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 .
Priority
Applicant’s submission of a certified English translation of each foreign application in accordance with 37 CFR 41.154(b) and 41.202(e) is noted. As a result, Applicants are entitled to the benefit of the filing dates of the foreign priority documents and each claim is examined with an effective filing date of August 27, 2021.
Response to Remarks and Amendments
Applicant’s response filed June 25, 2026 has been entered and is considered herein. Any rejection not reiterated herein is withdrawn.
With regard to the objection of claim 17, the issue is overcome by the cancellation of claim 17.
With regard to the rejection of claims 40-44 (now claims 40 and 42-45) under 35 USC 112(a), Applicants argue that the state of the art at the time of filing was that PARP1-specific inhibitors could be used to treat multiple cancer types, specifically citing approval of particular PARP inhibitors for the treatment of breast, ovarian, pancreatic and prostate cancers. The arguments have been considered but were not found to be persuasive for at least two reasons.
Firstly, the approval of particular PARP1 inhibitors for the treatment of particular cancers does not provide enablement for the entirety of the claimed scope. It does not follow that any compound which inhibits PARP1 will also treat those cancers effectively. However, even assuming arguendo that such were the case, only the compound actually demonstrated as being inhibitors of PARP1 would be enabled for this use. There is such a substantial degree of variation within the generic structure that a person of ordinary skill in the art would not expect each member of the claimed genus to act as an inhibitor of the same enzyme. Only the compounds of claim 36, which exclusively have a pyrazole ring at the Z ring position, each of A1-A3 as carbon, and the B1-B4 ring being phenyl or pyridine, were actually shown to be PARP1 inhibitors.
Secondly, even if the claims were limited to those compounds actually demonstrating the necessary inhibitory activity, and those which are substantially chemically similar, said compounds would still only have the required nexus for cancers which have been demonstrated to be treatable by PARP1 inhibitors. Applicant’s arguments admit that “PARP1-specific inhibitors could be used to treat multiple cancer types” but the claims encompass all cancer types. Accordingly, for at least the foregoing reasons as well as those described in the original rejection, the rejection is still deemed to be proper and is maintained herein
Notably, new claim 45 would be considered enabled if it were amended to require the chemical structure of those compounds actually demonstrating the necessary inhibitory activity, and those which are substantially chemically similar.
With regard to the rejection of claims 16-44 under 35 USC 102 as being anticipated by US 11,795,173, the rejection is withdrawn in view of Applicant’s submission of certified translations of the priority documents. The instant claims are now examined with an effectively filed date of August 27, 2021, whereas the earliest effective filing date of the ‘173 patent was April 28, 2022. Accordingly, the ‘173 patent no longer qualifies as prior art over the instantly examined claims.
With regard to the rejection of claims 16-17 and 37-44 under 35 USC 102 as being anticipated by WO 2022/225934, the rejection is withdrawn in view of the claim amendment which no longer includes furan as a possible definition for the claimed Z ring in the instant claims. Since the prior art does not read on the claims as amended, the claims are no longer anticipated by the ‘934 publication and the rejection is withdrawn.
Finally, with respect to the rejection of claims 16-35 and 37-44 (now 16, 18-35, 37-40 and 42-45) for nonstatutory double patenting over claims 1-19 of US Patent Application 18/846,265, Applicants request for the rejection to be held in abeyance. Since the rejection still applies to the pending claims, the rejection is maintained herein.
Status of Claims
Currently, claims 16, 18-40 and 42-45 are pending in the instant application and are under consideration herein. Claim 45 is newly added.
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 40 and 42-45 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 treating (but not preventing) particular types of cancer using compounds of Formula IIIb, does not reasonably provide enablement for a method of treating or preventing any and all diseases or conditions responsive to the inhibition of PARP activity. 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 enablement rejection is focusing in all cancers as claimed.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) as to undue experimentation. The factors include:
1) the nature of the invention;
2) the breadth of the claims;
3) the predictability or unpredictability of the art;
4) the amount of direction or guidance presented;
5) the presence or absence of working examples;
6) the quantity of experimentation necessary;
7) the state of the prior art; and,
8) the relative skill of those skilled in the art.
