DETAILED ACTION
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
Claims 1-9, and 12-18 are examined herein.
Claims 10, 11, 24, 39, 70, 81 and 82 are withdrawn (see restriction/election below).
Priority
This application is filed 1/12/2024 and claims the benefit of domestic priority as below:
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Information Disclosure Statements
Two IDS(s) received on 1/12/2024, and 9/5/2024 have been considered unless marked with a strikethrough. The references without English translations are also processed without consideration.
Election/Restrictions
Applicant elects Group I (claims 1-18), directed to methods of treating a cancer or enhancing immunotherapy in a subject in need thereof, comprising administering to the subject methanol, or a prodrug thereof. Applicant further elects the PD-1 inhibitor as the species of checkpoint inhibitor and DOCD3 as the species of methanol and species of Formula I. To the extent an election of a specific PD-1 inhibitor is required, Applicant hereby elects pembrolizumab as the species of PD-1 inhibitor, as the elected species in the reply filed on 5/27/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Accordingly, Claims 24, 39, 70, 81 and 82 (Group II) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method of use, there being no allowable generic or linking claim.
The applicant asserts that claims 1-9, and 12-18 in Group I are readable on the elected species PD-1 inhibitor/pembrolizumab species, and claims 1-18 are readable on the elected species DOCD₃ in Group I. Therefore, the Examiner finds that the claims 1-9, and 12-18 read on all elected species PD-1 inhibitor/pembrolizumab/DOCD₃. Claims 10 and 11 from Group I are withdrawn from consideration because these claims do not read on the elected species.
If the elected specie is not identified in the prior arts, the elected specie would be allowable if an independent claim were drafted with that specie alone, and Examiner expanded the search to additional species of the genus per MPEP 802.03.
The elected specie was not identified in the prior art. Further, the Examiner expanded the
search to alternative species, and subsequent examination is based on alternative species expansion.
The alternative specie was identified in the prior art, and claims 1-9, and 12-18 read on the elected species and alternative species, and will be examined on their merits. No further claims are withdrawn. With respect to the elected and alternative species, the art is rejected under 35 USC 112 and 35 USC 103 below.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because:
a. The lines, numbers and lettering are not well-defined in Figure(s) 2A, 2B, and 4A. See 37 CFR 1.84(l) and (q). The graphs, in particular, have significant overlap, making them difficult to interpret.
Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Interpretation
Claims are interpreted in accordance with the broadest reasonable interpretation (BRI) standard
consistent with the specification (See MPEP 2111).
Under the BRI consistent with the specification, the phrase “methanol, or a prodrug thereof” encompasses methanol releasing prodrugs having methyl ester type structures capable of providing methanol and/or methoxide equivalents under biological conditions. The specification defines methyl ester groups and describes de-esterification of such groups to provide methanol, and further identifies fumaric acid as a suitable residue for the disclosed methanol prodrugs (paragraph [0077], and [0194]). Accordingly, dimethyl fumarate (i.e., dimethyl ester of fumaric acid) is reasonably interpreted as falling within, or at least being suggested by, the claimed methanol prodrug genus. (see MPEP 2111.01; in re morris, 127 F.3d 1048 (Fed. Cir. 1997); and in re Smith Int’l Inc., 871 F.3d 1375 (Fed. Cir. 2017))
Claim Rejections - 35 USC § 112, first paragraph
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 1-9, and 12-18 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 for limited preclinical examples involving methanol, formate, or deuterated methanol in an anti PD-1 murine MC38 tumor model, does not reasonably provide enablement for the full scope of the claimed methods of treatment without undue experimentation. 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.
