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 .
Priority
This application filed on 09/13/2024 is a National Stage Entry of International Patent Application No. PCT/US2023/015933 filed on 03/22/2023, which claims priority to United States Provisional Application Number 63/322,443 filed on 03/22/2022.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 02/04/2025 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits, except where noted.
Status of claims
The preliminary amendment filed on 05/14/2025, that amended claims 5 and 6, and cancelled claims 7-9, is acknowledged.
Claims 1-6 are pending.
Claim interpretation
Examination requires claim terms first be construed in terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim. See MPEP § 2111. Under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. See MPEP § 2111.01. It is also appropriate to look to how the claim term is used in the prior art, which includes prior art patents, published applications, trade publications, and dictionaries. MPEP § 2111.01 (III). However, specific embodiments of the specification cannot be imported into the claims, particularly where the subject claim limitation is broader than the embodiment. MPEP § 2111.01(II).
Claim interpretation for diamines or spirocyclic diamines
Claim 6 recites “a method for treating an MPC related disease or condition in an animal comprising administering a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof to the animal.”
Instant specification described the MPC related disease or condition as:
MPC couples the two major energetic pathways, glycolysis and OxPhos, for energetic and biosynthetic needs of the rapidly proliferating cancer cells, Importantly, recent evidence suggests that highly oxidative cancer cell types exhibit increased levels of mitochondrial respiration and anabolic processes that drive cancer cell proliferation. Hence, targeting MPC has high therapeutic potential for the treatment of cancer. MCTs are members of the solute carrier 16-gene family consisting of 14 known isoforms. Of these only MCTs 1-4 have been shown to elicit the proton-linked transport of monocarboxylates such as lactate, pyruvate, and some ketone bodies. MCT1 and MCT4 are centrally involved in glycolysis to efflux the end product lactate out of the tumor cells to avoid an apoptotic decrease in intracellular pH. They also play an active role in the influx of lactate from cancer cells into the mitochondria of neighboring oxidative cancer cells for energy generation via OxPhos. Interestingly, the activity of MCT function is modulated by substrate accumulation in the cytosol and hence, reduced pyruvate uptake into the mitochondria via MPC inhibition has been shown to elicit feedback inhibition of MCTs. Hence, direct and/or feedback mediated inhibition of MCTs are important therapeutic targets for metabolism-directed cancer treatments. Currently there is a need for agents that are direct or indirect inhibitors of MCTs. Such agents would be useful for the treatment of MCT related diseases and conditions (e.g., cancer, non-alcoholic steatohepatitis, di chronic graft versus host disease). a method for inhibiting an MPC (in viva or in vitro), comprising contacting the MPC with a compound of formula (I) or a salt thereof, and for treating an MPC related disease or condition (e.g., cancer, non-alcoholic steatohepatitis, diabetes. obesity. or chronic graft versus host disease). [page 1-2]
the “MPC related disease or condition” is interpreted consistent with the specification as the diseases and conditions associate with MPC pathways, including cancer, non-alcoholic steatohepatitis, diabetes. obesity. or chronic graft versus host disease. Also, the specification draws the connection between inhibiting MPC and MCT, as well as these diseases and conditions.
Objection to the disclosure
The specification is objected to for typographical error. The specification recites “… such agents would be useful useful for the treatment of MCT related diseases and conditions …” [page 2, line 2]. Applicant must amend the specification by deleting the repeated word “useful” to correct the error.
Appropriate correction is required.
Rejections 35 U.S.C. 112(b)
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.
Claim 5 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites “a method for inhibiting an MPC (in vivo or in vitro), comprising contacting the MPC with a compound of formula (I) or a salt as described in claim 1.”
The recitation of the parentheses renders the claim indefinite because it is unclear whether the limitations in the parentheses are part of the claimed invention and further limit the inhibition method or are exemplary of the method. See MPEP § 2173.05(d).
Pursuant to 35 U.S.C. 112(b), the claim must apprise one of ordinary skill in the art of its scope so as to provide clear warning to others as to what constitutes infringement. MPEP 2173.02(II); Solomon v. Kimberly-Clark Corp., 216 F.3d 1372, 1379, 55 USPQ2d 1279, 1283 (Fed. Cir. 2000).
Claim Rejections - 35 USC § 112 (a)
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.
Claim 6 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for the treatment of the claimed scope of all MPC related diseases or conditions, e.g., cancer. 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.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)”. The “use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
By way of background, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to “The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors” using a small genus of compounds. The Court decided that human testing “limited to one compound and two types of cancer” was not “commensurate with the broad scope of utility asserted and claimed”.
