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 .
Application Status
The Amendments and Remarks filed 28 August 2026 in response to the Office Action 03 March 2026 are acknowledged and have been entered. Claims 1, 3, and 6 are amended. Claim 5 is cancelled. Claims 11-15 are newly added. Claims 1-4 and 6-15 are pending and being examined on the merits.
Any objection or rejection not reiterated herein has been overcome by applicant’s claim amendments.
Priority
This application is a 371 to PCT/US2020/063534 filed 12/07/2020 which claims priority to application 62/944,804 filed 12/06/2019.
Information Disclosure Statement
The information disclosure statement filed 12/01/2025 has been considered.
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 1-4 and 6-15 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 recites “wherein the administration reduces prostate cancer recurrence in the subject.” It is unclear what the claimed reduction in prostate cancer recurrence is relative to. For example, the claim does not specify whether recurrence is reduced relative to no treatment, a conventional IADT regimen, continuous androgen-deprivation therapy, the subject's prior treatment regimen, or another comparator. Because the scope of the claimed treatment depends upon achieving a “reduction” without establishing the reference against which the reduction is determined, one of ordinary skill cannot ascertain the metes and bounds of the claim with reasonable certainty.
Claim 1 further recites “a threshold probability of resistance (κ) in the subsequent cycle (κi).” The relationship between κ and κi is unclear. The specification appears to describe κi as the resistance threshold corresponding to treatment cycle i; however, the claim separately introduces the threshold as κ and thereafter recites “cycle i (κi).” It is therefore unclear whether κ and κi identify the same threshold.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 13 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 13 requires administration of “docetaxel or AA” when the subject has a PcaSC self-renewal rate ps greater than about 0.0270. The specification provides support for stratifying patients for docetaxel treatment according to PcaSC self-renewal rate, including administration of docetaxel to patients having ps at or above a median ps value and reported patient ps values near the presently claimed threshold. However, the specification does not reasonably convey possession of the separate embodiment in which abiraterone acetate is selected for administration based on the subject having ps of greater than about 0.0270. The abiraterone disclosure instead employs an adaptive treatment-response model based on fitted parameter dynamics and probability-of-resistance thresholds. Thus, the originally filed disclosure does not reasonably convey possession of the full scope of claim 13.
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.
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.
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, 4, 8, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Brady et al. (Cancer Res. 78(16 Suppl.): B014 (2018) (“Brady”)), in view of Enderling et al. (Front. Oncol. 3:76 (2013) (“Enderling”)), Portz et al. (AIP Advances 2, 011002 (2012) (“Portz”)), and Hirata et al. (Scientific Reports 8:2673 (2018) (“Hirata”)). This is a new rejection in view of applicant’s claim amendments.
Regarding claim 1, Brady states that “[w]e developed a mathematical model of prostate cancer stem cell dynamics during therapy as a plausible mechanism of resistance evolution,” simulated “division dynamics of cancer stem cells, non-stem cancer cells, and PSA concentration,” fit the model to “longitudinal data of 55 patients undergoing 2-4 cycles of intermittent androgen suppression,” identified “cancer stem cell proliferation patterns that correlate with patient outcomes,” and used the model to “accurately forecast evolution of resistance in individual patients.” [Abstract B014] Thus, Brady teaches longitudinal PSA measurements, a dynamic model comprising PcaSC and non-stem prostate-cancer populations, multiple IADT cycles, patient-specific modeling, and prediction of subsequent resistance.
Brady does not expressly identify the PcaSC self-renewal parameter as ps, calculate resistance probability p(Ω) from the relative change in that parameter between samples, or compare that probability with κi.
Enderling teaches that, in a cancer-stem-cell mathematical model, “Cancer stem cells (CSCs) divide symmetrically with fixed probability ps, and asymmetrically with probability 1- ps,” and analyzes and ps = 0.1, .025, .05, .075. and .099 [pg. 3, col. 2, para 2-4]. Enderling further teaches that increasing ps materially increases the CSC population and alters tumor growth [pg. 3, col. 2, para 2-4, entire manuscript]. It would have been obvious to use Enderling's established parameter to quantify the stem-cell “division dynamics” and “proliferation patterns” expressly modeled by Brady because the parameter performs its known function of quantitatively representing CSC self-renewal.