The instant claims are drawn to a method for treating cancer and a method of enhancing immunotherapy by administering a therapeutically effective amount of methanol or a prodrug thereof. The claims broadly encompass cancer treatment and immunotherapy enhancement without limitation to a particular cancer type, tumor biology, route, dose, schedule, patient population, biomarker defined population, or immunotherapy regimen. The claims further encompass additional therapeutic agents, immunotherapy generally, checkpoint inhibitors generally, PD-1 inhibitors including nivolumab, pembrolizumab, and cemiplimab, solid tumors, hematologic cancers, numerous listed cancers, methanol, deuterated methanol, and specific methanol isotopologues.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, and state and predictability of the art
The instant claims relate to cancer treatment and enhancement of immunotherapy using methanol or a prodrug thereof. The claims remain highly unpredictable because immune checkpoint response depends on numerous tumor specific and host specific variables, including tumor microenvironment, immune cell infiltration, checkpoint expression, tumor mutational burden, antigen presentation, cancer lineage, prior treatment history, dosing toxicity, and the particular immunotherapy used.
In view of Petitprez et al. (The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies, Front. Immunol., 11, 784, pub’d 5/7/2020), the composition of the tumor microenvironment affects response to immune checkpoint blockade, and checkpoint blockade depends on immune cell infiltration and the tumor microenvironment’s ability to support and antitumor immune response (abstract). Moreover, Yarchoan et al. (PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers, JCI Insight, 4(6), e126908, pub’d 3/21/2019) teaches that even major biomarkers such as PD-L1 expression and tumor mutational burden had “succeeded and failed” in predicting responders across different cancer types (abstract), and Barceloux et al. (American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning, Clinical Toxicology, 40(4), 415-46, pub’d 7/23/2002) teaches that methanol raises compound specific safety and dosing concerns because methanol toxicity is mediate by metabolism to toxic metabolites (abstract). Therefore, these references evidence the unpredictability of immune checkpoint response across tumor specific and host specific settings, and the amount of experimentation required to use methanol, deuterated methanol, and methanol isotopologues therapeutically across diverse cancer and immunotherapy settings.
Although, the specification provides certain preclinical data centered on MC38 tumor bearing mice treated with anti PD-1 antibody together with methanol, formate, or deuterated methanol, it does not provide a sufficient scientific or clinical framework for cancer treatment and enhancement of immunotherapy using methanol or a prodrug thereof across the full scope of the claims. Accordingly, in view of Petitprez, Yarchoan, and Barceloux, the therapeutic effect shown in a limited MC38 anti PD-1 model cannot be predictably extended to substantially the full scope of the claimed cancers, claimed immunotherapies, checkpoint inhibitors, recited PD-1 antibodies, methanol prodrugs, and methanol isotopologues without undue experimentation.
The breadth of the claims
The claims are very broad insofar as they recite methods of treating cancer and methods of enhancing immunotherapy using methanol or a prodrug thereof. Claims further encompass additional therapeutic agents and immunotherapy, enhancing immunotherapy without limiting the enhancement to a particular endpoint, cancer type, immunotherapy, checkpoint inhibitors, PD-1 inhibitors, specific PD-1 antibodies, cancer types, and methanol types. The claims cover broad therapeutic methods involving methanol, methanol releasing prodrugs, deuterated methanol, and methanol isotopologues across multiple cancer indications, immunotherapy regimens, checkpoint inhibitor classes, and clinically distinct patient populations.
First, "Cancer" as a proliferative disease is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in nearly and tissue or organ system. "The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally." (<https://www.uspto.gov/patents/laws/patent-examination-policy-mpep-staff-35-usc-112-1st-para-enablement#7f> ENABLEMENT DECISION TREE, Example F, situation 1). A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: "In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way". There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers. Accordingly, an effect in one murine tumor model does not, by itself, enable treatment of cancer generally.
Next, the claims recite “methanol or a prodrug thereof”. As discussed in the claim interpretation, “a prodrug thereof” refers to a prodrug of methanol and encompasses methanol releasing compounds, including, but not limited to, methyl ester type compounds capable of providing methanol and/or methoxide equivalents under biological conditions. However, the specification does not provide sufficient guidance showing how to select and use methanol prodrugs across the full scope of the claimed cancer and immunotherapy settings. Prodrugs can differ materially in absorption, distribution, metabolism, release rate, tissue exposure, pharmacological activity, toxicity, and effective dose. Zhang et al. (Drug metabolism in drug discovery and development, Acta Pharm. Sin. B, 8(5), 721-732, pub’d 09/08/2018) teaches that prodrugs of a drug can be new drug candidates distinct from the parent drug, therefore emphasizing the importance of designing prodrugs in a manner that requires the causes that necessitate the use of the prodrug approach be defined and clearly understood (Prodrugs or active metabolites as new drug candidates section). Thus, a person of ordinary skill would not reasonably expect all methanol prodrugs falling within the broad claim scope to have similar therapeutic properties, methanol release profiles, safety profiles, or immunotherapy enhancing effects.
