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 1-20 are pending and examined on the merits.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation without significantly more. The claims recite a method of predicting response to a hormone-directed therapy in a patient with prostate cancer comprising analyzing CTC in a blood sample from a patient with prostate cancer to generate a profile based on determination of a genotypic, morphometric and protein expression parameters for each individual CTC, and predicting the response of the patient to hormone directed therapy based on the profile. This judicial exception is not integrated into a practical application because the claim does not utilize the predicted response in a further concrete method step. Claims 2-20 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because claims 2-5 and 10-11 are data gathering steps required to use the correlation and do not add a meaningful limitation to the method as they are insignificant extra-solution activity. Claims 6-9 pertain to the correlation between a particular hormone directed therapy and the generated profile and are thus specific embodiments of the judicial exception which fail to integrate the judicial exception into a practical application. Claim 20 requires the repetition of steps (a)-(c) in claim 1 for sequential monitoring of the genotypic, morphometric and protein expression parameters. This fails to impart a meaningful limitation to the method because it is also data gathering steps which are insignificant extra-solution activity required to use the correlation.
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 1-20 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.
Claim 1 requires an enumeration of CTCs in the prostate cancer patient and the generation of a profile of genotypic, morphometric and protein expression parameters for each of the CTCs for the prediction of the patients response to hormone directed therapy. It is unclear how the enumeration of the CTCs contributes to the prediction of the response to hormone directed therapy because the claim indicates that only the profile of the CTC which is made up of genotypic, morphometric and protein expression parameters is used for the prediction.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5-15 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Miyamoto et al (Cancer Discovery, 2012, Vol. 2, pp. 995-1003 and supplemental Tables S1 and S2) in view of Navin and Hicks (Genome Medicine, 2011, Vol. 3, No. 31, 12 pages).
Claim 1 is drawn to a method of predicting the response to a hormone-directed therapy in a prostate cancer patient comprising immunofluorescent staining and morphological characterization of nucleated cells in a blood sample from the patient to identify and enumerate CTC; individual characterization of genotypic, morphometric and protein expression parameters to generate a profile for each CTC and predicting a response to hormone directed therapy based on the profile. Claim 2 specifies that the CTC are isolated prior to characterization of the genotypic parameters. Claim 3 specifies that the characterization of the morphometric and protein expression parameters precedes the isolation of the CTCs. Claim 5 specifies that the prostate cancer of claim 1 is metastatic castration-resistant prostate cancer.
Claim 6 requires that the hormone directed therapy is androgen deprivation therapy. Claim 7 requires that the ADT is a second line therapy. Claim 8 requires that the therapy of claim 7 blocks the synthesis of androgen. Claim 9 requires that the therapy of claim 8 is selected from a group including abiraterone acetate. Claim 11 requires that the genotypic parameters of claim 1 comprise copy number variation signatures. Claim 12 requires that the copy number variation signatures comprise gene amplifications or deletions. Claim 13 specifies that the gene amplifications comprise genes associated with androgen-independent cell growth. Claim 14 requires, in part, that the genes of claim 13 comprise AR. Claim 15 requires that the protein expression parameters comprise quantifying protein expression level. Claim 18 specifies that the protein expression is AR expression. Claim 19 requires that the morphometric parameters comprise cell shape. Claim 20 embodies the method of claim 1 further comprising repeating steps (a) through (c) at one or more timepoints after initial diagnosis of prostate cancer to sequentially monitor said genotypic, morphometric and protein expression parameters.
