combine the teachings of application ‘344 and Kwak and Lee with Kim because Kim teaches the compound HM30181 and so it would have been obvious to use concentrations in the range of 15 mg doses because Kim teaches the compound HM30181 was saturated at doses lower than or equal to 15 mg. One would have been motivated to use doses in this range to limit any undesirable side effects from unnecessarily high doses. One would have a reasonable expectation of success because HM30181 and paclitaxel have already been shown to work in combination with each other and HM30181 has been shown to saturate at 15 mg or less.
It would have been prima facie obvious to a person of ordinary skill in the art prior to filing the instant application to combine the teachings of the FDA , Martin or Ten Tije references because they were previously known and approved treatment method for TAXOL alone with the combinations taught by Lee or Kwak since one would want to compare the oral administration to a well known i.v. method. One would expect the AUC of the combination of the two compounds to be higher because Kwak teaches that the AUC of a comparison was higher than the control i.v. paclitaxel. Additionally one would have a reasonable expectation that increasing bioavailability though HM30181A would increase plasma concentrations of paclitaxel which would be expected to increase AUC. One would have been motivated to do so to remove some of the disadvantages of the i.v. method as discussed above. It would have been obvious to have a significantly higher oral dose (and/or with more dosages) than intravenous to achieve a similar result as Kwak; a much higher AUC for the combination versus the control this would help teach the instant claims since the ratio of dose and dosages of oral versus intravenous has also not been specified in the instant claims. Additionally, since the active step of the instant claim has been rendered obvious, the therapeutic effect would necessarily follow via conducting the method. This helps to teach claims 68 and 79-80 and 83.
It would have been prima facie obvious to a person of ordinary skill in the art prior to filing the instant application to combine the teachings of Kwak and Lee with the teachings of Broder because all three teach on combining paclitaxel with an agent to enhance bioavailability. Thus it would be obvious to use the suggest amounts and time frame of Broder for paclitaxel in combination with HM30181 as the enhancing agent because it is just substituting known compound for the same purpose of enhancing the bioavailability of paclitaxel. One would have a reasonable expectation of success because all three teaches are for paclitaxel bioavailability enhancement and thus it has a reason expectation to work. One would be motivated to do so to enhance bioavailability of paclitaxel for cancer treatment.
Response to Arguments
Applicant's arguments filed 08/20/2025 have been fully considered but they are not persuasive.
The applicant has amended the claims to require a more specific range of dosages of compound A and argues the dosages of the references for paclitaxel are different than the instant claims (pages 7-8 of remarks). These arguments were not found persuasive because the dosages of paclitaxel of the instant invention do overlap with those of the references for instance Lee et al. teaches: an effective plasma concentration of paclitaxel was achieved at 120 mg/m2 (oral doses between 60 to 420 mg/m2(materials and methods section)) and absorption appeared to be limited at dosages above 300 mg/m2 in a study combining HM30181A and paclitaxel so it would be obvious to use paclitaxel in this range. Since the instant claims require about 100 mg/m2 to about 400 mg/m2 and the reference Lee teaches dosages in this range the argument that the reference Lee greatly exceeds the claimed amount was considered unpersuasive.
As the claims have now been amended to claim a range of Compound A from about 15 mg-30mg a new reference Kim has been added to the 103 rejection. Kim teaches that the P-gp inhibition effect of HM30181 was saturated at doses lower than or equal to 15 mg. One would have been motivated to use doses in this range to limit any undesirable side effects from unnecessarily high doses and thus it would have been obvious to use doses in this range. Thus the argument based on the amount of compound A are also considered unpersuasive.
Conclusion
Claims 67-69 and 79-86 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/A.A.S./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627