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 .
Claim Status
Applicant’s amendments received 06MAY2026 are acknowledged.
Claims 2-9, 11-13, 16, 18-19, and 22 have been canceled.
Claims 1, 10, 14-15, 17, and 20-21 have been amended.
Claims 23-25 are new.
Claims 1, 10, 14-15, 17, 20-21, and 23-25 are pending in the instant application and examined on the merits (i.e., Claim(s) 1 is/are independent).
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/EP2021/072865, filed 17AUG2021, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of European Patent Application No. 20191392.8 filed on 17AUG2020 has been received and is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 06MAY2026 is/are acknowledged and the references cited therein have been considered.
Claim Objections
Applicant’s arguments, see p 5, Objections to the claims section, filed 06MAY2026, with respect to objections to claim(s) 14 for informalities have been fully considered and said objections to claim(s) 14 have been withdrawn in view of claim amendments filed as part of said response.
As a result of claim amendments filed 06MAY2026, claim 1 is objected to because of the following informalities:
Claim 1 is objected to because the lines are crowded too closely together, making reading difficult (see lines 2-3). Substitute claims with lines one and one-half or double spaced on good quality paper are required. See 37 CFR 1.52(b). Appropriate correction is required.
Withdrawn Rejections
35 USC §112a-Enablement and Written Description
Applicant’s arguments, see p 5-7, Claim rejections – 35 USC §112a section, filed 06MAY2026, with respect to the rejection(s) of claim(s) 1 and 10-22 (i.e., rejection(s) of claim(s) 11-13 16, 18-19, and 22 are moot because claims have been cancelled) under 35 USC §112(a) have been fully considered and said rejections of claims 1, 10, 14-15, 17, and 20-21 have been withdrawn in view of the claim amendments filed as part of said response.
35 USC §102
Applicant’s arguments, see p 7, Claim rejections – 35 USC §102 section, filed 06MAY2026, with respect to the rejection(s) of claim(s) 1, 10-11, 14, and 16 (i.e., rejection of claim(s) 11 and 16 are moot because claims have been cancelled) under 35 USC §102 have been fully considered and are fully persuasive because of the claim amendments which add limitations not taught in the cited art. As such, said rejection of claim(s) 1, 10, and 14 under 35 USC §102 have been withdrawn.
35 USC §103
Applicant’s arguments, see p 7, Claim rejections – 35 USC §103 section, filed 06MAY2026, with respect to the rejection(s) of claim(s) 12-13 and 22, are moot because said claims have been cancelled.
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.
Applicant’s claim amendments received as part of the 06MAY2026 response have necessitated the following new grounds of rejection.
Claims 1, 10, 14-15, 17, 20-21, and 23-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling and having support for:
“A method for treating a tumor target site in a patient having cancer, comprising:
A) intratumorally administering a therapeutically effective amount of MgCl2,
B) intravenously administering a therapeutically effective amount of an anti-PD1 or anti-PDL1 antibody and intratumorally administering a therapeutically effective amount of MgCl2 at the same time, and
C) intratumorally administering a therapeutically effective amount of MgCl2 to maintain an effective concentration at the target site;
wherein the tumor is a solid tumor; and
wherein the anti-PD1 or anti-PDL1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, spartalizumab, atezolizumab, durvalumab and avelumab.” (claim 1); does not reasonably provide enablement or support for more.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention. Claims 10, 14-15, 17, 20-21, and 23-24 are also rejected since they depend upon claim 1 but do not remedy this deficiency.
