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
This application is a 371 of PCT/EP2019/086125, filed December 18, 2019, and claims foreign priority to EP1821548, filed December 21, 2018.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/18/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-2, 5, 12, 15, 18, 20-25, 28 and 32-36 are currently pending and subject to examination.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claims 1, 3-4, 12, 15, 23 and 24 under 35 U.S.C. 103 as obvious over Weger et al. (European Journal of Cancer, Vol. 86, November 2017, pages 217-225, Published October 12, 2017) (of record) in view of Zeldin & Petruschke (Journal of Antimicrobial Chemotherapy, 2004, Vol. 53, p. 4-9, Published December 4, 2003) is withdrawn.
The above rejection was overcome by Applicant’s amendments to the claims.
Claim Rejections – 35 USC § 103 – Previously Presented
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.”
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The rejection of claims 1-2, 5, 11-15, 23-25, and 31-36 under 35 U.S.C. 103 as being unpatentable over Weger et al. (European Journal of Cancer, Vol. 86, November 2017, pages 217-225, Published October 12, 2017) (of record) and Zeldin & Petruschke (Journal of Antimicrobial Chemotherapy, 2004, Vol. 53, p. 4-9, Published December 4, 2003), as applied to claims 1, 3-4, 11-15, and 23-24 above, and further in view of Ikezoe et al. (Cell and Tumor Biology, Vol. 64, No. 20, 2004, pages 7426-7431, Published October 15, 2004) (of record) is maintained.
The rejection of claims 1-5, 12, 15, 18, 20-25, 28 and 31 under 35 U.S.C. 103 as being unpatentable over Weger et al. (European Journal of Cancer, Vol. 86, November 2017, pages 217-225, Published October 12, 2017) (of record), Zeldin & Petruschke (Journal of Antimicrobial Chemotherapy, 2004, Vol. 53, p. 4-9, Published December 4, 2003), and Ikezoe et al. (Cell and Tumor Biology, Vol. 64, No. 20, 2004, pages 7426-7431, Published October 15, 2004) (of record), as applied to claims 1-5, 11-15, 23-25, and 31 above, and further in view of Hirth et al. (Clinical Cancer Research, Vol. 6, No. 4, 2000, pages 1255-1258, Published April 1, 2000) (of record) is maintained.
Response to Arguments
The Applicant argues that Zeldin relates to the treatment of HIV-infected patients with ritonavir and not cancer patients and therefore one of ordinary skill in the art would not apply the known dosage of ritonavir to cancer patients (Remarks, p. 9-10). These arguments were fully considered but are not persuasive. Weger teaches the combination of ritonavir (100 mg) and docetaxel and that ritonavir functions to increase docetaxel exposure. Zeldin teaches that doses of 100-200 mg of ritonavir can work to increase exposure to drugs metabolized by CYP3A4. A prima facie case of obviousness exists because it is not inventive to discover optimum or workable ranges by routine experimentation when the general conditions of a claim are known in the prior art (MPEP 2144.05.II). A skilled artisan would have no trouble optimizing the dose or timing of ritonavir in combination with docetaxel given that Weger teaches this combination and the general doses of ritonavir for CYP3A4 inhibition to increase exposure to a second agent are known.
The Applicant argues that Ikezoe is not relevant because Ikezoe lacks any clinical data for the combination of docetaxel and ritonavir (Remarks, p. 10). These arguments were fully considered but are not persuasive. Weger teaches the combination of docetaxel and ritonavir for the treatment of solid tumors, but does not specifically mention that the combination regimen is for prostate cancer. One of ordinary skill in the art would have a reasonable expectation of success to apply the claimed docetaxel and ritonavir regimen to prostate cancer because Ikezoe specifically teaches docetaxel and ritonavir for the treatment of androgen insensitive prostate cancer. Ikezoe also presents this effect in an animal model of androgen resistant prostate cancer:
Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFκB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.”
Ikezoe, Abstract (emphasis added).
Reiterated Rejection
Claims 1-2, 4-5, 11-15, 23-25, and 31-36 are rejected under 35 U.S.C. 103 as being unpatentable over Weger et al. (European Journal of Cancer, Vol. 86, November 2017, pages 217-225, Published October 12, 2017) (of record) and Zeldin & Petruschke (Journal of Antimicrobial Chemotherapy, 2004, Vol. 53, p. 4-9, Published December 4, 2003), and further in view of Ikezoe et al. (Cell and Tumor Biology, Vol. 64, No. 20, 2004, pages 7426-7431, Published October 15, 2004) (of record).
