Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1, 2, 5-17, and 19-33 of L. Snyder et al., US 18/799,339 (Aug. 9, 2024) are pending and under examination on the merits.
Family Prosecution History
Parent Application US 15/950,707 (Apr. 11, 2018)
Claim 37 (and its dependents) of parent application US 15/950,707 (Apr. 11, 2018), which is directed to the same subject matter as instant claim 1:
US 15/950,707, claim 37. A method for managing metastatic castration-resistant prostate cancer comprising
orally administering to a patient in need thereof a daily dose of about 30 to about 400 mg/day of niraparib administered once per day and
a daily dose of about 500 to about 1500 mg/day of abiraterone acetate administered once per day,
wherein the patient is biomarker positive for at least one biomarker selected from BRCA-1 or BRCA-2, FANCA, PALB2, CHEK2, BR1P1, HDAC2 and ATM.
was finally rejected under § 103 over the following five prior art references.
NCT01576172, Abiraterone Acetate and Prednisone With or Without Veliparib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer (ClinicalTrials.gov., 2012) (“NCT01576172”);
C. Logothetis et al., 13 The Lancet Oncology, 1210-1217 (2012) (“Logothetis”),
S. Sandhu et al., Phase I Study of a Poly(Adp)-Ribose Polymerase (PARP) Inhibitor MK-4827 (MK) With Antitumour Activity in Sporadic Castration Resistant Prostate Cancer (CRPC), 8 Asia-Pacific Journal of Clinical Oncology (page 33, Poster 112, 2012) (“Sandhu”);
J. Zhang 16 Asian Journal of Andrology, 401 (2014) (“Zhang”); and
NCT02500901, Enzalutamide and Niraparib in the Treatment of Metastatic Castrate-Resistant Prostate Cancer (CRPC), 1-7 (ClinicalTrials.gov., 2015) (“NCT02500901”).
See, Final Rejection in 15/950,707, page 2, dated October 20, 2021. The Examiner was affirmed on appeal by the Patent Trial and Appeal Board. Ex Parte Snyder, Appeal No. 2022-004874, 15/950,707 (PTAB 2023). On further appeal, the U.S. Court of Appeals for the Federal Circuit issued a Rule 36 judgment affirming the Board’s ruling without issuing an opinion. In re Snyder, No. 2023-1763, 2024 BL 235920 (Fed. Cir. July 11, 2024).
Parent Application US 17/680,553 (Feb. 25, 2022)
Claim 36 (and its dependents) of parent application US 17/680,553 (Feb. 25, 2022), which are also directed to the same subject matter as instant claim 1, were subject to a non-final rejection under § 103 over the same prior art references mentioned above. See, Non-Final Rejection in 17/680,553, dated August 3, 2023. On March 11, 2024, the application was abandoned.
Parent Application US 18/429,778 (Feb. 1, 2024)
Claim 1 (and its dependents) of parent application US 18/429,778 (Feb. 1, 2024), which are also directed to the same subject matter as instant claim 1, were subject to a final rejection under § 103 over the same prior art references mentioned above. See, Final Rejection in 18/429,778, dated June 12, 2025. Applicant filed a request for continued examination on December 5, 2025 in this application.
Effective Filing Date
The effective filing date of a claimed invention is determined on a claim-by-claim basis. MPEP § 2152.01. At least independent claim 1 is entitled to the priority date of US 62/485,164 (Apr. 13, 2017) because it is fully supported therein pursuant to § 112(a).
Claim Interpretation
Examination requires claim terms first be construed in terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim. See, MPEP § 2111.
The Claims
Independent claim 1 recites:
1. A method for managing metastatic castration-resistant prostate cancer comprising
administering to a patient in need thereof a daily dose of about 30 to about 400 mg/day of niraparib administered once per day and
a daily dose of about 500 to about 1500 mg/day of abiraterone acetate administered once per day,
wherein the mCRPC is biomarker positive for at least one biomarker selected from BRCA-1 and BRCA-2.
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Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. S. Sandhu et al., 14 The Lancet Oncology, 882-892, 882 (2013) (“Sandhu-2”). Abiraterone acetate is a selective androgen biosynthesis inhibitor that blocks CYP17 (a key enzyme in testosterone and dihydrotestosterone production) and therefore shuts down androgen production in the adrenals and testes and prostate cancer cells. C. Logothetis et al., 13 The Lancet Oncology, 1210-1217, 1211 (2012) (“Logothetis”)
Interpretation of the Claim 1 Preamble/ ‘wherein clause’ as a Claim Limitation
The determination of whether a preamble limits a claim is made on a case-by-case basis in light of the facts in each case; there is no litmus test defining when a preamble limits the scope of a claim. MPEP § 2111.02 (citing Catalina Mktg. Int’l v. Coolsavings.com, Inc., 289 F.3d 801, 808, 62 USPQ2d 1781, 1785 (Fed. Cir. 2002)). As a general rule preamble language is not treated as limiting. Arctic Cat Inc. v. GEP Power Prods., Inc., 919 F.3d 1320, 1327 (Fed. Cir. 2019). Exceptions arise where, for example, the preamble (1) recites essential structure or steps; (2) provides antecedent basis for terms in the claim body; or (3) was relied on during prosecution to distinguish the claimed invention from prior art. Catalina Mktg. Int’l, Inc. v. Cool savings.com, Inc., 289 F.3d 801, 808 (Fed. Cir. 2002). Further, claim scope is not limited by claim language that does not limit a claim to a particular structure. MPEP § 2111.04 (citing In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005) (a ‘whereby clause’ in a method claim is not given weight when it simply expresses the intended result of a process step positively recited).
Claim 1 recites the following bolded preamble and ‘wherein clause’:
1. A method for managing metastatic castration-resistant prostate cancer comprising
administering to a patient in need thereof a daily dose of about 30 to about 400 mg/day of niraparib administered once per day and
a daily dose of about 500 to about 1500 mg/day of abiraterone acetate administered once per day,
wherein the mCRPC is biomarker positive for at least one biomarker selected from BRCA-1 and BRCA-2.
Here, the recitation “administering to a patient in need thereof” gives life and meaning to the preamble statement of a “method for managing metastatic castration-resistant prostate cancer”; that is the preamble/‘wherein clause’ recites essential structure or steps. Jansen v. Rexall Sundown, Inc., 342 F.3d 1329, 1333 (Fed. Cir. 2003). Thus, to meet claim 1, the prior art must teach or suggest the claimed administration to a patient in fact suffering from metastatic castration-resistant prostate cancer, where “the mCRPC is biomarker positive for at least one biomarker selected from BRCA-1 and BRCA-2”. MPEP § 2111.04.
Interpretation of the Claim 1 Preamble Phrase “managing”
Claim 1 recites “a method for managing” in the following context:
1. A method for managing metastatic castration-resistant prostate cancer comprising
administering to a patient in need thereof a daily dose of about 30 to about 400 mg/day of niraparib administered once per day and
a daily dose of about 500 to about 1500 mg/day of abiraterone acetate administered once per day,
wherein the patient is biomarker positive for at least one biomarker selected from BRCA-1 or BRCA-2.
The specification does not define the term “managing”. There is only one mention of “managing” in the specification in the following context:
[0021] As used herein, and unless otherwise defined, the terms "treat," "treating" and "treatment" include the eradication, removal, modification, management or control of a tumor or primary, regional, or metastatic prostate cancer cells or tissue and the minimization or delay of the spread of prostate cancer.
Specification at page 5, [0021]. The prosecution history is relevant to the meaning of “managing”. In the non-final Office action dated September 29, 2024 (the “Non-Final Rejection”), the Examiner made the following § 112(a) enablement rejection with respect to the claim set dated August 29, 2024 (where the subject claim 1 recited “a method for treating metastatic castration-resistant prostate cancer”):
Claims 1, 2, 5-17, 19-25, 29-31 and 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for management of prostate cancer, does not reasonably provide enablement for eradication or removal thereof.
Non-Final Rejection at page 6, ¶ 8. In response (“solely to expedite prosecution”), Applicant amended claim 1 (to its present form) to recite “[a] method for managing treating metastatic castration-resistant prostate cancer”. Reply dated December 26, 2024, at pages 7-8 of 26. In the final Office action dated February 5, 2025 (the “Final Rejection”) the Examiner withdrew the § 112(a) enablement rejection. With this background, the preamble phrase: a “method for managing treating metastatic castration-resistant prostate cancer” is broadly and reasonably interpreted, in accordance with its plain meaning, as mitigating, slowing or stopping the prostate cancer's progression and/or alleviating direct symptoms, rather than requiring eradication or removal of the prostate cancer.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under AIA 35 U.S.C. 103(a) 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.
The § 103 Rejections
Claims 1, 2, 5-17, and 19-33 are rejected under AIA 35 U.S.C. 103 as being unpatentable over the following references:
(1) S. Sandhu et al., The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial, 14 The Lancet Oncology, 882-892 (2013) (“Sandhu-2”);
(2) T. Zhang et al., Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer, 16 Expert Opinion on Pharmacotherapy. 473-485 (2015) (“Zhang-2”)
(3) C. Logothetis et al., 13 The Lancet Oncology, 1210-1217 (2012) (“Logothetis”);
(4) A. Auerbach et al., US 8,822,438 (2014) (“Auerbach”);
(5) H. Farmer et al., Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, 434 Nature, 917-921 (2005) (“Farmer”)
(6) NCT01576172, Abiraterone Acetate and Prednisone With or Without Veliparib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer (ClinicalTrials.gov., 2012) (“NCT01576172”);
(7) J. Zhang 16 Asian Journal of Andrology, 401 (2014) (“Zhang”); and
(8) NCT02500901, Enzalutamide and Niraparib in the Treatment of Metastatic Castrate-Resistant Prostate Cancer (CRPC), 1-7 (ClinicalTrials.gov., 2015) (“NCT02500901”).
S. Sandhu et al., The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial, 14 The Lancet Oncology, 882-892 (2013) (“Sandhu-2”)
Sandhu-2 reports the results of clinical trial NCT00749502, A Study of MK4827 in Participants With Advanced Solid Tumors or Hematologic Malignancies (MK-4827-001 AMS), 1-11 (ClinicalTrials.gov., 2013) (“NCT00749502”).
Sandhu-2 teaches that niraparib (MK4827) is an orally bioavailable PARP-1 and PARP-2 inhibitor. Sandhu-2 at page 883, col. 1. Sandhu-2 teaches that niraparib (MK4827) inhibits tumor growth in models with loss of BRCA and PTEN function. Sandhu-2 at page 883, col. 1. Sandhu-2 additionally teaches assessment of preliminary antitumor activity in carriers of BRCA1 and BRCA2 mutations and patients with high-grade serous ovarian cancer and prostate cancer. Sandhu-2 at page 883, col. 1.
Sandhu-2 reports a two-part (Parts A and B, 100 patients: 60 in part A and 40 in part B) investigation of the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumor (ovarian cancer, non-small-cell lung cancer, and prostate cancer) activity of niraparib. Sandhu at page 882 (Summary, Methods).
In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Sandhu at page 882 (Summary, Methods).
In part B, Sandhu-2 investigates the maximum tolerated dose (300 mg/day as determined in Part A) in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. Sandhu at page 882 (Summary, Methods). Sandhu-2 reports that of the 40 patients enrolled in Part B, 18 had castration-resistant prostate cancer and 22 had platinum-resistant high-grade serous ovarian cancer. Sandhu-2 at page 884, col. 1, Figure 1.