Portz teaches fitting individual biological parameters to longitudinal PSA data for prostate-cancer treatment modeling. Portz states that a model capable of predicting “the course of an individual case of prostate cancer would also be useful in developing a treatment schedule in a clinical setting,” [pg. 011002-3, para 3] and models androgen-dependent and androgen-independent cancer-cell populations and PSA production [pp. 011002-4–011002-5, equations 6–12 and Table I]. Portz further teaches individual model fitting to clinical PSA data and expressly states that although one parameter set was fitted to the full clinical time series, “there is no reason that the parameter values cannot be updated over time as more data points become available.” [pg. 011002-14, para 2]. It therefore would have been obvious to determine how ps or another responder parameter changes between successive patient measurements in order to quantify the longitudinal proliferation pattern Brady expressly uses to forecast resistance.
Hirata teaches the remaining probability-based prediction. Hirata generated “100 sets of parameter values for each patient by randomly resampling each patient's time points,” classified each set according to whether IAS prevents relapse, delays relapse, or is not beneficial, and used those simulations to determine an individualized hormone-treatment schedule [Abstract]. More specifically, Hirata generated 100 bootstrap samples from each patient's PSA measurements, fitted a mathematical model to each sample, and classified the resulting parameter values according to relapse behavior [pg. 2, para 3]. Hirata then uses the frequency of the classifications among the 100 parameter sets and shows that type (ii)/(iii) classifications correspond to an increased possibility of metastasis or castration resistance [pg. 3, para 3-7].
Regarding claim 4, Hirata describes PSA as “a serum tumor marker in blood for prostate cancer.” [pg. 1, para 1]. Thus, obtaining the claimed PSA levels as blood PSA levels would have been obvious.
Regarding claim 8, Brady expressly fits longitudinal data from patients “undergoing 2-4 cycles of intermittent androgen suppression.” Thus, Brady's modeling and prediction necessarily are performed after IADT has begun and during subsequent cycles.
Regarding claim 12, Portz determines additional model parameters including “Maximum proliferation rate,” “Baseline PSA production rate,” “AD PSA production rate,” and “AI PSA production rate.” [Table I]. Brady independently teaches identifying PcaSC “proliferation patterns.” It therefore would have been obvious to calculate at least a PcaSC proliferation parameter and/or PSA-production parameter together with ps, since these were known model variables affecting the modeled PSA and cell-population dynamics.
It would have been obvious to express Brady's predicted resistant outcomes as the proportion, i.e., probability, of simulated outcomes satisfying the resistance criterion and compare that probability with a decision threshold before selecting the subsequent IADT treatment. Hirata expressly teaches probabilistic classification from multiple patient-specific parameter realizations and using those predictions to decide treatment, including “when to reinstitute AS or whether to use CAS instead.” [p. 4, para 1]. The use of a numerical threshold κi to separate resistant from responsive predictions is a conventional implementation of that binary classification. One of ordinary skill would have reasonably expected success because Brady had already demonstrated patient-specific forecasting from PcaSC/PSA dynamics, Portz successfully fitted patient-specific longitudinal models, and Hirata demonstrated prospective prediction and treatment selection from fitted parameter distributions.
Claims 2-3, 6 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Brady et al. (Cancer Res. 78(16 Suppl.): B014 (2018) (“Brady”)), in view of Enderling et al. (Front. Oncol. 3:76 (2013) (“Enderling”)), Portz et al. (AIP Advances 2, 011002 (2012) (“Portz”)), and Hirata et al. (Scientific Reports 8:2673 (2018) (“Hirata”)), as applied above to claim 1, and further in view of Bruchovsky et al., (Cancer 109:858–867 (2007) (“Bruchovsky”)), Beer et al. (British Journal of Cancer (2003) 89, 968 – 970 (“Beer”)) and, as to claim 3, Scher et al. (J. Clin. Oncol. 26:1148–1159 (2008) (“Scher”)).
The teachings of Brady, Enderling, Portz, and Hirata discussed above as applied to claim 1 and similarly apply to claims 2, 3, 6, and 11. They do not expressly use 50% of pretreatment PSA as the IADT stopping threshold.
