DETAILED ACTION
All rejections and objections not listed below have been withdrawn.
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 .
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in CH00308/21 on 03/22/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/06/2026 is being considered by the examiner.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 3, 6-11, 14, 23-24, 32-37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wong ( Wong et al., "Pharmacological depletion of ERF1 or ERF3A enhances effect of aminoglycosides on CFTR premature termination codon readthrough," PEDIATRIC PULMONOLOGY 20201001 JOHN WILEY AND SONS INC. NLD, Vol. 55, No. Suppl 2, 1 October 2020, page 61, Poster Session Abstract, IDS) in view of Matyskiela (Matyskiela et al., A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature volume 535, pages252–257 (2016), IDS) in view of Barillari (Barillari et al., Classical Bioisosteres, Bioisosteres in Medicinal Chemistry, First Edition. Edited by Nathan Brown 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA) in view of Zou( Zou et al., The novel protein homeostatic modulator BTX306 is active in myeloma and overcomes bortezomib and lenalidomide resistance, Journal of Molecular Medicine (2020) 98:1161–1173).
The reference Wong teaches “About 10% of all people with cystic fibrosis (CF) carry nonsense or premature termination codon (PTC) variants of the CFTR gene, usually leading to a loss of protein function and a severe reduction in mRNA levels due to nonsense-mediated mRNA decay (Nl\,ID). Multiple high-throughput screening (HTS) campaigns have been carried out to discover small molecule translational readthrough (TR) modulators beyond known aminoglycosides (eg, G418). To enhance expression and function of CFTR protein resulting from readthrough, TR modulators are often combined with a Nl\,ID inhibitor (eg, SMG li) and a CFTR corrector (eg, VX-809)” (paragraph 1).
The reference Wong teaches “We tested CC-885 in combination with G418/SMG liNX-809 in 16HBEge CFTR G542X cells and observed a synergistic effect on PTC readthrough. Treatment with G418/SMG li/VX-809 in combination with CC-885 (20 nM) for 48 hours, resulted in 7% mature CFTRprotein compared to CFTR wt from 16HBE14o- cells by WB. Combination treatment with G4 l 8 ( 100 μM) and CC-885 (30 nM) for 48 hours resulted in more than 3-fold increase in CFTR function (6.9±0.11 μA/cm2) compared to G418 alone (2.0±0.14 μA/cm 2)”(last paragraph) and “Multiple high-
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through put screening (HTS) campaigns have been carried out to discover small molecule translational readthrough (TR) modulators beyond known aminoglycosides (eg, G418)”(first paragraph).
The reference Matyskiela provides evidence of the structure of CC-885(figure 1), wherein, L1=C1 alkyl, X3=NH, X4=NH, L2=covalent bond, X1= C6 aryl substituted with halogen and linear C1 alkyl, L3=covalent bond, X2= H, n=1, Ra=H, formula Va.
The instant application recognizes G418 as geneticin (page 16).
This helps to teach claims 1, 2, 3, 6-11, 14, 23-24, 32-37.
The reference Wong does not teach the correct X3=O(all claims) or the treatment of cancer (claim 35). The reference Wong does not specific teach administration to a subject(all claims) or administered in a simultaneous manner or sequential manner ( claims 9 or 32) or have the compound of formula I, or pharmaceutically acceptable salt or stereoisomer thereof, and the aminoglycoside in form of one single pharmaceutical composition or separate compositions(claims 10, 33). The Wong and Matyskiela has been discussed supra and do not teach termination codon as UGA or UAG or UAA (claims 11). The reference also does not teach the TP53 codon (claim 34).
The reference Barillari teaches “The discovery and development of a candidate for clinical evaluation is a long process that involves small modifications to a lead compound to improve some of its properties, such as pharmacological activity, selectivity, and pharmacokinetics. This is often achieved by the medicinal chemists by replacing a functional group with groups sharing similar physical or chemical properties and maintaining similar activity, which are defined as bioisosteres. We will hereby provide a historical overview of the development and evolution of the concepts of isosterism and bioisosterism, followed by a selection of successful examples of bioisosteric modifications reported in the literature”(page 15).
The reference Barillari teaches the following bivalent bioisosteres(page 17):
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This helps to teach all claims.