Sandhu-2 teaches that eight (40% [95% CI 19–64]) of twenty BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Sandhu-2 at page 882 (Summary, Findings).
Sandhu-2 teaches that circulating tumour cells and archival tumour tissue in prostate patients were analyzed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. Sandhu at page 882 (Summary, Methods). Sandhu-2 teaches that patients enrolled into part B did not have a high-risk family history or previously known BRCA1 or BRCA2 mutation carrier status. Sandhu-2 at page 883, col. 2. Sadahu-2 teaches that no radiological responses were recorded, but decreases in circulating tumour cells of at least 30% were noted in several patients with castration-resistant prostate cancer, where three patients had clinically significant decreases in circulating tumour cells after receiving niraparib and durable disease stabilization lasting longer than 6 months. Sandhu-2 at page 890. However, Sandhu-2 recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. Sandhu at page 882 (Summary, Findings).
Sandhu-2 teaches that 9 (43% [95% CI 22–66]) of 21 patients with non-BRCA castration-resistant prostate cancer receiving niraparib at either 290 mg/day or 300 mg/day had stable disease for a median duration of 254 days. Sandhu-2 at page 890, col. 1 (referencing appendix Figure 4; see also, Appendix at page 6, Supplemental Table 2).
Sandhu-2 directly suggests to one of ordinary skill to explore the PARP inhibitgor niraparib in BRCA1/2 positive metastatic castration-resistant prostate cancer as follows:
Our study provides preliminary evidence that PARP inhibitors have antitumour activity in sporadic castration-resistant prostate cancer. Decreases in circulating tumour cells and stable disease for longer than 6 months were recorded in several patients with castration-resistant prostate cancer. However, a decrease in PSA concentration of at least 50% was noted in only one patient, and no RECIST responses were reported. Blocking of PARP has been reported to decrease transcription of AR and ETS; both are key oncogenes in castration-resistant prostate cancer.16,17,19 Castration-resistant prostate cancers commonly have loss of PTEN expression and ETS rearrangements that have been postulated to associate with sensitivity to PARP inhibition. However, we recorded no association between loss of PTEN expression or ETS rearrangements and time to disease progression or any other potential measures of antitumour activity, including decreases in circulating tumour cells. We do not fully understand the underlying basis for these findings. Nevertheless, next-generation sequencing studies indicate that prostate cancers can have homologous-recombination defects due to loss-of-function mutations in key genes, such as BRCA2, BRCA1, ATM, CHEK2, NSBP1 and FANCJ. These data collectively support further assessment of PARP inhibitors in prostate cancer
Sandhu-2 at page 891, col. 1.
Sandhu-2 summarizes in that niraparib has antitumor activity in carriers of BRCA1 and BRCA2 mutations and patients with sporadic cancers. Sandhu-2 at page 890, col. 2.
Sandhu-2 further concludes that Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. Sandhu-2 at page 882 (Summary, Interpretation). And Sandhu-2 teaches that many sporadic (non-inherited) cancers (e.g., prostate and high-grade serous ovarian cancers) harbour epigenetic and genetic disruption of genes that are crucial for the homologous recombination pathway, such as BRCA1, BRCA2. Sandu-2 at page 883, col. 1.
Note on Sandhu-2 with Respect to the Single Patient (patient 86) with BRCA2-mutant Prostate Cancer
First note that as summarized in more detail below, J. Zhang 16 Asian Journal of Andrology, 401 (2014) (“Zhang”) comments on the Sandhu-2 phase I study with 23 castration-resistant prostate cancer patients (where “only one had documented BRCA mutation”).
The Sandhu-2 study employes 100 patients, where 23 had prostate cancer. Sandhu-2, page 884, Table 1. Sandhu-2 further teaches that:
Overall, 77 patients had responses that were measurable by RECIST (figure 4).
. . .
Of the 77 patients whose disease could be assessed by RECIST,
29 patients from part A were confirmed carriers of BRCA1 or BRCA2 mutations: 22 had ovarian or primary peritoneal cancers, four had breast cancer, one had NSCLC, one had pancreatic cancer, and one had prostate cancer (table 1, figure 4).
. . .
Two BRCA2 mutation carriers were refractory to niraparib (one with prostate cancer given 300 mg/day for 49 days, and the other with pancreatic cancer given 80 mg/day for 57 days; figure 4)”.
Sandhu-2 at page 888, col. 2 (emphasis added). Per Sandhu-2, Supplementary Table 2, patient 86 (a known BRCA2 mutation carrier) was the only prostate cancer patient in the study with a BRCA mutation, and patient 86 was declared refractory to niraparib, presumably due to a liver metastasis. Sandhu-2 at Supplementary page 7 (last entry in Table 2).
T. Zhang et al., Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer, 16 Expert Opinion on Pharmacotherapy. 473-485 (2015) (“Zhang-2”)
Zhang-2 teaches that abiraterone acetate improves overall survival in patients with metastatic castration resistant prostate cancer. Zhang 2 at page 476, col. 1.
After establishing that [abiraterone acetate] improves [overall survival] in patients with mCRPC after chemotherapy, COU-AA-302 investigated the benefit of [abiraterone acetate] in patients who had not previously received chemotherapy
. . .
In the final analysis, reported at ESMO 2014, [abiraterone acetate] plus prednisone demonstrated a statistically significant improvement in [overall survival] of 4.4 months over prednisone alone (34.7 vs 30.3 months; HR: 0.80; 95% CI: 0.69 -- 0.93; p = 0.0027)
Zhang 2 at page 476, col. 1.
C. Logothetis et al., 13 The Lancet Oncology, 1210-- (2012) (“Logothetis”)
Logothetis teaches assessment of data for pain control and skeletal-related events prospectively collected as part of the randomized, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy. Logothetis at page 1210 under “Background”.
Logothetis teaches that abiraterone acetate is a selective androgen biosynthesis inhibitor that blocks CYP17 (a key enzyme in testosterone and dihydrotestosterone production) and therefore shuts down androgen production in the adrenals and testes and prostate cancer cells. Logothetis at page 1211, col. 1.
Logothetis teaches a COU-AA-301 trial that enrolled patients with metastatic castration-resistant prostate cancer in whom one or two lines of chemotherapy (one docetaxel based) had been unsuccessful and who had Eastern Cooperative Oncology Group performance statuses of 2 or less. Logothetis at page 1210 under “Methods”. Logothetis teaches that pain intensity and interference of pain with daily activities were assessed. Id. Logothetis teaches assessment of clinically meaningful changes in pain intensity and interference with daily living. Logothetis teaches that COU-AA-301 is registered with ClinicalTrials.gov, number NCT00638690. Id.
Logothetis teaches that study patients had 28-day cycles of treatment with either abiraterone acetate (1 g) or placebo orally once daily, in combination with 5 mg of oral prednisone twice daily. Logothetis at page 1211, col. 2, under “Methods”.
Logothetis teaches that in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, the combination of abiraterone acetate and prednisone offers significant benefits compared with prednisone alone in terms of pain relief, delayed pain progression, and prevention of skeletal-related events. Logothetis at page 1210 under “Interpretation”. Logothetis interprets these findings to be supportive of the hypothesis that persistent androgen receptor signaling is centrally implicated in castration-resistant prostate cancer in bone. Logothetis at page 1215, col. 1.
A. Auerbach et al., US 8,822,438 (2014) (“Auerbach”)
Auerbach teaches a method of treating cancer in which abiraterone acetate is administered to a patient, in combination with a therapeutically effective amount of at least one additional therapeutic agent including, but not limited to, an anti-cancer agent or steroid. Auerbach at col. 2, lines 9-20. Auerbach teaches that examples of the anti-cancer agent, include, but not limited to, mitoxantrone, paclitaxel, docetaxel, leuprolide, goserelin, triptorelin, seocalcitol, bicalutamide, flutamide, or a steroid including, but not limited to, hydrocortisone, prednisone, or dexamethasone. Auerbach at col. 3, lines 15-20.
Auerbach further teaches that the abiraterone acetate can be co-administered with prednisone in the treatment of cancer. Auerbach at col. 3, lines 5-11. Auerbach teaches that treatable cancers include prostate cancer. Auerbach at col. 3, line 35; Id. at claim 1.
Auerbach teaches doses of abiraterone acetate in the range of about 50 mg to about 500 mg; for example, Auerbach teaches the oral composition can comprise about 50 mg to about 500 mg of abiraterone acetate and an amount of about 0.25 mg to about 3.5 mg of the steroid, such as hydrocortisone, prednisone or dexamethasone. Auerbach at col. 15, lines 52-55.
H. Farmer et al., Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, 434 Nature, 917-921 (2005) (“Farmer”)
Farmer teaches that BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination1, and mutations in these genes predispose to breast and other cancers2. Farmer at page 917, col. 1. Farmer teaches that Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. Farmer at page 917, col. 1. Farmer teaches that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. Farmer at page 917, col. 1.
Farmer specifically suggest use of PARP inhibitors in the treatment of BRCA1- and BRCA2-associated cancers:
The results presented here and in the accompanying paper suggest a new mechanism-based approach for the treatment of patients with BRCA1- and BRCA2-associated cancers. Tumours in carriers of BRCA1 or BRCA2 mutations lack wild-type BRCA1 or BRCA2 but normal tissues retain a single wild-type copy of the relevant gene. This biochemical difference provides the rationale for an approach involving PARP inhibition to generate specific DNA lesions that require functional BRCA1 and BRCA2 for their repair, generating a potentially large therapeutic window. This approach is likely to be less toxic and more specific than standard cytotoxic chemotherapy. PARP inhibitors are relatively non-toxic and do not directly damage DNA, and Parp1 knockout mice are viable and healthy.
Farmer at page 919, col. 2.
NCT01576172, Abiraterone Acetate and Prednisone With or Without Veliparib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer (ClinicalTrials.gov., 2012) (“NCT01576172”)
NCT01576172 is a randomized phase II trial study to evaluate treatment with abiraterone acetate and prednisone together with PARP inhibitor veliparib to see how well it works compared to abiraterone acetate and prednisone alone in treating patients with castration-resistant prostate cancer that has spread from the primary site to other places in the body.1 NCT01576172 at page 1 of 14.
NCT01576172 postulates that giving abiraterone acetate together with prednisone and veliparib may work better than abiraterone acetate and prednisone alone in treating patients with castration-resistant prostate cancer. NCT01576172 at page 1 of 14.
In Arm I (abiraterone and prednisone), patients receive abiraterone acetate orally (PO) once daily (QD) and prednisone orally (PO) twice daily (BID) on days 1-28 and courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NCT01576172 at page 3 of 14. The dosage amounts do not appear to be disclosed.
In Arm II (abiraterone acetate, prednisone, and veliparib) patients receive veliparib orally (PO), twice daily (BID) on days 1-28 and patients also receive abiraterone acetate orally (PO), once daily (QD) and prednisone orally (PO) twice daily (BID) on day 1 (day 8 of course 1). NCT01576172 at page 3 of 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Id.
NCT01576172 states that the corresponding binomial confidence intervals will be reported for each arm. NCT01576172 at page 6 of 14. A logistic model including treatment group, fusion status, and prior ketoconazole use will be used to determine the interaction between the rates of PSA response between abiraterone and abiraterone + veliparib and ETS2 fusion status. NCT01576172 at page 6 of 14. Significantly, NCT01576172 does not report the results of this study.3
J. Zhang 16 Asian Journal of Andrology, 401 (2014) (“Zhang”)
Zhang is a review of the preclinical work and early-phase clinical trials in developing the PARP inhibitor as a new treatment for metastatic castration-resistant prostate cancer. Zhang at page 401, col. 2.
