DETAILED ACTION
This office action is in response to applicant’s filing dated December 5, 2025.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 5, 2025 has been entered.
Status of Claims
Claims 1-22 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed December 5, 2025. Acknowledgement is made of Applicant’s addition of new claims 21 and 22.
Information Disclosure Statement
The information disclosure statement filed May 5, 2025 and December 5, 2025 fail to comply with the provisions of 37 CFR 1.98(a)(4) because they lack the appropriate size fee assertion. Moreover, they fail to comply with the provisions of 37 CFR 1.97(a) because they lack the appropriate size fee set forth in 37 CFR 1.17(v). It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Response to Arguments
Applicant argues:
IDS size fee was not applicable for the submission filed May 5, 2025.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The Examiner acknowledges that the IDS filings prior to effective date of the IDS size fee rule had already exceeded 200 citations. Thus, no fee is required for the IDS that predates the effective date of the final rule. However, the IDS submission of May 5, 2025 would bring the cumulative count of items above 200 and includes a count of items above 200 in said IDS submission. Thus, an IDS fee in §1.17(v)(3) applies.
Maintained Objections and/or Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 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. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described in /n re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are (1) the nature of the invention, (2) the breadth of the claims, (3) the state of the prior art, (4) the predictability or unpredictability of the art, (5) the amount of guidance or direction presented, (6) the presence or absence of working examples, (7) the relative skill in the art and (8) the quantity of experimentation necessary. When the above factors are taken into consideration, the examiner's position is that one skilled in the art could not perform the invention commensurate in scope with the instant claim without undue experimentation.
Briefly, the instant claims are drawn to a method for treating a prostate cancer comprising administering to a patient in need thereof a daily dose of niraparib, a daily dose of abiraterone acetate and a therapeutically effective amount of prednisone. The present specification defines “treating” as:
[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.
As defined by the present specification, “treating” is inclusive of eradication or removal of prostate cancer, which is interpreted to mean that the disease will entirely cease to manifest after administration of the compound, i.e., cure. Applicant has not demonstrated curing of prostate cancer in-vitro or even in a mouse/rat model in order to provide some reasonable nexus between the compounds instantly claimed and curing of prostate cancer.
While the Applicants might be enabled for treatment, the Applicants are not enabled for curing prostate cancer in vitro or in vivo. The high degree of unpredictability associated with the claimed method underscores the need to provide teachings in the specification that would provide the skilled artisan with specific treatment regimens that achieve a therapeutic benefit; however, the specification does not provide such guidance and fails to provide evidence that the instantly claimed compounds actually cures any disease. Without such guidance in the specification and the lack of correlative working examples, the claims would require an undue experimentation without a predictable degree of success on the part of the skilled artisan.
Response to Arguments
Applicant argues:
As noted by the Office, 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." Because the definition of treating includes eradication or removal, or modification, or management, or control of prostate cancer, Applicant need not demonstrate a "cure" for prostate cancer, as the Office alleges. Moreover, the specification, at Example 2, details a method falling within the scope of claim 1 and recites "[t]he combination of niraparib and abiraterone showed the most dramatic inhibition of tumor growth from days 37-55(ranging38%-58%),when compared with the vehicle control group." (Application, at para. [0096]). Accordingly, Applicant's specification includes sufficient description of a method falling within the scope of the claims that would enable those of skill in the art to practice the claimed method without undue experimentation.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As noted by Applicant, the scope of the definition of treating encompasses eradication and removal. While the instant claims may be enabled for a method of managing a prostate cancer, the claims are not enabled for eradicating, removing, or otherwise curing prostate cancer in vitro or in vivo. The Examiner acknowledges that Example 2 does support inhibiting prostate tumor growth, the Example does not support the full scope of the instantly claimed method in view of Applicant’s definition of the terms “treat,” “treating,” and “treatment”. Thus, the rejection is maintained.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-22 are rejected under 35 U.S.C. 103 as being unpatentable over NCT01576172 (ClinicalTrials.gov., 2012, cited in the IDS filed April 10, 2024), Logothetis et al. (Lancet Oncol, 2012; 13:1201-1217, cited in the IDS filed April 10, 2024), Zhang (Asian J. of Andrology, 2014; 16:401-406, cited in the IDS filed April 10, 2024), Sandhu et al. (Asia-Pac J. Clin. Oncol., 2012; 8(suppl 1):29-34, cited in the IDS dated April 4, 2024) and NCT02500901 (ClinicalTrials.gov., 2015, cited in the IDS filed April 10, 2024) in combination.