In the instance of claim 1, the nature of the invention drawn to a method for treating essentially any cancer in a patient comprising intravenously administering a therapeutically effective amount of an anti-PD1 or anti-PDL1 antibody and essentially any amount of magnesium sulfate by essentially any route and at essentially any time, is not fully enabled and is not fully supported by the specification or prior art. The reason claim 1 is not fully enabled and supported is because:
i) The route of administration of the MgCl2 supported by the specification is intratumorally because the specification teaches that a high concentration of the LFA-1 mediator (i.e., Mg2+) at the target site may be beneficial for the anti-cancer immune response, while a high concentration of the LFA-1 signaling mediator (i.e., Mg2+) or the invention at a non-target site may induce unwanted effects (p 22 of the originally filed specification) and the data from the working examples support that intratumoral Mg2+ (i.e., MgCl2) application potentiated antitumor activity of memory CD8 T cells and that increasing intratumoral Mg2+ (i.e., MgCl2) concentration synergized with the PD1 blockade resulting in improved tumor suppression (emphasis added, p 55 of the originally filed specification);
ii) The support in the art that oral administration of magnesium leads to gastrointestinal irregularities because the poorly absorbable Mg2+ ions lead to an osmotic gradient in the intestine, which results in a fluid influx into the digestive tract having a laxative effect. Furthermore, administration of magnesium intravenously can result in respiratory arrest requiring slow intravenous injection, with other side effects including headache, palpitations, dizziness, nausea, and vomiting. Specifically, intravenous administration of a magnesium sulfate solution leads to a brief, strong increase in the serum magnesium level, which then decreases rapidly and therefore a bolus dose is not suitable to increase the magnesium level in the human body over a longer period, e.g., hours or days (WO 2015/040028 A1, Fresenius Medical Care Deutschland GMBH, et al., 26MAR2015, see technical area section). In this instance, because there are no specific administration/dose/dose regimen limitations, it is unclear how oral or intravenous administration of a magnesium salt, especially when it comprises magnesium sulfate will maintain a localized concentration of magnesium in the tumor target and not at an off-target site as highlighted in section i) supra and exemplified in the working examples of the specification. Although there has been retrospective evidence of cancer patients receiving immune checkpoint inhibitors that have been stratified by Mg2+ serum level abundance having improved overall survival, the retrospective nature of the analyses limits the significance of the associations detected (i.e., intravenous administration of a magnesium salt or oral administration of a magnesium salt resulting in an increase in serum magnesium levels requires additional studies to clarify the relevance of Mg2+ as an immunomodulatory agent in cancer medicine or as a predictive clinical biomarker for immune checkpoint inhibitor response) (Lötscher, et al., 2022, 185, 585-602, see Limitations of the study section and Feng, et al., Eur J Canc, 2024, 213, 1-8, see abstract and conclusions sections).
iii) The support of the art that anti-PD1/anti-PDL1 antibodies lack efficacy against essentially all cancers, for example in multiple myeloma (i.e., blood forming organ cancer or cancer of the immune system) anti-PD1 antibodies are ineffective because antigen presentation is often absent due to mutations and in some T cell malignancies have resulted in disease progression rates (Leokhin, et al., Canc Immunol Res, 2019, 7, 1224-1229, see abstract and Immune checkpoints and cancer therapy) and additionally there is no support provided by the specification, that administration of Mg2+, would result in treatment;
iv) The support of the art that anti-PD1/anti-PDL1 antibodies combined with Mg2+ can if not properly monitored result in excessive supplementation which can have negative impacts on immune function, for example hypermagnesemia can cause severe side effects, such as hypotension and respiratory depression, which may be particularly harmful in patients with lung cancer treated with immunotherapy and Mg2+ (i.e., the Mg2+ administration when used in combination with immunotherapy, requires specific dosing, dosing regimens, testing of serum magnesium levels of the patient, etc. to make certain that the patient does not experience an adverse effect and as discussed in section ii) supra) (Sambataro, et al., Nutrients, 2026, 18, 1-11, see the last paragraph of section 3); and
v) The support in the art that the combination of intratumoral injection of MgCl2 and anti-PD1 antibodies cannot be generalized to autochthonous tumors as they have more heterogeneous architecture, immune cell landscape, perfusion, etc., than cancer models and the long-term consequences of enhancing LFA1 outside-in signaling requires more chronic cancer models (Lötscher, et al., 2022, 185, 585-602, see Limitations of the study section).