Zhang notes that in the landmark phase I study with the PARP inhibitor olaparib, of the three prostate cancer patients, one patient was a BRCA2 mutation carrier that showed more than 50% reduction in prostate-specific antigen (PSA) levels and resolution of bone metastases, as shown by MRI. Zhang at paragraph bridging pages 401-402.
Zhang comments on the Sandhu-2 phase I study with 23 castration-resistant prostate cancer patients (where “only one had documented BRCA mutation”), with niraparib/MK4827 had by far the largest prostate cancer cohort among the single-agent PARP inhibitor trials. Zhang at page 402, col. 1
Although one could argue that radical prostatectomy samples may not recapitulate the downstream events of PTEN loss in late-stage prostate cancer, a recent phase I study with PARP inhibitor niraparib/MK4827 did not observe associations between loss of PTEN and antitumor activities in sporadic metastatic prostate cancer patients.
With 23 CRPC patients (only one had documented BRCA mutation); this recently reported phase I study with niraparib/MK4827 had by far the largest prostate cancer cohort among the single-agent PARP inhibitor trials. Although no radiological responses were noted, nine of the 21 patients (43%) treated at either 290 or 300 mg day−1 had stable disease for a median duration of 254 days (range 124–375 days). This is the first study to document clinical activity of a PARP inhibitor in sporadic CRPC. More importantly, this study took great effort to explore the association between clinical benefit and loss of PTEN expression or ETS rearrangement in circulating tumor cells as well as in tumor tissue. Although the marker studies are exploratory in this phase I trial, loss of PTEN by itself is probably not sufficient to predict defective HRR or sensitivity to PARP inhibition.
Zhang at page 402, col. 1 (emphasis added).4
Zhang teaches that the activity of the PARP inhibitor niraparib in sporadic prostate cancer provides a strong clinical rationale for developing PARP inhibitor-based therapies for metastatic CRPC. Zhang at page 405, col. 1. Significantly, Zhang notes that as presently shown, loss of PTEN or presence of ETS gene rearrangement by itself is unlikely to be sufficient to predict response to PARP inhibitor-based therapies.5 Id. Other than blocking DNA damage repair (DDR), PARP inhibitors have been shown to disrupt transcriptional regulation through androgen receptor (AR) and ETS fusion proteins (see footnote 2) in castration resistant prostate cancer (CPRC) preclinical models. Id. Zhang teaches that preclinical finding is being tested in an ongoing phase II study of abiraterone with or without veliparib in patients with metastatic castration resistant prostate cancer (CRPC) (NCT01576172). In this regard, Zhang teaches that a multicenter randomized phase II trial is evaluating whether adding the PARP inhibitor veliparib to abiraterone acetate and prednisone would improve the prostate-specific antigen response rate (primary objective) of the standard abiraterone acetate and prednisone regimen in patients with metastatic CRPC (NCT01576172). Zhang at page 404, col. 2.
NCT02500901, Enzalutamide and Niraparib in the Treatment of Metastatic Castrate-Resistant Prostate Cancer (CRPC), 1-7 (ClinicalTrials.gov., 2015) (“NCT02500901”)
NCT02500901 teaches treatment of metastatic castrate-resistant prostate cancer with the combination of enzalutamide6 (160 mg/day orally) and niraparib (100 mg/day or 200 mg/day or 300 mg/day orally). Page 3 of 7 under “Experimental Treatment”.
Subjects will receive enzalutamide 160 mg/day orally (PO) in a 28-day lead-in cycle to assess tolerability. If well-tolerated, cycle 1 of combined enzalutamide and niraparib will commence. NCT02500901 at page 3 of 7. Enzalutamide will continue at 160 mg orally (PO) daily. Niraparib will be administered in three dose-escalation cohorts of 100mg orally (PO), 200mg orally (PO) or 300 mg orally (PO), daily. Six subjects will be enrolled at each dose level. Each cycle will be 28 days. Id. Combination treatment will continue until documented progression, unmanageable toxicity, or subject or treating investigator decision to discontinue for any reason. Id.
Significantly, NCT02500901 does not report the results of this study. While not relevant to the § 103 rejection, Xu reports (after the instant effective filing date) that the study (NCT02500901) was terminated due to unmanageable toxicity. X. Hu et al., 230 European Journal of Medicinal Chemistry (2022).
Differences between the Cited Art and the Claims
Primary reference Sandhu-2 teaches niraparib alone to treat metastatic castration resistant prostate cancer, and Sandhu-2 and Zhang suggests that PARP inhibitors, such as niraparib, should be explored for treatment of BRCA-1 or BRCA-2-mutant metastatic castration resistant prostate cancer. The cited secondary references (Zhang-2. Logothetis and Auerbach) teach abiraterone acetate alone to treat metastatic castration resistant prostate cancer.
The cited art differs in that it does not reduce to practice the combination of niraparib and abiraterone acetate to treat BRCA-1 or BRCA-2-mutant metastatic castration resistant prostate cancer according to the claimed dosage regimen.
Obviousness Rationale
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose the idea of combining them flows logically from their having been individually taught in the prior art. MPEP § 2144.06 (citing In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (holding that the two claimed types of active agents, GABA-a agonists and angiotensin II receptor blocker, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine); see also, In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
One of ordinary skill is motivated to use niraparib to treat BRCA1 or BRCA2-mutant metastatic castration resistant prostate cancer because Sandhu-2 teaches that niraparib —an oral potent, selective PARP-1 and PARP-2 inhibitor— has favorable pharmacokinetics, inhibits PARP activity, is well tolerated up to the recommended phase 2 dose of 300 mg/day, and has antitumor activity in carriers of BRCA1 and BRCA2 mutations in patients with sporadic cancers. Sandhu-2 at page 890, col. 2.
As discussed above, Sandhu-2 directly suggests to one of ordinary skill to explore the PARP inhibitgor niraparib in BRCA1/2 positive metastatic castration-resistant prostate cancer. Sandhu-2 at page 891, col. 1. In this regard, Sandhu-2 provides the following hard clinical data:
(1) Sandhu-2 teaches that eight (40% [95% CI 19–64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Sandhu-2 at page 882 (Summary, Findings). Evidencing that niraparib is effective against BRCA-mutant cancers; and
(2) Sandhu-2 teaches that 9 (43% [95% CI 22–66]) of 21 patients with non-BRCA1 or BRCA2 positive castration-resistant prostate cancer receiving niraparib at either 290 mg/day or 300 mg/day had stable disease for a median duration of 254 days. Sandhu-2 at page 890, col. 1; see also, Appendix at page 6, Supplemental Table 2. 7 Evidencing that niraparib is effective against non-BRCA mutant prostate cancer.
Based on these investigations, Sandhu-2 recommends that niraparib be further explored in the treatment of such BRCA-1 or BRCA-2 positive cancers:
next-generation sequencing studies indicate that prostate cancers can have homologous-recombination defects due to loss-of-function mutations in key genes, such as BRCA2, BRCA1, ATM, CHEK2, NSBP1 and FANCJ. These data collectively support further assessment of PARP inhibitors in prostate cancer.
Sandhu-2 at page 891, col. 1.
Overall, niraparib was well tolerated and is a promising PARP inhibitor that should be further assessed for use in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer.
Sandhu-2 at page 891, col. 2.
Further motivation is provided by Zhang’s teaching that the activity of the PARP inhibitor niraparib in sporadic prostate cancer provides a strong clinical rationale for developing PARP inhibitor-based therapies for metastatic castration resistant prostate cancer (CRPC). Zhang at page 405, col. 1. One of ordinary skill is further motivated because Farmer specifically suggests use of PARP inhibitors in the treatment of BRCA1- and BRCA2-associated cancers. Farmer at page 919, col. 2.
One of ordinary skill exploring niraparib treatment of BRCA-1 or BRCA-2 positive metastatic castration-resistant prostate cancer, as suggested by Sandhu-2, Farmer, and Zhang, is further motivated to employ the combination of niraparib and abiraterone acetate because Zhang-2, Logothetis and Auerbach each teach that abiraterone acetate in combination with other anticancer agents is effective for treatment of prostate cancer. Further, secondary references NCT01576172 and NCT02500901 also contemplate use of PARP inhibitors, in combination with secondary agents such as abiraterone acetate or enzalutamide. In this regard, NCT01576172 postulates that giving abiraterone acetate together with prednisone and the PARP inhibitor veliparib may work better than abiraterone acetate and prednisone alone in treating patients with castration-resistant prostate cancer. NCT01576172 at page 1 of 14. Additionally, NCT02500901 teaches treatment of metastatic castrate-resistant prostate cancer with the combination of the androgen receptor ligand-binding domain antagonist enzalutamide (160 mg/day orally) and niraparib (100 mg/day or 200 mg/day or 300 mg/day orally).
The claimed dosage ranges of:
Claim 1 . . . a daily dose of about 30 to about 400 mg/day of niraparib administered once per day and a daily dose of about 500 to about 1500 mg/day of abiraterone acetate administered once per day . . .
Claim 9 . . . comprising administering about 1000 mg/day of the abiraterone acetate to the patient.
Claim 11 . . . comprising administering about 200 mg/day of the niraparib to the patient.
Claim 13 . . . comprising administering about 100 mg/day of the niraparib to the patient.
are obvious because one of ordinary skill is motivated to optimize dosage as a result-effective variable. “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276 (CCPA 1980) (quoting In re Antonie, 559 F.2d 618, 620 (CCPA 1977)); see also, MPEP § 2144.04(II)(A) (citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) ("[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”)). Here, Sandhu-2 teaches that the dosage of niraparib for treating cancer is a result-effective variable. That is, in part A, Sandhu-2 teaches that cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Sandhu-2 at page 882, (Summary, Methods). Sandhu-2 teaches that 300 mg/day was established as the maximum tolerated dose. Sandhu-2 at page 882 (Summary, Findings). Thus, Sandhu-2 teaches that niraparib dosage is clearly an optimizable, result-effective variable. MPEP § 2144.05(II)(B). One of ordinary skill exploring the combination niraparib and abiraterone acetate for the treatment of BRCA-1 or BRCA-2 positive metastatic castration-resistant prostate cancer (as directly suggested by the art) is motivated to optimize the dosage of niraparib to within the claimed ranges; particularly where Sandhu-2 teaches an optimizable daily dosage niraparib range of from 30 mg to 400 mg, and where the claimed niraparib ranges fall within this Sandhu-2 suggested range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. MPEP § 2144.05(I) (citing In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976)). Further, the instant specification teaches no criticality associated with the claimed niraparib dosage ranges.8 See specification at page 8, [0034]; Id. at pages 10-11, [0040]. The same rationale applies to the claimed dosage of abiraterone acetate. Logothetis teaches that study patients with metastatic castration-resistant prostate cancer had 28-day cycles of treatment with either abiraterone acetate (1 g) or placebo orally once daily, in combination with 5 mg of oral prednisone twice daily. Logothetis at page 1211, col. 2, under “Methods”. Thus, Logothetis specifically suggests a starting point for abiraterone acetate dosage optimization of 1000 mg/day that falls within the range of claim 1 and is the same as recited in claim 9. MPEP § 2144.05(I).