Bruchovsky teaches PSA-triggered intermittent androgen suppression: treatment was stopped when PSA was below the specified threshold and was “resumed when the serum PSA level reached ≥10 μg/L.” [ see “Design of Study”]. Bruchovsky additionally calculates the “percentage reduction” in PSA during each treatment cycle relative to the patient's baseline PSA and reports reductions of approximately 93–98% [Fig. 2 and Table 1]. Thus, PSA decline relative to pretreatment/baseline was a known result-effective variable for treatment response. However, once PSA reduction was known to control treatment interruption, selecting the amount of reduction was a matter of routine threshold optimization. A 50% PSA decline was also a conventional prostate-cancer treatment-response criterion ad Beer required a “50% reduction confirmed 4 weeks apart” before entering an intermittent-treatment holiday [see Materials and Methods]. It would therefore have been obvious to select a 50% pretreatment-PSA threshold in Bruchovsky's PSA-controlled intermittent-treatment framework, with a reasonable expectation that PSA decline would continue to provide an objective treatment-response trigger.
Regarding claim 3, the teachings discussed above to claims 1-2 similarly apply to claim 3. Brady, Enderling, Portz, Hirata, Bruchovsky, and Beer do not teach wherein one or more subsequent cycles of IADT are administered to the subject when PSA levels are at least 10% greater than pre-treatment levels of the subject. Scher teaches the accepted prostate-cancer PSA progression criterion of a PSA increase that is “≥25% and ≥2 ng/mL above the nadir,” with baseline used where appropriate [Table 5/discussion of PSA progression]. A 25% increase is within the claimed “at least 10% greater” limitation. Because Bruchovsky already teaches restarting intermittent androgen suppression upon a rising PSA threshold, it would have been obvious to use a recognized PSA-progression criterion as the trigger for administering a subsequent treatment cycle, with a reasonable expectation of identifying renewed disease activity before further progression.
Regarding claims 6 and 11, the teachings discussed above to claim 1 similarly apply to claims 6 and 11. Brady, Enderling, Portz, Hirata, Bruchovsky, and Beer do not teach wherein the two or more samples are isolated every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. Bruchovsky expressly teaches that “serum PSA and testosterone levels were monitored every 4 weeks” during cyclic androgen withdrawal [see “Design of Study”]. Four weeks falls expressly within the claimed 1–16 week alternatives. It would have been obvious to obtain Brady's longitudinal PSA samples at that established IADT monitoring interval. The skilled artisan would reasonably expect success because Bruchovsky used that schedule prospectively through multiple intermittent androgen-suppression cycles.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Brady et al. (Cancer Res. 78(16 Suppl.): B014 (2018) (“Brady”)), in view of Enderling et al. (Front. Oncol. 3:76 (2013) (“Enderling”)), Portz et al. (AIP Advances 2, 011002 (2012) (“Portz”)), and Hirata et al. (Scientific Reports 8:2673 (2018) (“Hirata”)) as applied to claim 1, and further in view of Peyromaure et al. (Urology 65:724–729 (2005) (“Peyromaure”)).
The teachings discussed above as applied to claim 1 similarly apply to claim 7. Brady, Enderling, Portz, and Hirata do not teach wherein the primary treatment is surgical resection of the tumor, neoadjuvant, or adjuvant androgen-deprivation therapy. Peyromaure teaches intermittent androgen deprivation specifically for “biochemical recurrence after radical prostatectomy,” with 57 post-radical-prostatectomy patients treated with IAD [Abstract, pp. 724–729]. Thus, Peyromaure teaches use of IADT after surgical resection as the primary treatment. It would have been obvious to apply Brady's patient-specific recurrence model to this known post-surgical IADT population in order to individualize subsequent treatment, with a reasonable expectation of success because IADT was already clinically used for PSA recurrence after prostatectomy.
Claims 9 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Brady et al. (Cancer Res. 78(16 Suppl.): B014 (2018) (“Brady”)), in view of Enderling et al. (Front. Oncol. 3:76 (2013) (“Enderling”)), Portz et al. (AIP Advances 2, 011002 (2012) (“Portz”)), and Hirata et al. (Scientific Reports 8:2673 (2018) (“Hirata”)) as applied to claim 1 and 8, and further in view of Sweeney et al., N. Engl. J. Med. 373:737–746 (2015) (“Sweeney”).
The teachings discussed above as applied to claims 1 and 8 similarly apply to claims 9 and 13-15.
