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 .
DETAILED ACTION
1. Claims 8-16 are pending in the current application.
2. This application is a 371 of PCT/EP2022/075848 09/16/2022 FOREIGN APPLICATIONS EP 21306287.0 09/17/2021.
Priority
3. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. EP 21306287.0, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The prior filed application is drawn only to the use of OTX015, while claims 12, 14 and 16 are drawn the compound B1894999. As such claims 8-11, 13, and 15 are afforded the date of 09/17/2021, while claims 12, 14 and 16 are afforded the date of the international filing, 09/16/2022.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
4. Claim(s) 8-16 is/are rejected under 35 U.S.C. 102(a)(2) and claims 12, 14 and 16 additionally under 102(a)(1)1 as being anticipated by Wang WO 2021175824 A1. Wang teaches the use of various BET inhibitors for treating cancer including OTX-105 of claims 12, 14, and 16 on page 11-12 as well as Compound 1, which is BI894999/Amredobresib. Additional compounds include GSK 525762, JQ1, TEN-010, CPI-0610, PLX51107, ABBV-075, ABBV-744, BMS 986158, TGI-1601, CC-90010, AZD5153, Compound 2, Compound 3 and Compound 4. These compounds are the subject of method of cancer treatment claims, 7-23, and the methods 1-6. According to claim 32 cancers to be treated include, “32. The BET inhibitor for use according to claim 1 or 6 to 31, the method for the treatment according to claim 2 or 6 to 31, the use of the BET inhibitor according to claim 3 or 6 to 31, or the methods according to claim 4 to 31, wherein the cancer to be treated is selected from the group consisting of …..cholangiocarcinoma….melanoma (including but not limited to uveal melanoma)…” With respect to the cancer being BAP1 deficient, according to the specification at page 27, “Genetic mutations leading to the inactivation of BAP1 are recurrent in UM (about half of patients) and other cancers such as clear cell Renal Carcinoma, cholangiocarcinoma or mesothelioma.” Therefore the cholangiocarcinoma and uveal melanoma melanoma patients described in Wang are inherently cancers being BAP1 deficient. With respect to the “preventing primary resistance in uveal melanoma” in claim 13, since the patient is the same and the drug and administration is the same, the steps are the same and any result is just the natural consequence of practicing the known method steps. Page 37 describes those patients with metastatic cancer in claim 10 “Patients with a histologically or cytologically confirmed diagnosis of an advanced unresectable and/or metastatic solid tumour, who have failed conventional treatment or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies”
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.
5. Claim(s) 8-10, 12, is/are rejected under 35 U.S.C. 103 as being unpatentable over Vazquez “ “Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts.” International Journal of Cancer, 2017, 140(1), 197-207 and Cigognetti “BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations” Modern Pathology (2015) 28, 1043–1057. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Vasquez in the abstract explains that OTX015 is useful for treating mesothelioma:
It has recently been reported that a large proportion of human malignant pleural mesothelioma (MPM) cell lines and patient tissue samples present high expression of the c-MYC oncogene. This gene drives several tumorigenic processes and is overexpressed in many cancers. Although c-MYC is a strategic target to restrain cancer processes, no drugs acting as c-MYC inhibitors are available. The novel thienotriazolodiazepine small-molecule bromodomain inhibitor OTX015/MK-8628 has shown potent antiproliferative activity accompanied by c-MYC downregulation in several tumor types. This study was designed to evaluate the growth inhibitory effect of OTX015 on patient-derived MPM473, MPM487 and MPM60 mesothelioma cell lines and its antitumor activity in three patient-derived xenograft models, MPM473, MPM487 and MPM484, comparing it with cis-platin, gemcitabine and pemetrexed, three agents which are currently used to treat MPM in the clinic. OTX015 caused a significant delay in cell growth both in vitro and in vivo. It was the most effective drug in MPM473 xenografts and showed a similar level of activity as the most efficient treatment in the other two MPM models (gemcitabine in MPM487 and cisplatin inMPM484). In vitro studies showed that OTX015 downregulated c-MYC protein levels in both MPM473 and MPM487 cell lines. Our findings represent the first evidence of promising therapeutic activity of OTX015 in mesothelioma Targeting both BD1 and BD2 (bromodomains).
