DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of metastatic castration-sensitive prostate cancer as the metastatic prostate cancer species and BRCA-1 as the DNA repair anomaly species in the reply filed on 03/24/2025 is acknowledged and maintained.
Priority
The present application is a continuation of U.S. Patent Application No. 16/131,772, filed September 14, 2018, which is a continuation of U.S. Patent Application No. 15/663,082, filed July 28, 2017, which claims the benefit of U.S. Provisional Application No. 62/368,466, filed on July 29, 2016, and U.S. Provisional Application No. 62/369,239, filed on August 1, 2016.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/01/2025 has been considered by the examiner.
Claims Status
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on August 01, 2025. Claims 1-6 and 9-19 are pending. Claims 7-8 are canceled. Claim 6 is withdrawn. Claims 1-5 and 9-19 are examined in accordance to the elected species.
Action Summary
The objection to claims 4, 17 and 18 is maintained.
Claims 1-3, 5, 7-10, and 12-16 rejected under 35 U.S.C. 103 as being unpatentable over Sandhu et al (“Phase I Study of Poly (ADP)-Ribose Polymerase (PARP) Inhibitor MK-4827 (MK) with Antitumour Activity in Sporadic Castration Resistant Prostate Cancer (CRPC)”, Asia-Pacific Journal of Clinical Oncology, 2012, Vol. 8(Supplement 1), pp. 29-34, Abstract 112) in view of Jones et al (J. Med. Chem. 2015, 58, 3302−3314), are withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Mateo et al (N Engl J Med 2015;373:1697-708).
Claims 1-5 and 9-14 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,207,311 B2. Although the claims at issue are not identical, they are not patentably distinct from each other, are maintained.
Claims 1-5 and 9-14 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,986,470 B2. Although the claims at issue are not identical, they are not patentably distinct from each other, are maintained.
Claims 1-5 and 9-14 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,992,486 B2. Although the claims at issue are not identical, they are not patentably distinct from each other, are maintained.
Claims 1-5 and 9-14 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 18/466,547(reference application), are maintained.
Claim Objections
Claims 4, 17 and 18 are objected to because of the following informalities: the recitation of oral dosage forms in the claims implies multiple oral dosage forms. It is not clear how one can administer multiple oral dosage forms once daily. Appropriate correction is required.
Applicant’s argument
Applicant argues that the specification explains that the recited doses can be administered using 100 mg oral dosage forms: A therapeutically effective amount of niraparib or a pharmaceutical composition thereof for the treatment of prostate cancer includes a dose range from about 30 mg/day to about 400 mg/day of niraparib, or any particular amount or range therein, in particular about 300 mg/day, and once daily oral administration in three 100 mg oral dosage forms. (Application, at page 13, lines 14-17). In addition, those of skill in the art would be familiar with using one, two, or three dosage forms, each containing 100 mg of niraparib or the salt thereof, to administer 100 mg, 200 mg, or 300 mg niraparib or the salt thereof. Accordingly, claims 4, 17, and 18 would be clear to those of skill in the art in view of the general knowledge in the art and in view of the specification.