Claim 1 recites:
A method, comprising orally administering a bi-daily once weekly dose of docetaxel in combination with a CYP3A inhibitor to a subject having breast cancer or prostate cancer, the breast cancer or the prostate cancer comprising tumor tissue,
wherein the CYP3A inhibitor is ritonavir,
wherein the bi-daily once weekly dose comprises a first administration and a subsequent second administration administered within a day of the first administration, wherein in the first administration, the docetaxel is administered orally in a dosage of 30 mg and the ritonavir is administered in a dosage of 200 mg and, in the second administration, the docetaxel is administered orally in a dosage of 20 mg and the ritonavir is administered in a dosage of 100 mg, and
wherein the dosage of ritonavir is sufficient to obtain docetaxel exposure levels in the tumor tissue that are comparable to a standard of care treatment for docetaxel.
Claim 1.
Weger teaches the treatment of cancer with an oral formulation of docetaxel and ritonavir, a CYP3A inhibitor:
“The anticancer agent docetaxel has proven antitumour activity and has been approved for the treatment of advanced solid tumours at an intravenous (iv) dose of 75 mg/m2 or 100 mg/m2 every 3 weeks [1].
Oral administration of taxanes is hampered by two factors: (1) poor water solubility and (2) high first-pass effect due to high affinity for drug transporters (e.g. P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2)) and metabolism by the cytochrome P450 enzyme (CYP) CYP3A4, all abundantly present in the intestine and the liver [2]. The poor water solubility has been improved by the development of two solid dispersion formulations for oral use ModraDoc001 capsule (10 mg docetaxel, freeze dried) and the ModraDoc006 tablet (10 mg docetaxel, spray dried) [3], [4]. The first pass-effect of docetaxel can be decreased by co-administration of an inhibitor of P-gp and/or CYP3A4 [3], [5], [6]. The protease inhibitor ritonavir could be an ideal booster drug as it is a strong inhibitor of CYP3A4 and a moderate inhibitor of P-glycoprotein (P-gp). Furthermore, it has been used for many years as a booster drug to increase plasma levels of other protease inhibitors [7].
The aim of the current study was to investigate safety and feasibility of the co-administration of oral docetaxel as ModraDoc001 capsule or as ModraDoc006 tablet, both in combination with ritonavir in a bi-daily once weekly (BIDW) schedule. Secondary objectives included pharmacokinetics (PK) and preliminary antitumour activity.”
Weger et al., page 218 (emphasis added).
Weger teaches to administer 30 mg of docetaxel in the morning and 20 mg of docetaxel in the afternoon, each with 100 mg of ritonavir bi-daily weekly for antitumor therapy:
“Introduction
Two solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored.
Methods
Adult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0.
Results
ModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1–2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration–time curve (AUC0–48) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment.
Conclusion
Oral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.”
Weger et al., Abstract (emphasis added).
Weger teaches that these doses are comparable to IV standard of care docetaxel and have promising antitumor activity:
The exposure to docetaxel in terms of AUC0–inf at the MTD for the ModraDoc006 tablet formulation was in the same range as once weekly iv docetaxel of 30–36 mg/m2 [18], [19], [20]. Furthermore the observed inter-patient variability for ModraDoc006 tablet/r is in line with those previously reported for iv docetaxel [20], [21]. Antitumour activity of ModraDoc001 capsule/r and ModraDoc006 tablet/r was reported in known docetaxel-sensitive tumours: partial responses were observed in 3 out of 21 patients with NSCLC (14%) and in 2 out of 3 patients with SCCHN (66%). This preliminary activity is considered promising [22], [23].
Weger, page 223.
While Weger does not teach to administer 200 mg of ritonavir in the first dose given in the morning, one of ordinary skill in the art would have a reasonable expectation of success to use 200 mg in the bi-daily dose instead of 100 mg because it is commonly known in the art that ritonavir has demonstrated efficacy and a good safety profile when administered as either 100 or 200 mg bi-daily. For example, Zeldin teaches that ritonavir 100-200 mg twice daily boosted patient exposure to a second agent and offers an excellent balance of efficacy and tolerability:
Boosted protease inhibitor regimens combine ritonavir with a second, 'boosted' protease inhibitor to enhance patient exposure to the latter agent, thereby preventing or overcoming resistance and allowing less frequent dosing, potentially improving adherence. The advantages offered by ritonavir boosting are primarily attributable to the drug's pharmacokinetic properties. Ritonavir's inhibition of the cytochrome P-450 CYP3A4 enzyme reduces the metabolism of concomitantly administered protease inhibitors and changes their pharmacokinetic parameters, including area under the curve (AUC), maximum concentration (Cmax), minimum concentration (Cmin) and half-life (t1/2). As a result, the bioavailability of the boosted protease inhibitor is increased and improved penetration into HIV reservoirs may be achieved. Boosted protease inhibitor regimens that utilize a low dose of ritonavir (100-200 mg) appear to offer the best balance of efficacy and tolerability. At this dose, ritonavir boosts the bioavailability of the second protease inhibitor without contributing significantly to the side effect profile of the regimen. In clinical trials, regimens boosted with low dose ritonavir have demonstrated high levels of viral suppression in both antiretroviral naïve patients and patients who previously failed antiretroviral therapy, including protease inhibitor therapy. Side effects observed have generally been similar to those associated with the boosted protease inhibitor. Based upon their enhanced drug exposure and demonstrated efficacy, the boosted ritonavir regimens should be among the first options considered for use in clinical practice.