NCT‘172 teaches the treatment of patients with metastatic castration-resistant prostate cancer with abiraterone acetate, prednisone and veliparib (See page 3, Experimental: Arm Il).
Logothetis et al. teaches patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, abiraterone acetate and prednisone offer significant benefits in terms of pain relief, delayed pain progression, etc. (See the entire article, especially Interpretation, page 1210; Discussion, pages 1215-1216). The reference teaches 28-day cycles of orally administered 1g abiraterone acetate in combination with 5mg of prednisone (see page 1211, Methods).
Zhang teaches the use of PARP inhibitors, such as, niraparib in the treatment prostate cancer, including those with BRCA1 or BRCA2 mutation (see the entire article, especially paragraph bridging pages 401-402; page 405, Conclusions). The reference also notes
the phase II study of NCT015761 72 involving the combination of abiraterone acetate, prednisone and veliparib as discussed above and cancer cells with defective homologous recombination repair are sensitive to additional blockage of DNA repair with PARP inhibitor (see the entire article, especially paragraph bridging pages 401-402; page 404, Combining the PARP inhibitor with androgen deprivation therapy; page 405, Conclusions).
Sandhu et al. teaches the use of 300 mg of PARP inhibitor niraparib orally in the treatment of castration resistant prostate cancer and that the compound have favorable toxicity in BRCA1/2 mutant carriers (see the entire article, especially Background and Methods).
NCT’901 teaches the use of 160 mg/day orally of enzalutamide and 100 mg or 200 mg or 300 mg daily niraparib in the treatment of metastatic castrate-resistant prostate cancer (see the entire article, especially page 3, Experimental: Experimental Treatment).
In essence, the art, as exemplified by the cited references, teaches the use of each of niraparib (100 mg, 200 mg or 300 mg), abiraterone acetate and prednisone for the treatment of metastatic castration-resistant prostate cancer.
The instant invention differs from the references by reciting the combination of niraparib, abiraterone acetate and prednisone for treatment of prostate cancer.
However, combination therapy for the treatment of prostate cancer is well-known in the medical art as evidenced by NCT’172, Logothetis, Zhang and NCT’901 discussed above. NCT’172 teaches the combination of a PARP inhibitor (veliparib), an androgen deprivation therapy (abiraterone acetate) and prednisone. Niraparib, like veliparib, is a known PARP inhibitor useful in treating prostate cancer. Therefore, the use of niraparib, instead of veliparib, in combination with abiraterone acetate and prednisone for treatment of prostate cancer is rendered prima facie obvious.
Additionally, as recognized by MPEP § 2144.06(I):
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Each of niraparib, abiraterone acetate and prednisone is known in the art, as evidenced by the cited prior art, for treatment of prostate cancer. Thus, the combination of niraparib, abiraterone acetate and prednisone to provide treatment of prostate cancer to a patient in need of treatment would have been prima facie obvious to the skilled artisan in the art at the time of the present invention. As noted above, the idea to combine flows logically from their having been individually taught in the prior art for treatment of the same disorder(s).
As noted by Sandhu et al. and Zhang, PARP inhibitors show favorable toxicity in BRCA1/2 mutant carriers or cancer cells with defective homologous recombination repair are sensitive to additional blockage of DNA repair with PARP inhibitor. Therefore, the skilled artisan in the art at the time of the present invention would have the reasonable expectation that the combination of a PARP inhibitor, such as, niraparib, with abiraterone acetate and prednisone would be more effective in treating prostate cancer with BRCA-1 and/or BRCA-2 mutation.
The instant claims further differ from the cited references by reciting (i) the use of various amounts of each compound (see instant claims 1 and 15-20, (ii) the administration of the compounds in a single composition or in separate compositions (see instant claims 5, 6, 13 and 14), (iii) wherein the patient underwent taxane-based chemotherapy or androgen receptor-targeted therapy prior to administration of niraparib and abiraterone acetate (see instant claims 11 and 12).
