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 .
DETAILED ACTION
This Office Action is in response to Applicant’s Arguments and Amendment filed, 05/07/2026, wherein the Amendment amended claims 1-4 and 6, cancelled claim 5, and added claims 11-12.
Claims 1-4 and 6-12 are pending and examined on the merits herein.
Priority
This application claims the following priority:
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REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
Claim Objections
Applicant’s amendments to the claims are sufficient to overcome these objections.
35 U.S.C. § 112(b)
Applicant’s amendments to the claims are sufficient to overcome these rejections.
35 U.S.C. § 103
Applicant’s amendment to independent claim 1 that adds the limitation “prior to subjecting a patient to a radiotherapy” is sufficient to overcome this rejection.
REJECTIONS-NEW
Applicant’s amendment to independent claim 1 that adds the limitation “prior to subjecting a patient to a radiotherapy” has resulted in the below new rejection.
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 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 1-4, 6-10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0029071 to Biswal (published 2012, PTO-892) in view of Morel (Parthenolide Selectively Sensitizes Prostate Tumor Tissue to Radiotherapy while Protecting Healthy Tissues In Vivo, published 2017, IDS of 06/06/2023), Tong (ACT001 reduces the expression of PD-L1 by inhibiting the phosphorylation of STAT3 in glioblastoma, published 05/01/2020, IDS of 06/06/2023), and Zhou (Ionizing radiation modulates vascular endothelial growth factor expression through STAT3 signaling pathway in rat neonatal primary astrocyte cultures, published 2019, IDS of 06/06/2023).
Biswal teaches a method for treating or preventing radiation injury in a subject comprising contacting a cell with an effective amount of a Nrf2 activator (claims 1-3), wherein parthenolide,
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, is taught as a Nrf2 activator (pg. 9 claim 10, Table 1A).
Biswal teaches the radiation injury as radiotherapy (pg. 9, claim 13).
Biswal teaches the Nrf2 activator as administered prior to radiation therapy (pb. 9, claims 16 and 18).
While Biswal teaches a method of treating or preventing radiation injury by administering an Nrf2 activator prior to radiotherapy, it differs from that of instant claim 1 in that it does not teach the instantly claimed compound.
Morel teaches parthenolide (PTL),
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, and dimethylaminoparthenolide,
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a PTL analog with increased bioavailability, as selectively sensitizing prostate tumor tissue to radiotherapy while protecting healthy tissues in vivo. Morel additionally teaches PTL as exhibiting anti-inflammatory and antitumor properties and selectively inducing radiosensitivity in prostate cancer cell lines, while protecting primary prostate epithelial cell lines from radiation-induced damage (title, abstract).
Thus, an ordinary skilled artisan would have been motivated to particularly select parthenolide as the Nrf2 activator in the methods of Biswal.
Tong teaches ACT001, the instantly claimed compound, as inhibiting STAT3 by reducing the expression of PD-L1 by inhibiting the phosphorylation of STAT3 (title, abstract; pg. 5954, Conclusion).
Tong teaches ACT001 as derived from the structural modification of parthenolide (PTL). However, PTL is unstable in both acidic and basic conditions, limiting its clinical application. Micheliolide (MCL),
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, has the same anticancer structure as PTL but has more persistent stability in the plasma than PTL. Dimethylaminomicheliolide (DMAMCL) is a dimethylamino Michael adduct of MCL, and ACT001 is the fumarate salt form of DMAMCL. Both ACT001 and DMAMCL release MCL slowly and consistently, and both drugs diffuse through the blood-brain barrier. ACT001/DMAMCL have shown potent anticancer and anti-inflammatory activity (pg. 5944, Col. 1).
Zhou teaches that radiation induced brain injury (RBI) usually occurs six months to three years after irradiation, causing cognitive dysfunction, epilepsy, and other neurological dysfunction, and can even cause cerebral edema and herniation. Zhou teaches that X-ray irradiation directly induces the activation of astrocytes and activated STAT3 signaling pathway (abstract).
Zhou teaches that after the addition of a STAT3pathway inhibitor, most of the Ast radiation activation was suppressed and the expression of high level expression of VEGF decreased after irradiation (pgs. 9-11, Discussion; particularly see the last paragraph of Discussion for a summary).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select ACT001, the instantly claimed compound as the Nrf2 activator in the method of Biswal, to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Morel teaches PTL as selectively inducing radiosensitivity in cancer cell lines, while protecting non-cancer cell lines from radiation-induced damage,
- Tong teaches ACT001 as derived from the structural modification of PTL,
-Tong teaches PTL as unstable in both acidic and basic conditions, limiting its clinical application, and teaches ACT001 as having more persistent stability in the plasma than PTL,
-a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities (MPEP 2114.09)
-Tong teaches ACT001 as inhibiting STAT3, and
-Zhou teaches that STAT3pathway inhibitors as inhibit radiation injury markers, thus treating radiation injury.
As such, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at a method of treating or preventing radiation injury by administering a more stable PTL derivative, ACT001 that more effectively treats or prevents radiation injury by providing more persistent stability in the plasma and by inhibiting STAT3.
Regarding claim 2, as evidenced by pg. 8 of the instant specification and the teachings of Tong, ACT001 is:
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Regarding claim 3, Biswal teaches the radiotherapy as treatment for a neoplasia, i.e., a tumor ([0054]), and Morel particularly teaches the treatment of prostate tumors, such as metastatic prostate tumors (abstract; pg. 508, first full paragraph; pg. 510, last full paragraph).
