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 OFFICE ACTION
This Office Action is in response to the papers filed on 20 October 2025.
PRIORITY
EP19161136.7, filed on 03/06/2019, is acknowledged.
CLAIMS UNDER EXAMINATION
Claims 1, 5-6 and 8-18 are pending and have been examined on their merits.
WITHDRAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment.
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 8 and 16 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 claims contain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites (a) administering the active (naltrexone). The claim has been amended to recite the active is administered such that the level of phosphorylated ERK (pERK) in peripheral blood mononuclear cells is not increased from prior to (a).
Claims 8 and 16 encompass doses of 4.5 mg of less naltrexone. The Instant Specification states “using a low dose naltrexone, or a metabolite or analogue thereof, increases the expression of pERK in a subject” (page 2, lines 20-22). The specification discloses a low dose of naltrexone is “no more than 4.5 mg … preferably from 3 mg to 4.5 mg” (see page 8, lines 1-7). Therefore, as evidenced by the specification, the amounts recited in claims 8 and 16 will increase expression of pERK. The specification does not provide support for a daily dose of no more than 4.5 mg that does not increase pERK as recited claims 8 and 16.
A consideration of the four corners of the specification does not reflect that applicants have actually invented the claimed invention, since the specification does not provide support for a dose of 4.5 mg or less than does not increase phosphorylated ERK.
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.
Claim 18 is 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.
Claim 18 recites (a) administering an active that is naltrexone. Step (b) has been amended to recite “measuring the level of pERK …after administration of the active in (a) administering a further treatment drug to the subject”. It is unclear if the claim means the “further treatment drug” is administered in step (a) or if the “further treatment drug” is administered after pERK measurement. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Dalgleish et al. (Priming of Cancer Cells with Low Dose Naltrexone. US2017/0119755 04 May 2017) in view of Griffin et al. (Method for Inducing a Sustained Immune Response. US20170239238A1), D’Souza et al. (previously cited; The Erk2 MAPK Regulates CD8 T Cell Proliferation and Survival. J Immunol. 2008 Dec 1;181(11):7617–7629) and Lu et al. (STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease. Blood (2008) 112 (13): 5254–525).
Dalgleish et al. teach a diagnostic test to monitor and assess the response of a subject to treatment with naltrexone or an analogue thereof (Abstract; [0009] [0017]). Low dose naltrexone (LDN) is administered in a first treatment phase prior ([0008]). A sample obtained from the subject who is or has been undergoing treatment with said first phase (i.e., low dose naltrexone) is analyzed ([0009]). Cancer cells are analyzed to determine whether the BAD protein is (1) upregulated and (2) not substantially in a phosphorylated state ([0009] [0045]). The art teaches these are positive indicators of BAD protein activity being stimulated through priming with LDN ([0042]). This also indicates the patient is suitable to undertake a second treatment phase ([0009]). LDN treatment increases sensitivity to a second treatment ([0019]).
Dalgliesh determines upregulation relative to a control comprising one or more untreated and/or unstimulated cells (i.e. in a basal state) of the same tissue type, when measured under analogous conditions, preferably in a sample taken from the subject prior to the first treatment phase ([0044]). The art teaches comparing protein expression in cells before and after the first treatment phase (naltrexone administration) ([0046]). Phosphorylation state can be determined using eastern blotting ([0059]).
The art also teaches the following:
LDN inhibits the growth of cancer cells ([0005]). LDN effects the levels of cellular proteins with a role in the regulation of apoptosis ([0005]). LDN upregulated pro-apoptotic proteins such as BAD ([0019]). BAD promotes apoptosis/cell death upon activation by neutralizing its anti-apoptotic partners) ([0020]).
Phosphorylation of BAD is inhibitory. Phosphorylation inhibits the ability of BAD to initiate apoptosis and neutralize pro-apoptotic proteins ([0020]).
It is noted the art teaches LDN is used for a range of immune-related pathologies and cancer ([0002]).
Dalgleish teaches a method to monitor and assess treatment with naltrexone.
Dalgleish administers naltrexone.
Dalgleish obtains a cell sample from a patient.
Dalgleish measures activation of a cell signaling protein to 1) assess LDN efficacy and 2) determine whether a second treatment will be administered.
Dalgliesh does not measure the level of phosphorylated ERK in peripheral blood mononuclear cells.
Griffin teaches naltrexone is an immunomodulator ([0009]) that can be administered to induce a sustained immune response in humans or animal patients suffering from HIV, AIDS, cancer, inflammation, and neurodegenerative diseases (Abstract; [0021]). The method comprises daily administration of an immediate release naltrexone ([0002]). Naltrexone increases proliferation and functional activities of CD4+T-cells and CD8+T-cells which play a role in anti-virus and anti-tumor activities ([0060] [0213]). It is well known in the art that T cells are PBMCs. Griffin administers 4.5 mg or less to treat the claimed disorders ([0065] [0088] [0099] [0110] [0132] [0216] [0221]) and [0228] –[0236]). As evidenced by the instant specification, a dose of 4.5 mg is a low dose of naltrexone that will increase the level of phosphorylated ERK when administered to a subject ” (page 2, lines 20-22; see page 8, lines 1-7). Therefore Griffin administers naltrexone such that the level of pERK in PBMCs would inherently be increased from prior to administration.