The relevant factors are addressed below in the basis of comparison of the disclosure, the claims, and the state of the prior art in the assessment of undue experimentation.
As set forth in In re Marzocchi et al., 169 USPQ 367 (CCPA 1971):
"[A] [s]pecification disclosure which contains the teachings of manner and process of making and using the invention in terms corresponding to the scope to those used in describing and defining subject matter sought to be patented must be taken as in compliance with the enabling requirements of first paragraph of 35 U.S.C. 112, unless there is reason to doubt the objective truth of statements contained therein which must be relied on for enabling support; assuming that sufficient reasons for such doubt exists, a rejection for failure to teach how to make and/or use will be proper on that basis, such a rejection can be overcome by suitable proofs that teaching contained in the specification is truly enabling."
Applicant’s invention is direct to a method for treating or preventing any and all diseases or conditions responsive to the inhibition of PARP activity by administering a compound of formula IIIb. Applicant demonstrates in the as-filed specification potentiation effects of compound formula IIIb on the growth inhibiting activity of BRCA mutant human breast cancer MDA-MB-436 cell line.
As of the time of filing, a method of treating any cancer was unknown and the prior art did not recognize that there was a single agent or therapy capable of successfully treat all cancers. Rouleau et al. teaches the development of PARP inhibitors as agents to treat tumours with certain sensitizing genetic lesions is based on the notion that cells with defects in DSB repair such as BRCA-deficient cells are more dependent on PARP1 and BER to maintain genomic integrity. This synthetic lethal approach has been validated in studies that show striking single-agent activity of PARP inhibitors in preclinical models of BRCA1 and BRCA2 inactivation in vitro and in vivo (BOX 3). Consistent with these results, the PARP inhibitor olaparib (previously known as AZD2281) has shown promising single-agent activity against BRCA1- or BRCA2-mutant tumours in early clinical testing. Because triple-negative (oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative and ERBB2- negative) breast cancer and sporadic serous ovarian cancer exhibit some of the properties of BRCA1- or BRCA2-deficient cells, PARP inhibitors are also being tested against these tumours. Likewise, the observation that cells deficient in other crucial homologous recombination proteins are sensitive to PARP inhibitors provides the rationale for testing PARP inhibitors in other cancers. For instance, with the recent finding that the tumour suppressor PTEN is important for expression of the repair protein RAD5, it was shown that PTEN-deficient cells are exquisitely sensitive to PARP inhibitors providing a rationale for ongoing studies of PARP inhibitors in PTEN-deficient tumours. As trials of PARP inhibitors in repair deficient tumours progress, it will be interesting to see how durable the responses are. Resistance to PARP inhibitors and carboplatin can arise in BRCA1- or BRCA2- deficient cancer cells concomitant with the reactivation of these genes by secondary mutations [p.296, col. 1-2]. Table discloses that specific PARP inhibitors in combination with others anticancer agents are evaluated for the treatment of glioblastoma multiforme, solid tumors leukemia, ovarian cancer, breast cancer, and pancreatic cancer. In addition, studies might also be required to better understand how PARP inhibitors exert their beneficial effects in tumor cells. Previous studies have demonstrated that PARP1 siRNAs or shRNAs are toxic to BRCA-deficient cells in vitro, leaving little doubt that PARP inhibitors kill these cells by diminishing the catalytic activity of PARP1. Some of the preclinical data, however, raise the possibility that BRCA2–/– cells might respond better to PARP inhibition than BRCA1–/– cells17. If this effect is confirmed in additional studies, it is not completely explained by current models of PARP inhibitor-induced killing. Whether PARP inhibitors also potentiate the chemotherapeutic effects of DNA-damaging therapy in the same fashion remains unclear, as earlier studies performed under cell-free conditions raised the possibility that catalytically inactive PARP1 will bind to DNA lesions and prevent their repair. Whether this mechanism contributes to chemosensitization in intact cells or in a clinical setting remains to be investigated. Finally, studies are also needed to improve our understanding of why PARP inhibitors sensitize tumour cells more to some DNA-damaging agents (for example, temozolomide and DNA topoisomerase I inhibitors) than others (DNA topoisomerase II inhibitors) [p.298, col. 1-2, para 1]. Finally, there are gaps in our understanding of the effects of long-term PARP inhibition. PARP1 is known to have effects on transcription and a wide variety of DNA repair pathways. Whether long-term PARP1 inhibition will have any deleterious effects such as secondary malignancies requires careful investigation, particularly when inhibitors are administered with DNA-damaging agents. Given the high potency of third generation PARP inhibitors and the reported tumour suppressor functions of PARP1, the long-term effects of near-complete PARP inhibition should be tested in animal models, as was done for earlier generations of inhibitors. It will be important, however, to weigh the risk of secondary malignancies — if they occur — against the benefits of improved treatment of currently intractable tumours. In view of the postulated roles of PARP1 in cardiovascular physiology and memory, any long-term effects of PARP inhibitors on cardiovascular or mental well-being, either beneficial or deleterious, should also be monitored [p.298-299, col. 3-1, para 2-1].