Examiner’s response
In response, Applicant’s argument is not persuasive. It may well be true that those of skill in the art would be familiar with using one, two, or three dosage forms, each containing 100 mg of niraparib or the salt thereof, to administer 100 mg, 200 mg, or 300 mg niraparib or the salt thereof. However, the Examiner contends that administer 100 mg, 200 mg, or 300 mg niraparib or the salt thereof using one, two, or three dosage forms, each containing 100 mg of niraparib or the salt thereof, is not in the claim. Again, the claimed language niraparib or a salt thereof is administered orally, once daily, in 100 mg oral dosage forms is not clear how one can administer niraparib or salt thereof 30 mg per day orally, once daily, in 100 mg oral dosage. Moreover, oral dosage forms encompass tablet, capsule, solution, syrup, and suspension. Therefore, it is unclear how one can administer 300 mg niraparib or a salt thereof each in a 100 mg tablet, a 100 mg solution, and 100 mg capsule.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The recitation of about 30 mg per day to about 400 mg per day renders the claim indefinite because it is not clear how the lower limit and the upper limit establish the boundaries of the range. The term “about” is not defined in the specification. As such, the specification does not provide a stander for ascertain the requisite degree, and one of ordinary skill in the art would not reasonably apprise of the scope of claimed range.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 5, 9, 10, and 12 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The broad recitation “… the prostate cancer….” of claims 5, 9, 10, and 12, all of which depend from claim 1, does not further limit the narrow metastatic prostate cancer recited in the independent claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 5, 9-10, and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Sandhu et al (“Phase I Study of Poly (ADP)-Ribose Polymerase (PARP) Inhibitor MK-4827 (MK) with Antitumor Activity in Sporadic Castration Resistant Prostate Cancer (CRPC)”, Asia-Pacific Journal of Clinical Oncology, 2012, Vol. 8(Supplement 1), pp. 29-34, Abstract 112) in view of Jones et al (J. Med. Chem. 2015, 58, 3302−3314) and Mateo et al (N Engl J Med 2015;373:1697-708).
Sandhu suggests that MK4827 (a.k.a. niraparib) “is an oral, potent, dual PARP 1/2 inhibitor with promising antitumor activity and favorable toxicity in BRCA1/2 mutant carriers. (See 1st paragraph.) Sandhu also discloses human patients having metastatic castration resistant prostate cancer were treated with daily oral administration of 100 mg, 200 mg or 300 mg MK4827 (niraparib) in combination with enzalutamide to a human patient. (See 2nd paragraph.) Treatment resulted in "[n]ine out of 21 patients had durable symptomatic benefit with disease stabilization for a median duration of 254 days … Seven of the 10 CRPC patients with evaluable CTC [circulating tumor cells] counts of >5 cells/7.5 ml blood at baseline had declines of between 29% and 92% [i.e., evidence of effectiveness against metastatic CRPC cells] ...Durable clinic benefit and CTC declines were observed in all molecular subgroups.” (See 3rd paragraph.) Sandhu concludes that MK4827 “was well tolerated with evidence of target modulation and promising antitumor activity of sporadic CRPC.” (See last paragraph.) The patient population also includes patient with ongoing androgen deprivation therapy. (See Inclusion Section.) While Sandhu does not expressly teach BRCA1/2 is a NDA repair anomaly which is a homozygous deletion, heterozygous deletion plus deleterious mutation, copy neutral loss of heterozygosity plus deleterious mutation, or mono-allelic deleterious mutation in the kinase catalytic domain, the instant specification and the election of BRCA-1/2 as the elected DNA repair anomaly species are taken as evidentiary that BRCA1/2 is a NDA repair anomaly which is a homozygous deletion, heterozygous deletion plus deleterious mutation, copy neutral loss of heterozygosity plus deleterious mutation, or mono-allelic deleterious mutation in the kinase catalytic domain.
Sandhu does not teach the metastatic prostate cancer harbors BRCA-1 or BRCA-2 and the metastatic prostate cancer is castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer. Moreover, Sandhu does not teach administering niraparib in the amount of about 30 mg to about 400 mg per day and 50 mg per day. Furthermore, Sandhu does not teach the prostate cancer human has been exposed to at least one line of enzalutamide-, apalutamide-, or abiraterone acetate-based antiandrogen therapy.
Jones teach Niraparib, a poly (ADP-ribose) polymerase (PARP) Inhibitor for the treatment of tumors with defective homologous recombination. (See Tittle.) Jones describes the selective killing of BRCA1 or BRCA2 deficient tumor cells by PARP inhibitors. In contrast, normal cells with an intact BRCA pathway are viable when treated with a PARP inhibitor, and minimal cytotoxicity is seen. BRCA1 and BRCA2 are known tumor suppressors and are key components involved in the repair of DNA double-strand breaks by HR, and mutations in these genes predispose individuals to hereditary breast and ovarian cancer. It has also been shown that BRCA1/2 mutations have been found in prostate, pancreatic, and other types of cancer. (See last paragraph of the right column of page 3303.) Jones further teaches niraparib demonstrated clinical validation of its mechanism of action and pharmacological properties amenable to once daily administration and resulted in significant antitumor activity in germline BRCA1 mutation (gBRCAmut) and sporadic cancers within a large therapeutically effective dosing window (60−300 mg/day). (See first paragraph of left column of page 3311.)
