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 .
Claims 1-24 are pending and examined on the merits.
Claim Objections
Claims 6 and 15 are objected to because of the following informalities:
(i)the typographical error of “therapay” in claim 6, and
(ii) the absence of the word “staining” between “comprises” and “pan cytokeratin” in claim 15.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-5, 7-15, 18 and 19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. Claims 1-5, 7-15 recite the evaluation of CTRC data to identify a mCRPC patient with an improve response to taxane therapy compared to androgen receptor signaling directed therapy. The “evaluation” of data is a step in abstract thinking which is a judicial exception. Claims 2-5 further require that mCRPC patients are identified as having an improved response to taxane therapy, resistance to androgen receptor signaling therapy and a positive response to taxane therapy, all based on nuclear localization of AR-V7 in CTCs; claims 18 and 19 require that nuclear localization of AR-V7 corresponds to resistance to androgen receptor signaling therapy and a positive response to taxane therapy, respectively. These correlates between the presence of AR-V7 in the nucleus of a CTC in a mCRPC patient and the resistance to androgen receptor signaling therapy and positive response to taxanes is a natural phenomenon. Applicant has observed these correlates but has not engineered them. The correlates are therefore a judicial exception of the natural phenomenon type. This judicial exception is not integrated into a practical application because the instant claims do not provide any concrete method steps based on the observed natural phenomenon. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no further activity is required by the claims and the judicial exception cannot integrate itself into a practical application.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10-12, 15, 21-24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The recitation of “CTCs” in claims 10 lacks specific antecedent basis in claim 1 which refers only to CTC data. Amendment of claim 10 to substitute “nucleated cells” for CTCs would overcome this portion of the rejection
The recitation of “detection of CTCs” in claim 12 lacks specific antecedent basis in claim 1 which refers only to CTC data and detecting the presence of an AR-V7. Amendment of claim 12 to substitute “analysis of nucleated cells” for “detect CTCs” would overcome this portion of the rejection.
Claim 15 is vague and indefinite in the recitation of “immunofluorescent staining to detect CTCs is pan cytokeratin, C45 and diamdino-2-phenylindole (DAPI) because recitation of antigens per se does not further elaborate immunofluorescent staining. Further, the recitation of “the immunofluorescent staining of nucleated cells to detect CTCs” in claim 15 lacks specific antecedent basis in claim 1 which refers only to CTC data and detecting the presence of an AR-V7. Amendment of claim 15 to recite “the immunofluorescent staining of nucleated cells comprises staining for pan cytokeratin, CD45 and diamdino-2-phenylindole (DAPI)” in place of “the immunofluorescent staining of nucleated cells to detect CTCs comprises pan cytokeratin, CD45 and diamdino-2-phenylindole (DAPI)” would overcome this rejection of claim 15.
The recitation of “distinct morphological characteristics in CTCs” in claim 21 lacks specific antecedent basis in claim 16 which refers only to CTC data and morphological characterization of nucleated cells rather than morphological characterization of CTCs.
The recitation of “detection of CTCs” in claim 23 lacks specific antecedent basis in claim 16 which refers only to the generation of CTC data. Amendment of claim 23 to recite “method of claim 16, wherein the method further comprises detecting CTCs by comparing the intensity of pan cytokeratin fluorescent staining of a nucleated cell to pan cytokeratin fluorescent staining of surrounding white blood cells in a field of view comprising CTCs and white blood cells”.
The recitation of “the immunofluorescent staining of nucleated cells to detect CTCs” in claim 24 lacks specific antecedent basis in claim 16 which recites “immunofluorescent staining of nucleated cells” and the “generation of circulating tumor cell data”, rather than the “detection of CTCs”. Amendment of claim 24 to recite “The method of claim 16, wherein the method further comprises detecting CTCs by immunofluorescent staining of nucleated cells for pan cytokeratin, CD45 and diamdino-2-phenylindole (DAPI).
Claims 11 and 22 are vague and indefinite in the recitation of “cell shape and nuclear to cytoplasm ratio”. It is unclear whether “cell shape” and “nuclear to cytoplasm ratio” are being considered together as a distinct morphological characteristic, or whether “cell shape” is a separate alternative to “nuclear to cytoplasm ratio” with respect to the morphological characterization. For purpose of examination, “cell shape” will be considered a separate embodiment from “nuclear to cytoplasm ratio”. Amendment of claims 11 and 22 to replace the conjunction “and” between “cell shape” and “nuclear to cytoplasm ratio” with a comma would overcome this portion of the rejection.
