DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Current Status of 18/540,119
This Office action is responsive to the amended claims of 03/22/2024. Claims 2, 7, 17, 24-26, 28, 30, 31, 35, 39, 41, 50, 59, 60, 63, 85, 86, 87, and 89 are pending and have been examined on the merits.
Priority
The instant application is a continuation of PCT/CA2022/050970, filed 06/16/2022, which claims priority to U.S. Provisional Application No. 63/336,026, field 04/28/2022 and U.S. Provisional Application No. 63/211,354, filed 06/16/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/22/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The abstract of the disclosure is objected to because the abstract exceeds 150 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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 2, 7, 17, 24-26, 28, 30, 31, 35, 39, 41, 50, 59, 60, 63, 85, 86, 87, and 89 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). 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 relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claim 2 is drawn to a method of treating a cancer in a subject wherein the cancer has a loss of function of ATM, BRCA2, RNAse H2A, RNAse H2B, CDK12 or a combination thereof, or wherein the cancer is an ALT+ cancer through administering to the subject a therapeutically effective amount of an ATR inhibitor and a PARP inhibitor of formula (III) or (IV). Claim 17 is drawn to a method of inducing cell death in an aberrant cancer cell wherein the cancer has a loss of function of ATM, BRCA2, RNAse H2A, RNAse H2B, CDK12 or a combination thereof, or wherein the cancer is an ALT+ cancer through contacting the cell with a therapeutically effective amount of an ATR inhibitor and a PARP inhibitor of formula (III) or (IV). Claim 63 is drawn to a method of treating a cancer in a subject wherein the cancer has a loss of function of ATM, BRCA2, RNAse H2A, RNAse H2B, CDK12 or a combination thereof, or wherein the cancer is an ALT+ cancer through administering to the subject a therapeutically effective amount of an ATR inhibitor and a PARP inhibitor is ABT-888, BSI-201, 2X-121, CEP-9722, AZD2281, PF-01367338. These claims are directed to substantially similar methods of treating cancers with the same loss of function mutations with a combination therapy comprising an ATR inhibitor and a PARP inhibitor. Thus, the claims taken together with the specification imply the combination therapy of any ATR inhibitor in combination with any compound of formula (III), (IV), or the PARP inhibitors listed above in claim 63 are capable of treating any form of cancer bearing these mutations. Thus, the scope of the claims is extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The art recognizes ATR inhibitor/PARP inhibitor combination therapy as a potential cancer treatment strategy (see Kim 2017, found in IDS filed 03/22/2024; Lloyd 2020, found in IDS filed 03/22/2024; and Kim 2020 Kim, Hyoung, et al. "Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models." Nature communications 11.1 (2020): 3726.). However, these same references show that such combinations require empirical testing, biomarker selection, and schedule optimization because efficacy and tolerability were not predictable. Lloyd teaches that the full spectrum of this combination therapy and biomarkers that predict their tumor selectivity is not fully explored (pg. 4870 left col, final para), and further discusses the need for optimized dose scheduling, with toxicity being dose and schedule limiting (pg. 4880, right col, third para). Kim 2017 teaches that PARP inhibition increases reliance on ATR/CHK1 for survival, and that the combination was more effective than PARPi alone, demonstrating that the combination therapy was known (Abstract). Kim 2020 shows that such combinations require empirical development, including drug doses optimized for synergy and further notes that in some resistance models the means of increasing reliance is unclear (pg. 5, right col, last para). These teachings highlight the need for empirical data to assess the effectiveness of ATR inhibitor PARP inhibitor combination therapy regimens.
(5) The relative skill of those in the art:
The artisan would have experience in medicinal chemistry, pharmacology, oncology, or a related field. The artisan would be experienced in the development of small-molecule therapeutics including familiarity with cancer biology, DNA damage response pathways, and the administration of chemotherapeutic agents. The artisan would have experience in evaluating drug efficacy and toxicity, including in the context of combination therapies. Despite the technical skill in the art, the artisan’s skill would be insufficient to overcome the inherent uncertainty of combination oncology treatments. The artisan would be unable to reliably predict effective dosing regimens for drug combinations without empirical testing.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for the biological rationale for combination therapy comprising an ATR inhibitor and a PARP inhibitor, including identifying classes of compounds suitable for such compositions (see [0003-0006]). The disclosure also describes high-level concepts of administration and co-administration of the claimed compounds (see [0205-0209]).