Claims’ breadth is not commensurate with the limited working examples. The specification does not establish a general principle by which methanol, methanol prodrugs, deuterated methanol, or the listed isotopologues can be expected to treat the breadth of the claimed cancer or enhance the breadth of the claimed immunotherapy. In view of Yarchoan, the failure of major biomarkers to uniformly predict checkpoint response across tumor types underscores that response to immunotherapy is cancer specific. In view of Petitprez, the tumor microenvironment further affects whether checkpoint blockade can generate an effective antitumor response. Accordingly, the broad cancer and immunotherapy genera recited in claims 1-9, and 12-18 exceed what would have been reasonably enabled by the disclosed data.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides working examples for limited anti PD-1 based murine tumor experiments. Those examples may provide guidance for a narrow embodiment involving methanol or deuterated methanol in connection with anti PD-1 therapy in an MC38 tumor model. However, the specification does not provide sufficient guidance on how to use substantially the full claimed genus to treat the full scope of the claimed disease settings, immunotherapy regimens, methanol prodrugs, and mutation defined populations without undue experimentation.
The disclosure does not provide therapeutic guidance addressing the full scope of the cancer generally with methanol or methanol prodrugs, and it does not establish that one of ordinary skill in the art could extrapolate from the disclosed preclinical data to the full therapeutic scope of claims without undue experimentation. The disclosure also does not provide representative data for hematologic cancers, for the full list of cancers recited in claim 15, for LAG-3 inhibitor embodiments recited in claim 7, or for immunotherapy classes beyond the limited anti PD-1 context. It also does not show that methanol, methanol prodrugs, or deuterated methanol enhances each of nivolumab, pembrolizumab, and cemiplimab across the claimed cancer types.
Petitprez, and Yarchoan reinforces the deficiency by showing that immune checkpoint response depends on numerous tumor specific and host specific variables, and that the limited examples in the specification do not provide sufficient guidance for predicting which cancer/immunotherapy combinations will respond. Barceloux further shows that additional guidance would also be needed to identify therapeutically effective and tolerable dosing regimens for methanol and related isotopologues across the full scope of claims. Accordingly, the instant specification lacks sufficient therapeutic direction and representative working examples commensurate with the full scope of the claimed methods of treatment.
The quantity of experimentation necessary
Given the limited predictability of the art, the breadth of the claims, and the absence of sufficient guidance or representative working examples, a person having ordinary skill in the art would be required to engage in extensive experimentation to practice the full scope of the claimed invention.
Such experimentation would include determining which cancer types respond to methanol or methanol prodrugs, which cancers respond to deuterated methanol or the specific isotopologues of claim 18, which immunotherapies are enhanced, whether CTLA-4, PD-1, PD-L1 and PAG-3 checkpoint inhibitors are enhanced, whether nivolumab, pembrolizumab, and cemiplimab are each enhanced in each claimed cancer type, what dose, route, and schedule are effective, and whether the treatment can be administered with acceptable toxicity.
As discussed above, Yarchoan shows predictive biomarkers for checkpoint response vary by cancer type, and Petitprez shows immune checkpoint response is affected by tumor microenvironment composition. Barceloux further teaches methanol exposure has toxicity considerations requiring careful dose and safety evaluation. These references show that practicing the full scope of the claims would require substantial screening, selection, framework development, and/or optimization across claimed treatment context.
Accordingly, the instant claims 1-9, and 12-18 do not comply with the enablement requirement of §112, because practicing the full scope of the claimed therapeutic methods would require undue experimentation by a person of ordinary skill in the art without reasonable assurance of success.
Claim Rejections - 35 USC § 112, second paragraph
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.
Claims 4-9, and 12 are 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.
