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 .
Current Status
This action is responsive to the amended claims of 11/25/2025. Claims 1, 3-5, 7, 9-10, 12, 14-15, 24, 26, 28, and 34 are pending and have been examined on the merits.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/25/2025 has been entered.
Election/Restrictions
The response of 11/25/2025 did not overcome the rejections of the office action of 08/27/2025. The search for the elected species (i.e., onvansertib and abiraterone) retrieved art (see SEARCH 5-7 of the attached search notes). Thus, the Markush search will not be unnecessarily extended in this action, in accordance with Markush search practice.
Priority
The effective filing date is 03/28/2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/25/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Examiner acknowledges receipt of and has reviewed the remarks and amendments of 11/25/2025.
The objection to claim 7 is withdrawn since Applicant has amended the claim in line with the Examiner’s suggestion.
The 35 USC 102 rejection of claims 1, 3-4, 7, and 9 over ZHANG evidence by WATSON is modified below in response to Applicant’s filing of an RCE. Applicant's arguments filed 11/25/2025 have been fully considered but they are not persuasive (Pg. 4-5). Applicant argues that the LuCap35CR taught by ZHANG is castration-resistant and the LuCaP35 taught by WATSON is androgen-sensitive, thus, the two cell lines should not be considered the same and the Examiner has not established that the LuCap35CR of ZHANG is characterized by AR-V7. While the Examiner agrees that the two cell lines are described as castration-resistant and androgen-sensitive, respectively, Examiner maintains that LuCaP35CR is a subtype of LuCaP35 and is characterized by AR-V7. To support this argument, Examiner has replaced WATSON with MOSTAGHEL (Mostaghel, E. A. et al., Clin. Cancer Res., 2011, 17(18), 5913-5925) as an evidentiary reference in the modified rejection below. In short, MOSTAGHEL discloses LuCaP35CR is characterized by AR-V7 (Pg. 17 Fig. 4).
The 35 USC 103 rejection of claims 1, 3-5, 7, 9-10, 12, 14-15, 24, and 26 over CARDIFF evidenced by BERIA and ZHANG is modified below in response to Applicant’s filing of an RCE. Applicant's arguments filed 11/25/2025 have been fully considered but they are not persuasive (Pg. 5-6). Applicant argues, using the same logic as discussed in ¶9 above, that LuCaP35 and LuCaP35CR should not be considered the same. This argument did not address the merits of the pending rejection since the examiner relied on a different reasoning here than what was put forth in the 102 over ZHANG & WATSON. Examiner cited ZHANG’s teaching of AR-V7 expression in a CRPC cell line 22Rv-1 (Pg. 6642 Left Col. P2 & Pg. 6643 Fig. 4 Description & Part C). The teaching of CRPC 22Rv-1 as having measurable AR-V7 expression (i.e., characterized by) and the effect of PLK1 inhibition on response to abiraterone (ZHANG Fig. 4E) was not addressed by the response. To further clarify and support the merits of the rejection, the Examiner adds in MOSTAGHEL (recited above) as an evidentiary reference.
The 35 USC 103 rejection of claims 1 and 28 over CARDIFF evidenced by BERIA, ZHANG, and EPIC is modified below in response to Applicant’s filing of an RCE. Applicant's arguments filed 11/25/2025 have been fully considered but they are not persuasive (Pg. 6-7). For the same reasons as discussed in ¶10, above, Applicant’s arguments are not persuasive. To further clarify and support the merits of the rejection, the Examiner adds in MOSTAGHEL (recited above) as an evidentiary reference.
Claim 34 has been recast as an independent claim. Upon further search and consideration, prior art was found for claim 34 (see SEARCH 5-7). Thus, in response to the filing of an RCE, Examiner has provided a new rejection below addressing the limitations of instant claim 34.
Response to Amendment & RCE
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 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.
Claims 1, 3-4, 7, and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ZHANG (Zhang, Z., et al., Cancer Res., 2014, 74(22), 6635-6647, provided in IDS of 10/19/2022) as evidenced by MOSTAGHEL (Mostaghel, E. A. et al., Clin. Cancer Res., 2011, 17(18), 5913-5925).
