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 18/863,014
This Office Action is responsive to the amended claims of 10/29/2025. Claims 1-12 and 14-19 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/EP2023/061588, filed 05/03/2023, which claims priority to EP Patent Application No. 22171914.6, filed 05/05/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/10/2025 is 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 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 2 is directed to a compound of claim 1 wherein n is 0. Claim 1 expressly recites that n is 1, 2, or 3. Thus, claim 2 does not further limit the subject matter of claim 1, but instead broadens the scope of the variable n beyond the permitted values defined by claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 14-19 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 Alzheimer’s disease or Ab-associated cognitive dysfunction, does not reasonably provide enablement for the prophylactic treatment of the claimed disease, nor does the specification provide a reasonable basis for concluding that the claimed compounds would be effective for treating the full range of diseases encompassed by the 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 methods of treatment, including prophylactic treatment, of neurodegenerative diseases comprising administering a pharmaceutically effective amount of any compound of Formula I. The scope of “neurodegenerative brain diseases” encompasses a broad array of diseases that have different modes of action and different origins. The term covers such diverse diseases as Alzheimer’s disease, dementia, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, genetic brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease, prion disease, tauopathies, front-temporal lobar degeneration, British and Danish dementias and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Thus, the claims taken together with the specification imply that an effective amount of any compound of Formula I is capable of treating and preventing all neurodegenerative diseases.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The state of the prior art is that the treatment and prevention of neurodegenerative diseases remains highly unpredictable. Dawson et al. teaches that no animal mode of AD, PD, FTD, or ALS fully phenocopies human disease and instead merely recapitulate the initial proteinopathy or pathological features of the disorder (pg. 1370, left col., second para.). The reference additional teaches that mouse models have poor predictive power for drug efficacy in human neurodegenerative diseases (pg. 1370, left col., second para.). Dawson et al. further teaches that different neurodegenerative diseases involve different pathological processes. The reference teaches that amyloid-b (Ab), a-synuclein, tau, and TDP-43 are known hallmarks of neurodegenerative diseases, and specifically describes Ab plaques as characteristic of AD, a-synuclein pathology in PD, and TDP-43 pathology in ALS/FTD, highlighting that the claimed disorders cannot be simply treated as one biologically homogeneous neurodegenerative condition. Dawson et al. additionally teaches that evaluation of a compound’s therapeutic potential in neurodegenerative disease should include testing across multiple-disease relevant models, particularly where a broadly applicable neuroprotective effect is proposed (Box 3, pg. 1374). Dawson et al. concludes that there has been limited success in translating findings from mouse models into effective therapies for human neurodegenerative disease and recommends more thorough evaluation of potential therapeutics across multiple models (Concluding thoughts, pg. 1376). This teaching highlights the uncertainty associated with extrapolating results obtained in one model to the treatment of a heterogeneous group of neurodegenerative diseases.
Pasteuning-Vuhman et al. teaches that neurodegenerative diseases constitute a heterogenous group of disorders and that the phenotypic heterogeneity, lack of robust biomarkers and limited translation potential of available experimental models have hindered the development of effective therapies for these diseases (Abstract, Highlights). The reference explains that neurodegenerative disease drug development is complicated by heterogeneity in disease etiology and pathogenesis and that available in vitro and in vivo models reproduce only a subset of disease phenotypes and have limited ability to predict clinical drug efficacy (Concluding Remarks). These teachings further demonstrate the unpredictability of the art and the limited ability to extrapolate therapeutic efficacy observed in a single experimental disease model across the heterogeneous group of neurodegenerative diseases encompassed by the instant claims.
(5) The relative skill of those in the art:
The level of ordinary skill in the art is high. The artisan would have experience in medicinal chemistry, pharmacology, or a related field. The artisan would have experience and knowledge in the pathophysiology and preclinical evaluation of neurological diseases, including neurodegenerative disease.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for the preparation of the claimed compounds ( [0128]-[0153]), including characterization data. The specification also provides guidance on how to evaluate the permeability and MDR1-mediated efflux of the claimed compounds to evaluate their potential for CNS exposure ( [0154]-[0157]). The specification further provides guidance for evaluating compounds in Ab1-42-induced mouse models of Alzheimer’s disease, including guidance on compound administration, dosage, formulation, and evaluation of short-term spatial memory ( [0158]-[0187]).
