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 of 18/717,962
This Office Action is responsive to the amended claims of 06/07/2024. Claims 1-21, 43-49, 51, and 53-54 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/US2022/052740, filed 12/13/2020, which claims priority to U.S. Provisional Patent Application No. 63/290,509, filed 12/16/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/03/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
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.
Claims 43-49 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 in vitro methods of reducing stimulated secretion of TNF-a, IL-6, IL-1b, IFN-g, and IL-10 and inhibiting 5-LOX and 15-LOX enzymatic activity using compounds XXII-XVIII, does not reasonably provide enablement for treating, ameliorating or preventing the recurrence of the listed inflammatory conditions of the recited claims. 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 factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating, ameliorating or preventing the recurrence of the listed inflammatory conditions of the recited claims using any compound of formula (I) and (Ia). Thus, the claims taken together with the specification imply that any compound of (I) or (Ia) are capable of treating any inflammatory condition.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The art recognizes that inflammatory cytokines biology is complex and unpredictable. Kany teaches that numerous studies have implicated inflammatory cytokines in various inflammatory diseases, but that their specific roles are not always consistent (Abstract). Kany also teaches that the effects of cytokines depend on the targeted cell, making them pleiotropic and further teaches that different cytokines may have the same effect and are therefore redundant (pg. 2, second para. of Cytokines section). Accordingly, the art recognizes that cytokine biology is complex and context dependent, such that in-vitro suppression of selected cytokines in PBMCs would not have predictably established treatment of all the broadly claimed inflammatory and inflammation-associated diseases.
Steeland teaches that the effects of TNF can diverge and that TNF is no only destructive but also has essential roles (Abstract). The reference also teaches that anti-TNF treatment of multiple sclerosis resulted in unexpected exacerbations of the disease as well as paradoxical side effects (pg. 22, second para.). The reference further reinforces that cytokine modulation is both disease- and context-dependent, establishing that in-vivo suppression of cytokines would not predictably establish treatment of all claimed diseases.
(5) The relative skill of those in the art:
The artisan would have experience in organic chemistry, pharmaceutical sciences, medicinal chemistry, or a related field. The artisan would have experience in the synthesis and development of small molecule inhibitors for use in the treatment of inflammatory disease and related conditions.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for in-vitro PBMC cytokine-secretion assays, recombinant 5-LOX, and 15-LOX enzyme assays, cell-viability assays, and CB1/CB2 agonist assays for compounds II and XXII-XVIII (Table 3, [0278]).
However, the specification does not provide guidance for treating the claimed diseases using all compounds of (I) and (Ia).
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to context specific nature of cytokine inhibitors and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
Claim 51 is 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 in vitro methods of reducing stimulated secretion of TNF-a, IL-6, IL-1b, IFN-g, and IL-10 and inhibiting 5-LOX and 15-LOX enzymatic activity using compounds XXII-XVIII, does not reasonably provide enablement for treating, ameliorating or preventing the recurrence of any disease using any compound of formula (I) or (Ia). 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 factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating, ameliorating, reducing, or preventing the recurrence of one or more symptoms of a disease comprising administering a compound of (I) or (Ia) to a patient in need thereof. Thus, the claims taken together with the specification imply that the administration of any compound of formula (I) or (Ia) is capable of treating or preventing any disease.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The art recognizes that inflammatory cytokines biology is complex and unpredictable. Kany teaches that numerous studies have implicated inflammatory cytokines in various inflammatory diseases, but that their specific roles are not always consistent (Abstract). Kany also teaches that the effects of cytokines depend on the targeted cell, making them pleiotropic and further teaches that different cytokines may have the same effect and are therefore redundant (pg. 2, second para. of Cytokines section). Accordingly, the art recognizes that cytokine biology is complex and context dependent, such that in-vitro suppression of selected cytokines in PBMCs would not have predictably established treatment of all the broadly claimed inflammatory and inflammation-associated diseases.
Steeland teaches that the effects of TNF can diverge and that TNF is no only destructive but also has essential roles (Abstract). The reference also teaches that anti-TNF treatment of multiple sclerosis resulted in unexpected exacerbations of the disease as well as paradoxical side effects (pg. 22, second para.). The reference further reinforces that cytokine modulation is both disease- and context-dependent, establishing that in-vivo suppression of cytokines would not predictably establish treatment of all claimed diseases.
(5) The relative skill of those in the art:
The artisan would have experience in organic chemistry, pharmaceutical sciences, medicinal chemistry, or a related field. The artisan would have experience in the synthesis and development of small molecule inhibitors for use in the treatment of inflammatory disease and related conditions.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for in-vitro PBMC cytokine-secretion assays, recombinant 5-LOX, and 15-LOX enzyme assays, cell-viability assays, and CB1/CB2 agonist assays for compounds II and XXII-XVIII (Table 3, [0278]).
However, the specification does not provide treating the claimed diseases using all compounds of (I) and (Ia).
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the context specific nature of cytokine inhibitors and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
Claim Rejections - 35 USC § 103
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.
Claims 1, 2, 7, 9, 11, 12, 14, 16, 20, 21, 43-46, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Blanco (EP 3666765, found in IDS of 09/03/2024).