Zeldin, Abstract (emphasis added);
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Zeldin, p. 7, Table 2.
The teachings of Zeldin demonstrate that 100-200 mg of ritonavir given twice daily is a well known result-effective variable to boost the pharmacokinetic profile of a second agent. It is therefore well within the level of ordinary skill to increase the dose of ritonavir from 100 mg bi-daily weekly as taught by Weger to 200 mg in the first bi-daily dose and 100 mg in the second bi-daily dose.
While Weger does not teach that the cancer is prostate cancer, one of ordinary skill in the art would have a reasonable expectation of success to apply the claimed combination regimen to prostate cancer because Ikezoe teaches the combination of docetaxel and ritonavir for androgen independent prostate cancer, and that ritonavir counteracts CYP3A mediated docetaxel resistance in this type of cancer:
“We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all–trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10−5 mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor κB (NFκB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFκB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.”
Ikezoe, Abstract (emphasis added).
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 2 recites: The method of claim 1, wherein: after orally administering the bi-daily once weekly dose, the dosage of docetaxel is adjusted to compensate for increased clearance of docetaxel in the subject having breast cancer or prostate cancer; and/or the dosage of the CYP3A inhibitor is sufficient to substantially diminish the increased clearance of docetaxel in subjects having mCRPC.
As shown above, Weger teaches that administering docetaxel with ritonavir enhances the bioavailability and drug exposure for oral docetaxel in patients with solid tumors. While Weger does not teach teach metastatic castration resistant prostate cancer (mCRPC), one of ordinary skill in the art would have a reasonable expectation of success to diminish the increased clearance of docetaxel in subjects with mCRPC because Ikezoe teaches the combination of docetaxel and ritonavir for androgen independent prostate cancer, and that ritonavir counteracts CYP3A mediated docetaxel resistance in this type of cancer:
“We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all–trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10−5 mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor κB (NFκB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFκB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.”
Ikezoe, Abstract (emphasis added).
Therefore, claim 2 was prima facie obvious at the time of filing.
Claim 5 limits the method of claim 4 to mCRPC. As previously stated in the rejection of claim 2, as Ikezoe teaches that ritonavir sensitizes androgen independent prostate cancer cells to docetaxel by inhibiting CYP3A expression and activity, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to apply the combination of docetaxel and ritonavir for the treatment of mCRPC.
Therefore, claim 5 was prima facie obvious at the time of filing.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 12 is directed towards the method of claim 1, wherein prednisone is not administered to the subject. Weger teaches that the drug combination was administered without premedication with corticosteroids (prednisone is a corticosteroid):
“Of note, no hypersensitivity reactions and in addition only 1 event (2%) of grade 3 fluid retention (well-known adverse events reported for the docetaxel iv formulation) were observed despite the lack of premedication with corticosteroids.”
Weger et al., page 222.
Therefore, claim 12 was prima facie obvious at the time of filing.
Claim 15 recites: “The method of claim 1, wherein the dose of the CYP3A inhibitor is sufficient to obtain docetaxel exposure levels of the tumor tissue which is comparable to a standard of care treatment of docetaxel given intravenously every three weeks.” Weger teaches that their oral formulations were comparable to once weekly IV injections (Weger et al., page 223). Weger teaches 50 mg of docetaxel and 200 mg of ritonavir bi-daily weekly, which is less than the dose as instantly claimed. If the dose taught by Weger, which is less than that of the instant invention, achieves exposure levels of docetaxel that are comparable to weekly injections, then it is clear that increasing the ritonavir dose by 100 mg as taught by Zeldin would also be sufficient to result in exposure that is comparable to standard of care treatment of docetaxel. Zeldin teaches that 100 or 200 mg bi-daily is sufficient to boost exposure to the second agent, as shown above.
Therefore, claim 15 was prima facie obvious at the time of filing.
