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 preliminary amendments received 01DEC2023 are acknowledged.
Claims 2-9 have been canceled.
Claims 1 and 10-15 have been amended.
Claims 16-22 are new.
Claims 1 and 10-22 are pending in the instant application.
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 02NOV2024 and 24FEB2023 (2x) is/are acknowledged and the references cited therein have been considered.
Claim Objections
Claim 14 is objected to because of the following informalities:
Claim 14 contains a typographical error: “ovary cancer” should be updated to “ovarian cancer” in line 4, “cervix cancer” should be updated to “cervical cancer” in lines 4-5, and other cancers should be updated appropriately, for example pancreatic, testicular, and esophageal. Furthermore, lung cancer is listed twice in lines 3 and 5. Appropriate correction is required.
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.
Scope of Enablement
Claims 1 and 10-22 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
In the instance of claim 1, the nature of the invention drawn to a method for treating cancer comprising administering to a patient (a) a PD1/PDL1 inhibitor and (b) a salt comprising Mg2+, is not fully enabled. The reason claim 1 is not fully enabled is because:
The breadth of PD1/PDL1 inhibitors and salts of Mg2+;
The lack of support in the specification and lack of working examples which support the breadth of claim 1; and
The lack of predictability in the literature for using any PD1/PDL1 inhibitor or any Mg2+ salt without undue experimentation (i.e., screening) required for one of ordinary skill in the art to make and use the instantly claimed method. Claims 10-22 are also rejected since they depend from claim 1, but do not remedy this deficiency.
The specification discloses that the combination of a immune modulator, which in this instance is a checkpoint inhibitor (CPI), and a Lymphocyte function-associated antigen 1 (LFA-1) signaling mediator, such as a Mg2+ salt can be used to selectively and significantly enhance anti-cancer immune response (p 1, first paragraph on the page). The specification further discloses that a CPI refers to a molecule that totally or partially reduces, inhibits, interferes with or modulates one or more checkpoint proteins (p 19). The LFA-1 mediator requires a two-step screening process (p 16-17); of which one of the LFA-1 mediators which may have the desired properties from the screening process is/are similar to the properties of Mg2+ (p 16). Working example 1 of the specification is the only example of a method of treatment, which requires a very specific method of administration (i.e., intratumoral) of a specific Mg2+ salt (i.e., MgCl2) and a specific CPI (i.e., an anti-PD1/PDL1 antibody), wherein the salt was administered prior, concurrently, and following CPI administration in a single dosing cycle (i.e., specific dosing regimen). Although, this example supports the intratumoral administration of an anti-PD1/PDL1 antibody (i.e., CPI) and MgCl2 (i.e., LFA-1 mediator) utilizing a specific dosing regimen to reduce tumor volume and overall survival, it is unclear whether this same effect could be observed with any PD1/PDL1 inhibitor and any Mg2+ salt, administered iv or subcutaneously, and which utilized an alternate dosing regimen (i.e., wherein the Mg2+ salt and PD1/PDL1 inhibitor are administered simultaneously and/or sequentially, and/or the PD1/PDL1 inhibitor is administered prior to the Mg2+ salt, claims 17-19). In this instance, there is no disclosure or guidance provided regarding using the invention as currently claimed. Furthermore, the literature teaches that there are several PD1/PDL1 inhibitors such as small molecules BMS-1001 or BMS-1166, antibodies nivolumab, pembrolizumab, atezolizumab, durvalumab, or avelumab, or utilizing non-coding RNAs for post-transcriptional regulation of PDL1 (Skalniak, et al., Oncotarget, 2017, 8, 72167-72181 and Lin, et al., Molecular Canc, 2024, 23, 1-50, see entire documents). Additionally, per any general chemistry book, it is well known that Mg2+ salts come in a variety of formulas including ones that are insoluble or poorly soluble in water, such as Mg(OH)2 (see OA.APPENDIX for solubility chart). Therefore, the implementation of the invention in view of the breadth of variables (i.e., PD1/PDL1 inhibitors or Mg2+ salts), lack of support in the specification and working examples, and the lack of predictability in the art, would require undue experimentation for one of ordinary skill in the art to make and/or use the invention as currently claimed. Examiner notes that “A method for treating cancer comprising intratumorally administering to a subject having a solid tumor:
(a) a therapeutically effective amount of an anti-PD1 antibody or anti-PDL1 antibody and
(b) a therapeutically effective amount of MgCl2 salt;
wherein the MgCl2 salt is administered at least twice, 2-4 days prior to simultaneous administration of MgCl2 and the anti-PD1 antibody or anti-PDL1 antibody and the MgCl2 salt is administered 3-11 days following the simultaneous treatment, and
wherein the administration of MgCl2 and/or the anti-PD1 antibody or anti-PDL1 antibody is every 2-5 days for a total of 26 days” is enabled.