Regarding claim 4, the phrase “enhancing an immunotherapy” in claim 4 is a relative term which renders the claim indefinite. The phrase “enhancing an immunotherapy” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim 4 does not identify the endpoint, comparator, threshold, or measurement method for determining whether immunotherapy has been enhanced. Specifically, it is unclear whether enhancement is measured relative to immunotherapy alone, no treatment, methanol or prodrug treatment alone, or another baseline.
Claims 5-9, and 12 depend directly from claim 4 and are indefinite for the same reason.
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 (i.e., changing from AIA to pre-AIA ) 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.
The following prior art rejection is made in the alternative. Although the claims are rejected under 35 USC 112 for lack of enablement and indefiniteness, this rejection applies to the claimed subject matter can reasonably understood by specification.
Claim(s) 1-9, and 12-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Romero et al. (WO 2019/140188, pub’d 7/18/2019), in view of Ron-Harel et al. (Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation, Cell Metab., 24(1), 104-17, pub’d 02/28/2017), and in further view of Liesivuori et al. (Methanol and formic acid toxicity: biochemical mechanisms, Pharmacol Toxicol., 69(3), 157-63, pub’d 03/21/1991).
With respect to independent claim 1, the claim recites that a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of methanol, or a prodrug thereof.
Under the claim interpretation consistent with the specification, “a prodrug thereof” encompasses methanol prodrug compounds having methyl eater type structures capable of providing methanol/methoxide equivalents. The instant specification identifies fumaric acid as a residue for the disclosed methanol prodrug compounds (paragraph [0077], and [0194]). Dimethyl fumarate (DMF) is a dimethyl ester of fumaric acid. Accordingly, DMF is reasonably interpreted as falling within, or at least being suggested by, the claimed genus of “methanol, or a prodrug thereof”.
Romero teaches coadministration of the disclosed Des 1 inhibitor compounds and pharmaceutical compositions with dimethyl fumarate (paragraph [0362], and [0395]). Specifically, Romero teaches synergistic activity against multiple sclerosis upon coadministration with a therapeutic selected from fingolimod, a sphingosine-1-phosphate receptor modulator, teriflunomide, dimethyl fumarate, and other agents (paragraph [0362], and [0395]). Romero further teaches that the disclosed compounds and pharmaceutical compositions are useful in the treatment or prevention of cancer. (paragraph [0368], and [0369]), and the disclosed compounds and pharmaceutical compositions are optionally used in combination with other therapeutic regents that are selected for their therapeutic value for the condition to be treated (paragraph [0399]).
Romero fails to teach that DMF is administered in the cancer embodiment as a methanol prodrug.
Ron-Harel teaches that T-cell activation induces mitochondrial biogenesis and proteome remodeling leading to enrichment of one carbon metabolism, and that one carbon metabolism supports T-cell activation and survival (introduction and Enzymes of the one carbon metabolism are induced in vivo during T cell activation section).
Combination teaching of Romero and Ron-Harel does not expressly state metabolism of methanol, and its toxicity.
Liesivuori teaches that metabolism of methanol, methyl ethers, esters, and amides gives rise to formic acid (abstract).
It would have been obvious to a PHOSITA at the time of the invention to administer DMF, a methanol releasing methyl ester compound, in the cancer treatment method suggested by Romero in order to provide a methanol/formate related metabolic source capable of supporting one carbon metabolic demand associated with activated immune cells. The advantage or improvement would have been to support T-cell activation and survival, thereby improving immune mediated antitumor activity in the cancer treatment setting taught by Romero. For example, Romero teaches tumor killing through enhancement of the immune system’s ability to kill tumors and further teaches synergy with immune checkpoint inhibitors, and adding a methanol releasing methyl ester such as DMF would have been expected to add the metabolic support for activated T cells taught by Ron-Harel through the methanol/formate pathway taught by Liesivuori.