In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to “the treatment of certain specified cancers in humans” by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted “affidavits, publications and data” for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to “A therapeutic method for reducing metastasis and neoplastic growth in a mammal” using a single species. The decision notes that such utility “is no longer considered to be “incredible””, but that “the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence.” Note also that there is also a dependent claim 5 which specified “wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma.” The decision notes that “even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy.”
In Ex parte Stevens, 16 USPQ2d 1379 a claim to “A method for therapeutic or prophylactic treatment of cancer in mammalian hosts” was refused because there was “no actual evidence of the effectiveness of the claimed composition and process in achieving that utility.”
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required:
(1) The breadth of the claims
(2) The nature of the invention
(3) The state of the prior art
(4) The level of one of ordinary skill
(5) The level of predictability in the art
(6) The amount of direction provided by the inventor
(7) The existence of working examples
(8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(1) The breadth of the claims:
The presently claimed invention is directed to “a method for treating an MPC related disease or condition in an animal comprising administering a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof to the animal.” Examples of MPC related diseases and conditions are identified in the instant specification at page 2, lines 25-26 to include cancer, non-alcoholic steatohepatitis, diabetes. obesity. or chronic graft versus host disease. Thus, “MPC related disease or condition” is a broad term.
Moreover, Buchanan (J. Buchanan et al., Biomolecules. 2020 Aug 8; 10(8):1162, “Buchanan” cited in the PTO-892), teaches the role of MPC on diseases such as cancer, diabetes, [Abstract], liver fibrosis and inflammation, which are hallmarks of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [page 10, 1st para.]. Cancer is not a single disease, or a cluster of closely related disorders. There are hundreds of proliferative diseases, 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 every part of the body. The specification and the art of record fail to disclose a validated marker or method for predicting a benefit from the instantly claimed compounds. Therefore, the scope of the diseases covered is deemed very broad and cannot be considered enabled by the instant specification. In addition, treating cancer encompasses thousands of anti-cancer/antitumor agents under the classes such as small molecular chemotherapy, antitumor antibiotic substance, a platinum-based agent etc. is deemed very broad, and cannot be considered enabled by the instant specification. Buchanan teaches that diabetes mellitus is a metabolic disease that is categorized into type 1 diabetes (T1D) and type 2 diabetes (T2D), with T1D includes destroying of pancreatic beta cells and the ability to produce insulin. Buchanan teaches that MPC loss impairs glucose-stimulated insulin secretion and worsens T2D, however, studies are limited, and the mechanisms are less clear. [page 9, 1st para.].
The Examiner also notes that the specification at page 3, lines 13-24 provides several definitions for “treat”, “treatment”, or “treating” to include therapeutic, prophylactic, or preventative measures (lines 15-17) and also defines these terms to mean “prolonging survival as compared to expected survival if not receiving treatment” (lines 23-24). Therefore, recitation of “treating” in claim 6, as defined by Applicant in the specification, is also broad.
(2) The nature of the invention:
The present claims describe a method for every cancer, diabetes (T1D, T2D), NAFLD, NASH, etc. That is, in order to be enabled to practice the present invention, the skilled artisan would have to accept that by administering a compound of formula (I) to a patient with MPC related disease, for example cancer, such therapeutic objectives could actually be achieved. However, in light of the fact that the specification fails to provide the skilled artisan with any direction or guidance as to how the treatment of cancer in general could be achieved, or how the compound of formula (I) dose or regimen will be selected for treating any particular kind of MPC-related disease i.e., cancer, the present specification is viewed as lacking an enabling disclosure of the entire scope of the claimed invention.
