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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 11, 2025, has been entered.
Response to Arguments
Applicant amended the claims to alter the preamble to require the method to be for reducing “exposure to bioavailable paclitaxel relative to intravenous administration of paclitaxel in treating” angiosarcoma is a subject. Applicant further, includes a bioavailability provided by the claimed administration.
Applicant argues that the bioavailability is drastically reduced compared to IV administration when administered in combination with compound A. Applicant appears to be arguing that the unexpected results is that the lower bioavailability is efficacious.
Applicant reiterates many of the same arguments attacking the references individually. Many of Applicant’s arguments are reiterated from a previous response. For those responses, the examiner reiterates his position.
Applicant’s arguments and allegations of unexpected results have been fully considered in their entirety.
The prior art 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 at these dosages. For example, there were almost no hematologic toxicities reported by Lee resulting from administration of the claimed combination. Kim also notes that HM30181 increased the oral bioavailability of paclitaxel by >12 times in rats. This provides a motivation to arrive at the claimed method and a clear road-map to optimize known result-effective variables. Paclitaxel is taught to be administered orally at a claimed dosage.
The examiner has added a New Matter Rejection below based on the Specification teaching enhanced oral bioavailability of the claimed combination. Moreover, the examiner maintains the obviousness rejection because the claimed active steps are rendered obvious by the cited prior art, as described in more detail below.
Penel teaches administering paclitaxel to treat angiosarcoma and Fujisawa independently teaches chemotherapeutic approaches to treat advanced cutaneous angiosarcoma include administration of paclitaxel. Fujisawa teaches 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. Thus, there is a reasonable expectation of success that paclitaxel will treat the claimed subject population and the oral bioavailability will be enhanced when combined with HM30181.
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 the prior art and the combination exhibits a dose linearity for PK parameters, Cmax and AUC.
Applicant argues that a dose of paclitaxel would be expected to yield a reduction of 87% relative to IV administration. This is equivalent to 27.5 mg/m2 according to Applicant.
The examiner notes that Applicant seems to be referencing paragraph 3569 of the Specification rather than the stated 3596. However, the 13.4% bioavailability seems to refer to orally administered paclitaxel without a P-gp inhibitor. 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.
More particularly that Kwak teaches: HM30181 increase oral bioavailability and therapeutic efficacy of paclitaxel. Kwak explains that co-administration of 10 mg/kg HM30181 increase oral bioavailability of 20 mg/kg paclitaxel from 3.4% to 41.3%, while Tmax and T1/2 did not change significantly. When 40 mg/kg paclitaxel and 20 mg/kg HM30181 were administered orally, tumor growth was inhibited by 94% and a remission was induced until day 47, which was superior to 20 mg/kg IV paclitaxel. Kwak explains that they are waiting validation in clinical trials that shows HM30181 increases in bioavailability and therapeutic efficacy of paclitaxel.
Moreover, if combination therapy with HM30181A and paclitaxel are well tolerated and Cmax and AUC exhibit dose linearity below a dosage of 300 mg/m2 paclitaxel, Applicant needs to show that that the claimed dosage is critical and note merely predictable in view of the known PK. Even further, the “lower dose” being administered is also presently being claimed for administration at least 3 time per week. Lee teaches administration approximately once weekly on days 1, 8, and 15. Similarly, Penel teaches administration on days 1, 8, and 15 on a 4-week cycle. Thus, it is not clear that a lower dose claimed to be administered 3-5 times per week, e.g., is different than a proportionally higher dose administered once weekly. Applicant could ultimately be claiming administration of an identical weekly dose that is spread out over 3 separate administrations. Even further, Kwak indicates that the tumor inhibitory strength of the combination of paclitaxel and HM30181 is equal to or greater that of intravenous paclitaxel. See Abstract. Thus, using a low dose of paclitaxel administered at least 3 times weekly would be expected to yield a benefit when the oral bioavailability is higher.
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. Whether or not described by the cited prior art, it is not clear how the claimed active steps undertaken on a same subject population would produce a different result and/or provide an unexpected showing. Further, part of optimization includes monitoring how well paclitaxel is working and what adverse events are resulting from treatment. Dose optimization includes not only how much API is administered at once, but also how frequent administrations are made.
As explained in the previous action, this is not an inherency argument, but rather a statement that the burden has been shifted to applicant to explain what specific structural limitations and/or steps distinguish over the cited prior art. The amendments to the claims are directed to a result of method steps that are rendered obvious by the cited prior art. The claimed combination, subject population, route of administration, and dosages for both claimed agents are rendered obvious by the cited prior art. Further, the claimed combination is taught by multiple prior art references.
As such, Applicant’s arguments are not persuasive.
Status of the Claims
Claims 11, 15, 16, and 20 are pending and examined.
Claim Rejections - 35 USC § 112
Claims 11, 15, 16, and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The claims are amended to recite that the claimed method reduces exposure to bioavailable paclitaxel relative to IV paclitaxel. The instant Specification discusses the exposure of orally administered paclitaxel when co-administered with compound A and in each instance recites: “wherein the plasma exposure of the orally administered paclitaxel, as measured by AUC), is equal to or greater than the plasma exposure, as measured by AUC), of intravenously administered paclitaxel…”. These statements appear to indicate that the result of the claimed method is to increase exposure of paclitaxel rather than to decrease it. The examiner also notes that the term AUC0-inf. refers to the total exposure of a drug. See Specification at p269, line 4. It is not clear that the goal to decrease paclitaxel oral exposure relative to IV exposure was contemplated to be reduced.
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 11, 15, 16, and 20 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.
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 1 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 inhibitor. However, 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 a 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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475
1434
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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. 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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328
987
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Kim teaches the following regarding a dose equal to 15 mg HM30181A.
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158
956
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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.
Applicant is claiming a result of combination therapy that is rendered obvious by the cited prior art. The claimed combination, subject population, and dosages of both of the claimed active agents are rendered obvious by the cited prior art. Applicant can incorporate distinct steps and/or structural limitations into the claims and explain how they obviate the obviousness of the combinations of teachings of the cited prior art as a whole.
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, Lee, Penel, Fujisawa, and Kim 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 to treat angiosarcomas 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. 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, which includes the claimed range of paclitaxel. Absent evidence to the contrary, the claimed dosage regimens are optimizable result-effective variables in view of the teachings 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