Note: the following rejection is based upon art which was found incidental to the search for the elected species. This is not indicative that the entire scope of the claims has been examined; however, the following art is being applied in an effort to promote compact prosecution of the case.
Regarding claims 1, 4, 7, and 9, ZHANG teaches LuCaP35CR tumors were inoculated into castrated mice and the mice were intravenously injected twice per week with BI2536, which is a PLK1 inhibitor (Pg.6636 Left Col. ¶3), and abiraterone (Pg. 6645 Fig. 6 description); tumor volume shrunk relative to the vehicle after administration of the combined BI2536 and abiraterone treatment and serum PSA levels decreased in the treatment group relative to the increasing PSA levels in the vehicle group as measured over 7 weeks (Pg. 6645 Fig. 6 A-B and D, respectively). ZHANG teaches serum PSA levels were measured once a week (Pg. 6638 Left Col. ¶5). ZHANG also teaches the LuCaP35CR tumors are castration-resistant (Pg. 6642 Right Col. Last ¶). Thus, Examiner understands ZHANG to teach a method of treating CRPC wherein the patient has rising PSA levels measured in at least two samples at different times and administration of the PLK1 inhibitor BI2536 and abiraterone. The Examiner understands a step of administration to necessarily require a step of recommending treatment (i.e., the treatment would not be administered if it were not recommended).
ZHANG is silent as to the altered androgen receptors in LuCaP35CR tumors, so Examiner cites MOSTAGHEL as an evidentiary reference. MOSTAGHEL discloses LuCaP35CR is characterized by AR-V7 (Pg. 17 Fig. 4). Furthermore, ZHANG teaches elevation of AR-Vs contribute to resistance to AR inhibitors in CRPC, thus, the combination of BI2536 and abiraterone could be a novel avenue to overcome such resistance (Pg. 6642 Right Col. ¶1). Thus, Examiner understands ZHANG to teach a method of treating a patient with CRPC (i.e., LuCaP35CR), which is characterized by AR-V7, by administering the PLK1 inhibitor BI2536 and abiraterone.
Regarding claim 3, Figure 6D of ZHANG shows the rise in serum PSA (ng/mL) over 7 weeks in the vehicle and treatment groups (Pg. 6645). Based on the graph, Examiner understands the weekly measurements of PSA in the vehicle group to show a rise of at least 0.1 ng/mL and at least one confirmatory value not showing a decline (e.g., weeks 4, 5, and 6 wherein 4 to 5 is at least a 0.1 ng/mL rise and 5 to 6 is a confirmatory value not showing a decline; Pg. 6645 Fig. 6D).
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 (i.e., changing from AIA to pre-AIA ) 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.
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, 3-5, 7, 9-10, 12, 14, 24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over:
CARDIFF (Cardiff Oncology, Jan. 2018, NCT03414034, ClinicalTrials.gov,clinicaltrials.gov/study/NCT03414034?intr=Onvansertib&rank=5&a=1&tab=history, accessed 12/20/2024, provided by Examiner 01/16/2025),
as evidenced by:
BERIA (Beria, I., et al., Bioorganic & Medicinal Chemistry Letters, 2011, 21, 2969-6974, provided by Examiner 08/27/2025),
In view of:
ZHANG (Zhang, Z., et al., Cancer Res., 2014, 74(22), 6635-6647, provided in IDS of 10/19/2022),
As evidenced by:
MOSTAGHEL (Mostaghel, E. A. et al., Clin. Cancer Res., 2011, 17(18), 5913-5925).
