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 .
Status of Claims
Claims 1-15 and 18-20 are pending in the instant application. Claims 3-6, 8-13, 15 and 18-20 are amended and claims 16-17 are cancelled via the amendment filed November 20th, 2024.
Priority
This is a 35 U.S.C. 371 National Stage filing of International Application No. PCT/SG2023/050202 filed March 28th, 2023, which claims priority under 35 U.S.C. 119(a-d) to SG10202205354V, filed May 20th, 2022. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d).
Information Disclosure Statement
The Information Disclosure Statements (IDS) filed December 2nd, 2024, and May 18th, 2026, have been considered by the Examiner.
Claim Objections
Claim 11 is objected to because of the following informalities:
It is recommended that Applicant amend the claim to insert “the group consisting of” after “selected from” and insert “and” before the last compound of the claim.
Claim Rejections – 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.
Claims 1-15 and 18-20 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.
The instant specification, while being enabling for the disclosed compounds or salts thereof, does not reasonably provide enablement for generation or use of solvates or prodrugs that would be metabolized in a host to generate the compounds claimed in the instant application. The specification does not enable any person having ordinary skill 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.
Further, the instant specification, while being enabling for the treatment of mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer and colorectal cancer, does not reasonably provide enablement for the treatment of all cancers.
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 and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to a compound of formula I, and methods of treatment of all cancers.
Breadth of the claims:
The claims are broadly directed at a compound of formula I, or a salt, solvate or prodrug thereof and a method of treating cancers with said compound, salt, solvate or prodrug thereof.
Level of ordinary skill in the art:
The artisans using Applicant’s method would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity and which cancerss would benefit from this activity.
For example, a prodrug is a compound that is metabolized in the host to form the compound of the present disclosure. Specific prodrugs, however, are not disclosed, and the unpredictability of metabolites formed when a composition is administered requires the support of specific in vitro or in vivo screening to verify the formation of the disclosed compounds.
With regard to the treatment of cancer, the relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
State of the prior art and predictability in the art:
With respect to the use of prodrugs, Walther et. al. (Adv. Drug Deliv. Rev., 2017, 65-77) represents the state of the prior art.
Prodrugs are typically employed when, for example, the parent drug compound has poor aqueous solubility, poor absorption from the gastro-intestinal tract into the blood, poor rates of cell entry, or various other reasons (Table 1 of Walther). Design strategy for a prodrug depends on the structural features of the parent drug molecule and availability of the appropriate chemical functionalities that can be used to mask pharmacodynamic activity of the drug through an attachment of a modifying group. Typically, an enzymatic process is relied upon for drug release.
As such, without undue experimentation, a person having reasonable skill in the art would not be able to ascertain which prodrugs are reasonable due to the unpredictability of the formation of metabolites in the host.
With regard to the treatment of all cancer, as discussed above, the relative skill in the art is high.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity.); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art, the examiner cites Gura et al (Science, 1997, 278:1041-1042), Johnson et al. (British Journal of Cancer, 2001, 84:1424-1431), Kunnumakkara et al (Experimental Biology and Medicine, 2019; 244:663-689).
With regard to unpredictability, Kunnumakkara, cited for evidentiary purposes, teaches cancer is a group of more than 200 neoplastic diseases caused by diverse deregulated cell signaling cascades (page 633, left, 1st paragraph); consumption of tobacco and alcohol, obesity, insufficient physical activity, exposure to ultraviolet radiation, and various dietary factors which include insufficient fruit, non-starchy vegetables, and fiber; red/processed meat are predicted to be strongly associated with the risk of diverse cancer types; cancer occurs as a result of the dysregulation of as many as 500 different genes which may happen over a very long duration of time (20–30 years) till the symptoms become apparent (page 633, right, last bridge paragraph). Kunnumakkara further teaches there exists a missing connection between preclinical data and clinical findings; although, a significantly huge amount of money is spent in the pre-clinical settings for target validation and drug optimization, most of the therapies fail in the clinical trials; this can be due to the reason that the models used in the pre-clinical setting are not the adequate ones to effectively mimic human responses (page 664, right, 2nd paragraph); although highly convenient, cancer cell line models are associated with several limitations as well; for example, existence of genomic instability which may result in differences between the original tumor and the respective cell line, culture conditions that can alter the morphology, gene expression pattern, genomic profile, cellular pathways and culture environment from that of the original tumor, loss of natural tumor heterogeneity; the generic transformations that occur upon culturing of the cancer cells are not restored when regrown in vivo; and cancer cells in the in vitro condition grow in absence of stroma which include lymphatic vessels and blood, associated fibroblasts and immune cells, and lack a complex extracellular matrix; therefore, in vitro data often exhibits fundamental mismatch with those obtained from clinical findings and hence this can be regarded as one prime reason behind the failure of novel drug development (page 665, last bridge paragraph). Kunnumakkara teaches the foremost shortcomings of the use of animal models are their inability to recapitulate the link between the tumor and its microenvironment completely and the requisite of an immunocompromised host; basically, these animal models do not have the ability to reflect all the features of human cancer impeccably. Kunnumakkara teaches despite the advances in understanding of cancer biology and deriving different novel therapeutic targets, the translation of these understanding into therapies is poor due to higher failure rate (90%). The high failure rate could be due to non-consideration of factors such as clinical translation, drug delivery, drug pharmacokinetics, pre-clinical models, and tumor physiology, which are critical factors.