Furthermore, one of ordinary skill seeking to treat metastatic castration resistant prostate cancer generally (i.e., regardless of whether it is BRCA positive or not) with the combination of niraparib and abiraterone acetate (as prosed above) reads on the claimed invention. That is, a portion of the patient population of metastatic prostate resistant cancer patients will be BRCA1 and/or BRCA2 positive. Sandhu-2 teaches that many sporadic (non-inherited) cancers (e.g., prostate and high-grade serous ovarian cancers) harbor epigenetic and genetic disruption of genes that are crucial for the homologous recombination pathway, such as BRCA1 and BRCA2. Sandhu at page 883, col. 1.
In view of the foregoing, claims 1, 9, 11, and 13 are obvious.
Claim 2 is obvious because Zhang-2 and Logothetis specifically teaches the claimed additional inclusion of prednisone. For example, Zhang-2 teaches that abiraterone acetate plus prednisone demonstrated a statistically significant improvement in [overall survival] of 4.4 months over prednisone alone. Zhang 2 at page 476, col. 1. In Logothetis, the study patients with metastatic castration-resistant prostate cancer had 28-day cycles of treatment with either abiraterone acetate (1 g) or placebo orally once daily, in combination with 5 mg of oral prednisone twice daily. Logothetis at page 1211, col. 2, under “Methods”. Auerbach further suggest the combination of abiraterone acetate and prednisone in the treatment of prostate cancer. Auerbach at col. 15, lines 52-55. In this regard, NCT01576172 postulates that giving abiraterone acetate together with prednisone and the PARP inhibitor veliparib may work better than abiraterone acetate and prednisone alone in treating patients with castration-resistant prostate cancer. NCT01576172 at page 1 of 14.
Claims 5-8 are obvious because one of ordinary skill is clearly motivated to administer niraparib and abiraterone acetate to the patient (per base claims 1 or 2) in the same dosage form in the form of a table to capsule.
The dosages of claims 10, 12 and 14 are obvious for the same reasons as claims 9 and 11.
Claims 15-17 are obvious because the one of ordinary skill is motivated to optimize the dosage of prednisone administered per base claim 2, for the same reasons discussed above for the dosage ranges of niraparib or abiraterone acetate. Auerbach specifically teaches optimizing prednisone to within the claimed ranges. Auerbach teaches treatment of cancer (where the claimed cancer is prostate cancer, see Auerbach claim 1) with 500 mg/day to about 1500 mg/day of abiraterone acetate and an amount of about 10 mg/day to about 250 mg/day of prednisone. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. MPEP § 2144.05(I) (citing In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976)).
Claims 19 and 20 are obvious because one of ordinary skill is motivated to optimize the dosage of niraparib as discussed above for claim 1. For example, for a particular patient, the treating physician may recommend increasing the dosage of niraparib over time to increase the efficacy.
The oral administration limitation of claim 21 is clearly met by the proposed reference combination.
Claims 22 and 23 are obvious because one of ordinary skill is motivated to change a cancer treatment regimen involving taxane-based or androgen receptor-targeted chemotherapy to the claimed method, for example, if the patient is refractory to such chemotherapy.
Claims 24 and 25 are obvious because the dosage form is not a patentable distinction. The specification provides no indication of what a “separate dosage form” means. Specification at page 9, [0038]. Under a broadest, reasonably interpretation a “separate dosage form” encompasses the case where a single capsule of niraparib is administered and a single capsule of abiraterone acetate is administered at about the same time (two separate dosage forms) rather than as a combined formulation. MPEP § 2111. This concept is contemplated by the proposed obviousness rational.
Claim 26 and 27 are obvious because one of ordinary skill is motivated to administer “a composition comprising niraparib and abiraterone acetate in a single oral dosage form”, rather than as two separate dosage forms, for ease of administration and patient compliance.
The further dosage limitations of claims 28-33 are obvious for the same reasons discussed above for claims 1, 15-17, 24 and 25.
(I)(A) Applicant’s Argument -- The cited references do not teach or suggest the claimed combination therapy -- Sandhu-2 does not teach or suggest the efficacy of niraparib in managing mCRPC with BRCA mutations
Applicant points out that the Sandhu-2’s single metastatic-prostate-cancer patient with BRCA2 mutation carrier (patient 86) did not respond to niraparib and developed new liver metastases. Reply at page 8 (citing Sandhy-2 at Supplementary page 7). Applicant argues that this single patient in combination with evidence that BRCA mutant prostate cancers are notoriously difficult to treat suggest that one of ordinary skill does not have a reasonable expectation of success (per claim 1) in managing BRCA(1)/(2)-positive metastatic castration-resistant prostate cancer. Reply at page 8
Examiner Response
This argument is not persuasive for the following reasons. Obviousness does not require absolute predictability, but at least some degree of predictability is required. MPEP § 2143.02(II). Of course, due weight must be given to Sandhu-2’s teaching that the single BRCA positive metastatic prostate cancer patient (patient 86) was refractory to niraparib. However, on balance, one of ordinary skill would expect a percentage of cancer patients will be refractory to treatment; particularly in a difficult-to-treat cancers. Here, the implication is that patient 86 was declared refractory and left study after only 56 days because of a new liver metastasis; that is, the prostate cancer was progressing/metastasizing. Sandhu-2, Appendix page 7, Table 2, last row. One of ordinary skill could reasonably postulate that the disease had progressed to the point where no treatment would be effective.
This single refractory BRCA positive prostate cancer patient is not so significant (data set too small) as to negate a reasonable expectation of success. For example, not every patient non-BRCA prostate cancer patient responded to niraparib, that is Sandhu-2 teaches that nine (43% [95% CI 22–66]) of 21 patients with non-BRCA castration-resistant prostate cancer receiving either 290 mg/day or 300 mg/day had stable disease for a median duration of 254 days. Sandhu-2 at page 890, col. 1. Note also that Sandhu-2 teaches that eight (40% [95% CI 19–64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Sandhu-2 at page 882 (Summary, Findings). Evidencing to one of ordinary skill that niraparib is effective against BRCA-mutant cancers.
(I)(B) Applicant’s Argument -- The cited references do not teach or suggest the claimed combination therapy -- Zhang and Farmer do not teach or suggest the efficacy of niraparib in managing mCRPC with BRCA mutations
Applicant argues that with respect to the claimed sub-type of prostate cancer (mCRPC), neither Zhang nor Sandhu-2 discloses the efficacy of niraparib in patients having metastatic prostate cancer and a BRCA DNA repair anomaly as claimed. Reply at 10. Applicant points out that Zhang notes that loss of PTEN or presence of ETS gene rearrangement by itself is unlikely to be sufficient to predict response to PARP inhibitor-based therapies. Id. Applicant argues that Farmer does not once mention niraparib or CRPC, and certainly Farmer does not mention CRPC with BRCA mutations. Reply at 11.
Examiner Response
This argument is not persuasive because while each reference individually does not teach the claimed invention, the combination is the basis for the obvious rationale. MPEP § 2145 (IV). Zhang’s teaching that ETS gene rearrangement by itself is unlikely to be sufficient to predict response to PARP inhibitor-based therapies is not entirely relevant to the obviousness rejection. For example, one of ordinary skill is motivated to predict response to PARP inhibitor-based therapies per Sadahu-2’s teaching that decreases in circulating tumour cells of at least 30% were noted in several patients with castration-resistant prostate cancer, where three patients had clinically significant decreases in circulating tumour cells after receiving niraparib and durable disease stabilization lasting longer than 6 months. Sandhu-2 at page 890.
And while as argued by Applicant, Farmer does not teach niraparib or CRPC, Farmer does teach that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. Farmer at page 917, col. 1. This motivates one of ordinary skill to explore PARP inhibitors, such as niraparib, in BRCA1/2 positive cancers, such as metastatic castration-resistant prostate cancer.
(I)(C) Applicant’s Argument -- The cited references do not teach or suggest the claimed combination therapy -- None of the secondary references cure the deficiencies of Sandhu-2, Zhang and Farmer
Applicant’s Argument
Applicant argues that none of Zhang-2, Logothetis, Aurbach, and NCT’172 t teach or suggest the efficacy of niraparib in treating mCRPC patients with BRCA mutations. Reply at pages 11-12.
Examiner Response
This argument is not persuasive because he above § 103 rejection does not rely only on these references. MPEP § 2145 (IV). As discussed above, Sandhu-2 directly suggests to one of ordinary skill to explore the PARP inhibitor niraparib in BRCA1/2 positive metastatic castration-resistant prostate cancer. Sandhu-2 at page 891, col. 1. Farmer and Zhang bolster this suggestion. Farmer specifically suggests use of PARP inhibitors in the treatment of BRCA1- and BRCA2-associated cancers. Farmer at page 919, col. 2.
Applicant’s Argument
With respect to NCT’172, Applicant argues that the Office, has assumed, without evidence, that PARP inhibitors have interchangeable therapeutic efficacy when administered in combination with another drug. Reply at page 12. Applicant argues that this overly simplistic approach ignores the reality that development of new prostate cancer therapies is a highly complex undertaking, involving numerous experiments (both pre-clinical and clinical), data gathering, data and ethical analysis, followed by new experimental designs that produce new data that, in tum, informs the cross-functional team for decision making to the next step. Reply at page 12.
Examiner Response
Here, the § 103 rationale does not assert or assume that all PARP inhibitors are interchangeable when administered in combination with another drug. Rather, the assertion is that based on the combination of references, one of ordinary has a reasonable expectation that niraparib would be effective in managing BRCA(1)/(2)-positive metastatic castration-resistant prostate cancer. And one of ordinary skill is further motivated to employ niraparib in combination with abiraterone acetate because Zhang-2, Logothetis and Auerbach each teach that abiraterone acetate in combination with other anticancer agents is effective for treatment of prostate cancer.
With respect to Applicant’s argument that the § 103 rational takes an overly simplest approach, it is true that practically implementing the instantly claimed treatment for the difficult to treat BRCA positive metastatic castration resistant prostate cancer is a complex undertaking. However, the cited art clearly provides motivation to one of ordinary skill to undertake and develop the claimed treatment method and the requisite reasonable expectation of success.
Applicant’s Additional Argument
Applicant argues that Sandhu-2 provides no data supporting the efficacy of niraparib in treating the claimed patient population (i.e., mCRPC patients with BRCA mutations). Reply at page 14. Applicant argues that here, as in OSI, a lack of data in a highly unpredictable art would prevent one of skill in the art from developing a reasonable expectation of success for the drug combination. Reply at page 14 (citing OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 2019 U.S.P.Q.2d 379681 (Fed. Cir. 2019))
Examiner Response
It is true that Sandhu-2 does not provide representative9 data was for administering niraparib to a patient with BRCA(1)/(2)-positive metastatic castration-resistant prostate cancer. However, this is different from Osi Pharm, where none of the cited art provided data regarding the subject compound’s (erlotinib) efficacy:
But the asserted references do not disclose any data or other information about erlotinib's efficacy in treating NSCLC. The record does not contain any clinical (human) data or pre-clinical (animal) data. It does not even include in vitro (test tube) data regarding erlotinib's effect on NSCLC. At the same time, it is undisputed that NSCLC treatment was highly unpredictable with an over 99.5% rate of failure for drugs entering Phase II clinical studies. On this record, we are not persuaded that a reasonable factfinder could conclude that a person of ordinary skill would have reasonably expected success based on the combination of Schnur and Gibbs or Schnur and OSI's 10-K.
OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1383 (Fed. Cir. 2019). However, different from the facts of Osi Pharm, reference Sandhu-2 provides the following hard clinical data respecting BRCA1 or BRCA2 mutation carriers with ovarian cancer and patients with non-BRCA1 or BRCA2 positive castration-resistant prostate cancer receiving niraparib:
(1) Sandhu-2 teaches that eight (40% [95% CI 19–64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Sandhu-2 at page 882 (Summary, Findings). Evidencing that niraparib is effective against BRCA-mutant cancers; and
(2) Sandhu-2 teaches that 9 (43% [95% CI 22–66]) of 21 patients with non-BRCA1 or BRCA2 positive castration-resistant prostate cancer receiving niraparib at either 290 mg/day or 300 mg/day had stable disease for a median duration of 254 days. Sandhu-2 at page 890, col. 1; see also, Appendix at page 6, Supplemental Table 2. Evidencing that niraparib is effective against non-BRCA mutant prostate cancer.
Applicant’s Additional Argument
Applicant argues that, the Office has not identified any reason to believe that the disclosure in NCT '901 would have motivated one of ordinary skill to replace enzalutamide with either of the functionally and structurally distinguishable abiraterone acetate or prednisone (see diagram), and they certainly did not identify any reason to believe that NCT '901 would have motivated one of ordinary skill to replace enzalutamide with both abiraterone acetate and prednisone.
Examiner Response
This argument is not persuasive because the § 103 rational does not rely solely on NCT '901 but rather a combination of references; further the § 103 rational is not based on replacing enzalutamide. Secondary references NCT01576172 and NCT02500901 are cited because they evidence that one of ordinary skill (at the relevant time) contemplates use of PARP inhibitors (veliparib or niraparib), in combination with secondary agents such enzalutamide (an androgen receptor ligand-binding domain antagonist). In this regard, NCT01576172 postulates that giving abiraterone acetate together with prednisone and the PARP inhibitor veliparib may work better than abiraterone acetate and prednisone alone in treating patients with castration-resistant prostate cancer. NCT01576172 at page 1 of 14. Additionally, NCT02500901 teaches treatment of metastatic castrate-resistant prostate cancer with the combination of the androgen receptor ligand-binding domain antagonist enzalutamide (160 mg/day orally) and niraparib (100 mg/day or 200 mg/day or 300 mg/day orally). In sum, these are merely supporting references that evidence at the relevant time, those of ordinary contemplated treatment of metastatic castrate-resistant prostate cancer by combinations of PARP inhibitors (veliparib or niraparib) and androgen receptor antagonists and/or steroids such as prednisone. The motivation to combine stems from the fact that Sandhu-2 and NCT’901 are both directed to niraparib in combination with secondary agents such enzalutamide (an androgen receptor ligand-binding domain antagonist)
(I)(D) Applicant’s Argument -- The cited references do not teach or suggest the claimed combination therapy -- The cited references do not teach or suggest that BRCA-mutant mCRPC would be manageable with the claimed combination therapy
Applicant’s Argument
Applicant argues that none of the cited references taught or suggested that mCRPC that is biomarker positive for BRCA-1 or BRCA-2 would be manageable with niraparib alone, much less with the combination of niraparib and abiraterone acetate. Reply at page 16. Applicant argues that, in fact, the cited references demonstrate that niraparib is not effective for this patient population. Id. And even if, arguendo, the art were to suggest treating the claimed cancer with niraparib, there is no suggestion that further combination with abiraterone acetate would lead to an effective treatment with any reasonable expectation of success. Id.
Examiner Response
This argument has already been made and addressed in detail above.
(II) Applicant’s Argument -- Those of ordinary skill in the art would have had no reasonable expectation of success in achieving the claimed therapy based on the cited references
Applicant further cites A. Tenuta et al., 113 BJUI International, E82-E89 (2013) (“Tenuta”). Applicant states that Tenuta teaches that reports that the cumulative pass rate for prostate cancer therapies which were in clinical trials between 1998 and 2011 was just 3%, with less than a quarter of phase III trials succeeding and "phase III failures were high, despite equally high failures during phase II”. Reply at page 16 (citing Tenuta at Abstract). Applicant argues that the standard for obviousness is not whether there is "some predictability" in the field, but rather whether a person of ordinary skill in the art would have had a reasonable expectation of success and there is no evidence of record that that reasonable expectation existed in the field at the time of the application's earliest priority date. Id. Applicant argues that the lack of unpredictability in the field is borne out by articles reporting on the outcomes of the NCT '172 and NCT '901 publications and Hussain, et al., which reports on the results of the NCT '172 trial ("Hussain"). Reply at page 17 (citing M. Hussain et al., 36 Journal of Clinical Oncology, 991-999 (2018) (“Hussain”) (published December 20, 2017)).
Applicant argues that similar evidence of unpredictability in the field of prostate cancer therapeutics is provided an article by X. Hu et al., 230 European Journal of Medicinal Chemistry (2022) ("Hu'), which reports on the results of the NCT '901 publication. As noted by the Office, Hu "later reports (after the instant effective filing date) that the study (NCT02500901) was terminated due to unmanageable toxicity." (Action at p. 35; emphasis added). Reply at page 18. Applicant argues that together, Hussain and Hu provide strong additional evidence of unpredictability in the field of clinical-stage prostate cancer therapeutics. Id.
Examiner Response
This argument is not persuasive. Tenuta evidences, what is widely accepted, that cancer treatment is highly unpredictable. See, OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1377 (Fed. Cir. 2019)). However, obviousness does not require absolute predictability, but at least some degree of predictability is required. MPEP § 2143.02. Here, in view of the cited art and the hard clinical data provided by Sandhu-2, one of ordinary skill has a reasonable expectation that the instantly claimed combination of niraparib and abiraterone could manage BRCA-mutant metastatic castration resistant prostate cancer. While the success rate for FDA approval may be low, one of ordinary skill seeking solutions to cancer treatment is still motivated to seek promising research avenues as suggested by the prior art.
Furthermore, neither Hussain nor Hu are relevant to an obviousness analysis. Neither of these post-filing date references were available for consideration by one of ordinary skill as of the instant effective filing date. These references can neither be considered by the Examiner for the evidence of teaching away nor for the art’s predictability. See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1073 (Fed. Cir. 2012) ("[o]bviousness must be assessed at the time the invention was made").
(III) Applicant’s Argument -- PARP inhibitors were not considered to be interchangeable at the priority date
Applicant’s Argument
Applicant states that Office alleges that one of skill in the art would substitute veliparib (as disclosed in NCT '172) with niraparib (presumably from Zhang or Sandhu) to arrive at the claimed therapy. Reply at page 18 (citing previous Office action at pp. 31-32). Applicant argues that there is simply no evidence of record indicating that those of ordinary skill viewed veliparib and niraparib as therapeutically interchangeable, especially in difficult-to-treat disease states such as metastatic prostate cancers. Indeed, this overly simplistic approach ignores the reality that development of new prostate cancer therapies is a highly complex undertaking, involving numerous experiments (both pre-clinical and clinical), data gathering, data and ethical analysis, followed by new experimental designs that produce new data that, in tum, informs the cross-functional team for decision making to the next step. Reply at page 19. The Office failed to identify any evidence indicating that those of ordinary skill in the art shared its view that agents that are used in clinical studies are modular components that can be readily exchanged. Id. The Office failed to provide any reasoning how those of ordinary skill in the art would have had a reasonable expectation of success at replacing one drug in a drug combination with another and obtaining a therapeutically effective combination, when the art knows that drug combinations require careful studies evaluating drug-drug interactions (as discussed in more detail below). Id.
Examiner Response
Neither the previous Office action nor the above § 103 rationale assert that one of ordinary skill would substitute veliparib (as disclosed in NCT '172) with niraparib (presumably from Zhang or Sandhu) to arrive at the claimed therapy. Further the above arguments have already been made and addressed in detail above.
Applicant’s Argument
Applicant argues that the Office's position relies on the assumption that PARP inhibitors as a class could be combined with abiraterone acetate with a reasonable expectation of success. Reply at page 19. And contrary to the Office's assertion, the NCT '172 publication provides no evidence to support this position. NCT '172 focuses on an individual PARP inhibitor (veliparib), and Applicant has provided unrebutted evidence that one of skill in the art would not generalize the results from one PARP inhibitor (veliparib) to all PARP inhibitors as a class given their differences in potencies, pharmacokinetics and clinical characteristics. Id. Moreover, PARP inhibitors were not considered to be interchangeable at the priority date. Reply at page 20.
Examiner Response
Again, neither the previous Office action nor the above § 103 rationale assert that one of ordinary skill would substitute veliparib (as disclosed in NCT '172) with niraparib (presumably from Zhang or Sandhu) to arrive at the claimed therapy. Further the above arguments have already been made and addressed in detail above.
Applicant’s Argument
Applicant argues that as of the effective filing date, there was a lack of understanding such that some commentators considered that the true mechanism of action of PARP inhibition was not known. Reply at page 20 (citing Carlson et al, "PARP Inhibitors Show Promise Against Metastatic Triple-Negative Breast Cancer in Early Studies" Oncology Times, 31(15):p 10-11, 2009; Murai et al, "Trapping of PARP 1 and PARP2 by Clinical PARP Inhibitors", Cancer Res; 72(21); 5588-99, 2012).
Applicant argues that thus, the skilled person - who generally adopts a conservative approach and does not take incalculable risks or enter unpredictable areas - would have been wary of making assumptions about PARP inhibitors. Reply at page 21. Certainly, the skilled person would not have made untested and unsuggested combinations (for example the claimed combination) with an expectation of success. Id.
Examiner Response
This argument is not persuasive for the following reasons. The unpredictability in the art is already acknowledged. Further, neither Carlson nor Murai teach away from the claimed invention because these references do not criticize, discredit, or otherwise discourage the solution claimed. MPEP §2142.02 MPEP § (III)(VI); MPEP § 2145(X)(D). The rejection has been clearly set forth above on the merits. Other than for relevance to the state of the art or for teaching away, it is not seen how these references are relevant.
The Examiner knows of no legal precedent defining a person of ordinary skill as adopting a conservative approach. MPEP § 2141.03. A person of ordinary skill will considere the “sophistication of the technology”. MPEP § 2141.03(I). The hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art. MPEP § 2141.03(I). Here, the art is cancer chemotherapeutic development, which one of ordinary skill understands is a risky and unpredictable endeavor.
(IV) Applicant’s Argument -- The claimed therapeutic combination exhibits surprising and unexpected results
A. EVIDENCE FROM PRE-CLINICAL MURINE STUDIES
Applicant argues that the specification data demonstrates surprising and unexpected results for the claimed treatment methods, where the vivo experiment of Example 2 provides the first proof-of-concept for the treatment of prostate cancer with a combination of PARP inhibitors and androgen biosynthesis inhibitors. Reply at page 22 (citing specification at pages 24 et seq.).
Applicant argues that the comparative data given in the present application clearly show that the combination of niraparib/abiraterone acetate effectively inhibits tumor growth (see, e.g., the results of Group 4 in Table 3). See, specification at page 25.