Given that it was not known that any specific agent will be able to treat all cancers (or prevent any cancers), one of ordinary skill in the art would not be able to predict that all cancer could be treated using the presently claimed composition comprising compound of formula IIIb without enabling a set of species representative of the full scope of cancers known in the art. The artisan would have required sufficient direction as to how, at minimum, a representative set of a cancers could be effectively treated with the claimed composition comprising the genus of compounds of formula IIIb and, further, how the artisan could have reasonably extrapolated such results from a progressive and unpredictable condition and would actually show sensitivity to the presently claimed method. Such that the artisan would have been imbued with at least a reasonable expectation of success in treating any cancer. Such success would not have been reasonably expected for the method of treating any cancer as claimed given the highly complex and variable nature of the disease known in the art. To the artisan, the concept of single agent effective to treat a complex and progressive disease would not have been considered representative or suggestive of the same efficacy in the treatment symptom of the disease itself.
MPEP §2164.03 states, "The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The 'amount of guidance or direction' refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004)...In applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required."
"Nascent technology…must be enabled with a 'specific and useful teaching'. The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004). See MPEP §2164.03.
As established supra, the method of treating all cancer comprising administering a composition of compounds of formula IIIb was unpredictable at the time of the invention, given that the art recognized the complexity of cancer, the art clearly lacked information in regards to how to treat effectively any cancer with any compound of formula IIIb. Thus, the method of treatment of the invention must be considered nascent, since the state of the art at the time of the invention did not recognize the claimed objective could be accomplished with any reasonable expectation of success. As a result, the amount of guidance required from Applicant necessarily is high, since Applicant cannot rely upon what is known in the art about the nature of the invention for such guidance.
In the as-filed specification, Applicant demonstrates in the as-filed specification potentiation effects of compound formula I on the growth inhibiting activity of MMS in SW620 (human colorectal cancer cells), T47D (breast cancer cells) and BRCA-2 deficient CAPN-1 (pancreatic duck cancer cells) [p.86-95].
However, Applicant fails to provide adequate working examples for how to use the claimed composition comprising compound of formula IIIb in treatment or prevention of all conditions of diseases involving PARP inhibition, including all cancers. Applicant as failed to demonstrate how the IC50 activity would be extrapolated to the ability to treat and prevent every disorder encompassed by the claims, when there are so many factors lending to the unpredictability of medical treatment in this area.
The fact that Applicant has demonstrates IC50 activity in breast cancer cells alone does not address the high degree of variability in the art in terms of the pathophysiology, and mutations associated cancer. Applicant has also failed to provide any evidence, or describe any protocol, that addresses this variability in the art such that one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success in treating all cancers with the claimed composition comprising compounds of formula I based on the direction provided in the present specification.
The quantity of experimentation to use the claimed compounds in the treatment of all cancer encompassed by the claims would be an undue burden to one of ordinary skill in the medicinal, biological and pharmacological art, since the skilled artisan is given inadequate guidance for the reasons stated above. Even with undue burden of experimentation, there is not a reasonable expectation of success that one would be able to treat all cancers in the manner claimed in view of what was known in the prior art, as evidenced by the teachings of Rouleau et al. Since the reference disclosed the complexity of treating all cancer with compounds that are considered PARP inhibitors and the differences in manifestation depending on sex, age and severity/progression of the disease which in turn dictates the limited choice of therapy employed during treatment (i.e., only one therapy). While the lack of working examples cannot be the sole factor in determining enablement, the absence of substantial evidence commensurate in scope with the breadth of the presently claimed subject matter, in light of the unpredictable nature of the art and the absence of direction from Applicant, provides additional weight to the present conclusion of insufficient enablement in consideration of the Wands factors as a whole.