OTX015 is one of the most potent compounds tested according to Vasquez:
To our knowledge this is the first evidence that a BET inhibitor has activity in this neoplasm, known to be one of the most resistant tumors to anticancer therapies. The in vivo antitumor activity of OTX015 was not striking but was consistent in all xenograft models. Furthermore, its activity was more marked than that of the other drugs tested, i.e., cisplatin, pemetrexed and gemcitabine that are widely used in the clinic to manage mesothelioma. The negative data obtained in vitro with pemetrexed are difficult to interpret as it is known that the concentration of folic acid in the culture medium is much higher than that of human plasma. Likewise, the negative in vivo data are not necessarily relevant for the clinic as folate levels in rodent plasma are also much higher than those in humans.23 OTX015 appears to be active at concentrations of ~500 nM–1 mM, which are realistically achievable in patients treated with tolerable doses, as shown by OTX015 plasma levels in patients treated in a phase I study in hematologic malignancies, which are in the range of 50–500 nM.24–26 [Page 205].
According to Cigognetti BAP1 deficient mesothelioma is the worst kind,
In biopsies interpreted as reactive mesothelial proliferation BAP1 loss was 100% predictive of malignancy, as all 6 cases subsequently developed BAP1-negative mesothelioma, whereas only 3/36 (8%) BAP1-positive cases progressed to mesothelioma. On cytology/cell blocks, benign mesothelial cells were invariably positive for BAP1, whereas 64% of mesotheliomas showed loss of protein; all 6 cases showing BAP1 negativity were associated with histological diagnosis of BAP1-negative mesothelioma. BAP1 stain also showed utility in the differential of mesothelioma from most common pleural and peritoneal mimickers, such as lung and ovary carcinomas, with specificity and sensitivity of 99/70% and 100/70%, respectively. Our results show that BAP1 protein is frequently lost in mesothelioma, especially of epithelioid/biphasic subtype and is commonly associated with homozygous BAP1 deletion. BAP1 immunostain represents an excellent biomarker with an unprecedented specificity (100%) in the distinction between benign and malignant mesothelial proliferations. Finding BAP1 loss in mesothelial cells should prompt to immediately reevaluate the patient; moreover, it might be useful in mapping tumor extent and planning surgical resection. [abstract]
Cigognetti describes the discovery and history of BAP1 in the pathogenesis of mesothelioma:
Initially identified as a BRCA1-binding protein, BAP1 is a deubiquitinating enzyme with C-terminal active hydrolase domain (UCH) and N-terminal nuclear localization signals (NLS1, NLS2).41, 42 Its tumor suppressor functions have been recently described and it has been found that BAP1 plays a role in cycle-cell progression, DNA ionizing radiation breaks repair, gene expression regulation through hystone H2A deubiquitinase activity, and subsequent chromatin remodeling.42, 43, 44, 45, 46, 47, 48, 49 As further evidence of BAP1 as a tumor suppressor gene, somatic gene inactivating deletions or point mutations have been detected in the same types of neoplasms associated with BAP1-cancer syndrome.50, 51, 52, 53 Bott et al54 first reported BAP1 somatic variants in malignant mesothelioma, identifying gene losses and/or mutations in 22 of 53 pleural mesotheliomas (42%) that resulted in absent BAP1 immunoreactivity in tumor cells; interestingly, immunohistochemical analysis revealed a negative BAP1 staining also in eight cases in which mutations were not detected.54 Yoshikawa et al55 observed frequent deletion of the 3p21.1 region in mesothelioma primary cultures and cell lines; the same authors subsequently detected somatic biallelic BAP1 alterations in 14 of 23 cases of mesothelioma (61%);56 similar percentages of cases showing loss of BAP1 protein expression were found in other more recent studies.57, 58
In a recent study performed on tissue microarray containing 49 benign and 26 malignant mesothelial proliferations, Sheffield et al39 showed that BAP1 immunostain separates benign from malignant processes, with a 100% specificity and 27% sensitivity; sensitivity increased to 58% when BAP1 stain was combined with 9p21 FISH analysis. In their study, a roughly equivalent number of epitheloid/biphasic and sarcomatoid mesothelioma cases were included, but whether BAP1 reactivity differed between subtypes was not specified.
In this study, we evaluated the diagnostic utility of BAP1 expression using a large series of histological samples, including 12 benign mesothelial tumors, 42 simple or atypical reactive mesothelial proliferations, and 212 mesotheliomas. The results fully supported the diagnostic role of anti-BAP1 as biomarker to distinguish benign from malignant mesothelial proliferations; specificity and sensitivity reached 100% and 66%, respectively, the latter raising to 69% when only epithelioid/biphasic subtypes were included. FISH analysis of BAP1 gene demonstrated that homozygous deletion of the BAP1 locus was commonly associated with BAP1 protein loss. Finally, the utility of BAP1 immunohistochemistry was also proven on cytological and cell-block samples.” [Page 1044]
Ascertaining the differences between the prior art and the claims at issue.
