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 .
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in CH00308/21 on 03/22/2021. It is noted, however, that applicant has not filed a certified copy of the CH00308/21 application as required by 37 CFR 1.55.
Thus a priority date of 03/22/2022 was used.
Information Disclosure Statement
The information disclosure statement filed 06/04/2024 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because several references were not provided (see IDS form for exact missing documents). It has been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Interpretation
Claim 3 has the random phrase “odiesterase 10 inhibitor for the treatment of tourette syndrome" - Your Ref: NOE-001IL – ORa” in it. As this appears to be a typo it was ignored expect for the Ra at the end which is the only mention of the variable which was assumed to be linked to the variables a H or C1-4 alkyl in the following line.
Claim Objections
Claim 3 is objected to because of the following informalities: the phrase "odiesterase 10 inhibitor for the treatment of tourette syndrome" - Your Ref: NOE-001IL - O" seems to be floating unconnected to any claim within claim 3. 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 1-12 and 31 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 a specific disease of claim 12 mediated by a premature termination codon, does not reasonably provide enablement for treating any disease mediated by a premature termination codon including "mitochondrial" diseases of claim 12 since those use a different translation system. 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 specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. The specification does not provide sufficient information that all diseases caused by or
associated with a premature termination codon are treatable with pharmaceutical composition comprising compound of Formula I described in the method claims.
The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
(1). The Nature of the Invention:
AII of the rejected claims are drawn to an invention which pertains to a method of treatment of a disease by administering a pharmaceutical composition comprising compound of Formula I. The nature of the invention is complex in that it encompasses the treatment of all diseases or disorders caused by or associated with a premature termination codon administering a pharmaceutical composition comprising a compound of Formula I
(2). Breadth of the Claims:
The claims are very broad. The claims would reasonably encompass any disease or disorders caused by or associated with a premature termination codon which could be the treatment of unknown diseases in a mammal by administering a pharmaceutical composition comprising compound of Formula I. The coverage of diseases in the claim is immense. The breadth of the claims includes hundreds of diseases such as cancers, obesity, cystic fibrosis, severe myoclonic epilepsy of infancy, lung disease, etc.
(3). Guidance of the Specification /(4). Working Examples::
The guidance given by the specification as to how one would administer the claimed compounds to a subject in order to treat any disease is Iimited. All of the guidance given by the specification is the in vitro inhibitory properties of the compounds using assays. See pages 325-336 of specification.
There are no working examples for the treatment of a disease using pharmaceutical compositions comprising compounds of Formula (I).
(5). State of the Art:
While the state of the art is relatively high with regard to treating specific disease, the state of the art with regard to treating any disease caused by or associated with a premature termination codon generally is underdeveloped. In particular, there is no known compound which is effective against all diseases. For example, there are compounds that treat a range of diseases, but no one has ever been able to figure out how to get a compound to be effective against any disease generally. Thus, the existence of such a ''silver bullet'' is contrary to our present understanding in pharmaceutical art. This is true in part because diseases arise from a wide variety of sources, such as viruses (e.g. EBV, HHV-8, and HTLV-I), exposure to chemicals such as tobacco tars, genetic disorders, ionizing radiation, and a wide variety of failures of the body's cell growth regulatory mechanisms.
(6) The predictability or unpredictability of the art:
The invention is directed to treatment of any disease caused by or associated with a premature termination codon in general. It is well established that ''the scope of enablement various inversely with the degree of unpredictability of the factors involved,'' and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839 (1970).