(3) The state of the Prior Art:
The instant claims are directed to “a method for treating an MPC related disease or condition in an animal comprising administering a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof to the animal.” However, as taught by Chakraborty (S. Chakraborty, et al. Ecancermedicalscience. 2012, 14;6:ed16, “Chakraborty” cited in the PTO-892), “the cure for cancer is like the Holy Grail since most of the existing treatments are not effective enough to provide full protection from this disease”. Chakraborty teaches that “in recent years the burgeoning of sophisticated genomic, proteomic and bioinformatics techniques has made it possible for us to get a glimpse of the intricate interplay of numerous cellular genes and regulatory genetic elements that are responsible for the manifestation of cancerous phenotypes. With the use of modern genomic technologies, we are now beginning to understand the enormous complexity of cancer, however, there are few success stories as far as the treatment of cancer is concerned, [Abstract]. Chakraborty teaches that the non-specific nature of cancer symptoms makes diagnosis difficult (let alone treatment and prevention). Chakraborty teaches examples of cancer with diagnosis difficulties including esophageal cancer, prostate cancer, and pancreatic cancer. [Page 3-4]. Moreover, Zafar (A. Zafar, et al. Med Res Rev. 2021;41:961–1021, “Zafar” cited in the PTO-892), teaches the challenges associated with neuroblastoma treatment. Zafar teaches that standard treatment in children all lead to relatively poor outcomes for NB treatment. It is also important to note that oncology drugs have the lowest LOA (likelihood of approval) from phase I (6.7%) compared with drugs used for other diseases (allergy, dermatology, urology, autoimmune disease, and ophthalmology).45 Complicating matters, the current treatments approved for NB have limited targeted specificity. [Page 964, 1st para.]. Buchanan teaches that involvement of MPC with diabetes and NASH cannot yet be fully attributed to MPC inhibition. [page 10, 2nd para.]. Buchanan teaches that the effect of MPC activity and contribution to physiology or pathology of the MPC diseases remain unclear. [page 13, 3rd para.]. Numerous mechanisms have been proposed as methods of treating assorted cancers a selection of which follow. Cytotoxic agents could be applied directly to the tumor’s cells, directly killing them. Immunotherapy to stimulate the patient's immune system to attack cancer cells, either by immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Increasing the amount or activity of the body’s tumor suppressor genes, PTEN, APC and CD95, which can, for example, activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. Angiogenesis inhibitor strategies based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells.
A number of these approaches – and others as well – have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, these approaches have yet to produce a drug which can claim such a goal.
Specifically, the prior art demonstrates that there never has been a compound capable of treating cancers generally. “The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally.” 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 determine how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally, and the existence of such a single treatment for cancer is contrary to our present understanding in oncology. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from an exceptionally wide variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses, exposure to environmental chemicals (e.g. tobacco tars, alcohol, toxins), ionizing radiation, and unknown environment factors.
Accordingly, there is substantive “reason for one skilled in the art to question the objective truth of the statement of utility or its scope” (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
Similarly, In re Novak, 134 USPQ 335, 337-338, says “unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them.” There is no such evidence in this case. Likewise, In re Cortright, 49 USPQ2d 1464, states: “Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient” does what the specification surmises that it does. That is exactly the case here. Moreover, even if applicants’ assertion that cancer in general could be treated with these compounds were plausible, which it is not, that “plausible” would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.”
(4) The skill of those in the art:
The skill of those in the art is expected to be high, requiring advanced training in chemistry, medicine, or pharmacology.
(5) The level of predictability in the art:
In view of the above discussion, the association of MPC inhibition on the treatment of the claimed diseases and condition is highly unpredictable. For example, with specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] …anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). With this in mind the level of predictability in the art is sufficiently low that even with hundreds of successful examples of chemotherapy there has yet to be shown any single method of treating the vast scope of cancers known. The level of unpredictability in the art renders the scope of instant claim to be not enabled.
(6) The amount of direction provided:
While the treatment of MPC related disease and conditions is discussed in broad terms, the necessary specifics, i.e. dosing, therapeutic index, contraindications, interaction between the claimed compound with other agents, toxicity etc., are completely absent. And while the MPC inhibitors, for example, as anti-cancer agent therapy is discussed in board term the, only testing of the inhibition effect of the claimed compound of formula (I) on MPC and MCT1. The specification also describes pharmacokinetics studies of a compound of formula (I), compound MN-D7 [page 15]. The limited studies do very little to provide the necessary information, and, considering the immense diversity of MPC-related diseases and conditions, e.g., cancers and their varied reactions to treatment, the guidance provided is very limited.
(7) Working examples:
The examples of the treatment of MPC related diseases and condition, every type of cancer, diabetes (T1D, T2D), NAFLD, NASH, etc. are limited to in vitro assays and pharmacokinetics studies. Permeabilized cell assays were performed using Seahorse XFe96@-based respiratory experiments for pyruvate driven respiration, wherein the tested compound inhibits pyruvate driven respiration with ICso values of 14.4±0.5 nM in 4T1 cells and 17.8±4.9 nM in 67NR cells and inhibit MCT1 function. The specification also provides tolerability, toxicity pharmacokinetics and oral bioavailability studies, wherein compound of formula (I), MN-D7 administered to mice. The exceptional diversity of the MPC related diseases and conditions, and the treatment of them, is not well represented by these examples. It is well known that there is no single treatment that works for all kinds of cancers, diabetes (T1D, T2D), etc. so the experimentation required, based on solely limited cell line assays to practice the instant invention would be egregious.