Mateo teaches metastatic castration-resistant prostate cancers with DNA-repair defects can respond to poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibition with Olaparib. (See Abstract.) Moreover, Mateo teaches metastatic castration-resistant prostate cancer can have genomic aberrations that interfere with DNA repair and some of these aberrations have been associated with sensitivity to platinum and poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors, suggesting that treatment with a PARP inhibitor may exploit a synthetic lethal interaction. (See second paragraph of the left column of page 1698) Mateo teaches some patient with metastatic castration-resistant prostate cancer have somatic homozygous deletion of both BRCA1 and FANCA, had a response with a reduction in the circulating tumor-cell count from 12 to 0 cells per 7.5 ml. (See third paragraph of the left column of page 1704.) The patient that was treated with the poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors, Olaparib had received abiraterone or enzalutamide. (See the results section of the Abstract.) Mateo further teaches PARP inhibition has durable antitumor activity in men with metastatic, castration-resistant prostate cancer and deleterious germline BRCA2 mutations, a disease subset associated with a poor prognosis. (See third paragraph of the left column of page 1698).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer niraparib in the amount of about 50 mg to about 300 mg per day for treating mCRPC in a patient carrying BRCA-1/2 genetic lesion or anomaly that is homozygous deletion to a human subject that has been exposed to enzalutamide or apalutamide. to give Applicant’s claimed method. One would have been motivated to do so, because not only Sandhu suggests MK-4827, as an oral, potent, dual PARP 1/2 inhibitor with promising antitumor activity and favorable toxicity in BRCA1/2mutant carriers, but also because Jones clearly provides the efficacy and pharmacokinetics advantage for 60-300 mg/day in sporadic castration resistant prostate cancer (CRPC) and also because Mateo teaches PARP inhibition has durable antitumor activity in men with metastatic, castration-resistant prostate cancer and deleterious germline BRCA2 mutations, a disease subset associated with a poor prognosis suggest that and teaches Maateo some patient with metastatic, castration-resistant prostate cancer have somatic homozygous deletion of both BRCA1 and FANCA, had a response with a reduction in the circulating tumor-cell count from 12 to 0 cells per 7.5 ml and the patient that was treated with the poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors, Olaparib had received abiraterone or enzalutamide. One would reasonably expect the treatment of mCRPC in a patient carrying BRCA-1/2 genetic lesion or anomaly niraparib with about 50 mg to about 300 mg per day to be successful.
Acknowledgement is made of the receipt and entry of Applicant filed on August 01, 2025
Applicant’s argument
Applicant argues that Sandhu does not teach or suggest the use of niraparib for treating metastatic prostate cancer in a human carrying at least one DNA repair anomaly in a gene selected from BRCA-1 or BRCA-2. The loss of PTEN function/increased ERG expression characterized by Sandhu in its treated population is not the same as DNA repair anomaly in a gene selected from BRCA-1 or BRCA-2. Sandhu's statement in its "Background" section that MK4827 is an "oral, potent, dual PARP1/2 inhibitor with promising antitumor activity and favorable toxicity in BRCA1/2 mutant carriers," is nothing more than speculation. Sandhu is silent regarding treatment of any prostate cancer patients with Sandhu does not identify the Phase I study by any clinical trial identifier. As such, it is not clear to which clinical trial Sandhu refers. Moreover, Sandhu falls short of demonstrating actual treatment of men with metastatic prostate cancer. Sandhu describes preliminary safety and symptomatic data along with anti- tumor activity in circulating tumor cells (CTCs) and companion biomarker data. Said differently, there is no reason to believe that those of skill in the art would have viewed Sandhu as demonstrating an actual treatment for metastatic prostate cancer, even less for metastatic prostate cancer with BRCA alterations, nor is there any reason to believe that a skilled artisan would have had a reasonable expectation that niraparib would ever represent an actual treatment for the disease.
