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
1. This application is a 371 of PCT/EP2021/069897 07/15/2021; FOREIGN APPLICATIONS: EP 20186249.7 07/16/2020.
2. Claims 1-3, 6-15 are pending.
Claim Rejections/Objections Withdrawn
3. The rejection of claims 14-15 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of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn in view of the amendments. The rejection of claims 1-2, 13-15 under 35 U.S.C. 103 as being unpatentable over Piu WO 2008033894 A2 in view of Fleming “Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore.” J. Med. Chem. 2010, 53, 7902–7917 is withdrawn in view of the amendments. The rejection of claims 1-3, 13-15 under 35 U.S.C. 103 as being unpatentable over Bartholomeus WO 2019122265 A1 (cited on the IDS) in view of Silverman, R.B. The Organic Chemistry of Drug Design and Drug Action 1992, Academic: New York, pg 19 is withdrawn in view of the amendments.
New Grounds of Rejection
4. A new ground of rejection is set forth below.
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.
5. Claim 14 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 treating the diseases of claim 15, does not reasonably provide enablement for a KEAP 1 mediated disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to the following:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
According to the specification on page 1 the compounds find utility in the inhibition of KEAP 1-NRF2, protein-protein interaction perhaps by inhibition of KEAP1 although this is unclear. The specification uses an engineered cell line with the Pathhunter technology to show that the compounds inhibit KEAP 1 – NRF 2 interaction. Claim 14 is drawn to treating any “KEAP 1 mediated disorder”. However not all KEAP 1 interactions involve NRF2. “The role of Keap1, however, has been attributed mainly to Nrf2 repressor function and redox sensor. Still, thanks to its extraordinary structure and reactivity, Keap1 undergoes numerous post-translational modifications, has a very rich interactome, and, thus, is involved in various cellular processes.” (Aleksandra Kopacz “Beyond repression of Nrf2: An update on Keap1” Free Radical Biology and Medicine, Volume 157, September 2020, Pages 63-74, page 63 col. 1). The signaling of KEAP 1 involves a large number of proteins and their relationship to any disease has not been demonstrated. KEAP1 is required for the proper regulation and activation of the chaperone protein HSP90 during stress responses like lipopolysaccharide (LPS) exposure. Alterations in KEAP1 functionality directly impair downstream COX-2 activity independent of NRF2 transcription. KEAP1 acts as a broad substrate adaptor for the Cullin-3 ubiquitin ligase complex, targeting non-NRF2 proteins for ubiquitination and degradation. KEAP1 acts on PGAM5 (Phosphoglycerate Mutase 5): A mitochondrial outer membrane protein that binds to KEAP1 via a conserved ETGE-like motif (NXESGE), undergoing KEAP1-dependent ubiquitination and proteasomal degradation; SQSTM1 / p62: An autophagy receptor that interacts with KEAP1, serving as both a target of KEAP1-mediated ubiquitination and a competitive binder that disrupts KEAP1-substrate interactions during selective autophagy; Sp1 (Specificity Protein 1): A transcription factor shown to directly interact with and be subjected to ubiquitination by KEAP1, linking KEAP1 activity to the regulation of downstream genes like CUL4A; BPTF (Bromodomain and PHD Finger Containing Transcription Factor): Identified via proteomic and biocuration profiling as a direct target of the CUL3-KEAP1 E3 ligase complex for ubiquitination and degradation; it mLST8 (Mammalian Lethal with Sec13 protein 8): Binds to KEAP1 which induces non-degradative ubiquitination, modulating the assembly and downstream signaling of the mTORC2 complex. Many others are involved.
Moreover it is unclear of the molecular mechanism of the inhibition of the KEAP 1-NRF 2 interaction such that drawing any conclusions solely based on this assay is not possible. It does appear based on the applicant citations that NRF 2 is involved in certain kinds of neurodegeneration through mechanisms that are not entirely clear. Applicant provides two citations on page 3 which reviews NRF 2 as a therapeutic target one citation is to Li and in another to Johnson & Johnson. Both of these documents are cited on the IDS of April 25, 2023. Johnson discusses the relationship of NRF2 to some of the diseases in claim 15, including Alzheimer’s disease on page 255 and Parkinson’s disease on page 256 and ALS on page 257 and Huntington’s disease on page 259 and MS on page 259. All of the animal models for neurodegenerative disease are non-correlative to the actual conditions. ALS models are particularly bad and there are no effective animal models of ALS see Petrov “ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?” Frontiers in Aging Neuroscience | www.frontiersin.org 1 March 2017 | Volume 9 | Article 68, 1-11 page 4:
The analysis of CTs presented in this systematic review is a testament to the extraordinary complexity of the ALS disease mechanisms. Even though academic science has made significant progress in attempting to elucidate molecular, genetic, epigenetic and environmental aspects of motor neuron degeneration, the slow translational progress with only one approved drug on the US and European markets suggests that existing preclinical models are not fully representative of human disease process. The absence of the fully characterized and validated rodent ALS models is increasingly recognized as a major hurdle in clinical development. In a recent study by ALS Therapy Development Institute (ALS TDI), researchers performed rigorous animal tests on multiple compounds which failed in CTs. Surprisingly, the improvement in survival which was previously published for all those drug candidates (including riluzole) could not be replicated in an ALS TDI study (Perrin, 2014). Authors emphasize the need for community effort in the area of preclinical model development both by the public and private agencies. In the meantime, currently available preclinical models should be considered useful only to a certain extent, with the ultimate test of the potential efficacy of any novel pharmaceutical having to come from large-scale human CTs. [Emphasis Added].
While Johnson discusses some relationship of KEAP1 and Nrf2 to AD, “It is well-established that widespread transcriptional changes accompany the onset and progression of Alzheimer’s disease. Because of the multifactorial nature of this neurodegenerative disorder and its complex relationship with aging, however, it remains unclear whether such changes are the result of nonspecific dysregulation and multisystem failure or instead are part of a coordinated response to cellular dysfunction.” (Ciryam “A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation” PNAS |April 26, 2016, vol. 113 no. 17, 4753–4758). Researcher have investigated the levels of aberrant protein expression in AD, “To date, about 90 proteins have been proposed to be associated to AD pathogenesis.16,36 In the current study, we were able to identify and quantify 69 significantly differentially regulated proteins among which 46 have been previously implicated in AD pathogenesis. The remaining 23 proteins comprise novel proteins that have not previously been reported to be related to AD. Among the 69 significantly regulated proteins, 28 proteins showed a significance of p < 0.01 (Figure 2).” (Musunuri “Quantification of the Brain Proteome in Alzheimer’s Disease Using Multiplexed Mass Spectrometry” J. Proteome Res. 2014, 13, 2056−2068.) The diseases claimed are multifactorial illnesses with no clear etiology and have very few therapies where the failure rate is extremely high. Beyond the diseases of claim 15 there is no evidence that these compounds would find utility in the treatment of all KEAP 1 mediated disorders as claimed.
Objections
6. Claim 15 is objected to for depending from a rejected base claim, but would be allowable in independent format with all the limitations of the base claim and any intervening claim.
Conclusion
7. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
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