Claim 23 is directed towards:
“The method of claim 1, further comprising, after administering the docetaxel in combination with the CYP3A inhibitor the steps of:
- determining plasma levels of docetaxel in the subject;
- comparing the levels of docetaxel to a reference level;
- determining the docetaxel dosage for administration of a subsequent combination of the CYP3A inhibitor and docetaxel; and
- administering the subsequent combination of the CYP3A inhibitor and docetaxel.”
Claim 23.
Weger administered the CYP3A inhibitor and docetaxel to patients, measured their plasma levels, determined the dosage for administration of a subsequent combination of the CYP3A inhibitor and docetaxel, and administered the subsequent combination of the CYP3A inhibitor and docetaxel:
“Pharmacokinetic (PK) blood sampling was performed on day 1 and 15 of treatment for the capsule formulations and on day 1 and 8 for the tablet formulation. Samples were drawn pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 7, 7.5, 8, 8.5, 9, 10, 11, 24 and 48 h after the first administration. The second administration of the study drug was performed 7 h after the first administration. Samples were collected in lithium heparin tubes of 4 ml and centrifuged within 1 h at 1500 g, for 10 min at 4 °C. Plasma was stored in a pre-labelled 2 ml eppendorf tubes at −20 °C until quantification. Docetaxel concentrations were determined in plasma by a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method as described by Hendrikx et al. [12]. Stable isotopically labelled docetaxel was used as internal standard. The lower limit of quantification of the assay was 0.5 ng/ml docetaxel. The assay fulfills current US Food and Drug Administration (US FDA) guidelines for bioanalytical validation [13].”
Weger et al., page 219;
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Weger et al., page 219.
Weger also compared the plasma levels to the reference level for iv docetaxel when selected the optimized dosage:
The exposure to docetaxel in terms of AUC0–inf at the MTD for the ModraDoc006 tablet formulation was in the same range as once weekly iv docetaxel of 30–36 mg/m2 [18], [19], [20]. Furthermore the observed inter-patient variability for ModraDoc006 tablet/r is in line with those previously reported for iv docetaxel [20], [21].
Weger et al., page 223.
Therefore, claim 23 was prima facie obvious at the time of filing.
Claim 24 recites:
“The method according to claim 23, wherein the dosage of docetaxel of at least the subsequent combination of the CYP3A inhibitor and docetaxel is sufficient to obtain docetaxel exposure levels of the tumor tissue comparable to a standard of care treatment for docetaxel.”
Claim 24.
Weger teaches 50 mg of docetaxel and 200 mg of ritonavir bi-daily weekly, which is less than the dose as instantly claimed. If the dose taught by Weger, which is less than that of the instant invention, achieves exposure levels of docetaxel that are comparable to weekly injections, then it is clear that increasing the ritonavir dose by 100 mg as taught by Zeldin would also be sufficient to result in exposure that is comparable to standard of care treatment of docetaxel. Zeldin teaches that 100 or 200 mg bi-daily is sufficient to boost exposure to the second agent, as shown above.
Therefore, claim 24 was prima facie obvious at the time of filing.
Claim 25 is directed towards:
“The method according to claim 23, wherein the method for the treatment of a cancer comprises multiple administrations of a combination of the CYP3A inhibitor and docetaxel, wherein after each administration the levels of docetaxel are determined, for determining the docetaxel dosage for administration of a subsequent combination of the CYP3A inhibitor and docetaxel.”
Claim 25.
As shown in the rejection of claim 23, Weger teaches determining the plasma level of docetaxel on days 1 and 15 of treatment, and dose adjustment during treatment with multiple administrations. While they do not teach adjusting the dose after each administration, Ikezoe teaches that CYP3A is involved in the acquisition of drug resistance (Ikezoe, Abstract). Therefore, one of ordinary skill in the art would be motivated to test plasma levels of docetaxel after each administration and to adjust the drug doses based on altered drug clearance.
As such, claim 25 was prima facie obvious at the time of filing.
Claim 31 recites: “A kit for use in the method of claim 1, the kit comprising- a pharmaceutical composition comprising Docetaxel- and a pharmaceutical composition comprising ritonavir.” Weber teaches that docetaxel and ritonavir are contained in separate compositions and simultaneously administered:
“In this phase I, open-label, dose-escalation study two oral docetaxel formulations, ModraDoc001 capsule [3] and ModraDoc006 tablet [4] were investigated. Dosing of patients occurred in a BIDW schedule. A dose of 100 mg ritonavir (Norvir®, Abbott, Illinois, United States of America (USA)) was co-administered with ModraDoc formulations.”
Weger, page 218.
A kit contains multiple compositions and instructions for use. Thus, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to formulate a kit for the method of claim 1.
As such, claim 31 was prima facie obvious at the time of filing.