In the instant case the unpredictability of the art is very high because there are thousands of diseases which have fundamentally different mechanism and different causes. The method of diagnosing or treating one disease or condition does not necessitate the treatment or diagnosis of another disease or condition since diseases and conditions have unique chemical pathways by which they are expressed. Additionally, a single disease or condition can be diagnosed via multiple biochemical pathways and treated via multiple biochemical pathways. Thus, the treatment and diagnosis of diseases and conditions is highly unpredictable. For example, the instant specification states that “Thus, research has focused on compounds with readthrough activity of premature termination codons (PTCs) as a potential treatment strategy for nonsense mutation- mediated genetic disorders. For example, the aminoglycoside antibiotics class (e.g., gentamicin, paromomycin, G418 and its derivatives NB74 and NB84) has been shown to have the ability to induce readthrough of PTC (Keeling and Bedwell, 2005; Zingman et al., 2007). The therapeutic potential of aminoglycosides has been evaluated for many different genetic models, such as cystic fibrosis (see, e.g., Du et al., 2002, J. Mol. Med. 80:595-604; Howard et al., 1996; Bedwell et al., 1997), muscular dystrophy (see, e.g., Loufrani et al., 2004, Arterioscler. Thromb. Vasc. Biol. 24:671-676; Howard et al., 2000; Loufrani et al., 2004), and others. In addition, clinical trials have also indicated that aminoglycosides can induce some functional protein production; however, the therapeutic benefits seem to be limited, for example because the systemic toxicity of most commercial aminoglycosides in mammals (Mingeot-Leclercq and Tulkens, 1999, Antimicrob. Agents Chemother. 43:1003-1012; 5 Guan et al., 2000, Hum. Mol. Genet. 9:1787-1793)” See page 1-2. Thus the treatment of any disease caused by or associated with a premature termination codon is highly unpredictable with regard to therapeutic effects.
(7). The Quantity of Experimentation Necessary:
In order to practice the claimed invention, one of skill in the art would have to first envision a combination of a compound of Formula I with an appropriate pharmaceutical carrier, a dosage for each, the duration of treatment, route of treatment, etc. and, in the case of human treatment, an appropriate animal model system for one of the claimed compounds. One would then need to test the combination in the model system to determine whether or not the combination is effective for treating any disease caused by or associated with a premature termination codon. If unsuccessful, one of skill in the art would have to then need to envision a modification of the combination of the compound with an appropriate pharmaceutical carrier, compound dosage, duration of treatment, route of administration, etc. and appropriate animal model system, or envision an entirely new combination of the above and test the system again. In order to practice Applicant's invention, it would be necessary for one to conduct the preceding experimentation for each type of disease because there is no known drug effective for treating all types of diseases. Therefore, it would require undue, unpredictable experimentation to practice the claimed invention to treat any disease caused by or associated with a premature termination codon in a mammal including unknown diseases by administration of a pharmaceutical composition of Formula I.
(8) The quantity of experimentation necessary:
Since every disease and disorder has its unique chemical pathway of expression, diagnosis and treatment of individual diseases and condition cannot be predicted a priori but must be determined from case to case by painstaking experimental study and when the above factors are weighed together, one of ordinary skill in the art would be burdened with undue ''painstaking experimentation study'' to determine which compounds of Formula I treats which diseases/conditions. For example, chemical modification of biomolecules may alter the biological property that is important in the use of that particular, and also other properties such as solubilities in aqueous media, binding affinities etc. Thus variety of compounds encompassed by formula (I) will have different biological properties. Considering variety of compounds covered by Formula I and the multitude of different diseases to be treated, this is a very large degree of experimentation.
Genetech, 108 F.3d at 1366 states that “a patent is not a hunting Iicense. It is not a reward for search, but compensation for its successful conclusion'' and ''[p]atent 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.''
Therefore, a method for treating any disease caused by or associated with a premature termination codon in general by administering a pharmaceutical composition of Formula I of the claims is not considered to be enabled by the instant specification.
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.
Claims 3, 4, 6, 12, 15, 24 are 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.
Regarding claims 3, 4, 6, 24, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 4, 6, 24, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 12 is indefinite because of the parenthesis around “(juvenile/medullary cystic kidney disease)” because it is unclear if hyperuricaemic nephropathy has to be juvenile/medullary cystic kidney disease or not.
Claim 15 is indefinite because of the parenthesis around “(dystrophin)” because it is unclear if DMD has to be dystrophin or not.
Claim 12 is indefinite because of the parenthesis around “(type 1 and type 2)” because it is unclear if diabetes mellitus has to be type 1 and type 2 or not.
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.