Applicant states that in this experiment, mice were injected subcutaneously with prostate cancer cells (VCaP), castrated, and then dosed in four groups: 1) control vehicle; 2) niraparib; 3) abiraterone; and 4) niraparib and abiraterone. Reply at page 22. Regarding the VCap cancer cells the specification teaches:
[0091] The human VCaP prostate tumor line was derived from a vertebral metastasis of a patient with castrate-resistant prostate cancer. The VCaP tumor cells carry a TMPRSS2-ERG fusion, and express the androgen receptor.
Specification at page 24, [0091] (emphasis added). Applicant states that human VCaP prostate tumor cells can therefore be used to assess the efficacy of niraparib and abiraterone acetate in prostate cancer), which have an anomaly in DNA-repair gene MLHI, a mismatch repair gene. Reply at page 22. Applicant states that tumor growth and survival were assessed for each group, and the combination of abiraterone and niraparib provided significant improvement in tumor growth inhibition (Figure 1) and survival (Figure 2) compared to abiraterone and niraparib alone. Reply at page 22.
Applicant cites specification Table 4 which shows that the increased lifespan of mice that received the combination of niraparib and abiraterone is 31 % compared to -0.6% for niraparib alone and 13.1 % for abiraterone alone. Reply at page 23.
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Reply at page 23 (citing Specification at page 27, Table 4). Applicant argues that this improvement is statistically significant (p value of <0.001) and surprising given that the increase in lifespan is synergistic, i.e., not merely additive of niraparib (-0.6%) and abiraterone acetate (13.1 %). Reply at page 23.
Examiner Response to Proffered Results in the Specification, Example 2
If the evidence is to be given substantial weight in the determination of obviousness or nonobviousness, evidence of secondary considerations must be relevant to the subject matter as claimed, and therefore the examiner must determine whether there is a nexus between the merits of the claimed invention and the evidence of secondary considerations. MPEP § 716.01(b) (citing Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 305 n.42, 227 USPQ 657, 673-674 n. 42 (Fed. Cir. 1985)).
The proffered results are unpersuasive for the following reasons. First, Applicant has not explained how the VCaP prostate tumor cells, where the VCaP tumor cells carry a TMPRSS2-ERG fusion, and express the androgen receptor (see specification at [0091]) are relevant to claims to treat BRCA1/2 metastatic castration resistant prostate cancer. The TMPRSS2-ERG fusion leads to the aberrant overexpression of its product, a truncated ERG protein, which has a role in tumor initiation and progression, in particular if associated with other genomic alterations, such as the loss of the tumor suppressor PTEN. See, J. Fontugne, Chapter 23, DNA Damage Repair, in Precision Molecular Pathology of Prostate Cancer, 405-417 (2018) (“Fontugne”) (see page 410).10 On the other hand, BRCA proteins, BRCA1 and BRCA2, play a critical role in DNA damage response, specifically in repair of double-strand breaks through homologous recombination. Fontugne at page 23. Fontugne teaches that germline DNA-repair gene mutations among men with metastatic prostate cancer are significantly higher (11.8%) than the incidence in men with localized disease and mutations were found in 16 genes including BRCA2, ATM, CHEK2, BRCA1, RAD51D, and PALB2. Fontugne at page 23. Thus, absent Applicant’s explanation (which is Applicant’s burden), it is not seen how the proffered mouse model results directed to VCaP prostate tumor cells are probative of unexpected results regard the claims to treat BRCA1/2 metastatic castration resistant prostate cancer.
Looking at the results themselves, Specification Table 4 indicates a niraparib-alone median lifespan of 79 days (versus 77.5 days for the control), an abiraterone median lifespan of 88 days and that the combination of niraparib and abiraterone gave a median lifespan of 105.5 days (an increased lifespan (ILS) of 31%). Thus, the claimed combination of niraparib and abiraterone acetate gives an improved result. This improved result is expected, based on the cited art (particularly the combination of Sandhu-2 and Zhang-2). It is expected that the combination of niraparib and abiraterone acetate, will outperform either niraparib alone or abiraterone alone, which is the result proffered in specification Example 2 (albeit in a mouse model). What is significant in the proffered mouse model, is that niraparib alone did not result in statistically increased lifespan; leading to Applicant’s assertion of synergy. However, this finding regarding niraparib alone is not probative of the claimed combination. MPEP § 716.01(b).
The proffered results are unpersuasive for the following additional reasons. The proffered results are based on a mouse model, rather than a “patient in need thereof” as claimed. In this regard, Applicant does not define the claim 1 term “patient” in the specification. But every specification reference to “patient” is to human patients. Further, Applicant’s arguments in the reply are all directed to unpredictability and reasonable expectation of success with human patients. As such, the claim 1 term “patient in need thereof” is clearly primarily directed to human patients. The proffered results, where claim 1 is primarily directed to human patients, should therefore be probative of unexpected results in human patients. In this regard, it is not clear, nor has Applicant provided an explanation (which is Applicant’s burden), as to why the proffered mouse-model results are probative of treatment in humans as the claims are directed. The fact that niraparib alone did not result in statistically increased lifespan in Applicant’s proffered mouse model is not consistent with Sandhu-2’s teaching with respect to human patients:
(1) Sandhu-2 teaches that eight (40% [95% CI 19–64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Sandhu-2 at page 882 (Summary, Findings). Evidencing that niraparib is effective against BRCA-mutant cancers; and
(2) Sandhu-2 teaches that 9 (43% [95% CI 22–66]) of 21 patients with non-BRCA1 or BRCA2 positive castration-resistant prostate cancer receiving niraparib at either 290 mg/day or 300 mg/day had stable disease for a median duration of 254 days. Sandhu-2 at page 890, col. 1; see also, Appendix at page 6, Supplemental Table 2. Evidencing that niraparib is effective against non-BRCA mutant prostate cancer.
This evidences that the proffered mouse-model does not necessarily correlate with (is probative of) human treatment. Also, as noted in the Board’s opinion in parent case 15/950,707, directed to essentially the same claims (Ex Parte Snyder, Appeal No. 2022-004874, 15/950,707 (PTAB 2023) (see pages 14-15)), Zhang teaches, regarding mice, that "veliparib with temozolomide, not temozolomide alone, inhibited the growth of orthotopic and intratibial mouse prostate cancer xenografts," while, by contrast, Zhang teaches regarding humans treated with the same combination, that "only two of the 25 evaluable patients had a confirmed PSA response". Zhang at page 404, col. 1. Thus, Zhang evidences that mouse-model success with PARP inhibitor treatment of prostate cancer does not necessarily correlate with (is probative of) human treatment.
Additionally, the proffered results are unpersuasive because they are not be commensurate in scope with the claimed subject matter that is, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. MPEP § 716.02(d). As noted above, the proffered mouse model results cannot be said to be predicative of treatment of BRCA1/2 prostate cancer or what occurs in humans, as encompassed by the claims. MPEP § 716.02(d). This was found in the Board’s opinion in parent case 15/950,707, directed to essentially the same claims (Ex Parte Snyder, Appeal No. 2022-004874, 15/950,707 (PTAB 2023) (see pages 14-15).
Applicant’s Arguments to the Above Analysis
Applicant argues that Zhang does not state that mouse models do not correlate with human treatment. Rather, Zhang summarizes data showing that a specific combination of the active compounds (i.e., veliparib and temozolomide) that are not used in the combination therapy that is at issue here was more effective in mice than in humans. (See Zhang at p. 404, col. 1, para. 3). Reply at page 24. Applicant argues that the Office has not identified any evidence or rationale supporting the proposition that Zhang's reporting regarding veliparib plus temozolomide is representative of the way that those working in the field of prostate cancer therapeutics regarded mouse testing of other active compounds, and certainly none establishing that those working in this field were of the view that success in mice does not strongly correlate with success in humans.
Examiner Response
This argument is not persuasive for the following reasons. It is Applicant’s burden to establish unexpected results. MPEP § 716.02(b). Zhang teaches that in prostate cancer with PARP inhibitors, a particular mouse model did not correlate with PARP inhibitor treatment of prostate cancer humans. Further, as discussed above, it is not clear how the proffered mouse model results directed to VCaP prostate tumor cells are probative of unexpected results regard the claims to treat BRCA1/2 metastatic castration resistant prostate cancer. This is not a case where the claims are directed to prostate cancer generally; rather Applicant has argued that it is the BRCA1/2 mutation aspect that is patentable over the art. As such, Applicant should proffer BRCA1/2 relevant results. It is not the Office’s burden to provide evidence or rationale proving that the proffered experiments are not probative of unexpected results. Rather, it is Applicant’s burden to provide results that are facially probative or if the results are not readily correlated with the claims, then it is Applicant’s burden to provide a reasonable explanation of how one of ordinary skill would understand the correlation.
(B) APPLICANT’S PROFFER OF RESULTS HUMAN CLINICAL TRIALS IN SUPPORT OF UNEXPECTED RESULTS
Applicant submits the Declaration of Dr. Peter Francis Pursuant to 37 CFR § 1.132 (November 11, 2025) (the “2nd Francis Declaration”) in support of unexpected results.
The 2nd Francis Declaration comments on the following three references, previously made of record:
M. Smith et al., “Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial” 23 The Lancet Oncology, 362-373 (2022) (“Smith”);
K. Chi et al., “Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer” 41 Journal of Clinical Oncology, 3339-3351 (2023) (“Chi”); and
K. Chi et al., “Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.” 34 Annals of Oncology, 772-782 (2023)) (“Chi-Annals”).
See, 2nd Francis Declaration, at ¶ 8.
2nd Francis Declaration avers that a person of ordinary skill in this field would not have expected the degree of response that the claimed therapeutic combination provides when compared with other available therapies for the population of patients recited in the claims from the cited art combination. 2nd Francis Declaration, ¶ 8.
2nd Francis Declaration avers that: (i) those with DNA repair gene defects such as BRCA mutations, are notoriously difficult to treat; (ii) "DNA repair gene defects (DRD), seen in approximately 12-23% of tumors in patients with metastatic prostate cancer when considering both germline and somatic alterations, are associated with cancer development, aggressiveness, and progression; and (iii) These DRD-altered tumors are not only frequent in metastatic disease, but are also associated with poor prognosis and potential resistance to systemic therapies. 2nd Francis Declaration, ¶ 10.
The 2nd Francis Declaration states that the first interim analysis (IA1) of the results from the phase III clinical trial NCT03748641 (hereinafter "MAGNITUDE trial") described in Chi investigated the effect of niraparib plus abiraterone acetate and prednisone (AAP) against a placebo arm (in which patients were administered a placebo with abiraterone acetate and prednisone (AAP), in the BRCA1/2 subgroup and then in the full HRR+ cohort. 2nd Francis Declaration at page 4, ¶ 10b. The Francis Declaration states that the median radiographic progression-free survival (rPFS) in the BRCA1/2 subgroup was significantly longer in the niraparib plus AAP group (16.6 months) compared with the placebo plus AAP group (10.9 months). 2nd Francis Declaration at page 4, ¶ 10b(i). 11,12
The 2nd Francis Declaration states that the second interim analysis (IA2) of the results from the phase III MAGNITUDE trial is described in Chi-Annals and shows an unexpectedly high response rate in the BRCA1/2 subgroup treated with niraparib plus abiraterone acetate and prednisone (AAP) when compared with the BRCA1/2 subgroup treated with placebo plus abiraterone acetate and prednisone (AAP) group. Specifically, the niraparib plus AAP arm outperformed placebo plus AAP arm in the primary endpoint (PFS) and secondary endpoints (time to symptomatic progression and time to cytotoxic chemotherapy). 2nd Francis Declaration at pages 4-5, ¶ 10c.