Claim 32 recites:
A method, comprising: orally administering a first bi-daily once weekly dose of docetaxel in combination with ritonavir to a subject having breast cancer or prostate cancer, the breast cancer or prostate cancer comprising tumor tissue, wherein the first bi-daily once weekly dose comprises 30 mg of docetaxel and 200 mg of ritonavir and
orally administering a subsequent second bi-daily once weekly dose of docetaxel in
combination with ritonavir to the subject within a day of the first bi-daily once weekly dose, wherein the second bi-daily once weekly dose comprises 20 mg of the docetaxel and 100 mg of ritonavir, and
wherein the dosage of docetaxel administered in a dose subsequent to the second bi-daily once weekly dose is adjusted to compensate for increased clearance of docetaxel in the subject having cancer.
Claim 32.
As shown in the rejection of claim 1, administering 30 mg docetaxel/ 200 mg ritonavir and 20 mg docetaxel/ 100 mg ritonavir bi-daily weekly is well within the level of ordinary skill. As shown in the rejection of claim 23, Weger also teaches determining the plasma level of docetaxel on days 1 and 15 of treatment, and dose adjustment during treatment with multiple administrations. Weger teaches to maintain the dose within the AUC for standard of care docetaxel. While they do not teach adjusting the dose after each administration, Ikezoe teaches that CYP3A is involved in the acquisition of drug resistance and that that patients with prostate cancer have increased clearance of decotaxel as shown above (Ikezoe, Abstract). Therefore, one of ordinary skill in the art would be motivated to test plasma levels of docetaxel after each administration and to adjust the drug doses based on altered drug clearance. As such, one of ordinary skill in the art would know to increase the dosage of docetaxel to compensate for increased clearance of the drug in this patient population.
Therefore, claim 32 was prima facie obvious at the time of filing.
Claim 33 recites: The method of claim 32, wherein the cancer comprises mCRPC and the dosage of ritonavir in the first bi-daily once weekly dose and in the subsequent second bi-daily once weekly dose is sufficient to substantially diminish the increased clearance of docetaxel.
As shown above, administering 30 mg docetaxel/ 200 mg ritonavir and 20 mg docetaxel/ 100 mg ritonavir bi-daily weekly is well within the level of ordinary skill. As shown above, Ikezoe teaches to administer ritonavir with docetaxel to increase docetaxel exposure in patients with prostate cancer. Therefore, it is well within ordinary skill to administer 30 mg docetaxel/ 200 mg ritonavir and 20 mg docetaxel/ 100 mg ritonavir bi-daily weekly in patients with mCRPC and this would inherently be sufficient to substantially diminish the increased clearance of docetaxel.
Therefore, claim 33 was prima facie obvious at the time of filing.
Claim 34 is a substantial duplicate of claims 32-33 and is rejected on the same grounds as these claims.
Claims 35-36 are directed towards the methods of claims 34 and 32, respectively, wherein the second bi-daily once weekly dose is administered 8-16 hours following the first bi-daily once weekly dose. Weger teaches that the “BIDW administrations of study drugs were performed with a 7–12 h interval.” (Weger, p. 218). As the intervals overlap, a prima facie case of obviousness exists. (MPEP 2144.05). Therefore, claims 35-36 were prima facie obvious at the time of filing.
Claims 1-5, 12, 15, 18, 20-25, 28 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Weger et al. (European Journal of Cancer, Vol. 86, November 2017, pages 217-225, Published October 12, 2017) (of record), Zeldin & Petruschke (Journal of Antimicrobial Chemotherapy, 2004, Vol. 53, p. 4-9, Published December 4, 2003), and Ikezoe et al. (Cell and Tumor Biology, Vol. 64, No. 20, 2004, pages 7426-7431, Published October 15, 2004) (of record), as applied to claims 1-5, 11-15, 23-25, and 31 above, and further in view of Hirth et al. (Clinical Cancer Research, Vol. 6, No. 4, 2000, pages 1255-1258, Published April 1, 2000) (of record).
Claim 18 is directed towards:
“The method of claim 1, further comprising the steps of:
- determining the activity of CYP3A in a subject;
- comparing the activity of CYP3A to a reference level;
- determining a suitable dosage of the CYP3A inhibitor based on the activity level of CYP3A determined in the subject; and
- administering the docetaxel combination of the CYP3A inhibitor at the suitable dosage”
Claim 18.