However, as evidenced above, the art teaches various amounts of niraparib in the amounts of 100 mg, 200 mg and 300 mg and Logothetis teaches 1g abiraterone acetate are useful in treating prostate cancer. In addition, determining the treatment regimen, for example, amount of each compound in combination or administration once or twice, etc. daily, that would result in optimum treatment of prostate cancer in a patient would have been within the level of skill of the ordinary artisan in the medical art at the time of the present invention. The court has held that merely selecting proportions and ranges is not patentable absent a showing of criticality. /n re Russell, 439 F.2d 1228, 169 USPQ 426 (CCPA 1971);
the administration of the active agents in a combination therapy as a single composition or separately is routinely done in the medical art (see for example, WO 2012/009475, paragraph 0143; WO 2014/089324, paragraph 0134); and as evidenced by Logothetis et al., patients with metastatic castration-resistant prostate cancer previously treated with another anticancer therapy, such as, docetaxel (a taxane-based chemotherapy), can be treated with a combination of other anticancer agents. Therefore, absence a showing of criticality, the use of the claimed combination to treat patient previously treated with taxane-based chemotherapy or androgen receptor-targeted therapy is rendered prima facie obvious.
The examiner notes the recitation “improving survival in a patient” or “improving objective response rate in patient” or “improving time to PSA progression in patient” or “inhibiting tumor growth in a patient with prostate cancer” wherein said improvement is relative to a control patient or population of patients who received abiraterone acetate without niraparib (see instant claims 15, 17, 19 and 21). The recitation of the effect of the combination on a patient does not lend patentability to an otherwise obvious treatment method. That is, said effects would flow naturally from the administration of an obvious combination. Determining the effect relative to a control patient or population of patients who received abiraterone acetate without niraparib would require only experimentation which would have been within the level of skill of the ordinary artisan in the art at the time of the present invention.
For the reasons given above, the claimed invention would have been obvious to the skilled artisan in the art at the time of the present invention.
Note: Applicant’s attention is directed to the Board’s decision in parent case 15/950,707.
Response to Arguments
Applicant argues:
NCT ‘172 does not teach or suggest the claimed combination therapy. The office has assumed, without evidence, that PARP inhibitors have interchangeable therapeutic efficacy when administered in combination with another drug. The Office has failed to identify any reason why a person of ordinary skill would have been motivated to modify NCT '172 to substitute veliparib for niraparib. In fact, there is good reason to believe that such a person would not have been motivated to modify the teaching of NCT'172 in the manner that the Office proposes. In the Board’s decision, the board concludes that Zhang provides a direct suggestion to use niraparib in treatment of prostate cancer as it has been experimentally sown to be effective in a form of the disease. Nowhere dose the Board’s decision state that this form of the disease is prostate cancer in patients who are biomarker positive for BRCA1/2. The Board’s decision also states that Sandhu discloses niraparib showed “promising antitumor activity and favorable toxicity in BRCA1/2 mutant carriers. Nowhere does the Board’s decision state that “BRCA1/2 mutant carriers” of Sandhu are prostate cancer patients who are biomarker positive for BRCA1/2.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Applicants are reminded that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As set forth above, combination therapy for the treatment of prostate cancer is well-known in the medical art as evidenced by NCT’172, Logothetis, Zhang and NCT’901 discussed above. NCT’172 teaches the combination of a PARP inhibitor (veliparib), an androgen deprivation therapy (abiraterone acetate) and prednisone. Niraparib, like veliparib, is a known PARP inhibitor useful in treating prostate cancer. Therefore, the use of niraparib, instead of veliparib, in combination with abiraterone acetate and prednisone for treatment of prostate cancer is rendered prima facie obvious.
As noted in the Board decision, Sandhu specifically teaches “MK4827 (MK) [niraparib] is an oral, potent, dual PARP 1/2 inhibitor with promising antitumour activity and favorable toxicity in BRCA1/2 mutant carriers.” The Board concluded that an ordinary artisan, informed that a particular drug has promising activity in patients BRCA 1/2 mutations, would have had reason to select patients with those mutations in particular for treatment with niraparib. The same applies to the instant claims.
