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 .
Status of Claims
Claims 1 – 20 are pending.
Claims 1 – 20 have been examined.
Claims 1 – 20 have been rejected.
Priority
Instant application 18/541,121, filed on 12/15/2023 claims priority as follows:
PRO 63/476,290, filed on 12/20/2022.
PRO 63/479,684, filed on 01/12/2023.
Acknowledgement is made of applicant’s claim for domestic benefit. It is noted, however, that neither claim 9 nor claim 11 of the current application appear in either provisional application and therefore are not granted benefit of the earlier filing date.
Information Disclosure Statement
Applicant has elected to not submit an IDS for this invention.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because:
The data points showing NQO1 and MET mRNA expression in lung cancer (Fig. 1-1A) or pancreatic cancer (Fig. 1-1B) cannot be differentiated from data points showing normal tissue in the required gray scale. It is recommended that each tissue type use a different shape instead of different colors.
Missing X-axis label (Fig. 1C)
Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
The phrase “less than 29mg/kg” should be rewritten as “less than 9 mg/kg” (paragraph 111, line 12).
Pancreatic ductal adenocarcinoma is abbreviated as “PDA” in the background of the invention (paragraph 0003, line 1) and referenced as such until it is redefined as “PDAC” (paragraph 00119, line 17). Applicant should use only one abbreviation to refer to the same word or phrase.
Appropriate correction is required.
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.
Claims 8 – 9 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 8 and 9 create a circular argument by virtue of claim 8 depending on claim 9 and claim 9 depending on claim 8. This lacks proper antecedent basis and therefore makes both claims unclear.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 7, 8, 16, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bhandare et al. (The FASEB Journal, 2022, 36(S1). https://doi.org/10.1096/fasebj.2022.36.S1.R4326; published May 13, 2022).
With respect to claim 1, Bhandare reports that a treatment combination of a cMET inhibitor with an NQO1 bioactivatable drug induces synergistic lethality in cancer cells (abstract).
With respect to claims 7 and 8, Bhandare specifies that the preferred NQO1 bioactivatable drug is β-lapachone (abstract).
With respect to claim 16, Bhandare specifies that this method utilizes a sublethal dose of β-lapachone (abstract).
With respect to claim 17, Bhandare specifies that this method utilizes a sublethal dose of cMET inhibitor (abstract).
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 1, 2, 5 – 10, 12 – 16, and 18 are rejected under 35 U.S.C 103 as being unpatentable over Huang, et al. (Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors. Cancer Cell, 2016, 30(6), 940–952. https://doi.org/10.1016/j.ccell.2016.11.006) in view of Singh, N. et al. (Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy. Cancers, 2020, 12(4), 972. https://doi.org/10.3390/cancers12040972), as evidenced by Bey et al. (PNAS, 2007, 104(28), 11832–11837. https://doi.org/10.1073/pnas.0702176104).
With respect to claim 1, Huang teaches that administration of poly(ADP-ribose) polymerase (PARP) inhibitors in combination with the NQO1 bioactivatable drug β-lapachone results in synergistic and selective antitumor activity (Summary, Results section “Synergy Results from β-Lap-Induced, NQO1-Mediated, Tumor-Selective DNA Damage and PARP Inhibition”).
Huang fails to disclose the potentiation of selective antitumor effects using a mesenchymal-epithelial transition factor (cMET) inhibitor.
However, Singh, N. teaches that cMET is overexpressed in certain cancers and is known to translocate into the nucleus where it binds and phosphorylates PARP1 to enhance the enzymatic DNA repair activity of PARP1. Further, Singh, N. states that using cMET inhibitors (e.g., crizotinib and foretinib) is a strategy to indirectly block PARP1-mediated DNA repair (Page 8: “7. Targeting cMET to Attenuate PARP1 Activity”).
Therefore, it would have been prima facie obvious to potentiate the antitumor activity of NQO1 bioactivatable drugs by inhibiting cMET instead of PARP1 to reach the same goal of aberrant cancerous DNA repair. A person skilled in the art would have been motivated to inhibit cMET because it is an easier target, residing on the cell membrane or localizing in the cytosol, whereas PARP1 is primarily an intranuclear protein.
With respect to claim 2, Huang teaches measuring NQO1 mRNA expression and that elevated levels associated with certain cancer types, particularly NSCLC and PDA (“NQO1:CAT Ratios Offer an Exploitable Therapeutic Window“, Figure 1, Figure S1).