As shown above, Weger and Ikezoe teach the concurrent administration of docetaxel and the CYP3A inhibitor ritonavir and Zeldin teaches that 100-200 mg of ritonavir bi-daily weekly are appropriate to boost the exposure to a second agent. Furthermore, Ikezoe teaches that CYP3A activity mediates docetaxel resistance in androgen independent prostate cancer and measured CYP3A expression following the administration of docetaxel and/or ritonavir:
“The ability of ritonavir to enhance antitumor effects of docetaxel also was studied using established DU145 xenografts (Fig. 7). Once tumor volume reached approximately a mean of 200 mm3, treatment was initiated. Ritonavir again significantly enhanced the ability of docetaxel to decrease tumor size (P = 0.01) and tumor weight (P = 0.008) of DU145 xenografts (Fig. 7,A and B). We measured apoptosis of DU145 tumor cells using terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. TUNEL-positive cells were negligible in control and ritonavir-treated mice. Conversely, docetaxel induced ∼8% of DU145 cells to become TUNEL positive. Importantly, when docetaxel was combined with ritonavir, TUNEL-positive cells increased to 16% (data not shown). At the end of this experiment, we sacrificed the mice, removed their tumors, extracted RNA, and measured levels of CYP3A4 by real-time PCR. At 16 hours before sacrifice, either docetaxel or ritonavir alone or in combination was administered to the mice. As shown in Fig. 7,C, docetaxel increased expression of CYP3A4 by approximately twofold in DU145 tumors; when docetaxel was combined with ritonavir, docetaxel-induced expression of CYP3A4 was blocked completely.”
Ikezoe et al., page 7430 (emphasis added).
While neither Weger, Zeldin or Ikezoe teach determining CYP3A activity prior to administration, this method is commonly known in the art. For example, Hirth teaches that docetaxel is metabolized by CYP3A4 and that CYP3A4 genetic variants can alter dose exposure. Consequently, Hirth measures CYP3A4 activity in patients to determine the dosage of docetaxel needed for optimal drug exposure:
“Patients and healthy individuals alike display significant differences in terms of efficacy and adverse effects after exposure to many drugs. An identical dosage of a drug can result in widely different concentrations of the therapeutically active compound or metabolites (1). The presence of genetic variability in the activity of enzymes involved in drug metabolism could lead to clinically important variations in efficacy or adverse effects for some drugs.
The cytochrome P450 system is a family of heme-containing enzymes responsible for the metabolism of nonendogenous substances, such as drug molecules and toxins (2). Specific isoenzymes are designated by the prefix “CYP,” and to date, over 30 isoenzymes have been purified, cloned, sequenced, and characterized in humans. CYP3A4 is found in the liver and small bowel. The CYP3A4 enzyme displays large interpatient differences in both content and catalytic activity in humans (3). These differences exist even in the absence of medications known to induce or inhibit the enzyme and are thus likely to reflect genetic variability (3).
The ERMBT3 specifically measures the in vivo activity of hepatic CYP3A4 (3, 4) and is therefore ideally suited for drugs given i.v., such as docetaxel. This test is based on the fact that CYP3A4 is the major enzyme responsible for erythromycin metabolism, liberating a carbon atom that is exhaled as carbon dioxide. After injecting a trace dose of radiolabeled erythromycin, the rate of radiolabeled carbon dioxide exhaled is measured. This test has been validated as a specific measure of CYP3A4 activity (3).
In vitro studies suggest that CYP3A4 is the major enzyme involved in docetaxel metabolism (5). Docetaxel is excreted in the feces with less than 8% excreted unchanged (6). It is highly bound to plasma proteins including AAG. Pharmacokinetic data show significant variation in CL between patients (7). Decrease in total body CL is associated with increased frequency and severity of side effects (8). Mulitvariate analysis demonstrates that interpatient variability of CL is predicted by body surface area, AAG plasma level, and elevated hepatic enzymes; however, these parameters do not account for total variability (7). Because docetaxel binds chiefly to AAG, high levels of this protein presumably limit the free fraction of docetaxel available for CL in the liver. Due to lower CL of docetaxel in patients with elevated transaminases, it is currently recommended in the United States package insert that patients with an ALT >1.5× the ULN concomitant with alkaline phosphatase > 2.5× ULN or bilirubin > ULN do not receive this drug. The European Summary of Product Characteristics alternatively recommends a dosage reduction of 25% in patients with concomitant elevations of ALT and alkaline phosphatase.
Previous studies have shown modest activity for docetaxel in patients with advanced sarcomas (response rates of 17% and 18%), thus we decided to try this agent in our sarcoma population (9, 10). We hypothesized that variability in CYP3A4 activity accounts for interpatient differences in docetaxel CL and toxicity. Thus, the ERMBT was used to measure CYP3A4 activity in sarcoma patients receiving docetaxel (Fig. 1).”
Hirth et al., pages 1255-1256 (emphasis added);
“Both the CL of docetaxel and CYP3A4 activity, as measured by the ERMBT, had marked interpatient variation in this study. All patients were required to have good hepatic function as described previously, and with the exception of dexamethasone, no patient received known potent inhibitors or inducers of CYP3A4. Thus, it appears that the variation seen could reflect genetic differences in the metabolism of docetaxel.”