It is not clear that the compound was given to mesothelioma patients, only patient-derived MPM473, MPM487 and MPM60 mesothelioma cell lines and patient-derived xenograft models, MPM473, MPM487 and MPM484. No mention of BAP1 is given in Vasquez.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness.
It would have been prima facie obvious at the time the invention was made to give the known anti-mesothelioma drug, OTX015, to mesothelioma patients deficient in BAP1. With respect to the BAP1 deficient patient, according to Cigognetti, “In conclusion, this study shows that BAP1 protein is frequently lost in malignant mesothelioma, especially of epithelioid/biphasic subtype (69%). This marker has an absolute specificity (100%) in the distinction between benign and malignant mesothelial proliferations, whereas sensitivity is
lower. Nevertheless, in cases with uncertain diagnosis the identification of loss of BAP1 protein in mesothelial cells should prompt to immediately reevaluate the patient with additional biopsies or close follow-up.” Since BAP1 deficiency is strongly correlated with malignant mesothelioma, these patients would naturally receive the drug.
6. Claim(s) 8-16 are rejected under 35 U.S.C. 103 as being unpatentable over Wang WO 2021175824 A1 as applied to claim 8-16 above, and further in view of van Essen “Prognostic parameters in uveal melanoma and their association with BAP1 expression.” Br J Ophthalmol. 2014;98:1738–1743. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Wang teaches the use of various BET inhibitors for treating cancer including OTX-105 of claims 12, 14, and 16 on page 11-12 as well as Compound 1, which is BI894999/Amredobresib. Additional compounds include GSK 525762, JQ1, TEN-010, CPI-0610, PLX51107, ABBV-075, ABBV-744, BMS 986158, TGI-1601, CC-90010, AZD5153, Compound 2, Compound 3 and Compound 4. These compounds are the subject of method of cancer treatment claims, 7-23, and the methods 1-6. According to claim 32 cancers to be treated include, “32. The BET inhibitor for use according to claim 1 or 6 to 31, the method for the treatment according to claim 2 or 6 to 31, the use of the BET inhibitor according to claim 3 or 6 to 31, or the methods according to claim 4 to 31, wherein the cancer to be treated is selected from the group consisting of …..cholangiocarcinoma….melanoma (including but not limited to uveal melanoma)…”
Van Essen explains, “Loss of BAP1 expression associated well with all of the methods currently used for prognostication and was itself predictive of death due to metastasis in uveal melanoma after enucleation, thereby emphasizing the importance of further research on the role of BAP1 in uveal melanoma” [ Page 1738]. “This loss of BAP1 plays an important
role in developing malignant tumour behaviour,27 and it may also be involved in the development of an inflammatory phenotype, as this was previously found to be associated with monosomy of chromosome 3.46… In summary, our results show that monosomy 3/8q gain and the class 2 gene expression profile are both highly associated with lower BAP1 gene expression and negative BAP1 immunostaining, and that both methods for assessing BAP1 levels are predictive for death due to metastasis in uveal melanoma after enucleation. [Page 1742].
Ascertaining the differences between the prior art and the claims at issue.
As discussed above, there is no difference since the patients with UM are inherently BAP1 deficient, and according to the specification at page 27, “Genetic mutations leading to the inactivation of BAP1 are recurrent in UM (about half of patients) and other cancers such as clear cell Renal Carcinoma, cholangiocarcinoma or mesothelioma.” If this is not seen or someone has a different idea of inherency, then the difference is choosing the BAP1 deficient patient.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness.
It would have been prima facie obvious at the time the invention was made to give the known UM drugs, BET inhibitors, to UM patients deficient in BAP1. Since BAP1 deficiency is strongly correlated with malignant UM, these patients would naturally receive the known drugs.
Conclusion
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 As discussed above claims 12, 14 and 16 have the priority date of 09/16/2022 which is after the publication date of the WO ‘824 application, 10/9/2021 and only they may be rejected under 102(a)(1). All claims are properly rejected under 102(a)(2) since both the international filing date and priority date of the WO ‘824 application are before any of the instant filing/priority dates.
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