The 2nd Francis Declaration states that at the time of data cut-off in IA2, with 8.1 months of additional follow-up from the first interim analysis (IA1), radiographic progression-free survival (rPFS) by blinded independent central review demonstrated a consistent and clinically meaningful treatment effect in the BRCA1/2 subgroup. 2nd Francis Declaration at page 5, ¶ 10c(i).
The 2nd Francis Declaration states that the risk of progression or death was reduced by 45% in patients who received niraparib plus AAP lengthening the median rPFS by 8.6 months for patients who received niraparib plus AAP (19.5 months) compared with placebo plus AAP (10.9 months). 2nd Francis Declaration at page 5, ¶ 10c(ii).
The 2nd Francis Declaration states that Chi-Annals summarizes the results from the IA2 of MAGNITUDE study as follows:
The results from IA2 of MAGNITUDE confirm that after a median follow-up of 24.8 months in patients with BRCA1/2 alterations, the combination of niraparib plus AAP continued to improve rPFS, demonstrating a 45% reduction in the risk of radiographic progression or death, which corresponded to an extension of the median rPFS by 8.6 months over placebo plus AAP, yielding a median rPFS of >1.5 years. The clinical relevance of the benefit in rPFS was supported by delays in time to symptomatic progression and time to initiation of cytotoxic chemotherapy for the BRCA1/2 subgroup and the total HRR+ population treated with niraparib plus AAP versus placebo plus AAP.
2nd Francis Declaration at page 5, ¶ 11 (citing Chi-Annals at page 779, col. 1) (emphasis in original).
The 2nd Francis Declaration states that altogether, with respect to the BRCA1/2 subgroup, Applicant achieved a 16.6 month median rPFS, which equates to a 5.7 month improvement, for the combination of niraparib plus AAP relative to placebo plus AAP at the first interim analysis (IAl) of the MAGNITUDE trial described in Chi. And Applicant achieved an even more impressive 19.5 month rPFS, which equates to a 8.6 month improvement relative to placebo plus AAP, at the second interim analysis (IA2) of the MAGNITUDE trial described in Chi Annals, which included 8.1 months of additional follow-up from the IAl. 2nd Francis Declaration at page 5, ¶ 12.
The 2nd Francis Declaration states that these human studies demonstrate an unexpected clinical benefit from administering the combination of niraparib and abiraterone acetate to patients who are biomarker positive for at least one biomarker selected from BRCA-1 or BRCA-2. And further states that “I do not believe that the magnitude of these benefits, and improvement over other therapies, would have been reasonably expected from NCT '172, Logothetis, Zhang, Sandhu, and NCT '901”. Francis Declaration at page 6, ¶ 13.
Applicant presents the following table summarizing the references relied upon in the 2nd Francis Declaration alongside prior art reference Sanhu-2:
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Reply at page 30.
Summary of Proffered Results
Applicant states that the first interim analysis (IAl) of the MAGNITUDE trial described in Chi shows a 16.6-month median rPFS (niraparib + abiraterone acetate for BRCA1/2) versus 10.9-month median rPFS (abiraterone acetate + placebo for BRCA1/2), which equates to a 5.7-month improvement, for the claimed combination in the BRCA1/2 subgroup relative to abiraterone acetate + placebo. Reply at page 30.
Applicant states that the second interim analysis (IA2) of the MAGNITUDE trial described in Chi Annals (which included 8.1 months of additional follow-up from the IAI) shows 19.5 month rPFS, which equates to a 8.6 month improvement of for the claimed combination of niraparib + abiraterone acetate for BRCA1/2 relative to abiraterone acetate + placebo for BRCA1/2. Reply at page 31.
Examiner Response to the 2nd Declaration of Dr. Peter Francis Pursuant to 37 CFR § 1.132 (April 18, 2025)
A greater than expected result and evidence of unobvious or unexpected advantageous properties are evidentiary factors pertinent to the legal conclusion of obviousness of the claims at issue. MPEP § 716.02(a)(I)/(II). However, the burden is on Appellant to establish that the evidence relied upon demonstrates that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. MPEP § 716.02(b). If the evidence is to be given substantial weight in the determination of obviousness or nonobviousness, evidence of secondary considerations must be relevant to the subject matter as claimed, and therefore the examiner must determine whether there is a nexus between the merits of the claimed invention and the evidence of secondary considerations. MPEP § 716.01(b) (citing Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 305 n.42, 227 USPQ 657, 673-674 n. 42 (Fed. Cir. 1985)).
Here the proffered results are a comparison of the BRCA1/2 subgroup treated with niraparib plus abiraterone acetate and prednisone13 (AAP) versus with the BRCA1/2 subgroup treated with placebo plus abiraterone acetate, giving respective rPFS14 improvements of 5.7 months (over a the AI1 16.7-month period) and 8.6 months (subsequent patient analysis at 28.8 months). The overall result is that the claimed combination of niraparib + abiraterone acetate/prednisone outperforms prior art abiraterone acetate/prednisone alone in the treatment of BRCA1/2 positive MCRP.
In response, tt is true that one of ordinary skill expects that abiraterone acetate in combination with prednisone will lead to an improved rPFS in MCRP treatment over no treatment. 15 But it is also true that one of ordinary skill expects that niraparib will improve the efficacy of abiraterone acetate/prednisone in sporadic cancers with homologous recombination DNA repair defects because abiraterone acetate/prednisone acts by a different mechanism (see footnote 15) than the PARP inhibitor niraparib, which targets BRCA. And this is what Sandhu-2 teaches.
For example, Sandhu-2 recommends that niraparib be further explored in the treatment of such BRCA-1 or BRCA-2 positive cancers:
next-generation sequencing studies indicate that prostate cancers can have homologous-recombination defects due to loss-of-function mutations in key genes, such as BRCA2, BRCA1, ATM, CHEK2, NSBP1 and FANCJ. These data collectively support further assessment of PARP inhibitors in prostate cancer.
Sandhu-2 at page 891, col. 1.
Overall, niraparib was well tolerated and is a promising PARP inhibitor that should be further assessed for use in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer.
Sandhu-2 at page 891, col. 2. Thus, the proffered results appear to be merely additive and not unexpected.16 This additive effect is evidence by reference M. Smith et al., 23 The Lancet Oncology, 362-373 (2022) (“Smith”) which is part of, and referenced by the 2nd Francis Declaration (and attached as an Exhibit to the 1st Francis Declaration) indicates a rPFS of 8 months for BRCA cohort mCRPC patients that received niraparib 300 mg alone orally once daily until treatment discontinuation, death, or study termination. SmithEx1 at page 369, Table 3. As suggested by Sandhu-2, Smith (which is not prior art, but is part of the part of the 2nd Francis Declaration) shows that niraparib alone is effective to treat BRCA cohort mCRPC patients and by itself demonstrated a rPFS of 8 months for BRCA cohort mCRPC patients.
Applicant’s Additional Argument Regarding Unexpected Results
Argument
Applicant argues that M. Smith et al., 23 The Lancet Oncology, 362-373 (2022) (“Smith”) -which was provided as an exhibit to Applicant's Declaration - is not prior art to the application and cannot be used to supply a data point for comparison to Applicant's combination therapy data or to in any other way rebut Applicant's showing of unexpected results. Reply at page 32.
Examiner Response
Smith is part of the 1st and 2nd Francis Declaration. While Smith is date excluded as prior art, Smith can be considered in determining whether the proffered results are unexpected.
Argument
Applicant argues that if Sandhu-2 is taken as the closest prior art, there can be no dispute that Applicant's achievement of a 16.6-month or 19.5-month median rPFS is entirely unexpected when compared to a 0-month (i.e. refractory) rPFS for the single BRCA-positive prostate cancer patient (patient 86) who was administered niraparib monotherapy. Reply at page 31.
Examiner Response
On balance, one of ordinary skill would expect a percentage of cancer patients will be refractory to treatment; particularly in a difficult-to-treat cancers. Here, the implication is that patient 86 was declared refractory and left study after only 56 days because of a new liver metastasis; that is, the prostate cancer was progressing/metastasizing. Sandhu-2, Appendix page 7, Table 2, last row. One of ordinary skill could reasonably postulate that the disease had progressed to the point where no treatment would be effective.
This single refractory BRCA positive prostate cancer patient is not so significant (data set too small) to imply to one of ordinary skill that all BRCA prostate cancer patients are refractory to niraparib, particular where BRCA MCRP is accepted to be difficult to treat. For example, not every patient non-BRCA prostate cancer patient responded to niraparib, that is Sandhu-2 teaches that nine (43% [95% CI 22–66]) of 21 patients with non-BRCA castration-resistant prostate cancer receiving either 290 mg/day or 300 mg/day had stable disease for a median duration of 254 days. Sandhu-2 at page 890, col. 1. Note also that Sandhu-2 teaches that eight (40% [95% CI 19–64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Sandhu-2 at page 882 (Summary, Findings). Evidencing to one of ordinary skill that niraparib is effective against BRCA-mutant cancers.
Non-Statutory Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
Provisional Non-Statutory Double Patenting Rejection over 17/528,050
Claims 1, 2, 5-17, and 19-33 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over conflicting claims 1, 5, 7 and 8 of 17/528,050 (filed October 26, 2025), published as US 2022/0071980 (2022) for the reasons given the previous Office action as supplemented below. The rejection is provisional because the conflicting claims have not been patented. Conflicting claims 1 and 5 recite:
1. A method of treating metastatic prostate cancer in a human comprising administering niraparib or a salt thereof to the human in an amount of from about 30 mg niraparib /day per day to about 400 mg per day, wherein the human is carrying at least one DNA repair anomaly in a gene selected from the group consisting of BRCA-1 and BRCA-2.
5. The method of claim 1, wherein the prostate cancer is metastatic castration-sensitive prostate cancer or metastatic castration-resistant prostate cancer.
Conflicting claims 1 and 5 differ from instant claim 1 in that: (1) conflicting claim 8 does not recite “a daily dose of about 500 to about 1500 mg/day of abiraterone acetate administered once per day”; and (2) in reciting “treating” versus the instant claim 1 recitation of “managing”. Note that the conflicting claim 1 dosage of niraparib (i.e., 30 mg per day to about 400 mg per day) is the same as instantly claimed.
Instant claim 1 is patentably indistinct from the conflicting claims because one of ordinary skill leaning from conflicting claims 1 and 5 that niraparib is effective for treating BRCA-1 or BRCA-2 metastatic castration resistant cancer with a daily dosage of about 30 mg to about 400 mg of niraparib, is thereafter motivated to practice the instant claim 1 limitation of “a daily dose of about 500 to about 1500 mg/day of abiraterone acetate administered once per day” in order to manage the BRCA-1 or BRCA-2 metastatic castration resistant cancer, in view of the following secondary references:
C. Logothetis et al., 13 The Lancet Oncology, 1210-1217 (2012) (“Logothetis”);
A. Auerbach et al., US 8,822,438 (2014) (“Auerbach”);
NCT01576172, Abiraterone Acetate and Prednisone With or Without Veliparib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer (ClinicalTrials.gov., 2012) (“NCT01576172”); and
NCT02500901, Enzalutamide and Niraparib in the Treatment of Metastatic Castrate-Resistant Prostate Cancer (CRPC), 1-7 (ClinicalTrials.gov., 2015) (“NCT02500901”).
for the same reasons discussed in detail above in the § 103 rejection, thereby meeting each and every limitation of instant claim 1. Instant dependent claims 2, 5-17, and 19-33 are obvious over conflicting claims 1 and 5 in view of the secondary references for the same reasons discussed in detail in the § 103 rejection above.