(8) The quantity of experimentation needed:
In view of the above factors, the quantity of experimentation needed is expected to be great. The quantity needed to expand limited cell line assays and pharmacokinetics studies as a working example provided in the instant specification to a viable treatment for the claimed scope of all MPC-related diseases and conditions is untenable.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
§ 102 Rejection over Draoui
Claims 1-2 and 4-6 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by N. Draoui, et al. (US PG PUB 2016/0115146, 04/28/2016 "Draoui" cited in the IDS dated 02/04/2025).
Draoui teaches MCT inhibitor of formula A, pharmaceutically acceptable salts or solvates thereof for the treatment of cancer [[0011], [0021]]. Draoui teaches compound cpd 73 as species of formula A, [page 43, cpd. 73]:
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Therefore, Draoui anticipates claims 1 and 2.
Regarding claim 4, Draoui teaches a pharmaceutical composition comprising compound of formula A, e.g., cpd/ 73 in combination with a pharmaceutically acceptable carrier. [0254].
Regarding claims 5 and 6, Draoui teaches that the compounds of formula A are MCT and mitochondrial pyruvate carrier (MPC) inhibitors. Draoui teaches a method to inhibit lactate uptake and lactate influx in vitro or in isolated cells or in an animal, mammal or human by using the compounds of formula A. Draoui teaches a method of treating cancer, for example cancer expressing MCT. [[0004], [0005], [0353], [0256]]. Please see claim interpretation above for the connection of MCT and MPC.
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 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.
§ 103 Rejection over Draoui in view of Hodges
Claims 1-2 and 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over N. Draoui et al. (US PG-PUB 2016/0115146, 04/28/2026 "Draoui" cited in the IDS dated 02/04/2025) in view of W. Hodges et al. J. Biol. Chem. (2022), 298(2), 101554, “Hodges” cited in the PTO-892).
The disclosures set forth above in the 102 rejection over the same Draoui et al. reference are herein incorporated by reference.
Claims 1, 2 and 4 are anticipated by Draoui.
Regarding claims 5 and 6, Draoui differs from instant claimed method to the extent that one of ordinary skill in the art need to specifically pick compound cpd 73 from Draoui’s MPC/MIC inhibitors.
Hodges teaches MPC inhibitors for the treatment of metabolic related diseases e.g., type 2 diabetes. Hodges teaches MPC inhibitors, e.g, 7ACC2 potently inhibited pyruvate mediated respiration in isolated mitochondria, [Abstract]:
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Hodges teaches that ZACC2 is a potent MPC inhibitor, and 7ACC2 improve glucose tolerance, stimulating muscle glucose uptake via PDE inhibition, and 7ACC2 treatment enhanced liver insulin signaling (insulin induced phosphorylation of AKT-S473) [page 2, col. 1- col. 2]. Hodges teaches that 7ACC2 potently inhibited glucose production by isolated hepatocytes at 10 mM concentrations [page 6, col. 2, 2nd para.]. Hodges teaches the potential of 7ACC2 for therapeutics that interact with the MPC and modulate its activity for treating a variety of obesity-related metabolic diseases. [page 6, 4th para.].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to pick MPC inhibitor, cpd 73 form Draoui’s MPC inhibitors for in vitro and in vivo MPC inhibition and for treating cancer and type 2 diabetes in view of the teachings of Hodges. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because Hodges teaches that cpd 73 (7ACC2) is potent MPC inhibitor for the treatment of metabolic related diseases e.g., type 2 diabetes, 7ACC2 potently inhibited pyruvate mediated respiration in isolated mitochondria, 7ACC2 improve glucose tolerance, stimulating muscle glucose uptake, enhanced liver insulin signaling, and 7ACC2 potently inhibited glucose production by isolated hepatocytes. Moreover, Hodges teaches 7ACC2 inhibiting MPC and modulate its activity for treating a variety of obesity-related metabolic diseases and that 7ACC2 is a potential therapeutic for MPC related diseases. Therefore, the combination of Draoui and Hodges meet each and every limitation of claims 5 and 6.
§ 103 Rejection over Draoui in view of Hodges, Bookwala, Fitriani and Saal
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over N. Draoui et al. (US PG-PUB 2016/0115146, 04/28/2026 "Draoui" cited in the IDS dated 02/04/2025) as applied above to claims 1-2 and 4-6 in view of W. Hodges et al. J. Biol. Chem. (2022) 298(2) 101554, “Hodges” cited in the PTO-892), M. Bookwala, et al. Eur. J. Pharm. Biopharm. 2018 Oct; 131:109-119, “Bookwala” cited in the PTO-892), L. Fitriani et al. Crystals. 2022; 12(2):275, “Fitriani” cited in the PTO-892) and C. Saal, et al. European Journal of Pharmaceutical Sciences, 2013, Volume 49, Issue 4, Pages 614-623, ISSN 0928-0987, “Saal” cited in the PTO-892).