Applicant argues:
One of skill in the art would have had no reasonable expectation of success in treating prostate cancer based on NCT ‘172. There is no dispute that NCT'172 is a clinical trial registry posting that provides a proposal to try to administer investigational agents in a Phase II clinical trial. There is also no dispute that NCT’172 includes no data, let alone data supporting efficacy of a PARP inhibitor in combination with abiraterone acetate for the management of prostate cancer. NCT’172 provides no data regarding the efficacy of the investigation drug combination in treating prostate cancer. The skilled person in the art would have been aware that success in prostate cancer was challenging. The lack of unpredictability in the field is borne out by articles reporting outcomes in NCT’172 and NCT’901 publications. Hussain demonstrates how prostate cancer treatment with the planned therapy of NCT172 ultimately failed. Similar evidence of unpredictability in the field of prostate cancer is provided by Hu, which reports on the results of the NCT’901 publication. Together, Hussain and Hu provide strong additional evidence of unpredictability in the field of clinical-stage prostate cancer therapeutics.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
MPEP 2143.02 states:
Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018). In the instant case, as set forth above, NCT’172 teaches the combination of a PARP inhibitor (veliparib), an androgen deprivation therapy (abiraterone acetate) and prednisone. Zhang teaches the use of PARP inhibitors, such as, niraparib in the treatment prostate cancer, including those with BRCA1 or BRCA2 mutation. Sandhu et al. teaches the use of PARP inhibitor niraparib orally in the treatment of castration resistant prostate cancer and that the compound have favorable toxicity in BRCA1/2 mutant carriers. NCT’901 teaches the use of enzalutamide and niraparib in the treatment of metastatic castrate-resistant prostate cancer. As set forth above, combination therapy for the treatment of prostate cancer is well-known in the medical art as evidenced by NCT’172, Logothetis, Zhang and NCT’901 discussed above. NCT’172 teaches the combination of a PARP inhibitor (veliparib), an androgen deprivation therapy (abiraterone acetate) and prednisone. Niraparib, like veliparib, is a known PARP inhibitor useful in treating prostate cancer. Therefore, the use of niraparib, instead of veliparib, in combination with abiraterone acetate and prednisone for treatment of prostate cancer is rendered prima facie obvious.
With regard to the argument that NCT ‘172 provides no data and thus does not provide a reasonable expectation of success for the treatment of mCRPC, the issue is not whether there is data but whether the reference teaches or suggests utilization of a combination of abiraterone acetate, prednisone and a PARP inhibitor (veliparib) for the treatment of patients with metastatic castration-resistant prostate cancer. NCT ‘172 is a “randomized phase Il trial” which “studies abiraterone acetate and prednisone together with veliparib” and it notes that the combination of abiraterone acetate together with prednisone and veliparib may work better than abiraterone acetate and prednisone alone in treating patients with castration-resistant prostate cancer. In essence, it suggests the combination of abiraterone acetate, prednisone and veliparib for treatment of castration-resistant prostate cancer. Because it is a phase II trial, it would be obvious to the skilled artisan that the combination has gone thru phase I trial for the indicated treatment and was found promising. The absence of data does not nullify the suggestion/teaching as clearly set forth by the title and summary of NCT ‘172.
The Examiner notes that in the Board’s decision in parent case 15/950,707 dated February 2, 2023, the board concluded that in view of Zhang’s teachings, including treatments of prostate cancer using a variety of different PARP inhibitor compounds; and specific to the claims which are drawn to niraparib and not veliparib, Zhang teaches that while veliparib had
limited efficacy, Zhang teaches that niraparib had substantial efficacy in a phase I study, the ordinarily skilled artisan would have found it obvious that PARP inhibitors are generally useful treatments for some prostate cancers and would reasonably have found it obvious to use niraparib especially in treatment of CRPC. A "person of ordinary skill has good reason
to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense." Moreover, the board concludes that Zhang provides a direct suggestion to use niraparib in treatment in treatment of prostate cancer as it has been experimentally shown to be effective in a form of the disease.
With regard to the argument that Hussain demonstrates how prostate cancer treatment with the planned therapy of NCT172 ultimately failed. Similar evidence of unpredictability in the field of prostate cancer is provided by Hu, which reports on the results of the NCT’901 publication, this argument has not been found persuasive and has been addressed in the Board decision in the parent case. In particular, the Board concluded that Zhang recognizes that treatment is improved in prostate cancer when PARPl drugs are used to increase DNA double-strand breaks; and Hussain is a post-filing date publication and it has not been established that the information contained within Hussain was available before the effective filing date of the application. Similarly, the Hu reference is a post-filing date publication and it has not been established that the information contained within Hussain was available before the effective filing date of the application. The specification itself does not recognize or suggest that veliparib would not be useful. Thus, Hussain and Hu are not pertinent to the obviousness issue because obviousness is determined on the date when application was filed. Moreover, Hussain does not address niraparib and does not specifically discourage its use.