However, the specification does not provide sufficient operational guidelines to achieve the claimed therapeutic effect. The specification lacks any working examples, experimental data, and specific dosing/administration data necessary to treat the disease as claimed. The specification fails to teach how to use the compounds to achieve the claimed therapeutic results without undue experimentation.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regard to the lack of specific dosing or administration regimens, the absence of any experimental data supporting the claimed therapeutic effects of the combination therapy, and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
Claims 2, 7, 17, 24-26, 28, 30, 31, 35, 39, 41, 50, 59, 60, 63, 85, 86, 87, and 89 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are directed to methods of treating cancer or inducing cell death of aberrant cancer cells using combinations of ATR inhibitors and PARP inhibitors across a broad scope. However, the specification does not reasonably convey that the Applicants were in possession of the claimed methods at the time of filing. The disclosure provides only a general rationale for combining ATR inhibitors and PARP inhibitors and does not include working examples, experimental data, or representative species demonstrating that such combination are effective at treating cancer. In the absence of such disclosure, the specification fails to establish a correlation between the claimed combination therapies and the recited therapeutic efficacy. Accordingly, the claims are not supported by an adequate description.
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.
Claims 2, 7, 17, 26, 28, 87, and 89 are 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.
Claims 2 and 17 have the following structure of (III)
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. The nature of the bond between X2 and X3 is unclear, it cannot be determined from the disclosure whether the bond is single or double. The Examiner suggests amending these claims to include new figures depicting a defined bond between these substituents.
Claims 26, 28, 87, and 89 each list ATR inhibitors from the specification. However, the claims must be complete and stand on their own (see MPEP 2173). The Examiner suggests amending the claims to include the structures of the claimed compounds.
Claim 7 recites “wherein the therapeutically effective amount is a subtherapeutic regimen.” These limitations are internally inconsistent. A therapeutically effective amount is understood to be an amount sufficient to achieve a therapeutic effect (defined at [0120]), whereas a subtherapeutic regimen denotes an amount insufficient to achieve such an effect (defined at [0122]). The artisan would be unable to determine the metes and bounds on the claim as written due to this internal inconsistency.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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 2, 7, 17, 30, 31, 35, 39, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Lloyd (found in IDS filed 03/22/2024) in view of Packer (WO2021013735 A1, found in IDS filed 03/22/2024).
Lloyd teaches that the combination therapy of the PARP inhibitor Olaparib and the ATR-inhibitor AZD6738 induce cell death in several ATM-deficient cell lines (Abstract). The reference also demonstrates the efficacy of this combination therapy in vivo in xenograft and PDX mouse models with complete ATM loss (Abstract). Lloyd discloses a synergistic interaction between the PARP inhibitor and the ATR inhibitor in ATM-deficient cells which were cytotoxic in ATM-KO cells at various doses (pg. 4870, right col, second para; pg. 4871, right col, first para). Their data suggested a therapeutic window for the combination therapy in ATM-deficient cancers at a lower dose of each inhibitor compared to the monotherapies (pg. 4872, left col, first para). The combination therapy resulted in greater and faster induction of genome instability in ATM-KO cells (pg. 4875, final sentence of left col). ATM-deficient tumors were assessed in vivo and the combination therapy reduced tumor growth more effectively than in comparison to the single-agent treatments, demonstrating the preclinical synergy between the PARP inhibitor and the ATR inhibitor (pg. 4878, section Combined PARP/ATR inhibition promotes anti-tumour efficacy in xenograft and PDX models with ATM loss). The reference teaches that the combination therapy has the potential to induce equivalent or greater tumor toxicity in a shorter time frame with lower dosages. This could limit developing acquired resistance from prolonged high-dose drug exposure (pg. 4881, right col). Lloyd does not expressly disclose a PARP inhibitor of formula (III) or (IV).