The disclosures set forth above in the 102 rejection over the same Draoui et al. reference are herein incorporated by reference.
Draoui anticipates claim 1 as discussed above.
Draoui teaches pharmaceutically acceptable salts or solvates thereof of compound cpd 73 [0021]. Draoui teaches that the term “pharmaceutically acceptable salts” as used herein means the therapeutically active non-toxic salt forms which the compounds of formula A are able to form, especially pharmaceutically acceptable non-toxic salts containing, for example salts derived by combination of appropriate cations such as ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid, salts formed from acid addition of certain organic and inorganic acids to basic amines, salt of amino group, etc. [[0366] [0368]].
However, while Draoui teaches that compounds with carboxylic moiety form salt with amino counter ions, Draoui does not teach that the counterion salt is 2-amino-2-(hydroxymethyl)propane-1,3-diol salt of compound of formula A.
Hodges, Bookwala, Saal and Fitriani provide motivation to one of ordinary skill in the art to specifically utilize 2-amino-2-(hydroxymethyl)propane-1,3-diol as the counterion for the salt of the MPC inhibitor, cpd 73.
Hodges teaches that compound cpd 73 (7ACC2) has a poor solubility, and that the poor solubility hinders the potent effect of 7ACC2 as MPC potent inhibitor. [page 8, col. 2, last para., page 9, col. 2, 2nd para.].
Bookwala teaches that tromethamine, a highly water-soluble amino sugar with a pKa of 8.07 and a melting point of 171 °C, is usually selected as the salt forming base in view of the fact that it is an FDA-approved excipient commonly used as a salt former for oral and intravenous drug administration [21, 22]. [page 3, 2nd para.].
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Fitriani teaches that “one of the challenges faced by the pharmaceutical industry in developing solid dosage forms is the low solubility of the active pharmaceutical ingredients in the aqueous medium. The absorption process in the gastrointestinal tract of a drug that is poorly soluble in water is limited by the dissolution process. The dissolution process in the gastrointestinal tract fluid is a rate-limiting step, and in order to overcome this problem, it is important to improve the solubility and dissolution rate of active pharmaceutical compounds.” [page 1, 1st para.]. Fitriani teaches that “to enhancing the solubility and dissolution rates of poorly soluble drugs is to modify the solid forms of the drug by forming a multicomponent crystal containing active pharmaceutical ingredients with several safe coformers.” [page 2, 2nd para.]. Fitriani teaches that tromethamine is a GRAS excipient that is approved by the USFDA and is widely used as a coformer in several active pharmaceutical ingredients. [page 2, 2nd para.]. Fitriani teaches that the formation of tromethamine salt found to significantly increase the solubility and dissolution rate. [Abstract, page 12]
Saal teaches tromethamine as one of the counterion to form salts to improve solubility, dissolution rate, supersaturation, drug absorption and bioavailability of drugs, wherein tromethamine is approved for oral and intravenous administration. [page 615, col. 1, 1st para.].
In view of the above, it would have been prima facie obvious to one of ordinary skill in the are prior to the effective filing date of instantly claimed invention to select tromethamine as the counterion to form salt of the potent MPC inhibitor cpd 73 (7ACC2) taught by Draoui and Hodges. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because Draoui recommended salt of amino counterion for compound with carboxylic acid moiety, Hodges recognizes the poor solubility of the claimed compound and that the poor solubility hindered its potency as MPC inhibitor, Bookwala teaches that tromethamine is highly water soluble, its FDA approved, exhibited a maximal solubility, widely selected to form salt to increase the solubility and dissolution rate of acidic drugs, Fitriani teaches that tromethamine is widely used as a coformer in several active pharmaceutical ingredients to overcome the poor solubility of the active pharmaceutical ingredients in the aqueous medium, and to improve the solubility and dissolution rate of active pharmaceutical compounds, and Saal teaches that tromethamine is one of the counterion to form salts to improve solubility, dissolution rate, supersaturation, drug absorption and bioavailability of drugs for oral and intravenous administration. Therefore, Bookwala, Fitriani and Saal would motivate one of ordinary skill in the art already aware of poor solubility and bioavailability of cpd 73 (7ACC2) to use tromethamine as the counterion to form salt of the claimed compound.
Conclusion
Claims 1-6 are rejected. No claim is allowed.
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/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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