Examiner’s response
In response, Applicant’s argument is not persuasive. Contrary to Applicant’s assertion that Sandhu does not teach or suggest the use of niraparib for treating metastatic prostate cancer in a human carrying at least one DNA repair anomaly in a gene selected from BRCA-1 or BRCA-2. Sandhu clearly teaches Phase I Study of a Poly (ADP)-ribose Polymerase (PARP) inhibitor MK-4827 (MK) with antitumor activity in sporadic castration resistant phosphate cancer (CRPC). (See Title.) Moreover, Sandhu teaches twenty-one CRPC patients (median age: 67 years; ECOG PS 0–1, Gleason score: 7–9) were treated. Nine out of 21 patients had durable symptomatic benefit with disease stabilization for a median duration of 254 days (range: 124 to 375). Median baseline circulating tumor cells (CTC) counts were 11 (range: 0 to 730) and the Spearman correlation coefficient for the two baseline CTC samples was 0.9202, p < 0.0001. Seven of the 10 CRPC patients with evaluable CTC counts of >5 cells/7.5 ml blood at baseline had declines of between 29% and 92%. Durable clinic benefit and CTC declines were observed in all molecular subgroups. (See Abstract.) Therefore, Sandhu clearly teaches that MK in the amount of 300 mg daily exhibits a decline in CTC in patient with CRPC with a baseline CTC counts of >5 cells/7.5 ml, where CRPC with a baseline CTC counts of >5 cells/7.5 ml indicates cancer metastasis and is associated with a significantly poorer prognosis, shorter survival, and higher likelihood of disease progression in patients with metastatic cancers. Moreover, Sandhu does not expressly teach the use niraparib for treating metastatic prostate cancer in a human carrying at least one DNA repair anomaly in a gene selected from BRCA-1 or BRCA-2. However, the background of Sandhu clearly suggests to use MK4827 (MK) is an oral, potent, dual PARP 1/2 inhibitor with promising antitumor activity and favorable toxicity in BRCA1/2mutant carriers. PTEN loss and ETS gene rearrangements have been shown to confer hypersensitivity to PARP inhibition in preclinical models. Mateo further teaches PARP inhibition has durable antitumor activity in men with metastatic, castration-resistant prostate cancer and deleterious germline BRCA2 mutations, a disease subset associated with a poor prognosis. (See third paragraph of the left column of page 1698). Therefore, a person of ordinary skill in the art reading Sandhu would expect MK-4827 as an oral potent dual PARP1/2 inhibitor to treat metastatic castration prostate cancer that harbors deleterious germline BRCA2 mutations with success.
