DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicants’ amendments to the claims of May 27, 2026, in response to the Office Action of December 2, 2025, are acknowledged.
Response to Arguments
Applicant’s arguments and allegations of unexpected results have been considered by the examiner.
In view of Applicant’s amendments to the claims, the § 112 rejection is withdrawn.
Applicant argues that the oral route of administration with 15 mg compound A and paclitaxel at a dose of 100 to 205 mg/m2 shows a consistent and dose-dependent PK profile. Applicant argues that administration 3 times weekly provides for a lower hematologic toxicity relative to IV paclitaxel. Applicant argues that the results of the claimed method are inherent. Further, Applicant argues that the pharmacokinetic (PK) profile includes approximately 14.3% absolute bioavailability and reduced adverse events (AEs). Applicant argues that the prior art does not provide a reasonable expectation of success that the claimed method would provide a claimed benefit. Applicant argues that the Specification demonstrates that the combination administered demonstrates a consistent response that is dose-dependent rather than unpredictable or idiosyncratic. Applicant alleges that these properties are an “inherent pharmacokinetic consequence” when practiced.
The examiner notes that extrapolatable and relative dose-linearity, as well as consistency with respect to PK is not an example of an unexpected result, per se. It may be an indication of a clear roadmap for the optimization of known result-effective variables for a predictable outcome. Further, inherency is alleged by Applicant to show that the PK are a direct consequence of administration.
The examiner also notes that a criticality of claimed dosage has also not been established through a comparison to dosages outside of the claimed range. Unexpected results are not established merely because a result is inherent. It is not clear to the examiner why Applicant is alleging results to be inherent to the claimed active steps.
Applicant argues that the prior art does not teach that the claimed combination can provide a restricted bioavailability profile while reducing toxicity.
The examiner notes that the claims are directed at administering an optimizable combination of agents. When these two agents are optimized to increase efficacy and mitigate AEs, they would yield an optimal treatment regimen. The roadmap for optimization would be clear in view of the cited prior art. As shown below, the safety and efficacy of more frequent and less frequent administrations than that claimed are each established on the record.
For example, Lee teaches administering 120 mg/m2 to 300 mg/m2 paclitaxel. Combination treatment includes dosages of 30-210 mg/m2 HM30181A and up to 180 mg/m2 paclitaxel exhibited almost no hematologic toxicities. See Tables 2-4.
Applicant argues that that the prior art fails to provide a predictable optimization path and leads away from the claimed approach.
The examiner cites: Malingré et al., “A phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A,” Cancer Chemother Pharmacol (2001) 47: 347-354.
Malingré noted that twice daily 90 mg/m2 oral paclitaxel showed the highest systemic exposure with good safety. See Abstract. Cyclosporin A (CsA) is used because it is an inhibitor of P-gp. Similar to the claims, co-administration of CsA provides for an increase in systemic exposure from negligible to therapeutic levels. Once daily administration testing was encouraging and thus, twice daily administration was encouraged to further prolong systemic exposure. See p348, 1st full par. Malingré explains that multiple administrations per day yielded a different PK than a single daily dose. In particular,
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Malingré showed that oral paclitaxel administered even multiple times daily with a p-gp inhibitors is a feasible option for increasing systemic exposure with good safety. The use of fractionated or more frequent dosing was also shown to be safe with a relatively predictable PK profile.
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The above chart shows that there were less toxicities for 160 mg/m2 twice daily orally than there were for IV paclitaxel 175 mg/m2. This trend also appears for non-hematologic malignancies. See Table 2, p350.
In light of Malingré the predictability of administration of paclitaxel with a p-gp inhibitor as frequently as multiple times daily would be understood as safe and effective. The systemic exposure would increase while the incidence of AEs, including hematologic toxicities, would be expected to remain low at claimed dosages. This was the case with doses of up to 160 mg/m2 twice daily of oral paclitaxel. Thus, the safety of administering a substantially lower overall dose once every 2-3 days, as claimed, would appear to be understood in view of the safety of more rapid administration.
Kwak teaches: “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. The combination of HM30181 and paclitaxel is motivated by prior art.
Applicant is now arguing that the claimed method provides a “restricted bioavailability” profile when reducing toxicities.
The examiner is not clear on how bioavailability being more restricted with the claimed combination occurs and how this would be an unexpected result if it were.
According to Kwak, “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. Kim teaches that HM30181 increased the oral bioavailability of paclitaxel by >12 times in rats.