The references is directed to the same field of endeavor and address related to the application. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (G) in independent claim 1, it would have been prima facie obvious to combine Romero’s cancer/immunotherapy treatment method with the methanol/formate metabolic teachings of Ron-Harel and Liesivuori because the prior art provides a motivation to support activated T-cell metabolism in immune mediated cancer therapy. Romero teaches tumor killing through enhancement of the immune system’s ability to kill tumors and synergy with immune checkpoint inhibitors, Ron-Harel teaches that activated T-cells require enhanced one carbon metabolism for activation and survival, and Liesivuori teaches that methanol and methyl ester metabolism gives rise to formic acid/formate. Therefore, administering DMF, a methanol releasing methyl ester compound, would have predictably provided methanol/formate related metabolic support for activated T cells, yielding the expected advantage of improved immune mediated antitumor activity. (see MPEP 2141)
With respect to claims 2 and 5, the claims recite that administering to the subject an additional therapeutic agent, and administering to the subject the immunotherapy.
Romero teaches Des inhibitor compounds and compositions described herein are also optionally used in combination with other therapeutic reagents that are selected for their therapeutic value for the condition to be treated (paragraph [0399]). Romero further teaches the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against cancer upon coadministration with immune checkpoint inhibitors (paragraph [0371]).
With respect to claims 3 and 6, the claims recite that the additional therapeutic agent is an immunotherapy, and the immunotherapy comprises a checkpoint inhibitor.
Romero teaches the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against cancer upon coadministration with immune checkpoint inhibitors (paragraph [0371]). immune checkpoint inhibitors are immunotherapies. Therefore, claims 2 and 6 are taught by Romero.
With respect to claim 4, the claim recites that a method for enhancing an immunotherapy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of methanol, or a prodrug thereof.
Romero teaches the compounds and pharmaceutical compositions of the present disclosure are effective against tumor growth, angiogenesis, and chemoresistance, and potentially can facilitate tumor killing either by direct cytotoxicity (including induction of apoptosis) or indirectly by enhancing the immune system's ability to kill the tumor (paragraph [0370]). Romero further teaches that synergistic activity against cancer upon coadministration with immune check-point inhibitors or monoclonal antibodies directed at a target chosen from PD1, PD-L1, CTLA-4, CD47, and OX40 (paragraph [0371]-[0372]).
Romero fails to teach methanol or a methanol prodrug enhances immunotherapy.
However, as discussed above, Romero teaches immune mediated tumor killing and synergy with immune checkpoint inhibitors, Ron-Harel teaches that activated T-cells require enhanced one carbon metabolism for activation and survival, and Liesivuori teaches that methanol and methyl ester metabolism gives rise to formic acid/formate. It would have been prima facie obvious to administer a methanol releasing prodrug, such as DMF, to support one carbon metabolic demands of activated antitumor T-cells and thereby enhance the checkpoint immunotherapy taught by Romero. The advantage or improvement would have been to improve immune checkpoint therapy by metabolically supporting the activated T-cell response that mediates antitumor immunity. Therefore, claim 4 would have been obvious with the same rationale and motivation as discussed with respect to independent claim 1.
With respect to claims 7 and 9, the claims recite that the checkpoint inhibitor is an inhibitor of CTLA-4, PD-1, PD-L1 or LAG-3, and the checkpoint inhibitor is a PD-1 inhibitor as nivolumab, pembrolizumab or cemiplimab.
Romero teaches the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against cancer upon coadministration with monoclonal antibodies directed at a target chosen from PD1, PD-L1, CTLA-4, CD47, and OX40 (paragraph [0371]-[0372]), and the PD- inhibitor is selected from pembrolizumab, pidilizumab, AMP-224, AMP-514, PDR00I, and nivolumab (claim 59).
With respect to claims 12 and 15, the claims recite that the subject has a hematologic cancer as a solid tumor cancer, and the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, lymphoma, liver cancer, lung cancer, kidney cancer, skin cancer, stomach cancer, esophageal cancer, rectal cancer, pancreatic cancer, ovarian cancer or a solid tumor that is not able to repair errors in its DNA that occur when the DNA is copied.