Applicant’s argument
Applicant argues example 5 provides a multicenter open-label phase II study designed to assess a 300 mg once-daily dose of niraparib in prostate cancer patients whose disease has progressed despite at least one line of taxane-based chemotherapy and at least one line of antiandrogen therapy. In particular, Example 5 and Exhibit A (the GALAHAD trial Press Release 2019, hereinafter "Exhibit A," copy enclosed) shows that treatment with niraparib in prostate cancer patients with BRCA1/2 mutations achieved a 38% objective response rate and a 62% composite response rate and median progression free survival of greater than 6 months. (Exhibit A first and third paragraphs). These results are significantly better than expected for patients of this type administered currently available therapies (typically 15% objective response rate and 3 months progression free survival) (Exhibit A, paragraph spanning pages 1 and 2). Moreover, by comparison, treatment with niraparib in prostate cancer patients without BRCA mutations led to stable disease in 43% of patients: see the results section of Michie et al., 2013 (hereinafter "Exhibit B," copy enclosed). These promising preliminary results suggest that niraparib could play an important role in treatment of prostate cancer patients and led to the U.S. Food and Drug Administration (FDA) awarding "breakthrough therapy" designation to niraparib. See Press Release 2 (hereinafter "Exhibit C," copy enclosed). As Press Release 2 notes, "[t]he criteria for Breakthrough Therapy Designation require preliminary clinical evidence that demonstrates the drug may have Page 8 of Il substantial improvement on at least one clinically significant endpoint over available therapy." (Exhibit C, at para. 1, emphasis added). Altogether, these studies - and the resulting breakthrough therapy designation from the FDA - demonstrate an unexpected clinical benefit from administering niraparib to patients with metastatic prostate cancer and a DNA repair anomaly. Moreover, the magnitude of these benefits (38% vs. 15% objective response rates and >6 months vs. 3 months progression free survival), could not have been reasonably expected from Sandhu and Jones. Additionally, there had been a significant unmet need for treatment of metastatic prostate cancer with mutations in DNA-repair genes. Kiran Patel, M.D., Vice President, Clinical Development, Solids Tumors, Janssen Research & Development, LLC, stated that "Niraparib is a PARP inhibitor that we believe may help address an important unmet need for patients with metastatic castration-resistant prostate cancer who have mutations in DNA-repair genes." (Exhibit C, at para. 3, emphasis added). This sentiment is echoed in Smith et al, Lancet Oncol. 2022 March; 23(3): 362-373; hereinafter "Exhibit D" copy enclosed), which stresses that "[t]he activity of niraparib in the measurable BRCA cohort is notable given the heavily pretreated end- stage patient population with few therapeutic options." (Exhibit D, at p. 370, column 1, paragraph 2, emphasis added). Those of ordinary skill in the art would have had no reasonable expectation of success at treating metastatic prostate cancer in a human carrying at least one DNA repair anomaly in a gene selected from BR CA-1 and BRCA-2 from the disclosures of Sandhu and Jones because they would have concluded from the combination of these references that patients with metastatic prostate cancer and carrying a mutation in the BRCA-1 or BRCA-2 gene were not responding to niraparib.
Examiner’s response
In response, Applicant’s argument is not persuasive. The Examiner acknowledges and considers Exhibits A-D and the result in Example 5. Example 5 of the instant specification is a multicenter, open-label study that assesses the efficacy and safety of once daily dosing of 300 mg niraparib that is provided as (3 X 100 mg) capsules for once daily. However, no results were shown. Exhibit A highlighted that approximately 40 percent patients with metastatic castration resistant prostate cancer with BRCA1/2 receiving treatment with niraparib (300 mg daily) from the ongoing Phase 2 Galahad study. The Exhibits and example 5 may well demonstrate treating metastatic prostate cancer in a human carrying at least one DNA repair anomaly in a gene selected from BR CA-1 and BRCA-2 is achieved by the administration a once daily dosing of 300 mg niraparib that is provided as (3 X 100 mg) capsules. However, the Examiner contends such unexpected results are not commensurate in scope with the claims. Specifically, the claim broadly recites treating metastatic prostate cancer that harbors at least one DNA repair anomaly in a gene selected from BR CA-1 and BRCA-2, broadly recites an amount of from about 30 mg per day to about 400 mg per day, and broadly recites any route of administration. In contrast, the data presented in the asserted unexpected result requires the administration to be capsules, the amount to be 3 (100 mg capsules) once daily, the metastatic prostate cancer to be metastatic castration prostate cancer or metastatic resistant prostate cancer. Moreover, the asserted unexpected results would have been expected by the fact that Sandhu clearly teaches that MK in the amount of 300 mg daily exhibits a decline in CTC in patient with CRPC with a baseline CTC counts of >5 cells/7.5 ml, where CRPC with a baseline CTC counts of >5 cells/7.5 ml indicates cancer metastasis and is associated with a significantly poorer prognosis, shorter survival, and higher likelihood of disease progression in patients with metastatic cancers. Moreover, Sandhu does not expressly teach the use niraparib for treating metastatic prostate cancer in a human carrying at least one DNA repair anomaly in a gene selected from BRCA-1 or BRCA-2. Sandhu clearly suggests to use MK4827 (MK) is an oral, potent, dual PARP 1/2 inhibitor with promising antitumor activity and favorable toxicity in BRCA1/2mutant carriers. PTEN loss and ETS gene rearrangements have been shown to confer hypersensitivity to PARP inhibition in preclinical models. Mateo teaches PARP inhibition has durable antitumor activity in men with metastatic, castration-resistant prostate cancer and deleterious germline BRCA2 mutations, a disease subset associated with a poor prognosis. Therefore, a person of ordinary skill in the art reading Sandhu would expect MK-4827 as an oral potent dual PARP1/2 inhibitor to treat metastatic castration prostate cancer that harbors deleterious germline BRCA2 mutations with success.