However, the specification does not provide sufficient guidance to allow the artisan to extrapolate the limited biological results disclosed for an Ab1-42-induced model of cognitive impairment to the full scope of the claimed methods. The specification does not identify a common mechanism of action or pharmacological activity by which the claimed compounds would reasonably be expected to therapeutically or prophylactically affected the distinct diseases encompassed by the claims. The specification does not provide representative working examples, disease specific models, predictive biological endpoints, structure-activity relationships, or any other technical guidance that would permit the artisan to identify which compounds and treatment regimens would be effective for the treatment of the broadly encompassed diseases of the instant claims, without undue experimentation.
It is difficult to treat many of the disorders claimed herein. Instant claim language embraces disorders not only for treatment but the prevention/prophylaxis, which is not remotely enabled. It is presumed in the prevention of the diseases and/or disorders claimed herein there is a way of identifying those people who may develop a Alzheimer’s disease, Parkinson’s disease, etc. There is no evidence of record, which would enable the skilled artisan in the identification of the people who have the potential of becoming afflicted with the disorders claimed herein.
Where the utility is unusual or difficult to treat or speculative, the examiner has authority to require evidence that tests relied upon are reasonably predictive of in vivo efficacy by those skilled in the art. See In re Ruskin, 148 USPQ 221; Ex parte Jovanovics, 211 USPQ 907; MPEP 2164.05(a).
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. Tossing out the mere germ of an idea does not constitute enabling disclosure. Genentech Inc. v. Novo Nordisk 42 USPQ2d 1001.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the heterogeneity of the diseases encompassed by the broadly defined “neurodegenerative diseases,” the distinct etiologies and pathophysiologies underlying those diseases, the absence of a single experimental model capable of reliably predicting therapeutic efficacy across such disorders, and the recognized unpredictability of translating results from a single disease model to human therapeutic efficacy 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.
Conclusion
Claims 2 and 14-19 are rejected.
Claims 1 and 3-12 are allowed. The closest prior art of record is Hunt (WO 2021/262587 A1, found in IDS filed 02/10/2025). Hunt teaches compounds of Formula I
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(Claim 1) and further teaches that these compounds may be used for modulating glucocorticoid receptors (Abstract). The reference claims a method of treating a disorder or condition through modulating a glucocorticoid receptor comprising administering an effective amount of the compound and identifies Alzheimer’s disease as one such disorder (Claims 79-81). While Hunt’s compound of Formula I allows for any of A1-A4 to be selected from =CR2- or =N-, all exemplified compounds bear an indazole ring where each of A1-A4 are =CR2-. Example compounds 105-133 are the closest compounds of Hunt to the instantly claimed compounds because these are the only exemplified compounds where ring J is a nitrogen containing heterocycle where the nitrogen atom is directly bound to the indazole ring. However, these compounds differ significantly in terms of their structures compared to the instantly claimed compounds. Take compound 105 as an example
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. 105 further differs from the instantly claimed compounds in that the fluorophenyl substituent is at the 1 position compared to the 2 position and the connectivity of the sulfonyl amide is bound to ring J through the nitrogen atom rather than the sulfur atom, as required by the instant claims.
Hunt discloses glucocorticoid receptor (GR) binding assays and glucocorticoid activation of TAT for the exemplified compounds. No other biological assays or disease models are disclosed. Based on the structural differences in the compounds, the scant biological assays, and the recitation of Alzheimer’s disease as part of a laundry list of treatable diseases, the artisan would not have been motivated to make the required changes to the structure of the molecule to arrive at the instantly claimed compounds, nor would the expect that the resulting compounds would be useful in the treatment of Alzheimer’s disease.
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