Claim 14 is not fully enabled because while treatment of a solid tumor is enabled, there is no support when there is no solid tumor present, for example in a blood-forming organ cancer (e.g., leukemia in the bone marrow or lymphatic system), cancers of the immune system (e.g., lymphoma or myeloma) or a blood cancer (e.g., leukemia, lymphoma, myeloma).
Per the discussion supra, claims 17-19 are not fully enabled because there are no working examples wherein the method comprises or consists of administering the MgCl2 and the anti-PD1 antibody or anti-PDL1 antibody simultaneously and as similarly applied to claims 18 and 19. Working example 1 supports the MgCl2 salt is administered 2-4 days prior to simultaneous administration of MgCl2 and the anti-PD1 antibody or anti-PDL1 antibody and the MgCl2 salt is administered 3-11 days following the simultaneous treatment.
With regards to claim 20, drawn to administration of the Mg2+ salt repeatedly over a period of five years is not fully enabled because in addition to the deficiencies from depending on claim 1, there is no dose (i.e., how much and how often) specified and the specification does not provide any support or evidence for the administration of a Mg2+ salt for longer than 26 days (Figure 1G). Similarly for claim 21, drawn to administration of the Mg2+ salt every 2-7 days is not fully enabled because in addition to the deficiencies of claim 1, it is unclear for how long the Mg2+ salt is to be administered every 2-7 days. In this instance, the specification supports administration of the Mg2+ salt every 2-5 days for a total of 26 days. Administration of the Mg2+ salt every 2-7 days for an undetermined period of time is not enabled. Therefore, it would require undue experimentation for one of ordinary skill in the art to determine how often the Mg2+ salt should be administered over five years and for how long the Mg2+ salt should be administered every 2-7 days.
Written Description
Claims 1 and 10-22 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 claim(s) contains 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
Applicant has broadly claimed a method for treating cancer comprising administering to a patient (a) a PD1/PDL1 inhibitor and (b) a salt comprising Mg2+. The broadest claims do not require the PD1/PDL1 inhibitor to have any function apart from totally or partially reducing, inhibiting, interfering with or modulating PD1/PDL1 or the Mg2+ salt have any function apart from being a divalent Mg-based salt, with dependent limitations addition additional functional limitations, such as, the carrier is a membrane-forming molecule (i.e., claim 12), the membrane-forming molecule is a capsule-forming lipid (i.e., claim 13), or the carrier allows for targeted delivery (i.e., claim 16). No claims recite any specific or particular structure of the PD1/PDL1 inhibitor or the salt of Mg2+ that gives rise to the specific treatment of any cancer upon administration to the patient, with exception of claims 10 and 22, which independently define the PD1/PDL1 inhibitor and the salt of Mg2+, respectively. Claims 10-22 are also rejected since they depend from claim 1, but do not remedy this deficiency.
To support such broad claims, the specification teaches that the combination of a immune modulator, which in this instance is a checkpoint inhibitor (CPI), and a Lymphocyte function-associated antigen 1 (LFA-1) signaling mediator, such as a Mg2+ salt can be used to selectively and significantly enhance anti-cancer immune response (p 1, first paragraph on the page). The specification further discloses that a CPI refers to a molecule that totally or partially reduces, inhibits, interferes with or modulates one or more checkpoint proteins (p 19). The LFA-1 mediator requires a two-step screening process (p 16-17); of which one of the LFA-1 mediators which may have the desired properties from the screening process is/are similar to the properties of Mg2+ (p 16). Although the claims are drawn to a method for treating cancer comprising administering to a patient (a) a PD1/PDL1 inhibitor and (b) a salt comprising Mg2+, the experimental data teach a very specific method of administration (i.e., intratumoral) of a specific Mg2+ salt (i.e., MgCl2) and a specific CPI (i.e., an anti-PD1/PDL1 antibody), wherein the salt was administered prior, concurrently, and following CPI administration in a single dosing cycle (i.e., specific dosing regimen). For example, working example 1 teaches the intratumoral administration of a specific anti-PD1/PDL1 antibody and MgCl2 utilizing a specific dosing regimen to reduce tumor volume and overall survival.