Claims 4, 11, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Sandhu et al (“Phase I Study of Poly (ADP)-Ribose Polymerase (PARP) Inhibitor MK-4827 (MK) with Antitumour Activity in Sporadic Castration Resistant Prostate Cancer (CRPC)”, Asia-Pacific Journal of Clinical Oncology, 2012, Vol. 8(Supplement 1), pp. 29-34, Abstract 112; previously cited) in view of Jones et al (J. Med. Chem. 2015, 58, 3302−3314) and Mateo et al (N Engl J Med 2015;373:1697-708). as applied to claims 1-3, 5, 9-10, and 12-16, in further view of Foley et al (WO2009/087381 A1) and Giuseppe et al (Nature Communications, volume 5, Article number: 5548 (2014)).
The teachings of Sandhu, Jones, and Mateo have been discussed supra.
With respect to claims 4 and 17-19, Sandhu, Jones, and Mateo collectively do not teach 100 mg oral dosage form.
Foley teaches pharmaceutically acceptable salts of 2-{4-[(3s)-piperidin-3- yl] phenyl} -2h-indazole-7-carboxamide useful as mono-therapies in tumors with specific defects in DNA-repair pathways and as enhancers of certain DNA -damaging agents such as anticancer agents and radiotherapy. (See Title and Abstract.) This compound is the same as niraparib. Moreover, PARP inhibitors have been demonstrated as being useful for the specific killing of BRCA- 1 and BRCA-2 deficient tumors. (See page 2, lines 24-26.) Foley also teaches the compound can be formulated into a tablet or a capsule. (See lines 5-15.) This entails an oral dosage form or oral dosage forms. Additionally, Foley teaches a suitable dose of the compound is in the range of about 0.1 mg (100 µg) to about 250 mg per kilogram body weight of the subject per day. (See lines 1-2.) 0.1 mg/kg to 250 mg/kg for a 70-kg patient can result in 7 mg to 17,500 mg. Furthermore, Foley teaches a synergistic combination of the present compounds and another anticancer agent might allow the use of lower dosages of one or both of these agents and/or less frequent dosages of one or both of the instant compounds and other anticancer agents and/or to administer the agents less frequently can reduce any toxicity associated with the administration of the agents to a subject without reducing the efficacy of the agents in the treatment of cancer. In addition, a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side effects associated with the use of either agent alone. (See page 20, lines 5-13.)
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to formulate the daily oral administration of 100 mg, 200 mg, or 300 mg MK4827 taught by Sandhu in to a 100 mg-tablet or a 100 mg-capsule to give Applicant’s claimed invention. The motivation to do so is taught by Foley in order to adjust the amount as needed to tailor the treatment to the individual patient. For example, the dose would be adjusted to minimize toxicity, while maximizing therapeutic effect as taught by Foley.
The determination of the unit dosage amount of any particular pharmaceutical active agent is well within the capabilities of one of ordinary skill in the art. Factors controlling the unit dosage size of an agent include, for example, the dosage form (e.g., tablet, capsule, etc.), the amount of the carrier(s) needed for a particular dosage form, which determines the size of the dosage form (and thus the ability to swallow said dosage form), and the commercial availability of the formulated active agent. For instance, if niraparib were commercially available only as a 100 mg capsule, it would be obvious to give three capsules to achieve the desired dose of 300 mg/day. Applicants have presented no teaching of the criticality for the administration of niraparib as three 100 mg oral dosage forms once daily.