Claims 7, 9 and 10 are 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 7 includes the following groups in the location of X4 these improperly broaden the scope of X4 in claim 1 from which they depend:
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Claim 9 fails to properly further limit claim 2 from which it depends because it covers all possible outcomes when it states: administered in a simultaneous or sequential manner and thus does not limit claim 2. Claim 10 fails to properly further limit claim 2 from which it depends because it covers all possible outcomes when it states: 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 and thus does not limit claim 2. 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.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 22-23 is/are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by 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) 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) .
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.
This anticipates claims 22-23.
Claim(s) 1, 3, 4, 5, 6, 7, 11, 12, 13, 22, 31 is/are rejected under 35 U.S.C. 102(a)(2) as being clearly anticipated by GERALD (GERALD et al., WO 2022152822 A1, effective filing date 2021-01-13).
The reference GERALD teaches “ A method of treating a patient suffering from a Myc-driven tumor, comprising:
(a) determining the expression level of one or more Myc transcription factor biomarkers in a biological sample obtained from the patient;
(b) treating the patient with a treatment regimen comprising administering a therapeutically effective amount of a GSPT 1 negative modulator if the expression level of the one more Myc transcription factor biomarkers is greater than a reference level for the one more Myc transcription factor biomarkers”(reference claim 1) and “The present disclosure also relates to applications of these methods, which includes stratifying cancer malignancies, in particular identifying myc-driven cancers, and thereby devising optimized and personalized treatments for these cancer patients, as well as optimizing the selection of patient populations for respective clinical trials” (page 1)(reference claim 29), wherein L1=C1 alkyl, X3=NH or O, 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 IVa :
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The reference GERALD teaches “The term "GSPT1" (G1 To S Phase Transition Protein 1 Homolog) refers to polypeptides (i.e. polypeptides, peptides, proteins) comprising the amino acid sequence of any GSPT1 , such as a human GSPT1 protein (e.g., human GSPT1 isoform 1 , GenBank Accession No. NP_002085.3; or human CRBN isoform 2, GenBank Accession No. NP 001 1 23478.2 and others), and related polypeptides, including SNP variants thereof. Related GSPT1 polypeptides include allelic variants (e.g., SNP variants), splice variants, fragments, derivatives, substitution variant, deletion variant, insertion variant, fusion polypeptides, and interspecies homologs, which, in certain embodiments, retain GSPT1 activity and/or are sufficient to generate an anti-GSPT1 immune response. GSPT1 is a translation termination factor, which is involved in translation termination in response to the stop termination codons UAA, UAG, and UGA, and facilitates release of a nascent peptide from the ribosome”(page 47) and “In some embodiments, the cancer is a myc-driven cancer. In some embodiments, the cancer is a solid tumor cancer, such as breast cancer, colorectal cancer, lung cancer, e.g. SCLC, NSCLC, neuroendocrine cancer, e.g., neuroendocrine prostate cancer (for example, NEPC (castration-resistant neuroendocrine prostate cancer)) and lung neuroendocrine tumors (Lu- NETs), liver cancer, stomach cancer, pancreatic cancer, gastric cancer, esophageal cancer, bladder cancer, skin cancer, brain cancer, cervical cancer, ovarian cancer, melanoma and head and neck cancer”(page 11).
This anticipates claims 1, 3, 4, 5, 6, 7, 11, 12, 13, 22, 31.
Note that the mechanism of biological activity recited in instant claims 1 (promoting readthrough of a premature termination codon) although may not explicitly disclosed in reference applications was necessarily present as being inherent when treating cancer with a compound of instant formula I (see instant specification compounds 8 , 210, 261).
The applied reference has a common applicant and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Claim(s) 1, 3, 4, 5, 11, 12, 13, 22 is/are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being clearly anticipated by FLOHR (FLOHR et al., WO 2021069705 A1, 2021-04-15).
The reference FLOHR teaches “In a fourth aspect, certain embodiments comprise a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula I- IV, a pharmaceutical acceptable salt thereof or a composition described herein for use in treatment of diseases associated or caused by GSPTI , in particular the treatment of cancer associated with GSPT1 , such as glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, stomach cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testis cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma and multiple myeloma”(page 10).