Determining the Scope and Contents of the Prior Art:
CARDIFF teaches a method of administering PCM-075 (i.e., onvansertib) given orally once daily for 5 consecutive days every 21 days in adult patients with metastatic castration-resistant prostate cancer (mCRPC) who have disease progression while receiving abiraterone and prednisone therapy, to observe the effects of onvansertib in combination with abiraterone and prednisone on disease control (Pg. 8 Brief Summary). CARDIFF also teaches onvansertib is administered at 24 mg/m2 in combination with abiraterone administered orally once daily (Pg. 9-10 Arms and Interventions, Left Box). CARDIFF further teaches the inclusion criteria for patients to receive this treatment includes the subject currently receiving abiraterone and prednisone for CRPC and having two rising prostate specific antigen (PSA) values separated by at least 1 week, one showing a rise of at least 0.5 ng/mL and one confirmatory value not showing a decline (Pg. 12 Inclusion Criteria #6 and 8). Examiner interprets CARDIFF’s method of treatment as necessarily including a recommendation to receive the treatment. Further, Examiner interprets CARDIFF’s teaching of two rising PSA values as indicative of measurement of the patient’s PSA levels in two samples.
Examiner cites BERIA, as an evidentiary reference, wherein onvansertib is disclosed as a potent, selective, and orally available PLK1 inhibitor (Abstract & Pg. 2970 Scheme 4 7g). Thus, onvansertib is known to be a PLK1 inhibitor.
ZHANG teaches PLK1 is elevated in prostate cancer, where its expression is linked to tumor grade (abstract). ZHANG also teaches androgen receptor signaling is essential for prostate cancer development even after castration and there is a need to identify targets to overcome resistance to androgen signaling inhibitors (ASI) such as abiraterone (Pg. 6635 Right Col. ¶2). ZHANG further teaches androgen receptor signaling positively regulates PLK1, in particular, depletion of AR-V7 caused reduction in PLK1 protein levels in a CRPC cell line 22Rv-1 (Pg. 6642 Left Col. P2 & Pg. 6643 Fig. 4 Description & Part C). Moreover, treatment of the 22Rv-1 cells with the PLK1 inhibitor (Pg.6636 Left Col. ¶3) BI2536 and abiraterone inhibited androgen receptor signaling in a synergistic manner, thus, inhibition of PLK1 enhances cellular response to abiraterone in CRPC cells expressing AR-V7 (Pg. 6643 Fig. 4 Description & Part E). ZHANG states the data presented demonstrates that PLK1 plays a critical role in cellular response to ASI and that inhibition of PLK1 overcomes ASI resistance in CRPC (Pg. 6646 Right Col. ¶1).
Furthermore, ZHANG, as evidenced by MOSTAGHEL, teaches treatment of AR-V7 characterized LuCaP35CR tumors in mice by administration of BI2536 and abiraterone; see ¶15 above for all relevant teachings – these teachings are incorporated here by reference.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
CARDIFF does not teach wherein the CRPC is characterized by AR-V7.
ZHANG does not teach a method of treating a patient with onvansertib.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of methods of treating and evaluating progression of CRPC and possesses the technical knowledge necessary to make adjustments to the methods to optimize/enhance the outcomes of treatment. Said artisan has also reviewed the problems in the art regarding the androgen receptor variants associated with CRPC and understands the treatment solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references CARDIFF (evidenced by BERIA) and ZHANG (evidenced by MOSTAGHEL).
The artisan would be motivated to treat a patient having CRPC characterized by AR-V7 by administering onvansertib, as a PLK1 inhibitor, with abiraterone and prednisone in order to overcome abiraterone resistance in CRPC, as recognized by ZHANG (Pg. 6646 Right Col. ¶1). It would have been obvious for the artisan to substitute one functional equivalence (BI2536) with another (onvansertib) with an expectation of success, since both are PLK1 inhibitors. Further, CARDIFF teaches a method of treating a patient with CRPC by administration of onvansertib, abiraterone, and prednisone specifically to observe the effects of said combination on disease control (Pg. 8 Brief Summary). Thus, since ZHANG teaches inhibition of PLK1 enhances response to abiraterone in CRPC cells expressing AR-V7, both in vitro (Pg. 6643 Fig. 4 Description & Part E) and in vivo (see ¶15 above), the artisan would be motivated, with an expectation of success, to treat AR-V7 characterized CRPC by the method of CARDIFF in order to optimize disease control. Therefore, in view of the full teachings of CARDIFF, above, the practice of claims 1, 3-5, 7, 9-10, 12 ,14, 24, and 26 would be obvious.