However, these compounds are known PARP inhibitors. Packer discloses compounds of Formula (I)
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wherein
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(pg. 2, lines 16-25). These are the exact limitations of compound (III) in the instant claims. Packer identifies these compounds as PARP inhibitors and teaches the use of the compounds, and pharmaceutically acceptable salts thereof in the treatment of diseases where PARP inhibition has pharmacological significance (pg. 2, lines 7-10). The reference teaches methods of using the compounds for the treatment of cancer (claims 26 and 27) including cancers wherein the cancer cells have a BRCA1 and/or BRCA2 deficient phenotype (pg. 5, lines 7-13). The cancers to be treated with the compounds of Packer include cancers of the breast, ovary, pancreas, prostate, hematological, gastrointestinal such as gastric and colorectal, or lung cancer (pg. 2 line 32- pg. 3 line 6).
The artisan would have experience in medicinal chemistry, pharmacology, oncology, or a related field. The artisan would be experienced in the development of small-molecule therapeutics including familiarity with cancer biology, DNA damage response pathways, and the administration of chemotherapeutic agents. The artisan would have experience in evaluating drug efficacy and toxicity, including in the context of combination therapies.
The artisan would have been motivated to modify the combination therapy of Lloyd by substituting alternative PARP inhibitors, including those disclosed by Packer. PARP inhibitors were known in the art to act on the same biological pathway, and thus would have understood to be suitable alternatives in such combination therapies. The artisan would have been aware of the synergistic interactions of PARP inhibitors with ATR inhibitors disclosed by Lloyd, and would have been motivated by this to investigate whether other known PARP inhibitors likewise exhibit synergistic effects with ATR inhibitors. PARP inhibitors were known in the art and methods for evaluating combination therapies were routine in the art. The artisan would have found it obvious to substitute know PARP inhibitors, such as those of Packer, into the combination regimen of Lloyd and to evaluate their effects. Such substitution and screen constitute a predictable and routine extension of the prior art’s teachings.
Claims 63 is rejected under 35 U.S.C. 103 as being unpatentable over Lloyd in view of Donawho (Donawho, Cherrie K et al. “ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.” Clinical cancer research : an official journal of the American Association for Cancer Research vol. 13,9 (2007): 2728-37. doi:10.1158/1078-0432.CCR-06-3039).
The teachings of Lloyd are discussed above and are incorporated into this rejection by reference. The reference teach a combination therapy regiment for the treatment of cancer cells that are ATM deficient, comprising administering and PARP and ATR inhibitor in combination. The reference does not expressly disclose other PARP inhibitors apart from Olaparib.
Donawho discloses that ABT-888 is a potent inhibitor of PARP that is orally bioavailable and possesses an excellent efficacy and pharmacokinetic profile (Abstract).
The artisan would have experience in medicinal chemistry, pharmacology, oncology, or a related field. The artisan would be experienced in the development of small-molecule therapeutics including familiarity with cancer biology, DNA damage response pathways, and the administration of chemotherapeutic agents. The artisan would have experience in evaluating drug efficacy and toxicity, including in the context of combination therapies.
The artisan would have been motivated to modify the combination therapy of Lloyd by substituting alternative PARP inhibitors, including ABT-888 disclosed by Donawho. PARP inhibitors were known in the art to act on the same biological pathway, and thus would have understood to be suitable alternatives in such combination therapies. The artisan would have been aware of the synergistic interactions of PARP inhibitors with ATR inhibitors disclosed by Lloyd, and would have been motivated by this to investigate whether other known PARP inhibitors likewise exhibit synergistic effects with ATR inhibitors. PARP inhibitors were known in the art and methods for evaluating combination therapies were routine in the art. The artisan would have found it obvious to substitute know PARP inhibitors, such as ABT-888 of Donawho, into the combination regimen of Lloyd and to evaluate their effects. Such substitution and screen constitute a predictable and routine extension of the prior art’s teachings.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571)272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.K.E./ Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625