Griffin also teaches the following:
The effect of naltrexone is dependent on dose. If the naltrexone dose is too high, then naltrexone is still bound to the opioid receptor and the met-enkephalin cannot interact with the receptor. The end result and risk of taking such compositions is that either there will be no effect or the cancer cell growth ([0029]).
D’Souza teaches Erk1 and Erk2 are activated in T cells following TCR triggering by a well-studied signaling cascade that involves dual phosphorylation of Erka 1/2 (page 7617, right column, second paragraph). D’Souza isolates CD8 T cells from lymph nodes and spleens (see last paragraph of page 3). Therefore the cells are isolated from a subject. The art teaches said cells are found in peripheral blood (page 8, last paragraph). D’Souza measures Erka in wild type T cells using western blot analysis (see page 4; SDS-PAGE and Western blotting). The art teaches the magnitude of T cell response is determined by proliferation (Abstract).
Lu measures phosphorylated ERK1/2 in activated T cells to identify drug targets for GVHD (Abstract). As evidenced by Griffin, GVHD is an immune disorder ([0089]). Lu analyzes levels of phosphorylated ERK in T cells (Figure 1B). The art teaches ERK 1/2 activation is a prominent feature in activated T cells (page 5257, left column, third paragraph).
It would have been obvious to combine the teachings of the prior art by measuring phosphorylated ERK in T cells following treatment with naltrexone. Dalgleish teaches a measures activation of cell signaling proteins in patient cells to determine monitor and assess naltrexone efficacy. The skilled artisan would analyze T cells (a PBMC) since Griffin teaches naltrexone induces an immune response in patients by inducing activation and proliferation of T cells. One would measure phosphorylated ERK since D’Souza teaches it is an indicator of T cell activation. The skilled artisan would measure phosphorylated (activated) ERK to confirm LDN efficacy. The skilled artisan would administer a further treatment drug after confirming T cell activation since Dalgliesh teaches second treatment is more effective following LDN administration. One would have had a reasonable expectation of success since Lu teaches phosphorylated ERK can be measured in T cells to determine drug efficacy. One would have expected similar results since the references are directed to immune stimulation. Therefore claim 18 is rendered obvious.
Therefore Applicants invention is rendered obvious as claimed.
Claims 1, 5-6 and 8-17 are rejected under 35 U.S.C. 103 as being unpatentable over Dalgleish et al. in view of Griffin et al., D’Souza et al., Lu and Schuck et al. (Use of Titration as a Therapeutic Individualization Strategy: An Analysis of Food and Drug Administration–Approved Drugs. 21 February 2019. Clin Trans Sci (2019) 12, 236–239).
Regarding independent claim 1: The claim recites the active is administered such that the level of phosphorylated ERK in peripheral blood mononuclear cells is not increased from prior to (a). As evidenced by the specification, higher doses of naltrexone decrease the expression of pERK in a subject (page 2, lines 25-30). Therefore the claim limitation is interpreted to refer to the dose administered.
The teachings of Dalgleish are reiterated. Dalgleish teaches a method to monitor and assess treatment with naltrexone. Dalgleish administers naltrexone. Dalgleish analyzes a cell sample from a patient. Dalgleish analyzes the effect of LDN on the activation state of a cell protein following administration to assess treatment with naltrexone.
Dalgliesh does not analyze phosphorylated ERK in peripheral blood mononuclear cells.
Dalgliesh does not teach re-administering naltrexone because the level of pERK is not increased.
The teachings of Griffin are reiterated. The art teaches between about 0.01 to about 10 mg of naltrexone can be administered (Abstract; [0002]). Griffin teaches the effect of naltrexone is dose dependent. When the dose is too high, the end result is that either there will be no effect or the cancer cell growth ([0029]). The art teaches a dose dependent effect.
The teachings of D’Souza and Lu are reiterated.
Schuck teaches selecting a dose regimen that is both safe and effective for patients is one of the most critical elements of a successful drug development program (Abstract; page 236, left column, first paragraph). Optimal dosage selection requires identification of a dose regimen that produces the desired pharmacological effect while avoiding unwanted and potentially dangerous toxicities (page 236, left column, first paragraph).. Titrating the dose regimen of a drug based on patient response may help to identify safe and effective dosages at the individual patient level (See Abstract; see page 236, right column, second paragraph).
It would have been obvious to combine the teachings of the prior art by measuring phosphorylated ERK in T cells following treatment with naltrexone. Dalgleish teaches a measures activation of cell signaling proteins in patient cells to determine monitor and assess naltrexone efficacy. The skilled artisan would analyze T cells (a PBMC) since Griffin teaches naltrexone induces an immune response in patients by inducing activation and proliferation of T cells. One would measure phosphorylated ERK since D’Souza teaches it is an indicator of T cell activation. One would do so to determine if an effective dose of LDN has been administered. One would have had a reasonable expectation of success since Lu teaches phosphorylated ERK can be measured in T cells to determine drug efficacy. The skilled artisan would re-administration naltrexone at a different dose if pERK is not increased to find the optimal therapeutic dose. One would have expected similar results since the references are directed to immune stimulation. Therefore claim 1 is rendered obvious.