In the specific instance of claim 20, it is unclear how the magnesium sulfate is to be administered, how much magnesium sulfate is to be administered, and how often the magnesium sulfate is to be administered over a period of five years and additionally how administration of the magnesium sulfate relates to the intravenous administration of the anti-PD1 or anti-PDL1 antibody. Similarly for claim 21, it is unclear how the magnesium sulfate is to be administered, how much magnesium sulfate is to be administered, and how long the magnesium sulfate is to be administered every 2-7 days and furthermore how administration of the magnesium sulfate relates to the intravenous administration of the anti-PD1 or anti-PDL1 antibody. Additionally, it is unclear whether oral administration of [the] salt comprising magnesium [sulfate] to the patient in claims 24 and 25, will be effective as discussed in sections i) and ii) supra, how much magnesium salt is to be orally administered, when the magnesium salt is to be orally administered, and for how long the magnesium salt is to be orally administered or if it is only the first and second dose.
Therefore, the specification and the prior art supports intratumoral injection or at least a localized concentration of MgCl2 at the tumor target, wherein the tumor target is a solid tumor combined with intravenous injection of an anti-PD1 or anti-PDL1 antibody. Thus, claims 1, 10, 14-15, 17, 20-21, and 23-24 as presently claimed are rejected because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention in view of the unclear nature (i.e., dose, dose regimens, administration route, etc. for the Mg2+ administration), breadth of variables (i.e., essentially any cancer), the level of predictability in the art, and the lack of working examples in the specification.
Applicant argues that amended independent claim 1, reciting a method for treating cancer in a patient comprising: intravenously administering a therapeutically effective amount of an anti-PD1 or anti-PDL1 antibody and a salt comprising magnesium sulfate to the patient is fully enabled and that a person having ordinary skill in the art would be able to practice the claimed method without undue experimentation based on specified paragraphs of the specification and that there are clear examples of intravenous administration of anti-PD1 or anti-PDL1 antibody and a salt comprising magnesium sulfate for the treatment of cancer throughout the application as filed with examples of specified paragraphs. Examiner notes that the originally filed specification does not have paragraph numbers.
RESPONSE
Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as described supra.
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.
Applicant’s claim amendments received as part of the 06MAY2026 response have necessitated the following new grounds of rejection.
Claims 1, 10, 14, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/107389 A1 (SBI Pharmaceuticals co., LTD., et al., 06JUN2019), herein referred to as “’389.”
‘389 teaches pharmaceutical compositions comprising an immune checkpoint inhibitor, 5-ALA and a metal containing compound for the treatment of cancer (see entire document). Specifically, the anti-PD1/anti-PDL1 antibody inhibitors include but are not limited to nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab; the metal containing compound includes magnesium compounds including magnesium sulfate; the type of cancer may vary depending on the immune checkpoint inhibitor used; and is preferably administered simultaneously (see description of the embodiments section).
Therefore, because the method for treating cancer of the instant application comprises the step of administering a therapeutically effective amount of an anti-PD1/anti-PDL1 antibody and a salt comprising magnesium sulfate to a patient, the prior art anticipates the invention as presently claimed.
Claims 1, 10, and 14-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Piranavan, et al., (J Clin Endocrinol Metab, 2019, 104, 550-556), herein referred to as “Piranavan.”
Piranavan teaches a case study, wherein a 61 year old female was being treated for metastatic small cell lung cancer (i.e., solid tumor) with intravenous infusion of nivolumab and being admitted to the hospital for persistent nausea, vomiting, epigastric pain, constipation and generalized weakness, resulting in administration of intravenous calcium gluconate, followed by oral calcium carbonate and intravenous magnesium sulfate; however, the patient’s parathyroid hormone (PTH) levels remained low during hospitalization and initial outpatient follow-up despite adequate repletion of magnesium (see abstract and p 552, col 1). In this instance, a patient was treated for cancer comprising the intravenous administration of the anti-PD1 antibody, nivolumab and was also administered intravenous magnesium sulfate.
Therefore, the prior art anticipates the invention as presently claimed.
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.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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