With respect to claim 5, Huang teaches that β-lapachone can be utilized with PARP inhibitors to synergistically and efficaciously kill solid tumors that overexpress NQO1 (Significance). Singh, N expands upon this process by teaching PARP inhibitors can be replaced by cMET inhibitors (Page 8: “7. Targeting cMET to Attenuate PARP1 Activity”).
With respect to claim 6, Huang shows that combining a PARP inhibitor with β-lapachone results in robust, NQO1-dependent, tumor-selective single-strand breaks, double-strand breaks, and apoptosis in vitro and in vivo, with synergistic antitumor efficacy in mice bearing NQO1+ pancreatic or NSCLC orthotopic xenografts (Discussion). Singh, N. expands upon this process by teaching PARP inhibitors can be replaced by cMET inhibitors as an indirect method of causing PARP inhibition (Page 8: “7. Targeting cMET to Attenuate PARP1 Activity”).
With respect to claims 7 and 8, Huang discloses that β-lapachone achieves a synergistic antitumor effect when combined with another therapeutic drug that blocks DNA repair (Summary).
With respect to claim 9, Huang describes a method of administering β-lapachone to mice at 10, 15, or 22 mg/kg (page 7, “Analyses of biomarkers confirm synergistic responses in mouse tumor models after Rucaparib + β-lapachone”).
With respect to claim 10, Huang discloses that the β-lapachone combination therapy works in part by blocking DNA repair due to PARP inhibition (Discussion). Singh, N. teaches that cMET inhibitors (e.g., crizotinib and foretinib) are a strategy to indirectly block PARP1-mediated DNA repair (Page 8: “7. Targeting cMET to Attenuate PARP1 Activity”). A skilled artisan would recognize that cMET is an easier target to attack and would result in the same inhibition of PARP inhibition.
With respect to claim 12, Huang shows that the NQO1 bioactivatable drug being administered 2 hours after the administration of the PARP1 inhibitor (Figures 3 – 7, S3 – S6). Singh, N. explains that cMET inhibitors can be used in place of PARP1 inhibitors to result in the reduction of PARP1-mediated DNA repair (Page 8: “7. Targeting cMET to Attenuate PARP1 Activity”).
With respect to claim 13, Huang teaches the coadministration of a PARP inhibitor + various β-lapachone doses (Figure 3 – 7).
With respect to claim 14, Huang teaches that mice were treated with β-lapachone by tail vein injections once a day for five days, followed by five additional daily injections after a 7 day recovery period (Figure 8).
With respect to claim 15, Huang teaches that cells were pretreated with a PARP1 inhibitor and after two hours were exposed to that same PARP1 inhibitor with β-lapachone (Figures 4 – 7). Singh, N. explains that cMET inhibitors can be used in place of PARP1 inhibitors to result in the reduction of PARP1-mediated DNA repair (Page 8: “7. Targeting cMET to Attenuate PARP1 Activity”).
With respect to claim 16, the Specification defines the term “sublethal dosage” as “any drug concentration dose that inhibit or kill less than 50% of cancer cells” (paragraph 00106). For the purposes of this examination, the lethal dosage of β-lapachone is considered to be 5 µM as evidenced by Bey et al. Any dose of β-lapachone that is less than 5 µM is deemed “sublethal”.
Huang describes the administration of a sublethal dose of β-lapachone to the following species (dosage of β-lapachone shown in parenthesis):
Polymorphic ∗2 H596 NSCLC cells corrected for NQO1 expression and pretreated with rucaparib (0 – 4 µM, Figure 4).
NQO1+ MiaPaCa2 PDA cells pretreated with rucaparib (0 – 3 µM or 0 – 6 µM, Figure 4).
NQO1+ Suit2 (S2-013) PDA cells harboring a CMV-NQO1 overexpression vector pretreated with rucaparib (0 – 4 µM, Figure 4).
MCF-7 cells pretreated ± rucaparib (0 – 2.0 µM, Figure 5).
NQO1+ A549 NSCLC cells pretreated with rucaparib (3 µM, Figure 6).
NQO1+ A549 NSCLC cells (3 µM, Figure 7).
NQO1+ MCF-7 cells pretreated ± rucaparib (2 µM, Figure 7).
NQO1+ A549 NSCLC pretreated ± rucaparib (3 µM, Figure 7).
MiaPaCa2 PDA cells pretreated ± rucaparib (3 µM Figure 7).
With respect to claim 18, Huang confirms the necessity of measuring mRNA expression of NQO1, as its overexpression in certain cancer types offers an ideal therapeutic window into treating said cancers (page 3, Results, “NQO1:CAT ratios offer an exploitable therapeutic window”).
