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 .
Current Status
This action is responsive to the amended claims of 12/06/2024. Claims 1-13 and 16-18 are pending and have been examined on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date is 06/06/2023.
Claim Objections
Claims 1-13 and 16-18 are objected to because of the following informalities: the resolution of the structures recited in claims 1 and 12 is low. While still readable and therefore not indefinite, higher resolution images would improve the readability. The dependent claims 2-11, 13, and 16-18 are similarly objected to since they do not fix the underlying issue. Appropriate correction is required.
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.
Claims 1-13 and 16-18 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. This is a written description rejection.
MPEP 2163(I) states “The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant [inventor] has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee [inventor] was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005).”
Factors considered in making the determination as to whether the artisan would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing include: (a) Actual reduction to practice; (b) Disclosure of drawings or structural chemical formulas; (c) Sufficient relevant identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and knowledge in the art and (f) Predictability in the art.
The Instant Disclosure:
Claim 1 is broadly drawn to any possible prodrug of Formula (I) wherein prodrug is not limited to any defined structural subset. The dependent claims 2-13 and 16-18 do not provide any further limitations to these forms of Formula (I). Similarly, claim 12 is drawn to defined species of Formula (I) or prodrugs thereof with no further structural limitations given for the prodrugs. The claimed compounds are expected to have pharmacological utility in the treatment of diseases (claims 16-18). This lack of structural definition does not allow the artisan to envisage the compounds which are part of the invention (see Factors (b) and (c) above).
The specification defines the term “prodrug” as any compound that, when administered to a subject, products an active drug as a result of a chemical reaction (Pg. 9 ¶3). Examples of prodrug genera are given (e.g., caboxylates, carbonates, etc.); however, this is not limiting. The specification provides synthetic schemes for exemplary compounds of Formula (I) (Pg. 22-63) but does not call out any exemplary prodrugs of the Formula (I). Thus, Factors (a) and (d), above, are not met.
MPEP 2163(II)(A)(2) states “The disclosure of an element may be critical where those of ordinary skill in the art would require it to understand that inventor was in possession of the invention… Amgen, Inc. v. Chugai Pharm.Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) ("it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it").” After review of the specification and claims, the Examiner finds that Applicants have not defined the prodrug of Formula (I) in a way that distinguishes it from other materials and Applicants have not described how to obtain such forms of Formula (I). Thus, it has not been demonstrated that the Applicant was in possession of the invention that is claimed. Moreover, under the broadest reasonable interpretation (BRI), “prodrug” encompasses compounds which have not yet been discovered and/or those with uncharacterized metabolic pathways.
Level of Skill and Knowledge in the Art:
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 synthetic chemist and/or health practitioner with several years of professional experience. However, this factor is outweighed by the unpredictable nature of 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 prodrugs exhibit the desired pharmacological activity (e.g. the ability to inhibit TYK2).
HAN (Han, H., AAPS PharmsciTech., 2000, 2, 1-11) describes that some prodrug forms are not chemically or structurally related to their active form, for example, both glucose
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and hypoxanthine
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are prodrug forms of hydrogen peroxide
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(Pg. 5 Table 1). In view of HAN, the artisan would not have sufficient guidance as to what a “prodrug” of Formula (I) encompasses.
FDA (FDA Drug Safety Communication: Reduced Effectiveness of Plavix (Clopidogrel) in Patients Who are Poor Metabolizers of the Drug, 2017, pp. 1-2) states that a prodrug, Plavix, was found to have reduced effectiveness in patients who are poor metabolizers of Plavix leading to reduced effectiveness (Pg. 1 P4). As a result, predictability of “prodrug” efficacy in the art is understood as a challenge facing the artisan.
Without guidance as to what structures correspond to viable prodrugs of the Formula (I), Factors (e) and (f) are not met, especially since there is no prior art for Formula (I) and the claimed species thereof.
Conclusions:
Due to the breadth of “prodrug” of Formula (I), the lack of direction given in the claims/specification regarding embodiments of such which show the desired activity, and the challenges in the art, the artisan would not be able to immediately envisage the breadth of the prodrug of Formula (I).