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 1, 6-16, 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Hicks et al (WO2015/048740) in view of Antonarakis et al (New England Journal of Medicine, 2014, Vol. 371, pp. 1028-1038), and Onstenk et al (European Urology, ePub July 15, 2015, Vol. 68, pp. 939-945).
Claim 1 is drawn to a method of identifying a metastatic castration resistant prostate cancer (mCRPC) patient with an improved response to taxane therapy compared to AR targeted therapy comprising generating circulating tumor cell data by analyzing nucleated cells in a mCRPC patient blood sample by immunofluorescent staining, morphological characterization, and detection of an AR variant 7 in said cells, and evaluating the circulating tumor cell data to identify a mCRPC patient with an improved response to taxane therapy compared to AR signaling directed therapy. Claim 6, further requires the treatment of the patient identified in the method of claim 1 with taxane therapy. Claim 7 requires in the method of claim 1 an initial step of depositing the nucleated cells as a monolayer onto a slide. Claim 8 specifies that the analysis of the method of claim 1 comprises fluorescence scanning microscopy. Claim 9 requires that the microscopy of claim 8 provides a field of view comprising CTCs and at least 200 surrounding WBCs.
Claim 10 specifies that CTCs comprise distinct morphological characteristics compared to surrounding nucleated cells in the method of claim 1.
Claim 11 requires that the morphological characteristics of claim 10 comprise one or more of nuclear size, nuclear shape, hole in the nucleus, cell size, cell shape, nuclear to cytoplasm ratio, nuclear detail, nuclear contour, the presence of absence of nucleoli, the quality of cytoplasm or the quantity of cytoplasm
Claim 12 requires the comparison of the intensity of pan cytokeratin fluorescent staining to surrounding nucleated cells for the detection of CTCs in the method of claim 1.
Claim 13 further requires an initial step of obtaining a WBC count for the blood sample in the method of claim 1.
Claim 14 further requires an initial step of lysing erythrocytes in the blood sample in the method of claim 1.
Claim 15 specifies that the immunofluorescent staining of nucleated cells in claim 1 is staining for pan-cytokeratin, CD45, and DAPI.
Claim 16 is drawn to a method of analysis comprising immunofluorescent staining and morphological characterization of nucleated cells in a blood sample obtained from a metastatic castration resistant prostate cancer (mCRPC) patient to generate circulating tumor cell data, wherein the analysis comprises detecting the presence of an Androgen Receptor Variant 7 in said cells.
Clam 21 requires comprise distinct morphological characteristics compared to surrounding nucleated cells in the method of claim 1.
Claim 22 requires that the morphological characteristics of claim 21 comprise one or more of nuclear size, nuclear shape, hole in the nucleus, cell size, cell shape, nuclear to cytoplasm ratio, nuclear detail, nuclear contour, the presence of absence of nucleoli, the quality of cytoplasm or the quantity of cytoplasm
Claim 23 further specifies that the comparison of the intensity of pan-cytokeratin staining relative to surround nucleated cells is used to detect CTCs in the method of claim 16
Claim 24 requires that the immunofluorescent staining of nucleated cells in claim 16 is staining for pan-cytokeratin, CD45, and DAPI for the detection of CTCs.
Hicks et al teach a method of predicting response to a hormone-directed therapy in a prostate cancer (PCa) patient comprising (a) performing a direct analysis comprising immunofluorescent staining and morphological characterization of nucleated cells in a blood sample obtained from the patient to identify and enumerate circulating tumor cells (CTC) ; (b) individually characterizing genotypic, morphometric and protein expression parameters to generate a profile for each of the CTCs, and (c) predicting response to hormone-directed therapy in the prostate cancer PCa patient based on said profile (claim 1 of ‘740), wherein the prostate cancer is metastatic castration resistant prostate cancer (mCRPC) (claim 5 of ‘740), and wherein the immunofluorescent staining of nucleated cells comprises pan cytokeratin, cluster of differentiation (CD) 45, diamidino-2-phenylindole (DAPI) and androgen receptor (AR) (claim 10 of ‘740) which meets the limitations of claims 15 and 24, and the limitations of instant claims 1 and 16 with the exception that the type of androgen receptor is not specified as AR-V7/AR3. Hicks et al evaluate both AR and AR2 CTCs (pages 5-6, paragraph [0018]).