Claims 3 and 4 are rejected under 35 U.S.C 103 as being unpatentable over Huang, et al. and Singh, N, et al. as evidenced by Bey et al. and in further view of Singh, S. et al. (US 2016/0032403 A1; published 2016 Feb. 04).
The teachings of Huang and Singh, N. are disclosed above and at least those teachings are incorporated herein by reference.
Both Huang nor Singh, N. are silent on the practice of determining expression levels of cMET or PARP1. However, Singh, S. teaches a method of calculating the EGFR/cMET for the purpose of selecting a suitable NSCLC anticancer drug (page 1, lines 47 – 55). It would have been prima facie obvious for a person who is skilled in the art to conduct this measurement as up to 72% of lung tumors from patients with primary tumors exhibited increased cMET expression, and this treatment option would not be effective on those without overexpression.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Huang, et al. and Singh, N. et al. as evidenced by Bey et al., and in further view of Clark, et al. (Future Oncology 2020, 16(1), 4289–4301. https://doi.org/10.2217/fon-2019-0653).
The teachings of Huang and Singh, N. are disclosed above and at least those teachings are incorporated herein by reference.
Both Huang and Singh, N. are silent on the administered dose of crizotinib used. However, Clark teaches that the maximum tolerated dose of crizotinib is 250 mg twice daily. It is therefore obvious that administering 250 mg twice daily as described in the current invention would give the expected result of adequate cMET inhibition.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Huang, et al. and Singh, N. et al., as evidenced by Bey et al., in further view of Du, et al. (Nat Med 2022, 194–201, 2016. https://doi.org/10.1038/nm.4032), and further evidenced by Ding et al. (Int J Biol Sci 2020, 16(14):2595-2611. https://doi.org/10.7150/ijbs.45886). The Specification of the instant application defines the term “sublethal dosage” as “any drug concentration dose that inhibit or kill less than 50% of cancer cells” (paragraph 00107). For the purposes of this examination, the lethal dosage of cMET inhibitor is considered to be 4 µM (Crizotinib), as provided by Ding et al. Any dose of cMET inhibitor that is less than 4 µM is deemed “sublethal”.
The teachings of Huang and Singh, N. are disclosed above and at least those teachings are incorporated herein by reference.
Both Huang and Singh, N. are silent on the use of a sublethal dose of a cMET inhibitor to treat cancer. However, Du teaches that 2 µM Crizotinib sufficiently diminishes PARP1-mediated DNA repair functions (Figure 3). It would have been obvious for a skilled artisan to use a lower dose of a cMET inhibitor because, while cMET is overexpressed in cancerous cells, it is also present in healthy cells and can lead to adverse side effects at higher concentrations.
Claim 19 is rejected under 35 U.S.C. 103 for being unpatentable over Huang, et al. and Singh, N, et al., as evidenced by Bey et al. and Ding et al., and in further view of Hergenrother et al. (WO 2014/168991 A1, published 2014, Oct. 16).
The teachings of Huang and Singh, N. are disclosed above and at least those teachings are incorporated herein by reference.
Both Huang and Singh, N. are silent on the administration of an additional chemotherapeutic agent with an NQO1 bioactivatable agent and cMET inhibitor. However, Hergenrother discloses the use of an additional chemotherapeutic agent or radio therapy (claim 14) along with an NQO1 bioactivatable drug in combination with a PARP1 inhibitor (claim 1). It would be prima facia obvious for a skilled artisan to incorporate an additional chemotherapeutic agent for the purpose of causing a broad range of damage to cancerous DNA, its precursors, its replication, and its repair.
Claim 20 is rejected under 35 U.S.C 103 for being unpatentable over Huang, et al. and Singh, N, et al. as evidenced by Bey et al. and Ding et al., and in further view of Motea et al. (Clin Cancer Res. 2019, 25 (8): 2601–2609. https://doi.org/10.1158/1078-0432.CCR-18-2560).
The teachings of Huang and Singh, N. are disclosed above and at least those teachings are incorporated herein by reference.
Both Huang and Singh are silent on the use of radiotherapy with coadministration of an NQO1 bioactivatable drug and cMET inhibitor. However, Motea explains that β-lapachone works synergistically with low-dose radiotherapy to selectively inhibit PARP1-mediated repair of double strand breaks in NSCLC cells. It would have been prima facia obvious for one who is skilled in the art to include radiotherapy in treatment as it is known to potentiate the effects of a sublethal dose of β-lapachone, which has otherwise shown methemoglobinemia and haemolysis at high doses.
Conclusion
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/P.A./ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621