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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01 June 2026 has been entered.
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 01 June 2026.
PRIORITY
EP19161136.7, filed on 03/06/2019, is acknowledged.
CLAIMS UNDER EXAMINATION
Claims 1, 5-6, 9-15 and 17-18 are pending and have been examined on their merits.
WITHDRAWN REJECTIONS
The rejection of claims 8 and 16 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, has been withdrawn due to cancellation.
The rejection of claim 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, has been withdrawn due to claim amendment.
REJECTIONS
The rejections have been modified to address the amendments to claims 10-12 and 18.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 12 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 12 recites measuring pERK expression levels (plural) after administering of the active in (a). The claim is not further limiting because claim 1 recites measuring the level (singular) of pERK in a sample after administration of the active in step (a). Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1, 5-6, 9-15 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Dalgleish et al. (previously cited; Priming of Cancer Cells with Low Dose Naltrexone. US2017/0119755 04 May 2017) in view of in view of Griffin et al. (previously cited; 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), Goldeck et al. (Multi-parametric phospho-flow cytometry: A crucial tool for T lymphocyte signaling studies. Cytometry, 83A: 265-272, 2013) and Liu et al. (previously cited; Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy. International Journal of Oncology 49: 793-802. 2016).
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.
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 ([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 comprising a small molecule signaling inhibitor ([0009]). LDN treatment increases sensitivity to the 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 expression levels of said indicators 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 following treatment to 1) assess LDN efficacy and 2) determine whether a second treatment phase will be administered.
Dalgliesh does not measure the level of phosphorylated ERK in peripheral blood mononuclear cells.
The art does not teach re-administering naltrexone following the measurement step.
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]). Therefore the art teaches re-administration of naltrexone. 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 teaches 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]).
Griffin also teaches the following:
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 teaches the dose of naltrexone can be titrated up based on the effect of the drug (see [0242] [0290]).
D’Souza teaches Erk1 and Erk2 are activated in T cells (PBMCs) following TCR triggering by a well-studied signaling cascade that involves dual phosphorylation of Erka 1/2 (page 7617, right column, second paragraph). The art teaches the magnitude of T cell response is determined by proliferation (Abstract). 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 Erk in T cells using western blot analysis (see page 4; SDS-PAGE and Western blotting). While the art measures ERK using anti-ERK antibodies (page 4, third paragraph), it does not explicitly teach the ERK measured is phosphorylated.
Goldeck measures intracellular phosphorylation in T cells (Abstract). Goldeck explicitly teaches measuring pERK in activated T cells (Figure 3).
Liu et al. teach lower doses of naltrexone are able to reduce tumor growth by interfering with cell signaling as well as by modifying the immune system (page 793 left column, first paragraph). Liu teaches “We have evaluated the gene expression profile of a cancer cell line after treatment with low-dose naltrexone (LDN), and assessed the effect that adapting treatment schedules with LDN may have on enhancing efficacy. LDN had a selective impact on genes involved with cell cycle regulation and immune modulation” (see Abstract). Liu teaches ERK is used to assess the general signaling status of the cell (page 797, right column, first paragraph). Liu measures phosphorylated ERK (hence, activated ERK) (see Figure 2). It is noted that relative to untreated cells, Figure 2 indicates an increase in pERK with LDN treatment.
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 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 pERK indicates T cell activation and Liu teaches phosphorylated ERK can be measured to assess the signaling status of a cell following naloxone treatment. The skilled artisan would want to measure activated ERK to determine if an effective dose of LDN has been administered. One would have had a reasonable expectation of success measuring pERK in a T cell since Goldeck teaches phosphorylated ERK can be measured in T cells. The skilled artisan would re-administer naltrexone at a different dose if pERK is not increased to find the optimal therapeutic dose. One would have been motivated to do so since Griffin teaches titrating the dose based on efficacy. 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 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 48 hours after administration to assess the efficacy of the dose administered. Therefore claims 10-12 are 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 treats HIV+ patients undergoing antiretroviral treatment ([0215]). Therefore claim 17 is rejection.
Regarding independent claim 18:
The teachings of Dalgleish are reiterated.
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.
The teachings of Griffin, D’Souza and Goldeck are reiterated.
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 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 pERK since D’Souza teaches pERK indicates T cell activation and Liu teaches pERK can be measured to assess the signaling status of a cell following naloxone treatment. The skilled artisan would want to measure activated ERK to determine if an effective dose of LDN has been administered. One would have had a reasonable expectation of success measuring pERK in a T cell since Goldeck teaches phosphorylated ERK can be measured in T cells. 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 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.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 01 June 2026 are acknowledged.
Argument 1: The Applicant argues Dalgleish discloses the use of naltrexone, but is otherwise entirely irrelevant. The Applicant argues Dalgleish does not teach administering a second treatment based on cell activation or suggest monitoring immune cells.
Response to Argument 1: The Applicant has improperly argued the references separately. The rejection is not based on anticipation. Dalgleish teaches a method to monitor and assess treatment with naltrexone. Dalgleish administers naltrexone to a subject. Dalgleish obtains a cell sample from a patient. Dalgleish measures activation of a cell signaling protein (BAD) following treatment to 1) assess LDN (low dose naltrexone) efficacy and 2) determine whether a second treatment phase will be administered. The deficiencies of Dalgliesh are: 1) the reference does not measure the level of phosphorylated ERK in peripheral blood mononuclear cells. The art does not teach re-administering naltrexone following the measurement step (as recited in instant claim 1).
Griffin is relied upon because it teaches LDN activates T cells. T cells are a subset of PBMC. D’Souza teaches ERK is phosphorylated in activated T cells (a PBMC). Liu teaches treatment with LDN activates ERK in cells. Goldeck explicitly teaches ERK phosphorylation can be measured in T cells
Argument 2: The Applicant argues Griffin is entirely silent on intracellular signaling markers and does not teach any measurement or monitoring step.
Response to Argument 2: Applicant has improperly argued the references separately. The rejection is not based on anticipation. While the Applicant argues Griffin does not teach a measuring or monitoring step, the claims do not recite a “monitoring step”. Dalgleish teaches measuring a cell signaling protein and monitoring the response in the subject. Examiner notes Griffin teaches titrating the dose of naltrexone based on patient response. This is monitoring. Griffin is relied upon because it explicitly teaches LDN activates T cells (a subset of PBMC). The art provides a nexus between LDN and PBMC activation.
Argument 3: The Applicant argues D’Souza is only directed to the role of ERK in T-cell proliferation while “Lu” examines ERK phosphorylation in the content of GVHD. The Applicant argues Lu identifies interventions which suppress pERK. The Applicant argues the references provide no link to naltrexone.
Response to Argument 3: The Applicant has improperly argued the references separately. The rejection is not based on anticipation. D’Souza is relied upon because it teaches ERK phosphorylation is an indicator of T cell (a PBMC) activation. “Lu” is not cited as prior art. Goldeck relied upon because it teaches pERK can be measured in activated T cells. “Liu” is relied upon because it teaches LDN induces ERK phosphorylation in cells. Thus, Liu provides a link between LDN and ERK signaling.
Argument 4: The Applicant argues the rejections are based on impermissible hindsight reasoning.
Response to argument 4: The argument is not persuasive. Each claim element is taught in the prior art. The rejections only take into account knowledge which was within the level of ordinary skill at the time the claimed invention was made. See MPEP
MPEP 2145 XA.
Conclusion
No claims are allowed.
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) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
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