Methods of making compounds, in general, are known to the artisan, however the instant disclosure does not inform the artisan of what combination of elements are present in the instant metabolites/prodrugs and if such form possesses the required pharmacological activity. Accordingly, the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to the artisan that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Thus, claims 1-13 and 16-18 are rejected as lacking written description for the full scope of “prodrug” of Formula (I). To overcome this rejection, Applicants are encouraged to strike “prodrug” from the claims.
Claims 16-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of TYK2 kinase-mediated disease, does not reasonably provide enablement for prevention thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The Wands Factors used in a scope of enablement rejection include (per MPEP 2164.01(a)):
The breadth of the claims and nature of the invention:
The claims 16-18 are drawn to a method for the prevention of TYK2 kinase-mediated diseases by administering a compound of Formula (I). The claims are broad regarding the diseases treated – claim 16 is drawn to any TYK2 disease, while claims 17 and 18 recite a multitude of varied species thereof (e.g., cancers vs. autoimmune diseases). The claims are also broad regarding the compound administered – the Formula (I) itself is well defined; however, the prodrugs thereof are not defined by the claims or specification (see 112(a) written description rejection above).
The state of the prior art & predictability of the art:
No prior art teaches the instant compounds of Formula (I) or treatment/prevention of TYK2 kinase-mediated diseases by administration thereof. WANG (WO 2022/117016) teaches a compound analogous to instant Formula (I)
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(Pg. 105 compound 53); which differs at R1. The compounds of WANG are shown, by in vitro assays, to selectively inhibit TYK2 (Pg. 230-235 Tables). Further, a handful of WANG’s compounds, not including compound 53, are tested for their AUC and Cmax in vivo (Pg. 235 Table). However, WANG never provides in vivo data for treatment (e.g., tumor growth inhibition), let alone prevention, of any TYK2 kinase-mediated disease by the compounds analogous to Formula (I).
The instantly claimed genus of TYK2 kinase-mediated diseases is exemplified by cancers, including lymphoma, and autoimmune diseases, including Crohn’s disease (claims 17-18).
BLAKE (Ford-Martin, P., & Blake, S. (2020). Crohn’s Disease. In D. S. Hiam (Ed.), The Gale Encyclopedia of Alternative Medicine (5th ed.). Gale. Infobase. https://access.infobase.com/article/9911049-crohns-disease?aid=279753) teaches Crohn’s disease is a chronic, lifelong disorder, for which there is no known prevention (Pg. 10 ¶1).
KUNNUMAKKARA (Kunnumakkara et al., Experimental Biology and Medicine, 2019, 244, 663-689) teaches cancer is a group of more than 200 neoplastic diseases caused by diverse deregulated cell signaling cascades (Pg. 633 Left ¶1); 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 (Pg. 633 Right last ¶). Therefore, the art is unpredictable regarding how and when the development of cancers is triggered.
For example, BISPO (Bispo et al., Cold Harbor Spring Perspectives in Medicine, 2020, 10, 1-23) teaches most lymphomas are sporadic and the specific etiology remains elusive; these malignancies often develop in the context of genetic abnormalities, immunosuppression, and exposure to various risk factors (Pg. 1 Abstract). Further, BISPO stresses specific prevention efforts targeting these malignancies are nonexistent (Pg. 1 Abstract).
In view of the relevant prior art, the artisan is not enabled to use the instant compounds of Formula (I) to prevent TYK2 kinase-mediated diseases. Considering the lack of art teaching the compounds of Formula (I) and prevention of TYK2 diseases by compounds analogous to Formula (I), and the lack of predictability in such diseases, the art does not provide enablement for prevention of TYK2 kinase-mediated diseases.
The level of one of ordinary skill:
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 an M.D. degree and several years of experience. This factor is outweighed, however, by the unpredictable nature of the art (established above). 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).
The amount of direction provided by the inventor and the existence of working examples:
Inventors have provided direction as to making compounds of Formula (I) (see Pg. 22-63) and in vitro inhibition assays (Pg. 64-67).
The in vitro assays show exemplary compounds of Formula (I) selectively inhibit TYK2 kinase. However, none of the data provided is from a model of any TYK2 kinase-mediated disease, nor is any of the data from in vivo experiments. Further, the data does not show any disease is prevented by the administration of the instant compounds.