Hirth et al., page 1257.
Elaborating on what was cited previously, Hirth says that CYP3A4 activity was determined to be the most important variable for predicting the CL of docetaxel and that these data can be used to individualize the dose of docetaxel and other CYP3A4 substrates:
In conclusion, CYP3A4 activity was found to be the most significant independent variable for predicting the CL of docetaxel. The ERMBT, perhaps together with serum albumin or AAG, may be clinically useful in individualizing the dose of docetaxel and possibly other drugs that are CYP3A4 substrates, including several new antineoplastic agents. It may also be helpful in individualizing the dose of docetaxel in patients with markedly elevated hepatic enzymes who are currently excluded from treatment with docetaxel.
Hirth et al., page 1258.
Elaborating on what was cited previously, Hirth discusses patients with low CYP3A4 activity and high CYP3A4 activity, indicating that there is a reference level for CYP3A4 activity that separate patients with low activity from those with high activity:
Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals.
Hirth et al., Abstract.
Based on the common principle of dose-response, one of ordinary skill in the art would reasonably expect that lower doses of ritonavir would result in less inhibition of CYP3A and lower exposures to docetaxel and higher doses of ritonavir would result in greater inhibition of CYP3A and higher exposures to docetaxel. While neither explicitly teach dose adjustments based on CYP3A activity, Hirth teaches to measure CYP3A activity to tailor the dose of docetaxel and other drugs involved with CYP3A metabolism:
“In this study, single agent docetaxel was given, but docetaxel is now commonly included in combination regimens. Because the additional drugs are often myelotoxic but not CYP3A4-mediated, the ERMBT may be helpful in sorting out the specific effect docetaxel makes with regard to the toxicity of the regimen.
Logistically, the ERMBT is easy to administer and poses a minimal risk to patients. It proved to be highly reproducible. It was not significantly affected by dexamethasone premedication, and this observation is consistent with prior data (15) that showed no substantial effect of dexamethasone premedication on docetaxel CL. The test can therefore be done at a convenient time, days or weeks ahead of the planned administration of docetaxel.
In conclusion, CYP3A4 activity was found to be the most significant independent variable for predicting the CL of docetaxel. The ERMBT, perhaps together with serum albumin or AAG, may be clinically useful in individualizing the dose of docetaxel and possibly other drugs that are CYP3A4 substrates, including several new antineoplastic agents. It may also be helpful in individualizing the dose of docetaxel in patients with markedly elevated hepatic enzymes who are currently excluded from treatment with docetaxel.
We plan to initiate a study using tailored dosing of docetaxel based on CYP3A4 activity. We postulate that by tailoring the dose, variability in patient drug exposure could be diminished. Hopefully, modern pharmacogenetics can be put into practical use in the clinic and allow us to treat patients with better precision and less toxicity.”
Hirth et al., page 1258.
Accordingly, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to measure CYP3A activity in a subject prior to the administration of docetaxel and a CYP3A inhibitor and compare this to a reference level to optimize the dose of the CYP3A4 activity inhibitor administered.
Thus, claim 18 was prima facie obvious at the time of filing.
Claim 20 is directed towards the method according to claim 18, wherein the determining steps of the method are carried out prior to the first administration of the combination of the CYP3A inhibitor and docetaxel. Claim 21 is directed towards the method according to claim 18, wherein the steps of the method are carried out during the treatment comprising administration of the combination of the CYP3A inhibitor and docetaxel. Hirth teaches that the CYP3A4 activity test is performed before and after the administration of docetaxel:
“Three ERMBTs were administered to each patient at the GCRC. The test was done on three occasions in case either the dexamethasone premedication or the chemotherapy introduced variability. The first study served as a baseline and was done before admission for docetaxel(range, 1–19 days before admission). The second study was done 24 h after dexamethasone premedication was initiated and 1 h before the infusion of docetaxel. The third study was done 3 h after the infusion of docetaxel had been completed. A total of 3 μCi (<0.1 mmol) of [14C-N-methyl]erythromycin obtained from Metabolic Solutions, Inc. (Nashua, NH) was given i.v. Exhaled carbon dioxide was trapped in a solution of hyamine hydroxide,ethanol, and a blue indicator before and 20 min after the injection. The percentage of 14C exhaled/h =49.496 × (percentage of 14C exhaled/min at 20 min − baseline counts) (11).”
Hirth et al., page 1256 (emphasis added).
Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to measure CYP3A activity before and during the administration of the claimed drug combination.