Hicks et al teach an initial step of depositing nucleated cells as a monolayer onto a slide (claim 36 of ‘740) which meets the limitations of claim 7. Hicks et al teach that the analysis comprises fluorescent scanning microscopy (claim 37 of ‘740) which meets the limitation of claim 8. Hicks et al teach that the microscopy provides a view comprising CTCs and at least 200 surround WBCs (claim 38 of ‘740) which meets the limitations of claim 9. Hicks et al teach that the CTCs comprise distinct morphological characteristics when compared to surrounding nucleated cells (claim 40 of ‘740) which meets the limitation of claims 10 and 21. Hicks et al list the identical morphological characteristics as that of claims 11 and 22 (claim 41 of ‘740). Hicks et al teach the comparison of the intensity of pan-cytokeratin fluorescent staining to surrounding nucleated cells (page 21, lines 12-13 of paragraph [0066]) which meets that limitation in claims 12 and 23. Hicks et al teach an initial step of obtaining a WBC count for the blood sample (page 20, lines 1-2 of paragraph [0063]) which meets the limitation of claim 13. Hicks et al teach an initial step of lysing erythrocytes in the blood sample (page 20, lines 1-2 of paragraph [0064]) which meets the limitation of claim 14.
Although Hicks et al evaluate AR and AR2 CTCs , Hicks et al do not specifically teach the ARV7/AR3 as an androgen receptor of the claims, although nor does Hicks et al teach the prediction of a mCRPC patient to taxane therapy as having an improved response relative to AR targeted therapy.
Antonarakis et al teach that it is now accepted that castration-resistant prostate cancer is not androgen independent and continues to rely of androgen signaling (page 1029, first column, first sentence). Antonarakis et al teach that the drugs enzalutamide and abiraterone, which interferes with androgen signaling (page 1029, first column lines 4-22) and developed for the treatment of mCRPC, are not effective in all patients and that a large percentage of patients exhibit primary resistance (page 1029, second column, second paragraph, lines 1-7). Antonarakis et al teach that virtually all patients develop secondary resistance to enzalutamide or abiraterone (page 1029, second column, second paragraph, lines 7-9). Antonarakis et al suggest that resistance to enzalutamide or abiraterone may be due to the presence of androgen receptor splice variants which are constitutively active (page 1029, second column, second paragraph, lines 10-20). Antonarakis et al teach that multiple androgen-receptor variants have been identified, only AR-V7 encodes a functional proteins product that is detectable in clinical samples (page 1029, second column, lines 6-11 of the first full paragraph). Antonarakis et al carried out a study to correlate AR-V7 status in circulating tumor cells to predict a response or resistance to agents directed at the androgen receptor (page 1030, lines 1-5 under the heading “Study Design and Assessments”). Antonarakis et al conclude that AR-V7 can be detected reliably for circulating tumor cells and that the detection of AR-V7 in tumor cells appear to be associated with resistance to both enzalutamide and abiraterone (page 1036, lines 9-13).
Onstenk et al teach that the efficacy of cabazitaxel in CRPC is independent of the presence of AR-V7 in circulating tumor cells (title). Onstenk et al teach that because the response to cabazitaxel seems to be independent of the AR-V7 status of CTCs from metastatic castration resistant prostate cancer (mCRPC) patients, cabazitaxel might be a valid treatment option for patients with AR-V7 positive CTCs (abstract, following “Conclusions”).
It would have been prima facie obvious at the time of the effective filing date to carry out the method of Hicks et al using AR-V7/AR3 as the androgen receptor (claim 10 of ‘740) for the characterization of CTCs which are AR-V7 positive in order to predict the response of a mCRPC patient to enzalutamide, abiraterone or cabazitaxel. One of skill in the art would be motivated to do so by the teachings of Antonarakis et al that enzalutamide, and abiraterone, developed for treatment of mCRPC are ineffective in large percentage of patients and that patients who initially respond to enzalutamide, or abiraterone eventually develop resistance to the drugs, and AR-V7 status of circulating tumor cells in patients with castration resistance prostate cancer is indicative of resistance to enzalutamide, and abiraterone; and the teachings of Onstenk et al that the response to cabazitaxel is independent of the AR-V7 status of circulating tumor cells in mCRPC patients.
It would also have been prima facie obvious at the time of the effective filing date to treat the mCRPC patient with cabazitaxel if the patient were identified as having AR-V7 positive circulating tumor cells, because such cells are an indicator of resistance to the androgen-receptor signaling directed therapy of enzalutamide, and abiraterone, thus meeting the limitations of claim 6.
Claims 1-24 are rejected under 35 U.S.C. 103 as being unpatentable over Hicks et al, Antonarakis et al and Onstenk et al as applied to claims 1, 6-16, 21-24 above, and further in view of Nadiminty and Gao (World Journal of Urology, 2012, vol. 30, pp. 287-295).
Claim 2 requires in the method of claim 1, that the mCRPC patient is identified as having an improved response to taxane therapy compared to androgen receptor signaling directed therapy based on nuclear localization of the AR-V7 in the CTCs.
