DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-11, 13, and 15-22 are pending.
Priority
This application is filed on 06/20/2024 and claims the benefit of domestic priority as below:
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Information Disclosure Statement
One IDS(s) is received on 06/20/2024 has been considered unless marked with a strikethrough/cross out.
Claim Objections
Claims 2 and 10 are objected to because of the following informalities:
Claim 2 is objected to because the phrase “the compound of formula I having the structure of formula II” should be “the compound of formula I has the structure of formula II”.
Claim 10 is objected to because the phrase “a pharmaceutically acceptable salts” should be “a pharmaceutically acceptable salt”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 3-9, 13 and 15-22 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 claims 3-9, 13 and 15-22, the terms "preferably”, “more preferably" and/or “most preferably” render the claim indefinite because it is unclear whether the limitations following these terms constitute a required limitation of the claim or merely identify a non-limiting preference. As a result, the metes and bounds of the claims cannot be determined with reasonable certainty. For example, claim 3 recites that “preferably, R3 is selected from hydrogen or C1-C6 alkyl; more preferably, R3 is selected from hydrogen, methyl or cyclopropyl; more preferably, R3 is selected from hydrogen or methyl; most preferably, R3 is hydrogen.” It is unclear whether infringement requires satisfaction of only the initially recited broad limitation, one of the stated preferred limitations, or the most preferred limitation. See MPEP 2173.05(d).
Claim Rejections - 35 USC § 112 enablement
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 13 and 22 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 the demonstrated MAT2A dependent tumor models, does not reasonably provide enablement for the fu. 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.
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 8 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:
Nature of the invention:
The invention is drawn to a method for preventing and/or treating a MAT2A mediated disease or condition, comprising administering to a subject in need an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition wherein the MAT2A mediated disease, or condition is mediated by overexpression of MAT2A.
Breadth of the claims:
The claims are not limited to MTAP deficient tumors, colorectal cancer, or any particular cancer. Rather, they encompass any disease or condition characterized as MAT2A mediated. The specification identifies colorectal cancer as an example and separately states that MAT2A mediated disease may be mediated by MAT2A overexpression (page 6 lines 12-14).
Level of ordinary skill in the art:
The artisans using applicant’s method would be a collaborative team of synthetic chemists, biologists, and/or pharmacokinetic scientists, possessing commensurate degree and/or skill in the art, as well as several years of professional experience.
The diseases or conditions encompassed by the present claims are potentially broad and heterogeneous. However, the specification presents experimental evidence regarding only specific tumor models. The disclosure alone does not demonstrate whether MAT2A inhibition would yield a therapeutic effect across the entire range of diseases or conditions characterized as being mediated by MAT2A. Demonstrating this would require undue experimentation by a person of high skill in the art.
State of the prior art and predictability in the art:
The relevant art indicates that MAT2A dependence is biologically context dependent rather than a uniform feature of diseases associated with MAT2A. For example, Maldonado et al. (Exp Biol Med (Maywood), 243(2), 107-117, pub’d 11/15/2017) explains different mechanisms of MAT2A/MAT2B dysregulation across liver, colon, gastric, breast, pancreatic, and prostate cancers, indicating that MAT biology differs among tumor contexts (abstract, and MAT genes in other cancers section). Similarly, Marjon et al. (Annual Review of Cancer Biology, 5, 371-390, pub’d 12/22/2020) shows that MAT2A inhibition as a precision medicine strategy particularly associated with tumors having homozygous MTAP loss (abstract, and current efforts to drug prmt5 and mat2a section). Accordingly, Maldonado and Marjon support that MAT2A dependence is biologically context dependent, and inhibition of MAT2A would not predictably treat every disease encompassed by the broader functional term “MAT2A mediated disease or condition”.
Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The amount of direction provided and working examples:
The specification provides experimental support for particular tumor settings, including an HCT 116 MTPA-/- tumor model and a KP-4 tumor model, and measures both tumor inhibition and intratumoral SAM inhibition. This evidence provides guidance for the represented MAT2A-dependent HCT116/KP-4 cancer models.
However, the specification does not provide therapeutic efficacy across the broader class of MAT2A mediated diseases, nor does it provide a working example establishing treatment of a disease specifically mediated by MAT2A overexpression. The provided MATP-loss/MAT2A dependency mechanisms not necessarily equivalent to disease mediated by MAT2A overexpression.
See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”). See in re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed would constitute undue experimentation. One of skill in the art would need to determine, on a disease-by-disease basis, whether MAT2A is therapeutically causal or sufficiently required for the disease, whether inhibition of MAT2A produces the claimed therapeutic effect, and what compound and treatment conditions provide such effect.
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.
