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 18/728,106
This Office Action is responsive to the amended claims of 07/11/2024. Claims 1-7 and 9-12 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/EP2023/050382, filed 01/10/2023, which claims priority to European Patent Application No. 22150903.7, filed 01/11/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/11/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: the phrase “R1 is aryl optionally substituted by one or more from halogen atoms” is grammatically incorrect. Applicant is advised to amend the phrase to read “R1 is aryl optionally substituted by one or more halogen atoms.” Appropriate correction is required.
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.
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 9 and 10 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 a method of treating at least one selected from the group consisting of pulmonary fibrosis, idiopathic fibrosis, hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis, comprising administering an example compound selected from 1-23, does not reasonably provide enablement for treating any disease, disorder, or condition mediated by ALK5 signaling including any disease, disorder, or condition that involves fibrosis. 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 any disease, disorder, or condition associated with ALK5 signaling comprising administering any compound of formula (I). Thus, the claims taken together with the specification imply that any compound of formula (I), including those not disclosed in the specification, are capable treating any disease, disorder or condition mediated by ALK5 signaling. The treatment of any disease, disorder or condition is considered to be complex. In the instant case, the complexity is exacerbated by the broadness of the claims, which are not directed to a single disease or a single class of diseases, but which embrace the treatment of any disease, disorder, or condition mediated by ALK5 signaling and any disease or condition that involves fibrosis. Thus, the scope of the method is extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The ALK5 signaling pathway is implicated in a number of unrelated conditions, including fibrosis (Mansour, Mai A et al. “Advances in the discovery of activin receptor-like kinase 5 (ALK5) inhibitors.” Bioorganic chemistry vol. 147 (2024): 107332. doi:10.1016/j.bioorg.2024.107332) as well as cancers (Arai, Mai et al. “Discovery of HM-279, a Potent Inhibitor of ALK5 for Improving Therapeutic Efficacy of Cancer Immunotherapy.” Journal of medicinal chemistry vol. 68,7 (2025): 7106-7118. doi:10.1021/acs.jmedchem.4c02293), cerebral ischemia/reperfusion injury (Zhang, Keming et al. “ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b.” Cell death & disease vol. 10,5 360. 1 May. 2019, doi:10.1038/s41419-019-1596-z), neurogenesis and Alzheimer’s disease (He, Yingbo et al. “ALK5-dependent TGF-β signaling is a major determinant of late-stage adult neurogenesis.” Nature neuroscience vol. 17,7 (2014): 943-52. doi:10.1038/nn.3732), to name a few. To date, there is no known agent that can treat fibrosis (including any disease, disorder, or condition involving fibrosis) as well as any cancer, stroke, neurogenesis, Alzheimer’s disease, and the like.
(5) The relative skill of those in the art:
The artisan would have experience in the field of organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would have experience in the synthesis and development of small molecule drugs and would be familiar with synthetic methodologies and structure-activity relationship analysis for such compounds. The artisan would be familiar with the development of formulations to administer the compositions, including inhalation formulations.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has demonstrated that example compounds 1-23 exhibit antagonistic activity of the ALK5 receptor (pg. 57, line 21-pg. 59, line 10, Table 2).
However, the specification provides no evidence that any compound of formula (I) can treat any condition, including fibrosis (including any disease, disorder, or condition that involves fibrosis) as well as any cancer, stroke, neurogenesis, Alzheimer’s disease, and the like.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the complexity of treating any disease, let alone any disease, disorder, or condition associated with ALK5 signaling or one that involves fibrosis 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.
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.
Claim 1 is 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.
Claim 1 recites the limitation "The compound of formula (I)" in line 1 of the claim. There is insufficient antecedent basis for this limitation in the claim. The claims should be amended to read “A compound of formula (I).”
Close Art
The closest prior art is Pujala (WO 2020/012357 A1, found in IDS filed 07/11/2024). Pujala discloses compounds of Formula (I)
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which exhibit inhibitory activity against ALK5 and methods of treating conditions associated with excessive ALK5 activity using theses compounds (Abstract). One example compound disclosed by the reference is Example 31
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(pg. 144, line 17). The central pyridine ring of Example 31 bears a 5-chloro-2-flurophenyl and an aminopyridine moiety. This compound differs from the instantly claimed compounds in several respects. First, the core of the claimed compounds is a pyridazine not a pyridine. While each of the core heterocycles possess a chloro-fluorophenyl and an aminopyridine group, these core rings differ in that Example 31 possess a hydroxyl substituent and a dimethylamino group instead of a heterocyclic group, as required in the instant disclosure for R5. Additionally, the reference compound differs from the instant compounds in both the orientation and position of the amide substituent of the eastern pyridine ring. In the reference compound, the pyridine ring is bonded to the carbonyl carbon of an amide having C(O)NHR connectivity, whereas the instant compounds require the pyridine ring to be bound directly to the amide nitrogen with NR3C(O)R4 connectivity. The compounds also differ in the placement of these groups as the reference compound bears the amide at the 2-position, while the instant compounds require attachment at the 3-position.
The prior art of record does not teach or suggest reasons to modify the compounds of Pujala to arrive at the instantly claimed compounds. The compounds are therefore novel and nonobvious in view of the current prior art.
Conclusion
Claims 1, 9, and 10 are rejected.
Claims 2-7 and 11-12 are objected to for being dependent upon a rejected base claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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