With regard to carriers, the specification defines them as any pharmaceutically acceptable solvent, suspending agent, vehicle agent, drug composition, device, tool, or combination thereof that allows targeted delivery (p 24). Targeted delivery refers to a certain way of delivery that allows increasing a concentration and/or an effect of an active agent more in at least one target site than in at least one non-target site (i.e., by liposome encapsulation) (p 24). Furthermore, in certain embodiments the carrier comprises polymerizable lipid amphiphiles to generate crosslinked liposomes, wherein the lipid may be functionalized with a bioconjugation handle (p 24-25) or immune T cell linked synthetic nanoparticles are used as a carrier to the target site (p 25). However, while the specification provides reference to O’Brien, et al., Acc Chem Res, 1998, 31, 861-868 or US Patent No.: 10,307,491 for the targeting of the capsule-forming lipids, there are no working examples which suggest that the formulations provide targeted delivery of MgCl2 to a tumor and therefore would require undue experimentation with ordinary skill in the art to optimize the liposome structure, liposome formulation (i.e., amount of the MgCl2 salt) and the timing of dosing in addition to the deficiencies of claim 1, upon which claim 11 is dependent.
Furthermore, the literature teaches that there are several PD1/PDL1 inhibitors such as small molecules BMS-1001 or BMS-1166, antibodies nivolumab, pembrolizumab, atezolizumab, durvalumab, or avelumab, or utilizing non-coding RNAs for post-transcriptional regulation of PDL1 (Skalniak, et al., Oncotarget, 2017, 8, 72167-72181 and Lin, et al., Molecular Canc, 2024, 23, 1-50, see entire documents). In the instance of inhibitors, artisans are well aware that knowledge of a given antigen (for instance a specific epitope of PD1/PDL1) provides no information concerning the structure of the inhibitor that binds the given antigen. Additionally, per any general chemistry book, it is well known that Mg2+ salts come in a variety of formulas including ones that are insoluble or poorly soluble in water, such as Mg(OH)2 (see OA.APPENDIX for solubility chart).
It is noted that applicant has not claimed a product, but rather a method of administering a product. However, artisans must reasonably be in possession of a product in order to be in possession of methods of administering said product. As has been discussed above, the broadest claims describe the administered product based upon what it does, such as treat cancer including inhibiting PD1/PDL1 with a Mg2+ salt. However, as has been made clear by recent court cases as well as USPTO guidance, describing an inhibitor simply by what it inhibits is not sufficient to provide adequate written description for the recited genus, and has been mentioned while antibodies are members of the genus of inhibitors (see claim 10) it is not limited thereto. When it is considered that the agent doing the “inhibiting” can literally be anything including a small molecule, peptide, protein, nucleotide, etc., the size of the genus of administered reagents grows. As such describing the administered reagent based upon what it binds, where it binds, or its function as an inhibitor fails to necessarily provide a structure that gives rise to the aforementioned properties. Additionally, with regard to the divalent cation salt of Mg, the genus is significantly broad as there are a variety of Mg salts, in which it is unclear that all salts would function in the claimed method.
In this instance, the prior art supports that the PD/PDL1 inhibitor structure cannot be determined based on its function and that not all divalent cation Mg salts are water-soluble and presumably lack effectivity in treatment. As presently written, the claims recite that any PD1/PDL1 inhibitor and any Mg2+ salt functions to inhibit PD1/PDL1 and in combination treat cancer. However, the specification and working examples fail to disclose more than 1 example of the combination of a PD1/PDL1 inhibitors of the form of an antibody and Mg2+ salt of MgCl2 and therefore also fail to disclose any data indicating that the breadth of structures (i.e., PD1/PDL1 inhibitors and any Mg2+ salt) encompassed by the language of the instant claims will have the same function (i.e., treat cancer). Therefore, as presently written, the claimed broad genus of and PD1/PDL1 inhibitor and any Mg2+ salt lacks adequate written description because there does not appear to be any correlation between the structure of the inhibitor or the salt and the ability to inhibit PD1/PDL1 or effectively treat cancer. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of any PD1/PDL1 inhibitor and Mg2+ salt that inhibit PD1/PDL1 or effectively treat cancer, at the time the instant application was filed.