Furthermore, the artisan would also find it obvious to substitute onvansertib, in the method of CARDIFF, with BI2536 since they are functional equivalents and for the same reasons as discussed above; i.e., PLK1 inhibitor BI2536 enhanced response to abiraterone in CRPC cells expressing AR-V7, as recognized by ZHANG (Fig. 4E). The use of BI2536 reads on instant claims 1, 3-5, 7, 9, 14, and 26. For these reasons, the instant claims are obvious in view of the combined references regarding both the combination of 1) onvansertib + abiraterone + prednisone and 2) BI2536 + abiraterone + prednisone.
Claims 1 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over:
CARDIFF (Cardiff Oncology, Jan. 2018, NCT03414034, ClinicalTrials.gov,clinicaltrials.gov/study/NCT03414034?intr=Onvansertib&rank=5&a=1&tab=history, accessed 12/20/2024, provided by Examiner 01/16/2025),
As evidenced by:
BERIA (Beria, I., et al., Bioorganic & Medicinal Chemistry Letters, 2011, 21, 2969-6974, provided by Examiner 08/27/2025),
in view of:
ZHANG (Zhang, Z., et al., Cancer Res., 2014, 74(22), 6635-6647, provided in IDS of 10/19/2022),
As evidenced by:
MOSTAGHEL (Mostaghel, E. A. et al., Clin. Cancer Res., 2011, 17(18), 5913-5925) as applied to claim 1 above, further in view of ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53.
in view of:
ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
CARDIFF (evidenced by BERIA) and ZHANG (evidenced by MOSTAGHEL) teach the method of claim 1, see ¶20 above for the teachings and discussion.
ANSEL teaches the safe and effective dose of a drug depends on a number of
factors including characteristics of the drug, the dosage form, and a variety of patient factors (Pg. 48 Left Col. para 2) and the effective dose may be different for different
patients (Pg. 48 Left Col. para 4). ANSEL further teaches the schedule of dosage or the
dosage regimen is determined based on a drug’s duration of action, pharmacokinetics,
and characteristics of the dosage form (Pg. 40 Right Col. para 2).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
CARDIFF and ZHANG do not teach the instant dosage cycle.
ANSEL does not teach the instant method.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of methods of treating and evaluating progression of CRPC and possesses the technical knowledge necessary to make adjustments to the methods to optimize/enhance the outcomes of treatment. Said artisan has also reviewed the problems in the art regarding the androgen receptor variants associated with CRPC and understands the treatment solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references CARDIFF (evidenced by BERIA), ZHANG (evidenced by MOSTAGHEL), and ANSEL.
While CARDIFF and ZHANG do not teach exactly the claimed dosing cycle length, the artisan would be motivated to optimize the dosing cycle to optimize disease control and could utilize CARDIFF’s teachings as a starting point (i.e., once daily for 5 consecutive days every 21 days (Pg. 8 Brief Summary)).
MPEP 2144.05(II)(A) provides guidance about the routine optimization of prior art conditions: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").”
Furthermore, MPEP 2144.05(I) provides guidance about overlapping ranges: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
CARDIFF’s dosage regimen is considered to approach the instantly claimed PLK1 inhibitor cycle of “more than one administration cycle where there is 9 days or less” between cycles (see claim 15). Since ANSEL teaches the dosage regimen is based on duration of action, pharmacokinetics, and the dosage form (Pg. 40 Right Col. para 2) and the effective dosing may be different for different patients (Pg. 48 Left Col. para 4), the artisan would recognize the dosage regimen (i.e., cycle lengths) as a result-effective variable, i.e., a variable that achieves a recognized result. Thus, the dosage is analogous to the “concentration or temperature” recited in the MPEP and may be optimized by routine experimentation. Therefore, the determination of the optimum or workable dosage regimen (for both onvansertib and BI2536) would have been well within the practice of the artisan. Furthermore, absent any evidence demonstrating a patentable difference between the instant and prior art compositions and the criticality of the claimed dosage regimen, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the artisan.