Romero teaches the compounds and pharmaceutical compositions of the present disclosure can be useful in the treatment or prevention of cancer, and the cancer is chosen from a leukemia, a lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colorectal cancer), rectal cancer, bladder cancer, lung cancer (non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung),…, myelodysplastic syndrome, and a sarcoma (paragraph [0368]-[0369]). The specific hematologic (blood-related) cancers are a leukemia, a lymphoma, and myelodysplastic syndrome (paragraph [0369], and claim 53 ).
With respect to claim 16, the claim recites that administering to the subject a therapeutically effective amount of methanol.
Combination teaching of Romero and Ron-Harel fail to teach that the methanol or prodrugs thereof, is methanol.
Liesivuori teaches that methanol metabolism and it gives rise to formic acid/formate (abstract and Figure 1). As discussed above, Ron-Harel teaches that activated T-cells require one carbon metabolism for activation and survival, and Romero teaches cancer treatment and immune mediated tumor killing, including synergy with immune checkpoint inhibitors. Therefore, it would have been prima facie obvious to the same reason as discussed with respect to independent claim 1.
Claim(s) 1, and 16-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Romero et al. (WO 2019/140188, pub’d 7/18/2019), in view of Ron-Harel et al. (Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation, Cell Metab., 24(1), 104-17, pub’d 02/28/2017), and in view of Liesivuori et al. (Methanol and formic acid toxicity: biochemical mechanisms, Pharmacol Toxicol., 69(3), 157-63, pub’d 03/21/1991), and Russak et al. (Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals, Ann Pharmacother., 53(2), 211-216, pub’d 08/23/2018)
Claims 1 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Romero, Ron-Harel, and Liesivuori.
With respect to claim 17, the claim recites that the methanol is deuterated.
As discussed above, the combination teachings of Romero, Ron-Harel and Liesivuori teaches administering methanol as a methanol/formate related metabolic source in the cancer/immunotherapy setting.
Combination teachings of Romero, Ron-Harel and Liesivuori fail to teach that the methanol is deuterated.
Russak teaches that deuteration has gained attention because of its potential to affect the pharmacokinetic and metabolic profiles of drugs (abstract). Russak further teaches that stable heavy isotopes, including hydrogen and carbon isotopes, have been incorporated into drug molecules, and that deuterium labeled compounds my offer advantages compared with nondeuterated counterparts (introduction and Safety Issues section).
It would have been obvious to a PHOSITA at the time of the invention to use deuterated methanol or isotopic methanol species in place of, or as isotopic variants of, methanol in the method suggested by Romero, Ron-Harel, and Liesivuori in order to modify the metabolic and pharmacokinetic profile of the administered methanol/formate source. The advantage or improvement would have been the ability to adjust metabolic conversion, exposure, and/or toxicological profile while preserving the methanol/formate one carbon metabolic role taught by Liesivuori and used to support activated T-cell metabolism as taught by Ron-Harel.
Applying KSR example rationale (G) in the claim 17, it would have been prima facie obvious to combine the teachings of Romero, Ron-Harel, Liesivuori, and Russak. These arts provide a motivation to use methanol and isotopic variants thereof to modify metabolic or pharmacokinetic behavior in the cancer/immunotherapy method suggested by Romero. Therefore, selecting methanol, deuterated methanol, or isotopic methanol species would have predictably provided methanol/formate related metabolic support while allowing modification of metabolic conversion, exposure, or toxicological profile, yielding the expected advantage of improved immune mediated antitumor activity. (see MPEP 2141)
With respect to claim 18, the claim recites that the methanol is deuterated wherein the methanol is HOCH3, HOCD3, DOCD3,HO13CH3, HO13CD3 or DO13CD3.
HOCH3 is ordinary methanol and is therefore taught by Liesivuori’s teaching of methanol metabolism to formic acid/formate (Figure 1). The remaining recited species, including HOCH3, HOCD3, DOCD3,HO13CH3, HO13CD3 or DO13CD3, are deuterated and/or carbon isotope variants of methanol. Russak’s teaching that stable heavy isotopes, including hydrogen and carbon isotopes, may be incorporated into drug molecules would have suggested such isotopic variants. Therefore, it would have been prima facie obvious to the same reason as discussed with respect to claim 17.
Conclusion
Claim(s) 1-9, and 12-18 is/are rejected.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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