Claim 3 requires in the method of claim 2 that the nuclear localization of the AR-V7 in the CTCs corresponds to resistance to androgen receptor signaling directed therapy.
Claim 4 specifies that the nuclear localization of the AR-V7 corresponds to a positive response to taxane therapy compared to androgen receptor signaling directing therapy
Claims 5 and 20 specify that the nuclear localization comprises a staining pattern with a signal intensity of ≥3-fold higher than background staining from neighboring WBCs in the methods of claims 2 and 17, respectively.
Claim 17 require in the method of claim 16, that AR-V7 is localized to the nucleus of the CTCs.
Claim 18 specifies that the nuclear localization of the AR-V7 corresponds to resistance to androgen receptor signaling directed therapy for the mCRPC patient in the method of claim 17.
Claim 19 requires that the nuclear localization of the AR-V7 corresponds to a positive response to taxane therapy compared to androgen receptor signaling directing therapy for the mCRPC patient in the method of claim 18.
The combination of teachings of Hicks et al, Antonarakis et al and Onstenk et al render obvious the limitations of claims 1, 6-16, 21-24 for the reasons set forth above regarding CTCs which are positive for AR-V7 being indicative of improved response to cabazitaxel relative to enzalutamide and abiraterone because both of Antonarakis et al and Onstenk et al teach that CTCs positive for AR-V7 indicate resistance to enzalutamide and abiraterone, and the teachings of Onstenk et al regarding AR-V7 status in CTCs of mCRPC patients not being associated with resistance to cabazitaxel , and the suggestion of Onstek et al that cabazitaxel be used to treat mCRPC patients with CTCs positive for AR-V7.
Hicks et al further teach that due to the nature of measuring a signal over background noise, a CTC-specific immunofluorescent marker, even though absent on WBCs are visible in the WBCs as background signals; and that a cell cis positive for an immunofluorescent marker if its fluorescent signal for the marker is significantly higher than a fixed back ground signal, such as 2-fold, 3-fold, 5-fold, etc. higher than background (page 26, paragraph [0082]), which renders obvious the requirements of claims 5 and 20 with respect to ≥ 3-fold higher than background given the routine optimization within the purview of one of skill in the art.
Antonarakis et al further teach that Ar-V7 lacks a ligand binding domain (page 1028, lines 1-3 under “Background”).
None of Hicks et al, Antonarakis et al or Onstenk et al teach that method wherein CTCs are identified based on nuclear localization of AR-V7 in CTCs.
Nadiminty and Gao teach that AR-V7/AR3 is a constitutively activated AR variant characterized by nuclear localization in the absence of ligand (page 290, Table 1 and first column, lines 7-9).
It would have been prima facie obvious at the time of the effective filing date to use nuclear localization of AR-V7 in the CTCs of mCRPC patient required in claim 17. One of skill in the art would have been motivated to do so based on the teachings of Nadiminty and Gao that AR-V7/AR3 is a constitutively activated AR variant characterized by nuclear localization in the absence of ligand and because Antonarakis et al teach that AR-V7 lacks a ligand binding domain. Thus, one of skill in the art would conclude that AR-V7 is always present in the nucleus as the presence of a ligand would not influence it subcellular localization because of the inability of the ligand to bind to AR-V7
It would have been further obvious to use the nuclear localization to identify a mCRPC patient having
1. improved response to cabazitaxel compared to enzalutamide and abiraterone
2. resistance to enzalutamide and abiraterone, and
3. positive response to cabazitaxel compared to enzalutamide and abiraterone,
because Antonarakis et al and Onstenk et al teach that AR-V7 CTCs in CRPC are indicative of resistance to enzalutamide and abiraterone, which meets the limitations of claims 3 and 18, and Onstenk et al teach that response of mCRPC patients to cabazitaxel is independent of AR-V7 in CTCs and suggests that cabazitaxel be used to treat such patients. Because the patients with AR-V7 CTCs as manifest by AR-V7 nuclei are resistant to enzalutamide and abiraterone but are expected to respond to cabazitaxel, the requirement of improved response to cabazitaxel compared to enzalutamide and abiraterone and positive response to cabazitaxel compared to enzalutamide and abiraterone required in claims 2, 4 and 19 because any response to cabazitaxel in enzalutamide and abiraterone resistant patients would be an improvement or positive response over enzalutamide or abiraterone therapy.
All claims are rejected.
Conclusion
This is a CON of applicant's earlier Application No.15/762,076. All claims are identical to, patentably indistinct from, or have unity of invention with the invention claimed in the earlier application (that is, restriction (including lack of unity) would not be proper) and could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the earlier application. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action in this case. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643