The prior art also teaches administration of paclitaxel for treating angiosarcoma and advanced cutaneous angiosarcoma and is taught to have substantially enhanced oral bioavailability when co-administered with a p-gp efflux inhibitor, such as compound A. This is due to a main mechanism limiting oral bioavailability being p-gp efflux. Thus, the active steps of administering paclitaxel and compound A to treat angiosarcoma are motivated with a reasonable expectation of success. Moreover, the combination is taught to be well tolerated with Cmax and AUC parameters exhibiting a dose linearity below a dosage of 300 mg/m2 paclitaxel. Adverse events were also known to be limited to these dosages. For example, there were almost no hematologic toxicities reported by Lee resulting from administration of the claimed combination. Similarly, Kim also notes that HM30181 increased the oral bioavailability of paclitaxel by >12 times in rats. This provides motivation to arrive at the claimed method and a clear roadmap to optimize known result-effective variables. Paclitaxel is taught to be administered orally at a claimed dosage.
Unexpected results are not shown because it is not a surprise that paclitaxel treats angiosarcoma. It is also not a surprise that compound A, a known P-gp inhibitor, substantially increases the oral bioavailability and therapeutic efficacy of paclitaxel. It is further not a surprise that the claimed dosages work because they overlap those taught by prior art and the combination exhibits a dose linearity for PK parameters, Cmax and AUC. Further, it is not a surprise that hematologic toxicities were absent as this was shown to the case for claimed dosages.
Optimizing two known result-effective variables that are known to provide a synergistic bioavailability when administered orally- and exhibit a dose linearity PK profile, requires nothing more than routine experimentation. The combination of prior art teaches that twice daily administration can be safe as well as once daily administration, as well as less frequently. The prior art also teaches that fractionated administrations twice daily can have an effect of prolonging systemic exposure compared to a single daily dose. However, the PK of the claimed combination is established. There does not appear to be any showing provided of an unexpected result.
As such, Applicant’s arguments are not persuasive.
Status of the Claims
Claims 16, 20, and 22-34 are pending and examined.
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 16, 20, and 22-34 are rejected under 35 U.S.C. 103 as being unpatentable over Broder et al., (U.S. Pat. No. 6,610,735), 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, 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 Penel et al., “Phase II Trial of Weekly Paclitaxel for Unresectable Angiosarcoma: The ANGIOTAX Study,” Journal of Clinical Oncology, Vol. 26, No. 32, November 10, 2008, and in view of Fujisawa et al., “Cutaneous Angiosarcoma: The Possibility of New Treatment Options Especially for Patients with Large Primary Tumor,” Frontiers in Oncology, March 2018, Vol. 9, Article 46, and in view of Kim TE, Lee H, Lim KS, et al. Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers. Br J Clin Pharmacol. 2014;78(3):556-564, and in view of Malingré et al., “A phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A,” Cancer Chemother Pharmacol (2001) 47: 347-354.
Broder teaches a method of increasing the oral bioavailability of paclitaxel by co-administering an agent that enhances the oral bioavailability. See Abstract. In particular, coadministration with a P-gp efflux inhibitor is contemplated. A number are known, e.g. See col. 1, lines 53-59. It was surprisingly discovered that P-gp inhibitors can be used to substantially increase the oral bioavailability of paclitaxel. See col. 4, lines 14-20. Further, the dosage of the enhancing agent can be about 0.1 to about 15 mg/kg and this includes co-administration or administration at a similar time. See col. 13, lines 54-60. Further, paclitaxel can be administered at an oral dosage of 20 mg/m2 to 1000 mg/m2 in a single daily dose. See col. 14, lines 63-65. Even further, a dosing schedule includes a preferred oral dosing schedule of paclitaxel administered in a single daily dose of 20 mg/m2 to 1000 mg/m2 continued for 4 consecutive days. See col. 17, lines 52-53.
Kwak teaches: “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 is 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. Kwak teaches administration of HM30181A one hour prior to paclitaxel treatment. See p235, 4th full par.
Lee 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 inhibition. However, administration of HM30181A with paclitaxel is shown to be efficacious. 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 205 mg/m2 paclitaxel is above a dosage taught to be efficacious and below the MTD for paclitaxel.
Further, peak plasma concentrations occur rapidly including within 0.5-1 hr based on the rapid absorption. See p239, 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 predictability for routine dosage optimization. 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 tolerated than a three-week schedule. Both regimens should remain in consideration. 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).
Kwak and Lee do not teach paclitaxel for treatment of angiosarcoma.
Penel teaches that paclitaxel was administered to mice with angiosarcoma and it was well tolerated and demonstrated clinical benefit. See Abstract.