The reference Matyskiela teaches “We identified CC-885 as a potent anti-cancer agent eliciting broad spectrum growth inhibition against cancer cell lines and patient-derived acute myeloid leukaemia (AML) cells, indicating the clinical potential for this mechanism. We identified GSPT1 (eRF3a) as a novel CC-885-dependent cereblon substrate mediating the anti-pro liferative effects of CC-885. GSPT1 is a translation termination factor that binds eRF1 to mediate stop codon recognition and nascent protein release from the ribosome17–19” and “The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. We identified GSPT1 (eRF3a) as a novel CC-885-dependent cereblon substrate mediating the anti-pro liferative effects of CC-885.”(page 252). This helps to teach claim 35.
The reference Zou teaches “Another such novel compound is CC-885, which was found to have activity against pre-clinical models of acute myeloid leukemia through cereblon-mediated ubiquitination and later degradation of G1 to S phase transition 1 (GSPT1) [13, 14]. Also known as eukaryotic release factor 3a (eRF3A), GSPT1 is involved in the regulation of mammalian cell growth [15] and in translation termination in response to the termination codons UAA, UAG, and UGA”(page 1162).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Wong with Barillari because Wong teaches a drug candidate and Barillari teaches the modification of drug candidates to enhance properties. These changes include modifications from -NH- to -O- being obvious to one of ordinary skill in the art. One would have been motivated to do so to try and improve properties, such as pharmacological activity, selectivity, and pharmacokinetics. One would have a reasonable expectation of success because -NH- to -O- are both bivalent bioisosteres of each other and thus a small structural change.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the reference Wong to get the specific ratio of claim 24 because optimizing the ratio of a composition is routine experimentation. One would be motivated to optimize to improve the synergistic effect on PTC readthrough. One would have reasonable expectation of success because changing a ratio of a composition is a routine experimentation. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the reference Wong to treat subjects because Wong teaches 10% of all people with cystic fibrosis (CF) carry nonsense or premature termination codon (PTC) and that CC-885 in combination with G418/SMG liNX-809 caused a synergistic effect on PTC readthrough which would then be an obvious combination to treat cystic fibrosis in subjects that carry nonsense or premature termination codon (PTC). One would be motivated to do so because a combination treatment may also allow a dose reduction of TR modulator drugs and thus lessen toxicity concerns that exist for most readthrough drugs and one would have a reasonable expectation of success because it showed positive outcome in the cell model experiments.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the reference Wong with Matyskiela to use CC-885 for cancer treatment mediated by mediate stop codon recognition because Wong teaches CC-885 works by helping read through and Matyskiela teaches that CC-885 is a potent anti-cancer drug that targets GSPT1 which is the same pathway that mediate stop codon recognition. One would have been motivated to do so to treat cancer with a combination treatment may also allow a dose reduction of TR
modulator drugs and thus lessen toxicity concerns that exist for most readthrough drugs. One would have a reasonable expectation of success because CC-885 has already shown to be successful for both readthrough treatment and cancer treatment according to the cited references. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Wong to treat diseases with the TP53 codon because this would include all the listed diseases in claim 1. Since it is obvious to treat these diseases as previously mentioned it would be obvious to treat these diseases that include the TP53 codon as well. Thus one would have a reasonable expectation of success and a motivation to treat a diseases such as cancer because it is mentioned in the reference Matyskiela.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the reference Wong to administer the drug compositions administered in a simultaneous or sequential manner. As these are the only two possible options and are also common options one of two must have been used and thus would have been obvious. One would have been motivated to try both options to optimize outcome and one would have reasonable expectation of success since simultaneous or sequential drug administration is routine experimentation.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the reference Wong to have the compound of formula I, or pharmaceutically acceptable salt or stereoisomer thereof, and the aminoglycoside in form of one single pharmaceutical composition or in form of separate pharmaceutical compositions. As these are the only two possible options and are also common options one of two must have been used and thus would have been obvious. One would have been motivated to try both options to optimize outcome and one would have reasonable expectation of success since one single pharmaceutical composition or in form of separate pharmaceutical compositions is routine experimentation.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the reference Wong with Zou because both teach CC-885 activity via a mechanism that involves GSPT1. Thus it would be obvious to treat diseases wherein the premature termination codon is UGA or UAG or UAA because these are the codons that GSPT1 regulates. One would have been motivated to do so to treat cancer with a combination treatment that may also allow a dose reduction of TR modulator drugs and thus lessen toxicity concerns that exist for most readthrough drugs. One would have reasonable expectation of success because CC-885 activity is via a mechanism that involves GSPT1.