Claims 1 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over:
CARDIFF (Cardiff Oncology, Jan. 2018, NCT03414034, ClinicalTrials.gov,clinicaltrials.gov/study/NCT03414034?intr=Onvansertib&rank=5&a=1&tab=history, accessed 12/20/2024, provided by Examiner 01/16/2025),
As evidenced by:
BERIA (Beria, I., et al., Bioorganic & Medicinal Chemistry Letters, 2011, 21, 2969-6974, provided by Examiner 08/27/2025),
in view of:
ZHANG (Zhang, Z., et al., Cancer Res., 2014, 74(22), 6635-6647, provided in IDS of 10/19/2022),
As evidenced by:
MOSTAGHEL (Mostaghel, E. A. et al., Clin. Cancer Res., 2011, 17(18), 5913-5925) as applied to claim 1, further in view of EPIC (WO 2017/053763; provided in IDS of 10/19/2022).
in view of:
EPIC (WO 2017/053763; provided in IDS of 10/19/2022).
Determining the Scope and Contents of the Prior Art:
CARDIFF (evidenced by BERIA) and ZHANG (evidenced by MOSTAGHEL) teach the method of claim 1, see ¶20 above for the teachings and discussion.
EPIC teaches a method for selecting a therapy for a metastatic CRPC patient comprising detection of Androgen Receptor Variant 7 (AR-V7) in circulating tumor cells (CTCs) (Pg. 1 Para 2). EPIC further teaches CTCs released from tumors hold important information about the biology of the tumor and quantification and characterization of CTCs assists clinicians in selecting the course of therapy and to monitor how a patient’s cancer evolves; CTCs are a key tool to track tumor changes, treatment response, cancer recurrence, and patient outcome non-invasively (Pg. 2 Para 5).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
CARDIFF and ZHANG do not teach a method of evaluating CTCs to identify androgen receptor variants.
EPIC does not teach treatment by administration of a PLK1 inhibitor onvansertib (or BI2536).
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of methods of treating and evaluating progression of CRPC and possesses the technical knowledge necessary to make adjustments to the methods to optimize/enhance the outcomes of treatment. Said artisan has also reviewed the problems in the art regarding the androgen receptor variants associated with CRPC and how to measure and treat them and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references CARDIFF (evidenced by BERIA), ZHANG (evidenced by MOSTAGHEL), and EPIC.
The artisan would find it obvious to modify the method of CARDIFF and ZHANG, discussed in ¶20 above, by further evaluating CTCs to identify androgen receptor variants, in view of EPIC. The artisan would be motivated to do so since EPIC teaches CTCs are a key tool to track tumor changes, treatment response, cancer recurrence, and patient outcomes non-invasively (Pg. 2 Para 5). The artisan would have an expectation of success in identifying the androgen receptor variant AR-V7 in CTCs and then treating the patient having AR-V7 CRPC since ZHANG teaches inhibition of PLK1 enhances response to abiraterone in CRPC cells expressing AR-V7 (Pg. 6643 Fig. 4 Description & Part E). Thus, the artisan would expect identification of AR-V7 in CRPC to assist clinicians in selecting the course of therapy, as recognized by EPIC (Pg. 2 Para 5), such as administration of onvansertib and abiraterone, in view of CARDIFF and ZHANG (above 103, ¶20).
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over:
CARDIFF (Cardiff Oncology, Jan. 2018, NCT03414034, ClinicalTrials.gov,clinicaltrials.gov/study/NCT03414034?intr=Onvansertib&rank=5&a=1&tab=history, accessed 12/20/2024, provided by Examiner 01/16/2025),
As evidenced by:
BERIA (Beria, I., et al., Bioorganic & Medicinal Chemistry Letters, 2011, 21, 2969-6974, provided by Examiner 08/27/2025),
in view of:
ZHANG (Zhang, Z., et al., Cancer Res., 2014, 74(22), 6635-6647, provided in IDS of 10/19/2022),
As evidenced by:
RATHKOPF (Rathkopf, D.E. et al., Annals of Onocology, 2017, 28, 2264-2271) and
CAI (Cai, C. et al., Cancer Res., 2011, 71(20), 6503-6513).