Applicant argues:
PARP inhibitors were not considered to be interchangeable at the priority date. The person skilled in the art would not have substituted niraparib with veliparib because they would not have viewed PARP inhibitors in cancer treatment as being interchangeable. 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 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 turn, informs the cross- functional team for decision making to the next step. 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. 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. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. 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. Certainly, the skilled person would not have made untested and unsuggested combinations (for example the claimed combination) with an expectation of success.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth above, NCT ‘172 teaches the combination of a PARP inhibitor (veliparib), abiraterone acetate and prednisone. The only difference between NCT ‘172 and the claimed invention is the recitation of niraparib by the claimed invention. However, as shown by Zhang, Sandhu and NCT ‘901, niraparib (which is also a PARP inhibitor) is also useful in treatment mCRPC. Therefore, the utilization of niraparib instead of veliparib in the combination taught by NCT ‘172 for treatment of mCRPC would have been obvious to the skilled artisan in the medical art at the time of the present invention. Moreover, Zhang teaches that while veliparib had limited efficacy, Zhang teaches that niraparib had substantial efficacy in a phase I study, the ordinarily skilled artisan would have found it obvious that PARP inhibitors are generally useful treatments for some prostate cancers and would reasonably have found it obvious to use niraparib especially in treatment of CRPC.
Applicant argues:
Zhang and Sandhu do not teach or suggest the efficacy of niraparib in treating mCRPC patients with BRCA mutations. Zhang is alleged to be relevant for its disclosure that PARP inhibitors such as niraparib can be used to treat prostate cancer patients with BRCA1 or BRCA2 mutations. Zhang also has been alleged to be relevant for its mention of the NCT '172 clinical trial to assess the efficacy of administering veliparib with abiraterone acetate and prednisone. But there is no reason to believe that this disclosure would have led those of ordinary skill to ignore Hussain's teaching that the clinical trial failed to show any benefit in going through the trouble of administering a PAP inhibitor along with abiraterone acetate and prednisone.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As noted in the Board decision, Sandhu specifically teaches “MK4827 (MK) [niraparib] is an oral, potent, dual PARP 1/2 inhibitor with promising antitumour activity and favorable toxicity in BRCA1/2 mutant carriers.” The Board concluded that an ordinary artisan, informed that a particular drug has promising activity in patients BRCA 1/2 mutations, would have had reason to select patients with those mutations in particular for treatment with niraparib. The same applies to the instant claims.
Applicant argues:
Logothetis and NCT '901 do not cure the deficiencies of NCT '172, Zhang or Sandhu. Logothetis and NCT '901 do not counter the combined teachings of NCT '172, Zhang or Sandhu, nor are they alleged to do so. Logothetis describes a post-hoc analysis of data from a Phase III trial for pain control and skeletal-related events with abiraterone acetate and prednisone only versus placebo plus prednisone in mCRPC subjects. Logothetis does not teach or suggest combination of these investigational products with any other therapeutic agents, nor does it speak to any problems that would need to be solved by the combination studies. The Office has not identified any reason to believe that this disclosure would have led those of ordinary skill to administer another investigational product with the abiraterone acetate plus prednisone regimen, much less to administer niraparib specifically with the combination regimen. The Office alleges that NCT '901 “teaches the use of 160 mg/day orally of enzalutamide and 100 mg or 200 mg or 300 mg daily niraparib in the treatment of metastatic castrate-resistant prostate cancer.” But nothing in NCT '901 suggests that niraparib is efficacious in combination therapy with enzalutamide, let alone any other agent. Moreover, NCT '901 suffers from the same shortcomings as NCT '172 insofar as it is a registry posting that provides a proposal to try to administer investigational agents (here niraparib and enzalutamide). Additionally, NCT '901 is a proposal for a Phase I trial with the aim of determining “safety and feasibility of the combination” in subjects with mCRPC. NCT'901 provides no data whatsoever, least of all data that would allow one of skill in the art to draw any conclusions concerning the efficacy of the combination of niraparib with enzalutamide in treating prostate cancer.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The rejection is based on the combination of the teachings of NCT ‘172, Logothetis, Zhang, Sandhu and NCT ‘901. Applicant cannot show nonobviousness by attacking references individually where the rejection is based on combination of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As set forth above, combination therapy for the treatment of mCRPC is taught by NCT ‘172, Logothetis, Zhang and NCT ‘901.