Regarding claim 4, Biswal teaches the radiation injury as exposure to ionizing radiation ([0018]) and Morel teaches X-ray irradiation (pgs. 504, 509).
Regarding claim 6, Biswal teaches is compounds in composition with a pharmaceutically acceptable diluent, carrier or excipient in a unit dosage form.
Regarding claims 7 and 10, Biswal teaches liquid and capsule formulations ([0055]-[0056]).
Regarding claim 8-9, Biswal teaches intravenous and oral formulations ([0055]-[0056]).
Regarding claim 12, Biswal teaches administration of 0.01-1000mg/kg of the Nrf2 activator ([0058]), and where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (MPEP 2144.05). Moreover, Tong teaches administration of either 100 mg/kg or 400mg/kg ACT001 as therapeutically effective amounts for treating patients with tumors (paragraph spanning pgs. 5951-5952; pg. 5954). As such, an ordinary skilled artisan would have been motivated to modify the dosage amount of ACT001 in the combination of Biswal, Morel, Tong, and Zhou, to arrive at 200mg/kg, a dosage amount is most effective in treating radiotherapy injuries.
The optimization of known amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0029071 to Biswal (published 2012, PTO-892), Morel (Parthenolide Selectively Sensitizes Prostate Tumor Tissue to Radiotherapy while Protecting Healthy Tissues In Vivo, published 2017, IDS of 06/06/2023), Tong (ACT001 reduces the expression of PD-L1 by inhibiting the phosphorylation of STAT3 in glioblastoma, published 05/01/2020, IDS of 06/06/2023), and Zhou (Ionizing radiation modulates vascular endothelial growth factor expression through STAT3 signaling pathway in rat neonatal primary astrocyte cultures, published 2019, IDS of 06/06/2023), as applied to claims 1-4, 6-10 and 12 above, and further in view of Collett et al. (Basicmedical Key, Dosage regimens, published 06/02/2016, PTO-892)
Biswal, Morel, Tong, and Zhou are applied as discussed above, and incorporated herein.
While the combination of Biswal, Morel, Tong and Zhou teaches a method of treating radiation injuries comprising prior to subjecting a patient to a radiotherapy, administering the instantly claim compound, it differs from that of instant claim 11 in that it does not teach administration 17 days to 48 hours prior to administering the radiotherapy.
Collett teaches that the design of a dosage regimen determines the therapeutic benefit for patients. The principles of clinical pharmacokinetics are applied to design a dosage regimen for a patient that ensures the appropriate formulation of drug is chosen for an appropriate route of administration. One the basis of the patient’s drug handling parameters, which require an understanding of absorption, distribution, metabolism and excretion, the dosage regimen for the medicine in a particular patient, can be optimized. The pharmacist needs to ensure the appropriate regimen is prescribed to achieve optimal efficacy and minimal toxicity (pg. 2, 1st paragraph).
Collett teaches that clinical pharmacokinetics provides a basic understanding of the principles required to design a dosage regimen, wherein pharmacokinetics provides a mathematical basis to assess the time course of drug and their concentration in the body and enables absorption, distribution, metabolism, and excretion (ADME) to be quantified (pg. 2, 2nd paragraph).
Collett teaches that the design of the regimen, i.e. formulation, route of administration, dose size, and dose frequency, are important factors which influence what plasma concentration is achieved and maintained in the body over the prescribed course of drug treatment. Collett further teaches that other factors that require consideration are patients’ individuals needs and lifestyles (pg. 3, 3rd paragraph).
Collett teaches that to understand how the design of dosage regimen influences the time course of a drug in the body, consideration of the complex pharmacokinetic process of drug input, output, and distribution within the body must be considered (pg. 3, last paragraph). Collett teaches that pharmacokinetic models are hypothetical constructs which describe the fate of a drug in a biological system following its administration. The purpose of modeling is to characterize the ADME profile for a drug to indicate how the drug is handled by the patient and to characterize basic parameters (pg. 4, 1st paragraph).
Collett teaches that the greater the rate of drug input relative to the rate of drug output from the body compartment over the net absorption phase, the higher will be the peak concentration achieved in the body or plasma following oral administration of a single dose of drug.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select 17 days to 48 hours as the time period that is prior to administering the radiotherapy, in the combined method of Biswal, Morel, Tong, and Zhou, to arrive at instant claim 11. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Collett teaches that the design of a drug regimen is based on formulation of the composition, route of administration, dose size, and dose frequency to achieve and maintain a specific plasma concentrations,
-Collett teaches that the design of a dosage regiment determines the therapeutic benefit for a patient,
-Collett teaches optimizing the dosage regiment based on particular patients to achieve optimal efficacy and minimal toxicity, and
- "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II).
As such, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at a method that is optimized to reduce radiation injury.
Response to Arguments
The above rejection is new. The new rejection meets the limitations of the instant claims as amended and added.
Regarding the arguments directed toward unexpected results on pgs. 6-7, Remarks, as discussed in the above rejection, an ordinary skilled artisan would have reasonably expected ACT001 to radioprotect normal tissue since parthenolide and its derivatives, i.e., ACT001, are known in the art to have this property.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LAUREN WELLS/Examiner, Art Unit 1622
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