Determining the Scope and Contents of the Prior Art:
The teachings of CARDIFF (evidenced by BERIA) are above (see ¶20).
ZHANG teaches there is a need to identify targets to overcome resistance to androgen signaling inhibitors (ASI) such as abiraterone (Pg. 6635 Right Col. ¶2). ZHANG further teaches treatment of C4-2 cells with the PLK1 inhibitor (Pg.6636 Left Col. ¶3) BI2536 and abiraterone inhibited androgen receptor signaling in a synergistic manner, thus, inhibition of PLK1 enhances cellular response to abiraterone in CRPC C4-2 cells (Pg. 6643 Fig. 4 Description & Part D). ZHANG states the data presented demonstrates that PLK1 plays a critical role in cellular response to ASI and that inhibition of PLK1 overcomes ASI resistance in CRPC (Pg. 6646 Right Col. ¶1).
Examiner understands the CRPC cell line C4-2 to be characterized by ART878A, as evidenced by RATHKOPF and CAI. RATHKOPF discloses ART878A was formerly known as ART877A (Pg. 2265 Left Col. ¶2). CAI discloses the cell line C4-2 expresses ART877A (Pg. 6509 Left Col. ¶2). Thus, C4-2 is characterized by ART878A.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
CARDIFF does not teach the CRPC is characterized by ART878A.
ZHANG does not teach treatment of the C4-2 (ART878A) CRPC in a patient (i.e., only in vitro).
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of methods of treating and evaluating progression of CRPC and possesses the technical knowledge necessary to make adjustments to the methods to optimize/enhance the outcomes of treatment. Said artisan has also reviewed the problems in the art regarding the androgen receptor variants associated with CRPC and how to treat them and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references CARDIFF (evidenced by BERIA) and ZHANG (evidenced by RATHKOPF and CAI).
The artisan would be motivated to treat a patient having CRPC characterized by ART878A by administering onvansertib, as a PLK1 inhibitor, with abiraterone and prednisone in order to overcome abiraterone resistance in CRPC, as recognized by ZHANG (Pg. 6646 Right Col. ¶1). It would have been obvious for the artisan to substitute one functional equivalence (BI2536) with another (onvansertib) with an expectation of success, since both are PLK1 inhibitors. Further, CARDIFF teaches a method of treating CRPC in a patient by administration of onvansertib, abiraterone, and prednisone specifically to observe the effects of said combination on disease control (Pg. 8 Brief Summary). Thus, since ZHANG teaches inhibition of PLK1 enhances response to abiraterone in CRPC cells expressing ART878A (Pg. 6643 Fig. 4 Description & Part D), the artisan would be motivated, with an expectation of success, to treat patients with ART878A characterized CRPC by the method of CARDIFF in order to optimize disease control. Therefore claim 34 is obvious.
Furthermore, the artisan would also find it obvious to substitute onvansertib, in the method of CARDIFF, with BI2536 since they are functional equivalents and for the same reasons as discussed above; i.e., PLK1 inhibitor BI2536 enhanced response to abiraterone in CRPC cells expressing ART878A, as recognized by ZHANG (Fig. 4D). For these reasons, the instant claim is obvious in view of the combined references regarding both the combination of onvansertib + abiraterone + prednisone and BI2536 + abiraterone + prednisone.
Conclusion
Claims 1, 3-5, 7, 9-10, 12, 14-15, 24, 26, 28, and 34 are rejected.
To expedite time to allowance: Applicant may consider providing unexpected/surprising results that are commensurate in scope with the claims (see MPEP 716.02(a)). Note, if the results do not cover the broadest claim(s), the Examiner is still able to make obviousness-type rejections over the limitations of such claim(s).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA ELIZABETH BELL whose telephone number is (703)756-5372. The examiner can normally be reached Monday-Friday 9:00-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625