Like NCT ‘172, the title of NCT ‘901 clearly teaches/suggests the use of enzalutamide and a PARP inhibitor (Niraparib) for treatment of mCRPC. Whether there is data or not, the fact remains that the reference clearly teaches the use of the combination for treatment of mCPRC. Regarding the arguments directed to Logothetis, while Logothetis discloses AAP in mCRPC and reviews pain and skeletal events, the fact remains that the treatment is in mCRPC subjects and thus, although Logothetis discuses benefits in terms of pain relief and delayed pain progression said treatment would inherently result in treatment of mCRPC. Contrary to applicant’s arguments against Logothetis and NCT ‘901, the references render obvious the combination of abiraterone acetate, prednisone and a PARP inhibitor, niraparib, for the treatment of patients with mCRPC.
Applicant argues:
The claimed therapeutic combination exhibits surprising and unexpected results. The data that Applicant provided in the Examples of the instant specification demonstrate surprising and unexpected results for the claimed treatment methods. This is confirmed by the in vivo experiment described in Example 2 of the application, which provides the first proof-of- concept for the treatment of prostate cancer with a combination of PARP inhibitors and androgen biosynthesis inhibitors. The comparative data given in the present application clearly show that the combination of niraparib/abiraterone acetate effectively inhibits tumor growth. In particular, Table 3 demonstrates that niraparib or abiraterone as single agents inhibited growth of the VCaP tumors, but that the combination of niraparib/abiraterone was most effective to inhibit tumor growth. And as shown in Table 4 of the application, 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. 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.P%). Increased survival is arguably the ultimate measure of a successful treatment.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The Examiner notes that in the Board decision, the Board noted that unexpected results unpersuasive of nonobviousness because it is well settled that a showing of unexpectedness must be commensurate in scope with the claimed subject matter. The Board concluded that Applicant did not advance specific persuasive evidence suggesting that an ordinarily skilled artisan would have understood that a showing of unexpected superiority in mice necessarily demonstrates a showing of unexpected superiority in human patients. Zhang evidences that mouse model success does not strongly correlate with human treatment. Therefore an ordinary artisan would have recognized that testing in humans would be required to confirm the animal results and that the results are not commensurate in scope with the claims as it encompasses treatment in humans. The same applies to the instant claims.
Applicant argues:
Applicant also submits a declaration under 37 CFR.§ 1.132 by Dr. Peter Francis, which provides compelling evidence of unexpected results sufficient to rebut any prima facie case of obviousness. The first interim analysis of the results from the MAGNITUDE trial investigated the effect of niraparib plus abiraterone acetate and prednisone (AAP) against a placebo arm (in which patients were administered a placebo with AAP), in the BRCA1/2 subgroup and then in the full homologous recombination repair gene alterations (HRR+) cohort. As reported in Chi and confirmed by Dr. Francis, the results show an “unexpectedly high response rate in the niraparib plus AAP group compared with the placebo plus AAP in the primary endpoint of the trial, radiographic Progression Free Survival (rPFS).” In particular, median rPFS in the BRCA 1/2 subgroup was significantly longer in the niraparib plus AAP group compared with the placebo plus AAP group. And in the overall HRR+ cohort, rPFS was significantly longer in the niraparib± AAP group compared with the placebo+ AAP group. Dr. Francis reports that the second interim analysis (IA2) of the results from the phase III MAGNITUDE trial described in Chi Annals shows “an unexpectedly high response rate.” Specifically, Dr. Francis confirms that the niraparib plus AAP arm outperformed placebo plus AAParm in the primary endpoint (PFS) and secondary endpoints (time to symptomatic progression and time to cytotoxic chemotherapy). Dr. Francis concludes that “[t]hese 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.” Moreover, as confirmed by Dr. Francis, the magnitude of these benefits, and the improvement over the other therapies, would not have been reasonably expected from NCT'172, Logothetis, Zhang, Sandhu, and NCT '901.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The Examiner acknowledges that placebo plus AAP appears to be more slightly more effective in HRR+ cohort compared to the BRCA 1/2 subgroup (rPFS of 13.7 months vs 10.9 months). However, in a review of the data, rPFS in HRR+ cohort compared to the BRCA 1/2 subgroup, there appears to be no difference between the groups for treatment with niraparib plus AAP (16.5 months vs 16.6 months). Thus, the data provided does not appear to support 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. Moreover, MPEP 716.02(e) states, An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). In the instant case, as set forth above, NCT ‘172 teaches the combination of a PARP inhibitor (veliparib), abiraterone acetate and prednisone. The only difference between NCT ‘172 and the claimed invention is the recitation of niraparib by the claimed invention. Thus, Applicant has not provided a comparison to the closest prior art.
Conclusion
Claims 1-22 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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/Rayna Rodriguez/Primary Examiner, Art Unit 1628
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