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 .
DETAILED ACTION
Claims 1-13 are pending
Claims11-13 are withdrawn from examination as being drawn to a nonelected specie.
Claims 1-10 are under consideration in the instant office action.
Election/Restrictions
Applicant’s election without traverse of Group 1 (Claims 1-10) and the following species in their response dated 08/13/2026 is acknowledged.
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Examination of the claims are conducted to the extent they read on the elected species. Claims 11-13 are withdrawn from examination as being drawn to a nonelected specie.
Claims 1-10 are under examination and the requirement for restriction is made final.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/07/2024, 01/06/2025 and 04/06/2026 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. See attached copy of the PTO-1449.
Priority
This application claims priority under 35 U.S.C. § 119(b) to Chinese Application No. 2023106668256, filed June 7, 2023, Chinese Application No. 2023110594857, filed August 22, 2023, Chinese Application No. 2023115555083, filed November 21, 2023, and Chinese Application No. 202410227922X, filed February 29, 2024,
Claim Objections
Claims 8-9 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 1-7 and 10 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the elected certain species such as those listed in instant claim 8-9, is not considered enabled for the other compound species encompassed by Formula I. 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 standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
Nature of the Invention and Breadh of the claims: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.” In the instant case, the claims are drawn to a nitrogen containing heterocyclic compound of formula I shown below, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof: all of which are claimed to be useful in the method of RAS in a subject and treating RAS-related disease which is cancer.
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The formula contains several variables, each of them defined by additional variables. R groups include C6-20 aryl, 5-12 membered heteroaryl , heterocycycloalkyl carbocyclyl, cycloalkyl, all of which are further substituted with more further groups which are similar. The millions of compounds encompassed by the claims include salts, prodrug, stereoisomer tautomer and isotopically labeled compounds of each ot them. It is noted that just the prodrug exponentially increases the number of compounds encompassed here as it can included any modifications of each of the compounds encompassed here , which would eventually upon administration gets converted to that specific compound.
As such the compounds of the claim encompass molecules that widely vary in the physical and chemical properties such as size, molecular weight, acidity, basicity, and properties that are known in the art to greatly influence pharmacokinetic and pharmacodynamics parameters, not to mention the ability to productively bind to claimed biological target molecules. The claims cover compounds easily in the millions given the number of possible rings, ring systems and substitutions covered by the claims' scope along with varying choices for remaining variables and the prodrugs, stereoisomers, tautomer and isotopically labelled compounds thereof.
As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation”. Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “the specification 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 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry our the invention commensurate with the scope of his claims". Amgen, In.c, v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” As discussed above, the instantly claimed invention pertains to compounds of Formula I, which are alleged by the Specification to act as RAS inhibitors useful in the treatment of Cancer. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response.
Just taking into example the heterocyclic substitutions of the variables in the compounds, although the field of synthetic heterocyclic chemistry has several named reactions applicable to C, H, O, N, X, and S functional groups. Further, the term The terms "heterocyclyl", "heterocycle" or "heterocycloalkyl" in the instant application refer to a cyclic group having a specified number of ring atoms (c.g., 3-8 members), a specified number of heteroatoms (c.g., 1, 2, or 3) and specified heteroatom species (one or more of N, 0 and S), which is monocyclic, bridged, or spiro, and where each ring is saturated. Heterocycloalkyls include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl, piperidinyl, and the like
.However the state of the art of formula I as instantly claimed with several substituted moieties is very poor.
Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods. Deciding which technique to use would have been determined by the skilled artisan’s knowledge regarding the compound and target of interest. Ligand based drug design relies on knowledge of a compound or compounds of interest (i.e., ligands) to derive new compounds that will, in theory, similarly interact with the target of interest to elicit the activity of interest. Conversely, structure based drug design relies on knowledge of the three dimensional structure of the target of interest (i.e., receptor, ion channel, or enzyme) to derive new compounds that will, in theory, interact with the target of interest to elicit the activity of interest. In either case, the compounds derived from these techniques (applied alone or in combination) are then subjected to in vitro testing for validation.
The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure-based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target: ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised.
The invention is pharmaceutical in nature as it involves inhibition of RAS. The skilled artisan would view that the synthesis of all possible variations of the compounds of formula (I) would require much experimentation. The level of predictability in the synthetic chemistry art is low given that a change of substituent, reagent, catalyst in a reaction can lead to very different reaction products and/or different regioselectivity of the reaction. This being the case, one of ordinary skill in the art would not have reasonable assurance that each possible compound claimed and encompassed by formula I in the instant application would be feasible to make and use. 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 unpredictable. The pharmaceutical art is unpredictable and target compounds need to be individually assessed for viability.
The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification in discloses 162 structurally related compound species encompassed by Formula I and describe the in vitro RAS inhibitory activity of 109 compounds and PK data for just one compound 4 (see examples in the disclosure). It is noted that the disclosure does not show any examples of the prodrugs, or isotopically labelled compounds
As such it is noted that there is no enablement in the specification wherein the. The substituents include C10-20 aryl or C9-12 heterocyclyl among other things.
Amount of Experimentation Necessary and conclusion: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of Formula I, which are alleged by the Specification to act in the method of inhibiting RAS activity. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of Formula I with respect to the disclosure since Formula I encompasses thousands or millions of compound species, whereas the instant Specification discloses only 162 such compound species all of which have a similar core. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the hundreds of millions of compounds encompassed by Formula (I) would exert the alleged activity based on the limited disclosure of 91 compounds. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similar activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Thus, in order to identify usable compounds of Formula I, the skilled artisan (at minimum) would have to carry out ligand based drug design methods using the 91 disclosed compounds as a starting point and, assuming the structure of the target receptor was known, combine the findings with data derived from structure based drug design methods to arrive at a small library of “lead” compounds believed to possess the activity of interest. The skilled artisan would then synthesize lead compounds that are within Formula I for in vitro testing. At this point, however, even "the top scoring molecule could fail in vitro assays and “hit rates are on the order of one in ten”, It is highly unpredictable whether any compound within the subgenus of compounds of Formula (I) identified by rational drug design based on the instant disclosure would, in fact, be usable. Whether the other compounds of Formula (I) would be usable is even less predictable. As such, the only way to ascertain which of the hundreds of claimed compounds encompassed by Formula I are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Conclusion
Claims 1-10 are rejected. No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAVITHA M RAO/ Primary Examiner, Art Unit 1691
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