With respect to claim 11, Sandhu, Jones, and Mateo collectively do not teach the human has had at least one line of taxane- based chemotherapy.
Giuseppe teaches Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. (See Abstract.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the obvious method taught by Sandhu, Jones, and Mateo by including a human patient that has had at least one line of taxane-based chemotherapy to give Applicant’s claimed method. One would have been motivated to do so, because Giuseppe teaches Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. One would reasonably expect the inclusion of the obvious method taught by Sandhu and Jones to effectively and successfully treat mCRPC in a patient carrying BRCA-1/2 genetic lesion or anomaly niraparib and mCRPC that is resistant to taxane-based therapy.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s argument
Applicant argues Foley's and Giuseppe's disclosures do not cure the deficiencies of Sandhu and Jones with respect to claim I because Foley and Giuseppe do not teach or suggest treating metastatic prostate cancer in a human carrying at least one DNA repair anomaly in a gene selected from BRCA-1 and BRCA-2, claims 1-5 and 8-19. Because Sandhu, Jones, Foley, and Giuseppe do not teach or suggest treating metastatic prostate cancer in a human carrying at least one DNA repair anomaly in a gene selected from BRCA-1 and BRCA-2, claims 1-5 and 8-19 are not obvious over Sandhu, Jones, Foley, and Giuseppe.
Examiner’s response
In response, Applicant’s argument is not persuasive. It may well be true that Foley's and Giuseppe's disclosures do not cure the deficiencies of Sandhu and Jones with respect to claim I because Foley and Giuseppe do not teach or suggest treating metastatic prostate cancer in a human carrying at least one DNA repair anomaly in a gene selected from BRCA-1 and BRCA-2. However, the Examiner contends that Foley's and Giuseppe's disclosures are not cited in the rejection for such purpose. Foley and Giuseppe were cited to address the limitation of 100 mg oral dosage form and the recitation of the human has had at least one line of taxeme- based chemotherapy.
Double Patenting
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).
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.
Claims 1-5 and 9-14 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,207,311 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The U.S. patent claims teach a method of treating prostate cancer in a human in need of such treatment comprising administering to the human a safe and effective amount of niraparib or a salt thereof, wherein the prostate cancer is antiandrogen resistant and wherein the human (a) is not BRCA deficient or (b) is carrying at least one DNA repair anomaly selected from the group consisting of FANCA, PALB2, CHEK2, BRIP1, HDAC2, and ATM, wherein the prostate cancer is castration-resistant prostate cancer, wherein the human is carrying at least one DNA repair anomaly selected from the group consisting of FANCA, PALB2, CHEK2, BRIP1, HDAC2, and ATM, wherein the human is not BRCA deficient, wherein the prostate cancer is metastatic castration-resistant prostate cancer. (See claims 1-5.) The U.S. patent claims also teach niraparib or a salt thereof is administered orally, once daily, in 100 mg niraparib oral dosage forms. (See claim 8.) The U.S. patent claims teach a method of treating castration- and antiandrogen-resistant prostate cancer in a human comprising administering niraparib or a salt thereof in 100 mg niraparib oral dosage forms once daily to the human, wherein the human is (a) not BRCA deficient or (b) is carrying at least one DNA repair anomaly selected from the group consisting of FANCA, PALB2, CHEK2, BRIP1, HDAC2, and ATM, wherein the human has had at least one line of taxane-based chemotherapy, wherein the prostate cancer has been exposed to at least one line of enzalutamide-, apalutamide-, or abiraterone acetate-based chemotherapy, and niraparib or a salt thereof is administered in an amount of from about 30 mg niraparib/day to about 400 mg niraparib/day. (See claims 9-23.)
The U.S. patent claims anticipate the instant claims.