Blanco teaches chromenic phytocannabinoids of formula (I)
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[0006] wherein R is selected from the group consisting of C1-C6alkyl, a C2-C8 alkenyl moiety, a C4-C12 dienyl or a C6-C18 trienyl moiety; R1 is a C1-C6 alkyl moiety; R2 is H or a C1-C6 alkyl moiety; R3 is H or a C1-C6 alkyl moiety; and R4 is H, C1-C6 alkyl moiety, or a benzyl moiety. The reference identifies compounds (A)-(H) as preferred embodiments of the disclosed genus. Compounds (A)
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, (C)
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, and (D)
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overlap with the instantly claimed compounds. Applicants recognize this overlap, and have excluded these compounds through provisos from the claimed genus. The proviso may remove these exact species for novelty purposes, but does not nullify the reference’s teaching that the core scaffold, substitution patterns, and preferred analogs were known at the time of filing. Even with these provisos, the reference teaches close structural analogs to the instantly claimed genus of compounds. For example, consider compound (H)
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of Blanco. This compound reads on the instantly claimed compound of Formula (I) with the following substitutions: X and Y are both =O; RA and RB, and are each H; RC is benzyl; R1 is
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, wherein each of the dashed bonds are double bonds; R2 is a C5 alkyl group; and R3 is C1 alkyl group. The instant claims do not allow for RC to be benzyl, but this is the only structural distinction between the claimed genus and the reference compound. Blanco expressly identifies this position as a variable position, and teaches other non-benzyl substituents at this position, including hydrogen. The reference teaches pharmaceutical compositions comprising the compounds and at least one excipient (Abstract) and also teaches that the compounds are effective inhibitors of MAGL (Table 1). MAGL is involved in the regulation of physiological diseases and processes which include inflammation ( [0003] ).
It would have been obvious to the artisan to modify one of the preferred compounds of Blanco’s disclosure, such as (H), replacing the benzyl group of RC with one of the non-benzyl substituents taught by the reference while retaining the same core compound. The artisan would expect that such modification would result in a compound that would retain the disclosed MAGL inhibitory activity because the core of the scaffold responsible for the disclosed activity remain intact.
Claims 1, 8, 10, and 53-54 are rejected under 35 U.S.C. 103 as being unpatentable over Blanco in view of Silverman (Silverman, R. B., & Holladay, M. W. (2014). The Organic Chemistry of drug design and Drug Action. Academic Press.) and Fraley (CITATION).
The teachings of Blanco are discussed above and teach the limitations of claim 1. The above discussion is incorporated by reference into this rejection. Blanco does not disclose that the positions corresponding to RA and RC in the instant application can be substituted with a halogen.
Silverman teaches that bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties (2.2.4.3 Bioisosterism). Bioisosterism is and important tool for lead compound modification that is routinely used in medicinal chemistry. The reference also teaches that fluorine is a common bioisostere of hydrogen (Table 2.10).
Fraley teaches that halogenation is commonly used in medicinal chemistry to improve the potency of lead compounds (Abstract).
The artisan would have been motivated to substitute the variable positions identified in Blanco’s (I) by replacing hydrogen with known medicinal chemistry substituents. For example, the artisan would have been motivated to replace hydrogen with fluorine because fluorine is a known bioisostere of hydrogen. The artisan would have further been motivated to prepare additional halogen analogs, such as chloro-, bromo-, and iodo-substituted analogs, because halogenation of lead compounds was a known strategy for modulating ADME-related properties. The artisan would expect that because the active core of the molecule is retained that the compounds would still possess similar biological properties. Therefore, the substitution of halogens at the indicated positions amounts to an obvious modification that would have been done in routine lead compound modification.
Regarding the species of compound of claims 53 and 54. The compounds of Formulae VII and XVI are obvious halogenated analogs of Blanco’s (I). These compounds retain the same chromenic phytocannabinoid core and differ only by the replacement of hydrogen at the positions corresponding to RA-RC of the instant application. The references discussed above teach that the exchange of hydrogen for halogen is a routine modification in lead compound modification. Given that the core molecule contains only three positions hydrogen-bearing positions available for substitution, the claimed halogenated species represent routine variants obtained by screening halogen substitution across a small, finite set of positions.
Claims 1, 3, and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Blanco in view of Bian (Bian, Jinlei, et al. "Palladium (II)-Catalyzed C–H Bond Activation/C–C Coupling/Intramolecular Tsuji–Trost Reaction Cascade: Facile Access to 2 H-Pyranonaphthoquinones." Organic letters 17.14 (2015): 3410-3413., found in IDS filed 09/03/2024).
The teachings of Blanco are discussed above and are incorporated by reference into this rejection. The reference teaches the limitations of claim 1. Blanco does not teach or suggest the aryl moiety between RC and R2.
Bian teaches that 2H-Pyranonaphthoquinones are a recognized class of compounds with important biological activity including anti-inflammatory activity (pg. 3410, left col, first para.). The reference provides examples of these compounds in Figure 1
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. The disclosed compounds share the same core as the claimed compounds of claims 3 and 4. The claimed compounds retain the same core and differ only by peripheral substitution.
Bian teaches that the 2H-Pyranonaphthoquinone core is amenable to peripheral substitution, including alkyl and alkoxy substitution, while retaining the desired biological activity. The reference would have directed the artisan to use these disclosed compounds as a basis for developing close structural analogs by varying the peripheral substitutions of the known biologically active core. Because the claimed compounds preserve the active core, which is known to be associated with anti-inflammatory activity and differ only by peripheral substitution, the artisan would have reasonably expected that such modification would result in analogs that would retain this desired biological activity. In the absence of showing criticality or unexpected results for these compounds, the compounds of claims 3 and 4 represent obvious variants of the known anti-inflammatory core of Bian’s disclosure.
Conclusion
Claims 1-4, 7-12, 14, 16, 20-21, 43-46, 51, and 53-54 are rejected.
Claims 5, 6, 13, 15, 17-19, and 47-49 are objected to for being dependent upon a rejected base claim.
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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