Miyamoto et al teach single-cell measurement of AR signaling parameters in prostate CTC by quantitative four-color immunofluorescence (page 996, lines 1-3 under the heading “Single -Cell Measurement of AR-Signaling Parameters…”) to detect PSA and PSMA which meets the requirement of quantifying the protein expression in claim 15. Miyamoto et al teach that PSMA is indicative of AR signaling suppression (page 996, second column, lines 10-16), along with DAPI for nuclear morphology, which meets the limitation of a cell-shape morphology in claim 19 because nuclear shape is an intra-cellular shape, and anti-CD45 as a negative marker to exclude contaminating leukocytes (page 996, second column, lines 10-14 and 22-24 of bottom paragraph). Miyamoto et al teach that the patients included metastatic CRPC (supplemental Table S1) which meets the limitations of claim 5. Miyamoto et al teach that the hormone directed therapy in these patients was second line abiraterone (prost9-prost25) and ketoconazole (Prost6) which meets the limitations of claim 6-9. Miyamoto et al teach that potent new inhibitors of the AR pathway are under active development, their clinical deployment remains empiric. Miyamoto et al teach that given the interpatient variation in outcome there is an unmet clinical need for biomarkers that enable prediction of treatment response for individual patients (page 999, lines 7-12). Miyamoto et al teach that the activity of the AR pathway may be monitored “real-time” using CTCs reflecting the effects of cancer drugs on their therapeutic targets and the potential to identify early emergence of resistance to therapy (page 999, lines 12-19) which meets the limitations of claim 20 and claim 1(c) for “predicting the response to hormone directed therapy based on the profile.
Miyamoto et al do not teach characterization of genotypic parameters in the CTCs; isolating the CTCs before characterization of the genotypic parameters, or characterization of the morphometric and protein expression parameters prior to the isolation of the CTCs as required in claim 2 and 3. Miyamoto et al do not teach determining copy number variation signatures, including gene amplifications or deletions, such as genes associated with androgen independent cell growth or AR, as required in claims 11-14.
Miyamoto et al teach that the use of PSA and PSMA was an indirect method of determining expression of AR reactivation in CRPC (page 996, lines 1-6 under Single-Cell Measurements of AR Signaling Parameters..”). Miyamoto et al teach that potential mechanisms by which AR reactivation occurs in CRPC include variable levels of AR gene amplification, activating AR mutations, alternative RNA splicing, increased expression of AR transcriptional co-activators, activation of modulatory kinase pathways such as Ras and PI3K and tyrosine phosphorylation of AR (page 996, lines 17-23).
Navin and Hicks et al teach single cell sequencing of CTCs for genomic profiling to provide important information for monitoring cancer patients (page 6 of 12, lines 1-8 under the heading of “Early detection..”)including copy number aberrations (page 6 of 12, second column, lines 1-7 of the second full paragraph). Navin and Hicks teach that by profiling samples of CTCs, it would be possible to determine pathways of progression (page 6-12, second column, lines 7-10 of the second full paragraph). Navin and Hicks teach that the cell in question is isolated by micromanipulation or FACS (Figure 2(a) and (c)) prior the visualization of chromosomes in single cells, or WGA to provide the genomic profiling (Figure 2(d-f)).
It would have been prima facie obvious at the time of the effective filing date to isolate CTC individual cells which were positive for PSMA, PSMA, DAPI and negative for CD45 for determining the genomic copy number of AR, activating AR mutations, increased expression of AR transcriptional co-activators, activation of modulatory kinase pathways such as Ras and PI3K and tyrosine phosphorylation of AR which meets the limitations of claims (2 and 3) because the identification of PSA positive and PSMA positive cells would insure that the CTC were prostate cells and also meets the limitations of claims 11-14. One of skill in the art would be motivated to do so because the determination of AR copy number activating AR mutations, increased expression of AR transcriptional co-activators, activation of modulatory kinase pathways such as Ras and PI3K and tyrosine phosphorylation of AR are mechanisms that are taught by Miyamoto et al to provide AR reactivation in CRPC, and thus would be predictive of emergence of resistance to ADT allowing a change in treatment in patients being treated with by ADT. One of skill in the art would be motivated to include the genotypic parameter rather than relying only on PSA and PSMA because Navin and Hick teach that using genomic profiling allows for the determination of a pathway of progression. One of skill in the art would be motivated to do so in order to potentially counter the pathway of progression by a different therapeutic strategy.
Regarding clams 18, it would have been prima facie obvious to include AR protein expression as a protein expression parameter in place of CD45 in the method rendered obvious by the combination of Miyamoto et al and Navin and Hicks. One of skill in the art would have been motivated to do so in order to directly measure AR expression rather than indirectly through AR sensitive genes including PSA and PSMA. One of skill in the art would understand that the markers of PSA, PSMA and AR would not be expressed by leukocytes and therefore CD45 as a negative marker would not be necessary.
All claims are rejected.
Conclusion
This is a CON of applicant's earlier Application No.16/884,737. 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