Thus, claims 20-21 were prima facie obvious at the time of filing.
Claim 22 is directed towards:
“The method according to claim 21, wherein when the activity of CYP3A is increased during treatment, the dosage of the CYP3A inhibitor is increased in a subsequent administration, and wherein when the activity of CYP3A is decreased during treatment, the dosage of the CYP3A inhibitor is maintained or reduced in a subsequent administration, as compared with the previous dosage administered.”
Claim 22.
As shown above, Weger teaches that ritonavir inhibits CYP3A activity to increase drug exposure to docetaxel and Ikezoe teaches that treatment with docetaxel and/or ritonavir impacts CYP3A expression. Based on the common principle of dose-response, one of ordinary skill in the art would reasonably expect that lower doses of ritonavir would result in less inhibition of CYP3A and lower exposures to docetaxel and higher doses of ritonavir would result in greater inhibition of CYP3A and higher exposures to docetaxel. While neither explicitly teach dose adjustments based on CYP3A activity, Hirth teaches to measure CYP3A activity to tailor the dose of docetaxel and other drugs involved with CYP3A metabolism:
“In this study, single agent docetaxel was given, but docetaxel is now commonly included in combination regimens. Because the additional drugs are often myelotoxic but not CYP3A4-mediated, the ERMBT may be helpful in sorting out the specific effect docetaxel makes with regard to the toxicity of the regimen.
Logistically, the ERMBT is easy to administer and poses a minimal risk to patients. It proved to be highly reproducible. It was not significantly affected by dexamethasone premedication, and this observation is consistent with prior data (15) that showed no substantial effect of dexamethasone premedication on docetaxel CL. The test can therefore be done at a convenient time, days or weeks ahead of the planned administration of docetaxel.
In conclusion, CYP3A4 activity was found to be the most significant independent variable for predicting the CL of docetaxel. The ERMBT, perhaps together with serum albumin or AAG, may be clinically useful in individualizing the dose of docetaxel and possibly other drugs that are CYP3A4 substrates, including several new antineoplastic agents. It may also be helpful in individualizing the dose of docetaxel in patients with markedly elevated hepatic enzymes who are currently excluded from treatment with docetaxel.
We plan to initiate a study using tailored dosing of docetaxel based on CYP3A4 activity. We postulate that by tailoring the dose, variability in patient drug exposure could be diminished. Hopefully, modern pharmacogenetics can be put into practical use in the clinic and allow us to treat patients with better precision and less toxicity.”
Hirth et al., page 1258.
As such, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to increase the dose of ritonavir under conditions of enhanced CYP3A activity to block CYP3A induction by docetaxel and decrease the dose of ritonavir under conditions of diminished CYP3A activity to limit the toxicity of docetaxel.
Thus, claim 22 was prima facie obvious at the time of filing.
Claim 28 is directed towards:
“The method of claim 18, further comprising the steps of
determining plasma levels of docetaxel in the subject;
comparing the levels of docetaxel to a reference level; and
determining the docetaxel dosage and CYP3A inhibitor dosage for administration of a combination of the CYP3A inhibitor and docetaxel based on the CYP3A activity and the determined plasma levels of docetaxel.”
Claim 28.
As shown above, Weger teaches determining plasma levels of docetaxel in a subject, comparing the levels to the reference level for IV docetaxel, and altering the dose of docetaxel based on exposure and toxicity, and Ikazoe teaches that CYP3A activity is altered by the administration of docetaxel, and this effect can be blocked by ritonavir. As also shown above Hirth teaches tailoring the dose of docetaxel based on CYP3A activity. As stated above, based on the common principle of dose-response, one of ordinary skill in the art would reasonably expect that lower doses of ritonavir would result in less inhibition of CYP3A and lower exposures to docetaxel and higher doses of ritonavir would result in greater inhibition of CYP3A and higher exposures to docetaxel. Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to tailor the dose of docetaxel and the CYP3A inhibitor based on CYP3A activity and docetaxel exposure.
Therefore, claim 28 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing. It is well within the level of ordinary skill to administer 30 mg docetaxel with 200 mg ritonavir in the morning and 20 mg docetaxel with 100 mg of ritonavir in the afternoon/ evening to patients with cancer, including mCRPC. It is well known in the art that patients with mCRPC may have increased clearance of docetaxel due to CYP3A effects. It is well within the level of ordinary skill to adjust the dose of the chemotherapeutic (docetaxel) or CYP3A inhibitor (ritonavir) based on individual patient pharmacokinetics. The AUC effective dose for docetaxel is well known in the art. There is nothing unexpected or non-obvious in the instant invention. The drugs, doses, and patient populations are well known in the art as shown above.
Conclusion
No claim is found to be allowable.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629