Claims 1-5 and 9-14 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,986,470 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The U.S. patent claims teach a method of treating metastatic castration-sensitive prostate cancer in a human in need of such treatment comprising administering to the human a safe and effective amount of niraparib or a salt thereof, wherein the prostate cancer is antiandrogen resistant and wherein the human (a) is not BRCA deficient or (b) is carrying at least one DNA repair anomaly selected from the group consisting of FANCA, PALB2, CHEK2, BRIP1, HDAC2, and ATM, wherein the human is carrying at least one DNA repair anomaly selected from the group consisting of FANCA, PALB2, CHEK2, BRIP1, HDAC2, and ATM, wherein the human is not BRCA deficient, wherein the prostate cancer is metastatic castration-resistant prostate cancer. The U.S. patent claims also teach niraparib or a salt thereof is administered orally, once daily, in 100 mg niraparib oral dosage forms. The U.S. patent claims teach a method of treating castration- and antiandrogen-resistant prostate cancer in a human comprising administering niraparib or a salt thereof in 100 mg niraparib oral dosage forms once daily to the human, wherein the human is (a) not BRCA deficient or (b) is carrying at least one DNA repair anomaly selected from the group consisting of FANCA, PALB2, CHEK2, BRIP1, HDAC2, and ATM, wherein the human has had at least one line of taxane-based chemotherapy, wherein the prostate cancer has been exposed to at least one line of enzalutamide-, apalutamide-, or abiraterone acetate-based chemotherapy, and niraparib or a salt thereof is administered in an amount of from about 30 mg niraparib/day to about 400 mg niraparib/day.
The U.S. patent claims anticipate the instant claims.
Claims 1-5 and 9-14 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,992,486 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The U.S. patent claims teach a method of treating castration- and antiandrogen-resistant prostate cancer in a human comprising administering niraparib or a salt thereof in 100 mg niraparib oral dosage forms once daily to the human, wherein the human is (a) not BRCA deficient or (b) is carrying at least one DNA repair anomaly selected from the group consisting of FANCA, PALB2, CHEK2, BRIP1, HDAC2, and ATM, wherein the human has had at least one line of taxane-based chemotherapy, wherein the prostate cancer has been exposed to at least one line of enzalutamide-, apalutamide-, or abiraterone acetate-based chemotherapy, and niraparib or a salt thereof is administered in an amount of from about 30 mg niraparib/day to about 400 mg niraparib/day, wherein the human has had at least one line of taxane-based chemotherapy, wherein the prostate cancer has been exposed to at least one line of enzalutamide-, apalutamide-, or abiraterone acetate-based chemotherapy, and niraparib or a salt thereof is administered in an amount of from about 30 mg niraparib/day to about 400 mg niraparib/day. Treating castration- and antiandrogen-resistant prostate cancer includes metastatic castration-resistant prostate cancer
Claims 1-5 and 9-14 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 18/466,547(reference application). Although the claims at issue are not identical, they are not patentably distinct from each.
The copending claims teach a method of treating metastatic castration-sensitive prostate cancer in a human in need of such treatment comprising administering to the human a pharmaceutically acceptable amount of niraparib or a salt thereof, wherein the human is carrying at least one DNA repair anomaly in a gene selected from the group consisting of BRCA-1, BRCA-2, FANCA, PALB2, CHEK2, and BRIP], wherein the niraparib or a salt thereof is administered in combination with androgen deprivation therapy, wherein niraparib or a salt thereof is administered in an amount of from about 30 mg niraparib/day to about 400 mg niraparib/day, wherein niraparib or a salt thereof is administered orally, once daily, in 100 mg niraparib oral dosage forms, wherein the human has had at least one line of taxane-based chemotherapy. The copending claims anticipate the instant claims.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant argues that while Applicant does not necessarily agree with these rejections, a terminal disclaimer to the respective reference patents will be filed when the non-statutory double patenting rejections are the only remaining rejections.
In response, since the non-statutory double patenting rejections are not the only remaining rejections, a terminal disclaimer is required.
Conclusion
Claims 1-5 and 9-19 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628