The basis for the present rejection is not simply that experimentation would be required, since it is clear from the state of pharmaceutical, medical and chemical arts that experimentation in this art is not all uncommon, but that the level of experimentation required in order to practice these aspects of the invention in the absence of adequate enabling direction by Applicant would be undue. See In re Angstadt, 537 F.2d 498, 190 USPQ 214, 219 (CCPA 1976), which states, "The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.”
In view of the discussion of each of the preceding seven factors, the level of skill in the art is high and is at least that of a medicinal chemist or organic chemist with several years of experience in the art.
As the cited art and discussion of the above factors establish, the disclosure and supporting examples provided in the present specification, coupled with the state of the art at the time of the invention, fail to imbue the skilled artisan with a reasonable expectation or ability to use the full scope of the invention as instantly claimed. In order to actually use the claimed invention, it is clear from the discussion above that the skilled artisan could not rely upon Applicant’s disclosure as required by 35 U.S.C. 112(a) in order to practice the full scope of embodiments presently claimed.
Applicant is enabled for a method of treating (but not preventing) breast cancer by administration of the composition comprising compound of formula IIIb, however, the application is not enabling for the entirety of the claimed scope as described above.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 16, 37-40 and 42-45 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 8,541,417 (“the ‘417 patent).
The ‘417 patent teaches compounds of the formula
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as PARP inhibitors, and more specifically teaches the formula
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(Abstract, col. 20). In particular, several compounds are disclosed which anticipate instant Formula IIIb. As one particularly relevant example, the compound
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is disclosed as Compound 2 (col. 76-77). The compound reads on instant Formula IIIb where the Z ring is pyrrole; R4 is H; A1 is N; A2-A3 are each CR1 where R1 is H; B1-B4 are each CH; and one of R’ and R’’ is H and the other is ethyl. The compound in the prior art is also explicitly listed in instant claim 36 (see top of claim paged numbered 10). Nearly every exemplified compound in the prior art also anticipates the claimed genus of compounds. The reference further teaches pharmaceutical compositions of the anticipatory compounds as required by instant claim 37 (see Table 1, where the data for the compound examples is reported in units of molarity, indicating that the compounds were included in a solution reading on the claimed composition). Combinations with additional anticancer agents are also disclosed at columns 62-66 of the prior art. Finally, the instantly claimed methods of use are disclosed in the description of treating diseases in which PARP inhibition is beneficial, where the prior art exemplifies cancer having a BRCA1 or BRCA2 mutation (col. 48). Accordingly, since the prior art teaches all required limitations of the claimed invention, the claims are anticipated.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 16, 18-35, 37-40 and 42-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of US Patent Application 18/846,265. Note that the rejection is provisional in nature because the copending claims have not, in fact, been patented.
Although the claims at issue are not identical, they are not patentably distinct from each other because, the claims of the conflicting application are drawn the compound
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, and more specifically to compounds of the formula VIII
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(conflicting claim 12), where specific anticipatory compounds are recited in conflicting claim 16. As one example, the compound
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is claimed by its chemical name
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Regarding the claimed method of treatment, the conflicting claims recite the treatment of diseases responsive to PARP inhibition, including breast cancer (claim 17) and also explicitly claim medicaments with a combination of another known anticancer drug (claim 17). Pharmaceutical compositions are recited in conflicting claims 18-19. Accordingly, since the copending claims overlap with and completely encompass the instant claims, with anticipatory compounds taught in support of the claimed genus, a double patenting rejection is appropriate.
Conclusion
Claim 36 is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alicia L. Otton whose telephone number is (571)270-7683. The examiner can normally be reached on Monday - Thursday, 8:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Fereydoun Sajjadi can be reached on 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/ALICIA L OTTON/Primary Examiner, Art Unit 1699
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