Note that the mechanism of biological activity recited in instant claims 1 (promoting readthrough of a premature termination codon) although may not explicitly disclosed in reference applications was necessarily present as being inherent when treating cancer with a compound of instant formula I (see instant specification compounds 1).
The reference FLOHR teaches the following compound 1 (table 1, page 119) which is the same as instant compound 1, wherein, L1=C1 alkyl, X3=NH, X4=NH, L2=covalent bond, X1= C6 aryl un/substituted with halogen, L3=covalent bond, X2= H, n=1, Ra=H, formula IVa.
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This anticipates claims 1, 3, 4, 5, 11, 12, 13, 22.
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) 23-24 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) 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).
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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- 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.
This helps to teach claims 23-24.
The reference Wong does not teach the specific ratios of the composition of claim 24.
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.).
Claim(s) 1, 2, 3, 8, 9, 10, 12, 14 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) 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).
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).
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The reference Wong teaches “The small molecule CC-885 promotes eRF3a protein degradation. 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). Both the functional genomic
and pharmacological approaches point toward strategies that combine release factor reduction with readthrough modulators to enhance TR of PTCs. A combination treatment may also allow a dose reduction of TR modulator drugs and thus lessen toxicity concerns that exist for most readthrough drugs. Finally, these compounds represent valuable tools to further investigate the therapeutic potential of other TR reagents and to understand the basic mechanism of translation termination.”(last paragraph) and “Multiple high- 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, 8, 9, 10, 12, 14.
The reference Wong does not specific teach administration to a subject(all claims) or administered in a simultaneous or sequential manner( claim 9) 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 in form of separate pharmaceutical compositions (claim 10).
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 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.
Claim(s) 1 and 13 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).
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The Wong has been discussed supra and does not disclose cancer (claims 13).
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 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 teach claim 13.
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.
Claim(s) 1 and 11 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 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) 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) .
The Wong and Matyskiela has been discussed supra and do not teach termination codon as UGA or UAG or UAA (claims 11).
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 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) .
The Wong 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 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 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 .
Claim(s) 1, 4, 5 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 Nilova (Nilova et al., Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients, J. Med. Chem. 2020, 63, 13389−13396) 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).
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The Wong and Matyskiela have been discussed supra and do not teach the structures of claims (claims 4, 5 attachment point). Claims 4-5 only differ from CC-885 in the location of attachment to the phenyl ring (see diagram below).
The reference Nilova teaches “Rings have emerged as a motif of immense importance in drug discovery and development from a number of previous analyses.2a,b,4b−d,f,g Although heterocycles have long captivated the organic synthesis and medicinal chemistry communities,2a,4d,f−hTayloret al. found that benzenoid rings are,by an order of magnitude, the most frequently encountered ring system in small molecule drugs.4f Moreover, Brownetal. found that para-substituted phenyl rings are overrepresented relative to ortho- or meta-substituted congeners in medicinal chemistry programs as a result of historical bias in reagent selection.5 Our interest in reactivity trends of benzenoid rings and chemo informatics, and the overwhelming frequency that benzenoid rings occur in active pharmaceutical ingredients (APIs), prompted us to consider the broader distribution of their substitution patterns in small molecule drugs. Here, we provide a thorough analysis of small molecules APIs approved by the FDA through 2019 and identify those that contain benzenoid rings, the number of rings in each drug substance, and most importantly the substitution pattern of each benzenoid ring (Figure 1).We also discuss the connection between available synthetic methods and the distribution of substitution patterns. Finally, we assessed the link between benzenoid substitution pattern and common drug properties considered in the practice of medicinal chemistry, such as druglikeness,7 shape,8 structural complexity,9 and structural similarity.” (pages 13389-13390) and “It is worthwhile stating the obvious that the most available building blocks are easily obtained from SEAr of activated rings. The harder to access substitution patterns are likely also underrepresented in commercially available building blocks commonly used in drug discovery efforts. As an analogy to screening libraries with broadly diverse molecular shapes, we advocate that benzenoid substitution patterns are an underexplored vector in drug design and a worthwhile pursuit. The development of new synthetic methods that target under represented substitution patterns, as highlighted here, is an important area of continued development to address this disparity by increasing building block availability and enabling more facile synthesis during medicinal chemistry campaigns”(page 13394).