It is expected that the artisan could, with reasonable experimentation, treat TYK2 kinase-mediated diseases by administering the Formula (I) since the compounds thereof inhibit TYK2. Thus, Applicants have guidance/enablement in their Specification for treating TYK2 kinase-mediated diseases by administering compounds of Formula (I). However, this guidance does not support prevention of such diseases, especially in view of the relevant prior art.
The quantity of experimentation needed to make or use the invention:
Applicant’s TYK2 kinase-mediated disease prevention method comprising administration of a compound of Formula (I) requires a high level/quantity of experimentation. While Applicants have provided guidance in their Specification for treatment of such diseases via selective inhibition of TYK2, they have not provided enough evidence that Formula (I) can be used to prevent the scope of TYK2 kinase-mediated diseases per the BRI of instant claims 16-18. In view of the lack of data in the instant specification supporting prevention, the lack of prior art teaching compounds of Formula (I), and the lack of predictability in the art, the prevention of TYK2 kinase-mediated diseases is not enabled.
Therefore, claims 16-18 are rejected under 35 USC 112(a) for lacking scope of enablement for preventing TYK2 kinase-mediated diseases.
To render moot this scope of enablement rejection: Applicant should delete “prevent” and/or “prevention”/”preventing” from the claims.
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 1-13 and 16-18 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.
Claims 1-11 recite “the group is optionally substituted with one or more deuteriums” after lists of moieties for R1, R2, and R3. Use of the phrase “the group” is indefinite here since it is unclear whether “the group” is meant to encompass 1) all listed moieties for R1, R2, and R3 or 2) a specific moiety (group) from which moieties for R1, R2, and R3 are chosen, such as the moiety/group listed directly before the phrase “the group”. Thus, the metes and bounds of the claims are undefined rendering the claims indefinite. Dependent claims 12-13 and 16-18 are similarly rejected since they do not rectify the underlying issue.
To overcome: Applicant is encouraged to replace “the group” with the corresponding R group (R1, R2, or R3); e.g., “R1 is optionally substituted with one or more deuteriums”.
Regarding claims 2-4, 7-8, 13, and 17, the phrase "preferably" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention or if they are simply exemplary embodiments (not required). See MPEP § 2173.05(d). Thus, the metes and bounds of the claims are undefined rendering the claims indefinite.
To overcome: please strike “preferably” from the claims.
Conclusion
Claims 1-13 and 16-18 are rejected.
The close art is WANG (WO 2022/117016). WANG teaches a compound analogous to instant Formula (I)
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(Pg. 105 compound 53) wherein the analogous R1 is C1 alkyl, R2 is C1 alkyl, and R3 is C1 alkyl. However, the instant R1 cannot be a simple alkyl; the closest instant R1 is H or C1 haloalkyl. WANG does not teach any other compounds of instant Formula (I) and the compound 53 of WANG has at least two structural differences from any of the instantly claimed species (see claim 12). Further, the compounds of WANG are taught as inhibitors of TYK2 (Pg. 230-235 Tables); however, compound 53 is not tested for its inhibition of TYK2 (see Pg. 230 Table 1 & Pg. 234 Table 4). Moreover, the compounds selected for further pharmaceutical tests are structurally distinct from compound 53 and the instant Formula (I); e.g.,
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. Thus, the artisan would have no motivation or expectation of success in selecting compound 53 (out of 279 compounds) as a lead compound for optimization towards the instant Formula (I) without the aid of hindsight reasoning. Thus, the instant claims are free of the prior art.
Co-pending application 18/872,748 was briefly considered for double patenting but was ultimately found to be drawn to different subject matter. The claims are drawn to compounds analogous to the instant Formula (I); e.g.,
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which similarly to compound 53 of WANG, above, differs by the R1 moiety from the instant Formula (I). The co-pending application does not teach any compounds with the instant R1 group and, since there is no prior art for the instant compounds, the artisan would not have reason or motivation to modify the compounds of the co-pending application to match those of the instant application.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA ELIZABETH BELL whose telephone number is (703)756-5372. The examiner can normally be reached Monday-Friday 9:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/S.E.B./
Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
Prosecution Insights