Claim(s) 1 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wong ( Wong et al., "Pharmacological depletion of ERF1 or ERF3A enhances effect of aminoglycosides on CFTR premature termination codon readthrough," PEDIATRIC PULMONOLOGY 20201001 JOHN WILEY AND SONS INC. NLD, Vol. 55, No. Suppl 2, 1 October 2020, page 61, Poster Session Abstract, IDS) in view of Teng (Teng et al., Readthrough of nonsense mutation W822X in the SCN5A gene can effectively restore expression of cardiac Na1 channels, Cardiovascular Research (2009) 83, 473–480) as evidenced by Matyskiela (Matyskiela et al., A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature volume 535, pages252–257 (2016), IDS) in view of Barillari (Barillari et al., Classical Bioisosteres, Bioisosteres in Medicinal Chemistry, First Edition. Edited by Nathan Brown 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA).
The Wong, Barillari and Matyskiela have been discussed supra and do not teach DMD (dystrophin) (claims 15).
The reference Teng teaches “Studies of various genes have suggested that harmful consequences caused by nonsense mutation may be avoided or reduced to a tolerable level by enhancing the process known as translational readthrough, which enables ribosomes to ignore the stop codon and produce full-length proteins.10 Enhanced readthrough can be achieved in many ways. For example, disturbances to the ribosome, tRNAs, and the eukaryotic release factors eRF1 and eRF3a (a GTPase that binds eRF1 and facilitates the efficiency and accuracy of stop codon recognition)11 can all alter the level of readthrough. Pharmacological approaches to increasing the level of readthrough include the use of aminoglycosides and other small molecules that bind to the ribosome, suppressor tRNAs that recognize stop codons, eRF1-binding RNAs, and inhibition of eRF expression by small-interfering RNA (siRNA) molecules.12 Notably, amino glycosides and inhibition of eRFs can to some extent preferentially enhance readthrough of PTCs, which reduces the chances of translation beyond the natural stop codon and generation of proteins carrying extraneous amino acids.12 Extensive studies using these reagents, particularly the aminoglycosides, have been performed on nonsense mutations of several genes, such as CFTR gene mutations that cause cystic fibrosis13 and dystrophin gene mutations that cause Duchenne muscular dystrophy.14 In mouse models, both disorders can be effectively treated with the aminoglycoside gentamicin.15,16 Clinical trials have been conducted to test whether aminoglycosides and other ribosome-binding molecules are also effective in humans.10 Some studies have demonstrated that siRNA directed against mRNA encoding eRFs is also effective inhibitors of translation termination.11,12,17 Theoretically, this technique induces misreading only at stop codons;17 thus, it has the potential to be an alternative to the antibiotics without the drawback of global mistranslation”(page 474). This helps to teach claim 15.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the reference Wong and Barillari with Teng because both teach methods of enhancing readthrough to treat diseases caused by nonsense mutations. It would have been obvious to use the molecule that was shown to enhance readthrough in Wong or similar derivatives to treat the diseases caused by nonsense mutations such as dystrophin gene mutations that cause Duchenne muscular dystrophy taught in Teng. One would have been motivated to do so to treat Duchenne muscular dystrophy with a combination treatment that may also allow a dose reduction of TR modulator drugs and thus lessen toxicity concerns that exist for most readthrough drugs. One would have reasonable expectation of success because CC-885 activity is via a mechanism that involves GSPT1 which is a pathway that involves eRFs as mentioned by Teng as targets for such diseases .
Allowable Subject Matter
Claim 31 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Response to Arguments
Applicant’s arguments with respect to all claim(s) have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
Claims 1, 2, 3, 6-11, 14-15, 23-24, 32-37 are rejected.
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.
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/A.A.H./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627
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