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The claimed compounds differs from the prior art compound CC-885 solely in the position of attachment of the linker on the aromatic ring. Altering the substitution position on an aromatic system represents a routine structural modification that medicinal chemists are motivated to employ to explore structure-activity relationships and optimize biological properties. Since the change in structure is so minimal there is a reasonable expectation of similar properties. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). Because the fused ring provides a finite number of predictable substitution sites, it would have been prima facie obvious to evaluate alternative attachment positions with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1, 3, 6, 7, 11, 12, 13, 22 and 31 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-48 of copending Application No. 19/236,429 (reference application), over claims 1, 3-4, 8, 13-14, 27, 29, 31-34, 38, 43, -45, 60, 67, 72 of copending Application No. 19/016,780 (reference application), over claims 1-23 and 26-27 of copending Application No. 19/018,468 (reference application), over claims 1-27, 35, 43-44 of copending Application No. 18/485,766 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Note that the mechanism of biological activity recited in instant claims 1 (promoting readthrough of a premature termination codon) although may not explicitly disclosed in reference applications was necessarily present as being inherent when treating cancer with a compound of instant formula I(see compound 61 and instant compound 261 they are the same and 57 and 257 likewise).
The application ‘429 claims:
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68
679
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This anticipates claims 1, 3, 6, 7, 11, 13, 22 and 31.
The application ‘780 claims:
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121
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This anticipates claims 1, 3, 6, 7, 11, 12, 13, 22 and 31.
The application ‘468 claims:
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675
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This anticipates claims 1, 3, 6, 7, 11, 13, 22 and 31.
Claim 1, 3, 6, 7, 11, 13, 22 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27, 35, 43-44 of copending Application No. 18/485,766 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The application ‘766 claims:
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Further, it is generally noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963). Given that applicant did not provide unexpected or unobvious results of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to substitute the H group for a Me. 2144.08(II)(A)(4)(c)
This anticipates claims 1, 3, 6, 7, 11, 13, 22.
Note that the mechanism of biological activity recited in instant claims 1 (promoting readthrough of a premature termination codon) although may not explicitly disclosed in reference applications was necessarily present as being inherent when treating cancer with a compound of instant formula I.
Claims 1, 3, 5, 6, 7, 11, 13, 22 and 31 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of copending Application No. 18/271,954 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Note that the mechanism of biological activity recited in instant claims 1 (promoting readthrough of a premature termination codon) although may not explicitly disclosed in reference applications was necessarily present as being inherent when treating cancer with a compound of instant formula I(see instant specification compound 261).
The application ‘954 claims:
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112
639
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206
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This anticipates claims 1, 3,5, 6, 7, 11, 13, 22 and 31.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1, 3, 11, 13, 22 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-37 of copending Application No. 18/982,872 (reference application. Although the claims at issue are not identical, they are not patentably distinct from each other.
The application ‘872 claims:
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This anticipates claims 1, 3, 11, 13, 22.
Claims 1, 3, 6, 7, 11, 13, 22 and 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11912682 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The patent ‘682 claims:
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332
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Note that the mechanism of biological activity recited in instant claims 1 (promoting readthrough of a premature termination codon) although may not explicitly disclosed in reference applications was necessarily present as being inherent when treating cancer with a compound of instant formula I.
This anticipates claims 1, 3, 6, 7, 11, 13, 22 and 31.
Claims 1, 3, 6, 7, 11, 13, 22 and 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12391663B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The patent ‘663 claims:
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355
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351
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Note that the mechanism of biological activity recited in instant claims 1 (promoting readthrough of a premature termination codon) although may not explicitly disclosed in reference applications was necessarily present as being inherent when treating cancer with a compound of instant formula I.
This anticipates claims 1, 3, 6, 7, 11, 13, 22 and 31.
Conclusion
Claims 1-15, 22-24 and 31 are rejected.
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/A.A.H./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627