Applicant’s Argument
Applicant argues the combination of claims 1 and 5 of the '050 Application and Logothetis, Auerbach, NCT' 172, and NCT'901 does not teach or suggest the claimed methods nor does it provide any reasonable expectation of success for the claimed methods. Reply at page 33. Applicant argues that nowhere do the claims of the '050 Application disclose or suggest contemporaneous administration of niraparib with abiraterone acetate for managing mCRPC that is biomarker positive for BRCA-1 or BRCA-2. Logothetis, Auerbach, NCT' 172, and NCT'901 are similarly deficient because these references do not teach or suggest administration of niraparib with abiraterone acetate for managing mCRPC that is biomarker positive for BRCA-1 or BRCA-2. And even if the Office's proposed combination was made, there would have been no reasonable expectation of success that the combination therapy would have been effective in managing the difficult-to-treat mCRPC that is biomarker positive for BRCA-1 or BRCA-2. Reply at page 33.
This argument is not persuasive because the secondary references suggest that abiraterone acetate is an effective treatment for mCRPC. It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose the idea of combining them flows logically from their having been individually taught in the prior art. MPEP § 2144.06 (citing In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (holding that the two claimed types of active agents, GABA-a agonists and angiotensin II receptor blocker, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine); see also, In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Provisional Non-Statutory Double Patenting Rejection over 18/429,778
Claims 1, 2, 5-17, and 19-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over conflicting claims 1-20 of 18/429,778 (filed December 5, 2025, which have not been amended), published as US 2024/0245710 (2024), for the reasons given the previous Office action. The rejection is provisional because the conflicting claims have not been patented. Conflicting claim 1 recites:
Conflicting claim 1. A method for treating a prostate cancer comprising administering to a patient in need thereof a daily dose of about 30 to about 400 mg/day of niraparib administered once per day and a daily dose of about 500 to about 1500 mg/day of abiraterone acetate administered once per day, wherein the patient is biomarker positive for at least one biomarker selected from BRCA-1 or BRCA-2.
Conflicting claim 3. The method according to claim 1, wherein the prostate cancer is metastatic castration-resistant prostate cancer.
Conflicting claim 3 differs from instant claim 1 only in reciting “treating” versus the instant claim 1 recitation of “managing”. Instant claim 1 is patentably indistinct from conflicting claim 3 because the meaning of “treating” encompasses “managing”. See Claim Interpretation above. As such, conflicting claim 3 anticipates instant claim 1. Instant dependent claims 2, 5-17, and 19-33 are obvious over conflicting claims 2-20 because they track the instant claims with similar language and/or are obvious for the reasons given in the § 103 rejection above.
Applicant’s Argument
Applicant disagrees but nonetheless, without reaching the merits of the Office's position, Applicant requests that the Office hold this rejection in abeyance until allowable subject matter has been identified so that an informed decision on double patenting and how to address it may be made. Reply at page 34.
This argument is not persuasive to overcome the double patenting rejection because Applicant did not address the merits of the argument.
Provisional Non-Statutory Double Patenting Rejection over L. Snyder et al., US 15/950,707 (2018)
Claims 1, 2, 5-17, and 19-33 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over conflicting claims 37 and 39 of L. Snyder et al., US 15/950,707 (2018) (filed December 9, 2021), published as US 2018/0296574 (2018). The rejection is provisional because the conflicting claims have not been patented. Conflicting claims 37 and 39 recites:
Conflicting claim 37. A method for managing a prostate cancer comprising orally administering to a patient in need thereof a daily dose of about 30 to about 400 mg/day of niraparib administered once per day and a daily dose of about 500 to about 1500 mg/day of abiraterone acetate administered once per day, wherein the patient is biomarker positive for at least one biomarker selected from BRCA-1, BRCA-2, FANCA, PALB2, CHEK2, BR1P1, HDAC2, and ATM.
Conflicting claim 39. The method according to claim 37, wherein the prostate cancer is hormone-sensitive or castration-resistant prostate cancer.
Conflicting claim 39 differs from instant claim 1 only in reciting additional biomarkers in the alternative. Conflicting claim 37 therefore anticipates conflicting claim 1. Instant dependent claims 2, 5-17, and 19-33 are obvious over conflicting claims 38-44, 48-58, 60-62, and/or 64-77 because they track the instant claims with similar language and/or are obvious for the reasons given in the § 103 rejection above.
Applicant’s Argument
Applicant disagrees but nonetheless, without reaching the merits of the Office's position, Applicant requests that the Office hold this rejection in abeyance until allowable subject matter has been identified so that an informed decision on double patenting and how to address it may be made. Reply at page 34.
This argument is not persuasive to overcome the double patenting rejection because Applicant did not address the merits of the argument.
Terminal Disclaimer
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 J. Zhang 16 Asian Journal of Andrology, 401 (2014) (“Zhang”) comments on this study. Zhang at 404, col. 2; Id, at 405, col. 1.
2 In prostate cancer, certain ETS genes, particularly ERG, are often found to be rearranged with the TMPRSS2 gene, leading to increased expression and potentially contributing to cancer development. Z. Wang et al., 16 Molecular Medicine Reports, 5450-5428 (2017). The TMPRSS2:ERG gene fusion is the most frequent genomic alteration in prostate cancer cases and results in overexpression of the transcription factor ERG, which is present in both early- and late-stage prostate cancer (castration-resistant prostate cancer, CRPC). Wang at page 5451, col. 1.
3 Although not relevant to the § 103 rejection, it is noted here that M. Hussain et al., 36 Journal of Clinical Oncology, 991-999 (2018) (“Hussain”) (published December 20, 2017, and not prior art to the claims) discusses the results of NCT01576172. Hussain teaches that the result of NCT01576172 is that Veliparib and ETS status did not affect response. Hussain at page 991 under “Conclusion”. In this regard, Hussain teaches that there was no statistically significant difference between arms in confirmed PSA RR (arm A, 63.9%; arm B, 72.4%; P = .27), mRR (arm A, 45.0%; arm B, 52.2%; P = .51), or median PFS (arm A, 10.1 months; arm B, 11 months; P = .99; Table 2; Appendix Fig A1A). Furthermore, ETS fusion status did not predict PSA, mRR, or PFS (Appendix Fig A1B). Hussain notes that previous work teaches that in vivo, PARP1 inhibition with veliparib was as effective as castration in preventing tumor growth, and even greater inhibition was achieved with combination veliparib and castration. Hussain a page 992, col. 1. On the basis of these data, Hussain hypothesized that in patients with mCRPC, co-targeting AR and PARP1 would result in a better RR than AAP and the combination would be most effective in patients with ETS fusion–positive tumors. Hussain a page 992, col. 2. But as noted above, this was not the case. Again, it is noted that Hussain is not prior art to the instant claims and thus not available for consideration by one of ordinary skill as of the instant effective filing date.
4 Citing S. Sandhu et al., The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial, S. Sandhu et al., 14 The Lancet Oncology, 882-892 (2013) (“Sandhu-2”). Sandhu-2 is a discussion of NCT00749502, A Study of MK4827 in Participants With Advanced Solid Tumors or Hematologic Malignancies (MK-4827-001 AMS), 1-11 (ClinicalTrials.gov., 2013) (“NCT00749502”).
5 Zhang teaches that this Sandhu phase I study with PARP inhibitor niraparib/MK4827 did not observe associations between loss of PTEN and antitumor activities in sporadic metastatic prostate cancer patients. Zhang at page 402, col. 1 (citing Sandhu-2”).
6 Enzalutamide is known in the art as an androgen receptor ligand-binding domain antagonist. A. Wyatt et al., 2 JAMA Oncology, 1598-1606 (2016) (see page 1599, col. 1).
7 A certain portion of the patient population of metastatic prostate resistant cancer patients will be BRCA1 and BRCA2 positive. Sandhu-2 teaches that many sporadic (non-inherited) cancers (e.g., prostate and high-grade serous ovarian cancers) harbor epigenetic and genetic disruption of genes that are crucial for the homologous recombination pathway, such as BRCA1 and BRCA2. Sandhu at page 883, col. 1.
8 MPEP § 716.02(c) (to establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range (citing In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960)).
9 That is, Sandhu-2 teaches niraparib administration only to BRCA2-positive MCRP patient 86, who was refractory.
10 In prostate cancer, certain ETS genes, particularly ERG, are often found to be rearranged with the TMPRSS2 gene, leading to increased expression and potentially contributing to cancer development. Z. Wang et al., 16 Molecular Medicine Reports, 5450-5428 (2017). The TMPRSS2:ERG gene fusion is the most frequent genomic alteration in prostate cancer cases and results in overexpression of the transcription factor ERG, which is present in both early- and late-stage prostate cancer (castration-resistant prostate cancer, CRPC). Wang at page 5451, col. 1.
11 The HRR+ cohort consisted of patients with either monoallelic or biallelic pathogenic gene alterations in one of the following: ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2; the HRR- cohort included patients who had no detectable alterations in any of these genes. Chi, at page 3340, col. 2.
12 Where per Chi, patients in the HRR+ and HRR- cohorts were randomly assigned in a 1:1 ratio to receive either niraparib 200 mg once daily with abiraterone acetate 1,000 mg once daily plus prednisone 5 mg twice daily (niraparib + AAP group) or placebo + AAP. Treatment was continuous in 28-day cycles until unequivocal clinical progression, unacceptable toxicity, or death. Chi at page 3341, col. 1.
13 The 2nd Francis Declaration explains why the presence of prednisone in the proffered results of Chi and Chi-Annals should be discounted. 2nd Francis Declaration at page 6, ¶ 14.
14 Respecting the rPFS, Chi teaches that the primary end point was radiographic PFS (rPFS), defined as the time from random assignment to the first occurrence of radiographic progression assessed by blinded independent central review or death due to any cause. rPFS was determined by first observation of progression by bone scan (per Prostate Cancer Working Group 3) or progression of soft-tissue lesions by CT or MRI (per RECIST 1.1), with imaging done every 8 weeks for the first 6 months and every 12 weeks after. Chi at page 3341, col. 1.
15 See Applicant’s newly submitted reference in Information Disclosure Statement filed December 02, 2025, “Highlights of Prescribing Information ZYTIGA, Reference ID:2939553, April 2011, pp. 1-22” stating that “ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel” (page 1); “The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival in patients treated with ZYTIGA compared to patients in the placebo arm” (page 15). See also, S Hoy, 73 Drugs, 2077-2091 (2013) “Abiraterone acetate (Zytiga®) is an orally administered, selective inhibitor of the 17a-hydroxylase and C17,20-lyase enzymatic activities of cytochrome P450 (CYP) 17. CYP17 is required for androgen biosynthesis, with androgen receptor signalling crucial in the progression from primary to metastatic prostate cancer. Abiraterone acetate is approved in the European Union and the US, in combination with prednisone or prednisolone, for the treatment of men with metastatic castration-resistant prostate cancer (CRPC). When administered in combination with prednisone in a placebo-controlled, multinational phase III study, abiraterone acetate significantly prolonged overall survival and radiographic progression-free survival (rPFS) in men with metastatic CRPC who had previously received docetaxel”.
16 Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).