Logically, if applicant was not in possession of the agent which is being administered, applicant also was not in possession of methods of administering such reagents at the time the instant application was filed.
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.
Claims 1, 10-11, 14, and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CA 3109360 (Pai, et. al, 27FEB2020), herein referred to as “’360.”
‘360 teaches the use of pharmaceutical formulations comprising magnesium salts and a PD1/PDL1 antibody inhibitor to treat cancer (see entire document, specifically the abstract, p 17-18). Specifically, ‘360 teaches magnesium salts of ascorbic acid, dichloroacetic acid, and/or lactic acid, or ionic compounds produced or synthesized in the form of compounds combined with Mg ions (i.e., Mg2+) (p 17) co-administered anticancer drug such as pembrolizumab (i.e., PD1 inhibitor), which may have a superior effect in treating cancer compared to the anticancer drug alone (p 18), wherein the cancer can be lung, breast, etc. (p 19). ‘360 further teaches that the pharmaceutical composition for treating cancer may be formulated to include carriers, excipients, or diluents to form capsules, suspensions, emulsions, injections (i.e., intravenous, intramuscular, subcutaneous, etc.) inclusive of surfactants (i.e., capable of forming micelles or liposomes or membrane forming molecule), propylene glycol, polyethylene glycol, etc. (p 19-20 and 23). The composition can be administered using a certain apparatus capable of transporting the active ingredient into a target cell (i.e., targeted delivery) (p 23).
Therefore, the prior art anticipates the invention as presently claimed.
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.
Claims 12-13, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over CA 3109360 (Pai, et. al, 27FEB2020), herein referred to as “’360” as applied to claims 1, 10-11, 14, and 16 and in further view of WO 2015/040028 A1 (Fresenius Medical Care Deutschland GMBH, et al., 26MAR2015), herein referred to as “’028.”
The teachings of ‘360 are summarized above.
However, they do not teach: wherein the carrier is a membrane-forming molecule, or wherein the membrane-forming molecule is a capsule-forming lipid, or wherein the salt is MgCl2.
Nevertheless, ‘028 teaches MgCl2 encapsulated in liposomes when it is necessary to increase the Mg level in a patient (see entire document). ‘028 further teaches that Mg is the fourth most abundant cation in the human body and coenzyme of over 300 enzymes, and low levels of Mg are associated with endothelial dysfunction, inflammation, etc. (see Technical area). Furthermore, oral magnesium typically leads to gastrointestinal irregularities, with poorly absorbable magnesium ions leading to an osmotic gradient in the intestine and intravenous magnesium sulfate can lead to respiratory arrest, headache, palpitations, dizziness, nausea, and vomiting, which must be administered over hours or days in order to increase the magnesium level in the serum (Technical area). Liposomes on the other hand are used as a drug delivery system allowing for targeted and selective transport of drugs to those sites in the organism where they are needed. In this instance, ‘028 teaches magnesium liposomes encapsulating magnesium in the form of a water-soluble salt (i.e., magnesium chloride or magnesium sulfate) for delayed release of magnesium for intravenous administration over hours or days (see description of the invention section).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Mg2+ salt and the salt carrier disclosed by ‘360 by utilizing MgCl2 in a liposome as disclosed by ‘028 because it is able to provide intravenous administration over hours or days with reduced side-effects rather as opposed to alternative administration methods. One would have been motivated to do so, given the teachings of ‘360 that the magnesium salts could be administered in a variety of formulations inclusive of utilizing surfactants as carriers which can be used to form membrane-forming molecules. There would have been a reasonable expectation of success, given the knowledge that a liposome encapsulating a Mg2+ salt lead to the ability to deliver MgCl2 intravenously over longer periods of time with a reduced number of side effects, as taught by ‘028.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641