The amount of direction provided and working examples:
The only direction or guidance present in the instant specification is the disclosure of results obtained by administration of the disclosed compounds. No examples of suitable solvates or prodrugs have been given.
With regard to solvates, the present specification merely mentions the Applicant’s intention to make solvates, without teaching the preparation thereof. As stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190, 1194 (Fed.Cir. 1993):
The specification purports to teach, with over fifty examples, the preparation of the claimed compounds ... However ... there is no evidence that such compounds exist ... [T]he examples ... do not produce the postulated compounds ... [T]here is ... no evidence that such compounds even exist.
The same circumstance appears to be true here. There is no evidence that solvates of these compounds actually exist; if they did, they would have formed. Hence, applicants must show that solvates can be made, or limit the claims accordingly.
See MPEP 2164.01(a), discussed supra, justifying the conclusion of lack of enablement commensurate with the claims. Without guidance in the present application, undue experimentation will be required to practice Applicant’s claimed invention.
With regard to the treatment of all cancers, the specification only provides working examples in involving the select cancers, mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer and colorectal cancer.
The specification provides no particular direction or guidance for determining the particular administration regimens (e.g., timing, administration routes, etc.) necessary to treat all of the various cancers encompassed by the claims, particularly in humans. At best, an “effective amount” is exemplified as “a dosage sufficient to provide treatment for cancer”. While experimentation is presented for treatment of mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer and colorectal cancer, there is no experimentation or mechanism of action presented or discussed in the specification regarding treatment of the cancers that are not mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer and colorectal cancer.
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. As referenced above, a person having ordinary skill in the art would need to identify suitable prodrug candidates, determine the metabolites formed when said prodrugs are administered to a host, and evaluate the efficacy of these compounds in treating all cancers.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, none of the experimentation provided is drawn to the treatment of a cancer that is not mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer and colorectal cancer. A review of the state of the art fails to reveal that TEAD targeting compounds are useful as a therapeutic for the treatment of any cancers, except for mesothelioma, liver cancer, gastric cancer, metastatic non-small cell lung cancer and colorectal cancer. Determining if any particular claimed compound would treat any particular cancerous disease state would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants. As noted supra, even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
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.
The specification fails to provide enough support for the broad use of prodrugs and solvates of the claimed compounds and treatment of all cancers.
Genentech Inc. v Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person having ordinary skill in the art would have to engage in undue experimentation to determine suitable prodrugs and solvates with the compounds and compositions in the instant claims, and also the treatment of all cancers, with no assurance of success.
Claim Rejections - 35 USC § 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.
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 6-10 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.
In claim 6, variables R2 and R3 are undefined in formula (Ia). The claim only recites a definition of R2 and R3 when X3 and X4 are N or C, however X3 and X4 can also be O or S. It is unclear what R2 and R3 can be when X3 and X4 are O or S.
Claims 7-10 depend from claim 6 and do not resolve the issue of indefiniteness and as such, are also rejected under 112(b).
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.
Claim(s) 1-13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CAS registry No. 2224237-03-8, which entered STN on May 20th, 2018, as cited on the IDS dated December 2nd, 2024.
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Regarding claim 1, this compound is embraced by instant Formula (I), wherein n is 1 and Ar is a substituted heteroaryl.
Regarding claim 2, as seen above, Ar is a substituted heteroaryl.
Regarding claim 3, in the compound above, there is a heteroatom at a 2’ position relative to N of the amide moiety, sulfur.
Regarding claim 4, Ar is a thiazolyl.
Regarding claim 5, n is 1.
Regarding claim 6, the compound above is of formula (Ia), wherein n is 1, X1 is S, X2 is C, X3 is N and X4 is C, R1 is aryl, R2 is absent and R3 is alkyl.
Regarding claim 7, X1 is S.
Regarding claim 8, X3 is N.
Regarding claim 9, R1 is aryl.
Regarding claim 10, R3 is alkyl.
Regarding claim 11, the compound above is the first compound of the instant claim.
Regarding claim 12, the preamble of the instant claim “A modulator of Hippo pathway”, MPEP 2111.02(II) notes “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. As the compound above is a compound of Formula (I) according to instant claim 1, the compound reads on the claim.
Regarding claim 13, which is drawn to a composition comprising the compound and a pharmaceutically acceptable excipient, the CAS Registry entry includes predicted properties including mass and molar solubilities at varying pH values. MPEP 2131.02 states:
A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination.” Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015)
In this situation, a person having ordinary skill in the art in viewing the properties of the Registry entry would at once envisage a composition with the compound and water, which is a pharmaceutically acceptable excipient.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Anna Grace Kuckla whose telephone number is (703)756-5610. The examiner can normally be reached Monday-Friday 7:30-5.
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/A.G.K./Examiner, Art Unit 1626
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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