Dalgleish administers naltrexone to treat cancer. Therefore claim 5 is rejected.
The cancer can be breast cancer, lung cancer, a glioma or colon cancer ([0062]). Therefor claim 6 is included in this rejection.
Dalgleish administers a low dose of naltrexone daily ([0034]). Dalgliesh does not teach the daily low dose in milligrams. Griffin teaches administering 4.5 mg of naltrexone to treat immune diseases including cancer ([0065] [0088] [0099] [0110] [0132] [0216] [0221]) and [0228] –[0236] .
It would have been obvious to administer 4.5 mg as a low dose. One would have been motivated to do so since Griffin teaches this amount treats cancer. One would have expected similar results since both references administer LDN to treat an immune disease. Therefore claim 8 is included in this rejection.
Dalgleish administers naltrexone (supra). Therefore claim 9 is included in this rejection.
Dalgleish and Griffin teach daily administration of LDN (supra). Dalgleish teaches treatment with naltrexone for 48 hours before determining cellular proteins ([0014]).
The skilled artisan would measure pERK after 48 hours to assess the efficacy of the dose administered. Therefore claims 10-11 are included in this rejection.
Li measures expression phosphorylated ERK in cells treated with LDN (see Figure 2). Therefore claim 12 is included in this rejection.
Dalgliesh treats a subject with cancer (supra). Therefore claim 13 is included in this rejection.
Griffin teaches treating immunocompromised individuals being treated with radiation or chemotherapy ([0012]). Therefore claim 14 is included in this rejection.
Dalgleish teaches LDN is used to treat a range of immune-related pathologies and cancer ([0002]). Dalgleish does not treat HIV/AIDS. Griffin administers LDN to treating a patient with HIV/AIDS (supra). It would have been obvious to treat HIV/AIDS. Dalgliesh teaches LDN can treat immune-related diseases and Griffin teaches LDN can treat HIV/AIDS. One would have had a reasonable expectation of success since Griffin teaches LDN can be administer can treat HIV/AIDS. One would have expected similar results since both references administer LDN to treat an immune disease. Therefore claim 15 is included in this rejection.
Griffin teaches 4.5 mg is the most effective dose ([0219]). Therefore claim 16 is rejected.
Griffin treats HIV+ patients undergoing antiretroviral treatment ([0215]). Therefore claim 17 is rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 20 October 2025 are acknowledged. New grounds of rejection have been set forth above to address the amended claims.
Argument 1: The Applicant argues none of the prior art references disclose or suggest a dose-dependent relationship between naltrexone and pERK in PBMCs.
Response to argument 1: Griffin teaches low dose naltrexone (LDN) is an immunomodulator that increases proliferation and functional activities of CD4+ and CD8+ T cells. T cells are PBMCs. D’Souza teaches T cell activation is results in ERK phosphorylation (activation). This skilled artisan would measure pERK (hence, activated ERK) to assess the effect of LDN on immune stimulation.
Argument 2: The Applicant argues Griffin does not teach ERK or any intracellular signaling molecule.
Response to argument 2: The Griffin reference is relied upon because it teaches LDN enhances T cell activation and proliferation. T cells are a type of PBMC.
Argument 3: The Applicant argues D’Souza does not teach measure pERK in PBMCs.
Response to argument 3: D’Souza is relied upon because it teaches T cell activation is followed by phosphorylation and activation of ERK signaling proteins. As set forth above, Griffin teaches LDN administration stimulates an immune response by increasing T cell proliferation and activation. The skilled artisan would measure ERK activation (phosphorylation) to assess the effect of LDN on T cells.
Argument 4: The Applicant argues Liu measures pERK in cancer cells and does not teach immune cells or in vivo therapy.
Response to argument 4: The arguments are moot because Liu is not cited as prior art.
Argument 5: The Applicant argues Griffin and D’Souza operate in unrelated biological contexts.
Response to argument 5: Griffin teaches a method of inducing an immune response by administering an agent that increases T cell (a PBMC) proliferation and activation. D’Souza teaches T cell activation leads to ERK phosphorylation and activation. The references are related because they are both directed to T cell activation. Therefore the arguments are not persuasive.
Argument 6: The Applicant argues the references provide no basis to expect that pERK levels would remain unchanged or decrease following improper dosing.
Response to argument 6: Dalgleish teaches a method of monitoring the response of a subject following naltrexone administration. The art measures activation of a cell signaling protein to determine LDN efficacy. While Griffin teaches between about 0.01 to about 10 mg of naltrexone can be administered (Abstract; [0002]), Griffin teaches the effect is dose dependent. Griffin teaches when the dose is too high, the end result is that either there will be no effect or cancer cell growth ([0029]). Therefore Griffin recognizes LDN has a dose dependent effect. Because LDN stimulates T cell proliferation and activation when administered in an effective amount, one would measure pERK to assess T cell activation. The argument is not persuasive.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the APIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653