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 an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Claim Rejections - 35 USC § 112 written description
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, 3-9, 11, and 13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by applicants. (see MPEP 2163.02)
An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed. (Emphasis added)
Further, the MPEP states that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. (see MPEP 2161.01)
For instance, generic claim language in the original disclosure does not satisfy the written description requirement if it fails to support the scope of the genus claimed. Ariad, 598 F.3d at 1349-50, 94 USPQ2d at 1171 ("[A]n adequate written description of a claimed genus requires more than a generic statement of an invention’s boundaries.") (citing Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1405-06); Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002) (holding that generic claim language appearing in ipsis verbis in the original specification did not satisfy the written description requirement because it failed to support the scope of the genus claimed); Fiers v. Revel, 984 F.2d 1164, 1170, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (rejecting the argument that "only similar language in the specification or original claims is necessary to satisfy the written description requirement").
As set forth in the en banc decision in Ariad Pharmaceuticals Inc. v. Eli Lilly and Company, 94 USPQ2d 1161 (Fed. Cir. 2010) at 1171, the court stated as follows:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. At 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. At 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 [25 USPQ2d 1601] (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
Claim 1 broadly permits X, Y, Z, and W each to be a carbon based ring position or nitrogen, provided that “at most 2 of W, X, Y and Z are simultaneously N”. Thus, the claim encompasses numerous heterocyclic cores having materially different numbers and positional arrangements of ring nitrogens, in addition to extensive variation at R1 -R6.
However, although the specification recites the broad X/Y/Z/W alternatives of Formula I, the disclosed working examples and biological data provides substantially narrower structural and biological support. The disclosed embodiments and working examples are focused on particular aza fused heterocyclic series, and the specification identifies embodiments in which X = CR3, Y = CR4, Z = CR5, and W = N. (page 2, lines 23-26). The experimental data establishes MAT2A inhibition and antitumor activity for compounds within the represented structural series, but does not provide representative active species spanning the substantially different X/Y/Z/W arrangements permitted by claim 1.
This distinction is material because MAT2A activity is sensitive to structural changes within the inhibitor core. Fusco et al. (J. Med. Chem., 64(10), 6814-6826, pub’d 04/26/2021) shows that development of potent MAT2A inhibitors required fragment based discovery followed by systematic structure guided SAR optimization of an arylquinazolineone series (results and discussion section, Figure 1 and 2). Similarly, Konteatis et al. (J. Med. Chem., 64(8), 4430–4449, pub’d 04/08/2021) shows that iterative structure guided optimization produced greater than a 10,000-fold improvement in MAT2A potency, demonstrating substantial sensitivity of MAT2A inhibition to molecular structure and binding interactions.
Fusco and Konteatis are not cited to demonstrate the inactivity of a specific X/Y/Z/W arrangement. Rather, Fusco and Konteatis support the view that one cannot simply assume that structurally distinct heterocyclic cores constitute a single, functionally equivalent genus of MAT2A inhibitors.
Claims 3-9, 11, and 13 narrow selected structural variables and/or treatment using a compound of claim 1, but continue to encompass the broad substantially different X/Y/Z/W arrangements discussed above. Those additional limitations do not cure the written description deficiency.
As set forth in the en banc decision in Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010), to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention at the time of filing. Specifically, the specification must describe the claimed invention in a manner understandable to a person of ordinary skill in the art in a way that shows that the inventor actually invented the claimed invention at the time of filing. Id.; Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. (see MPEP 2161.01).
Accordingly, in view of the broad scope of X/Y/Z/W arrangements, the lack of a representative number of species encompassing the substantially different classes, and the unpredictability of functionality suggested by Fusco and Konteatis, the specification fails to reasonably convey to a person skilled in the art that the inventors were in possession of the full scope of the claimed invention at the time of filing.
Art of Record but not Applied
US 2024/0287063 A1 discloses MAT2A inhibitors having a fused bicyclic lactam scaffold and provides a cyclopropyl substituent and two 4-(difluoromethoxy)phenyl substituents (example 22) in compounds having a peripheral substitution pattern closely corresponding to that of the instant case. WO 2020/139991 A1 teaches aza heterobicyclic MAT2A inhibitors containing N-N units and additional ring nitrogen atoms. It further shows that compounds within this class can inhibit MAT2A, reduce cellular SAM, and inhibit proliferation of MTAP deficient cancer cells. However, these references fail to teach or suggest the core scaffold, pyrimido[1,2-b]pyridazin-8-one. Accordingly, neither reference appears to lack enough of the embodiments to qualify as 102 and 103 prior art.
Conclusion
Claims 1, 3-9, 11, 13, and 15-22 are rejected.
Claims 2, 10 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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/SEONG JONG KIM/Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