Fujisawa teaches chemotherapeutic approaches to treat advanced cutaneous angiosarcoma, including treatment with paclitaxel. As shown below in Table 3 of Fujisawa, response ratios of response to median survival in months has been shown to be as high as 78% and 89% for CAS. See Table 3, below.
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Kim teaches the following regarding a dose equal to 15 mg HM30181A.
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It is not unexpectedly superior to use 15 mg or a higher known safe dose of compound A, because is it used to increase therapeutic efficacy and oral bioavailability by inhibiting P-gp efflux. P-gp is overexpressed in cancer cells, which results in MDR. Kim also notes that HM30181 increased the oral bioavailability of paclitaxel by >12 times in rats.
As such, using the claimed dose of HM30181 is not only known, but it would also be optimizable because it is a known result-effective variable expected to provide a maximal benefit on efflux inhibition at approximately 15 mg. HM30181 is taught to be safe with low systemic absorption. Thus, 15 mg may be all that is needed to fully inhibit paclitaxel efflux and using a higher dose would not appear to substantially alter efflux inhibition.
Malingré noted that twice daily 90 mg/m2 oral paclitaxel showed the highest systemic exposure with good safety. See Abstract. Cyclosporin A (CsA) is used because it is an inhibitor of P-gp. Similar to the claims, co-administration of CsA provides for an increase in systemic exposure from negligible to therapeutic levels. Once daily administration testing was encouraging and thus, twice daily administration was encouraged to further prolong systemic exposure. See p348, 1st full par. Malingré explains that multiple administrations per day yielded a different PK than a single daily dose. In particular,
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Malingré showed that oral paclitaxel administered even multiple times daily with a p-gp inhibitors is a feasible option for increasing systemic exposure with good safety. The use of fractionated or more frequent dosing was also shown to be safe with a relatively predictable PK profile.
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The above chart shows that there were less toxicities for 160 mg/m2 twice daily orally than there were for IV paclitaxel 175 mg/m2. This trend also appears for non-hematologic malignancies. See Table 2, p350.
In light of Malingré the predictability of administration of paclitaxel with a p-gp inhibitor as frequently as multiple times daily would be understood as safe and effective. The systemic exposure would increase while the incidence of AEs, including hematologic toxicities, would be expected to remain low at claimed dosages. This was the case with doses of up to 160 mg/m2 twice daily of oral paclitaxel. Thus, the safety of administering a substantially lower overall dose once every 2-3 days, as claimed, would appear to be understood in view of the safety of more rapid administrations.
With regard to new claim 34, the examiner notes that a methanesulfonate hydrate salt form of compound A has been known since at least as early as May 25, 2017, in the STN database. See STN RN: 2097125-58-9. Further, the use of any known pharmaceutically acceptable salt form or hydrate of a known API does not obviate a prima facie showing absent evidence to the contrary.
It would have been primarily obvious to a person of ordinary skill in the art prior to filing the instant application to combine the teachings of Kwak, Lee, Penel, Fujisawa, Kim, and Malingré to arrive at the claimed methods. One would be motivated to do so because the combination of paclitaxel and HM30181 is taught to be co-administered and administered such that both agents are active in a subject at the same time. The use of paclitaxel is established for treating the claimed subject population. Further, they are taught to treat angiosarcomas because HM30181 potently and selectively inhibits MDR1, which pumps paclitaxel out of cells. Thus, the combination is expected to have a synergistic effect in enhancing the bioavailability of paclitaxel and, irrespective of the specific mode of action, there is a clear motivation to administer the claimed combination to a claimed subject population. Further, the combination has an effective concentration that is safe and effective when paclitaxel is administered in a range of 120 to 300 mg/m2. Malingré explains that multiple administrations per day yielded a different PK than a single daily dose. Fractionated multiple daily administrations yielded higher systemic exposure. Each of the claimed methods were shown to be safe with limited toxicities even as compared to intravenous doses. Further, paclitaxel is taught to be well tolerated and provide a therapeutic benefit in treating cutaneous angiosarcoma. Similarly, response ratios have been shown to be high when treating CAS with paclitaxel. As such, it would be obvious to administer a combination of paclitaxel with HM30181 to treat CAS and angiosarcoma in a subject because paclitaxel is known to treat this species of cancer and a POSA would begin optimization by administering a dosage that is shown to be effective and well tolerated. Absent evidence to the contrary, the claimed dosage regimens are optimizable result-effective variables in view of the prior art. This rejection is based on the obviousness of the active steps of administration.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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