Brady, Enderling, Portz, and Hirata do not teach wherein the IADT further comprises the administration of docetaxel or abiraterone acetate (AA). Sweeney teaches men with metastatic hormone-sensitive prostate cancer receiving “ADT plus docetaxel (at a dose of 75 mg per square meter ... every 3 weeks for six cycles)” and reports significantly longer overall survival with docetaxel added at the beginning of ADT [Abstract, Methods and Results, pp. 737–746]. Sweeney establishes, however, that docetaxel could predictably be combined with androgen-deprivation treatment to improve prostate-cancer outcome. It therefore would have been obvious to include docetaxel in Brady's androgen-deprivation regimen for a patient appropriate for chemotherapy, with a reasonable expectation of antitumor benefit based on Sweeney's phase III results.
Regarding claim 13, Brady, Enderling, Portz, and Hirata do not teach wherein docetaxel is administered to the subject when the subject has a PCaSc self-renewal rate ps of greater than about 0.0270. Enderling expressly evaluates CSC symmetric self-renewal probabilities ps of 0.1, 0.25, 0.5, 0.75, and 0.99, all of which are greater than the claimed value of “about 0.0270.” [pp. 3–4]. Enderling further demonstrates that increasing ps materially increases the CSC population and alters tumor growth [pg. 3, col. 2, para 2-4, entire manuscript], making ps a recognized result-effective variable. Brady teaches that PcaSC proliferation patterns correlate with patient outcome and resistance, while Sweeney teaches administering docetaxel with ADT. Accordingly, application of the docetaxel-containing treatment to a modeled patient having any of Enderling's expressly taught ps values would satisfy the claimed threshold. Alternatively, selecting a lower ps cutoff for identifying a more stem-cell-rich/aggressive modeled phenotype would have involved routine optimization of a known result-effective variable, with a reasonable expectation that increasing self-renewal would identify increasing CSC burden.
Regarding claim 14, Brady, Enderling, Portz, and Hirata do not teach wherein docetaxel is administered to the subject in a castration naive setting. Sweeney expressly administered docetaxel with ADT to men with metastatic hormone-sensitive prostate cancer, i.e., before development of castration-resistant disease, and administered the docetaxel “early during therapy.” [Abstract, pp. 737–746]. Thus, administering docetaxel in the claimed castration-naïve setting was expressly known and would have been expected to provide the established survival benefit.
Regarding claim 15, Brady, Enderling, Portz, and Hirata do not teach further comprising administering to the subject a chemotherapy. Sweeney expressly teaches administering the chemotherapeutic agent docetaxel together with androgen-deprivation therapy and demonstrates significantly improved survival and delayed progression [Abstract]. It therefore would have been obvious to further administer chemotherapy to an appropriate prostate-cancer patient treated according to Brady's personalized IADT method, with a reasonable expectation of therapeutic benefit.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Brady et al. (Cancer Res. 78(16 Suppl.): B014 (2018) (“Brady”)), in view of Enderling et al. (Front. Oncol. 3:76 (2013) (“Enderling”)), Portz et al. (AIP Advances 2, 011002 (2012) (“Portz”)), Hirata et al. (Scientific Reports 8:2673 (2018) (“Hirata”)) and Sweeney et al., N. Engl. J. Med. 373:737–746 (2015) (“Sweeney”) as applied to claims 1, 8, and 9, and further in view of Gao et al. (WO 2015/065919 A1 (“Gao”)).
The teachings discussed above as applied to claims 1, 8 and 9 similarly apply to claim 10. Brady, Enderling, Portz, Hirata, and Sweeny do not teach where the method further comprising calculating docetaxel cytotoxicity and adjusting dosage and timing of docetaxel. Gao teaches determining “[o]ptimum dosages, toxicity, and therapeutic efficacy” using standard pharmaceutical procedures, including LD50 and ED50 measurements, and identifying the therapeutic index as LD50/ED50 [0231]. Gao further teaches that optimum dosing schedules may be determined and that dosage and timing may vary with “the severity of the disease,” “previous treatments,” and other patient factors [0230-0232; 0236]. Thus, Gao teaches calculation of cytotoxicity/therapeutic efficacy and adjustment of dose and timing. It would have been obvious to perform such conventional dose optimization for the docetaxel treatment of claim 9 to maximize therapeutic effect while limiting toxicity, with a reasonable expectation of success because Gao expressly characterizes these as standard pharmaceutical procedures.
Response to Arguments
Applicant' s arguments with respect to the claims rejected under 35 U.S.C. 103 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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