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 .
Claim Objections
Applicant is advised that should claim 15 be found allowable, claim 20 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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.
Claims 1 – 2, 4, 14 – 16, 20 – 21, 30 – 31, 35 – 37, and 49 – 50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent Application Publication US 2017/0362206 A1 to Estrada et. al. (Estrada’206; cited on the ISR form).
Regarding claims 1 – 2, 4, 14 – 16, 20 – 21, 30 – 31, 35 – 37, and 49 – 50, Estrada’206 teach novel heteroaryl-substituted pyrimidines and their use as therapeutic agents as inhibitors of LRRK2. See page 1 paragraph 0002. Additionally, Estrada’206 teach pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds of the present disclosure. See page 1 paragraph 0006. See claims 1, and 35. Estrada’206 teach compounds of formula I of structure
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. See page 1 paragraph 0007. Specifically, Estrada’206 teach compound No. 78 of structure
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. See page 34 Table 1B-contitnued 1st column 2nd row. See claims 1, and 35. Furthermore, Estrada’206 teach that the disease or condition mediated, at least in part by LRRK2 is a neurodegenerative disease which includes Parkinson's disease (PD), Alzheimer's disease (AD), dementia (including Lewy body dementia and cascular dementia), amyotrophic lateral sclerosis (ALS). See page 54 paragraph 0285. See claim 1. Moreover, Estrada’206 teach that the disease or condition mediated, at least in part by LRRK2 also include cancers such as those of the thyroid, renal (including papillary renal), breast, lung, blood, and prostate cancers (e.g. solid tumor), leukemias (including acute myelogenous leukemia (AML)), or lymphomas. See page 55 paragraph 0286. Estrada’206 teach that pharmaceutical compositions comprising compound no. 78 can be administered in either single or multiple doses. See page 56 paragraph 0299. See claims 15 – 16, 20, and 50.
Furthermore, Estrada’206 teach that pharmaceutical composition comprising compound 78 can administered orally. See page 56 paragraph 0299. See claims 14, and 49. Additionally, Estrada’206 teach that pharmaceutical composition comprising compound 78 include the active ingredient diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. See page 56 paragraph 0301. See claim 35. Estrada’206 teach that when compositions comprising compound 78 are administered orally, the total daily dosage for a human subject can be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day. See page 57 paragraph 0309. See claims 1 – 2, 4, 21, 30, 35 – 37. Moreover, Estrada’206 teach that compounds of the present application or the compositions thereof can be administered once, twice, three, four, or more times daily. See page 57 paragraph 0310. See claims 15 – 16, 20, and 50.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 17 – 18 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication US 2017/0362206 A1 to Estrada et. al. (Estrada’206; cited on the ISR form) in view of Atashrazm et. al. ((2018), LRRK2-Mediated Rab10 Phosphorylation in Immune Cells From Parkinson’s Disease Patients, Movement Disorder, 34, 406 – 415; cited on the ISR).
The teachings of Estrada’206 as they relate to claim 1, from which claims 17 – 18 depend, are given previously in this office action and are fully incorporated here.
However, Estrada’206 fail to teach a method for treating Parkinson’s disease where the method results in a reduction in phosphorylated S935 LRRK2 (pS935) in whole blood of a subject. See claim 17. Estrada’206 fail to teach a method for treating Parkinson’s disease where the method results in a reduction in phosphorylated ras-related protein Rab 10 (pRab 10) in peripheral blood mononuclear cells (PBMC) of a subject. See claim 18.
Nevertheless, Atashrazm et. al. teach that leucine-rich repeat kinase 2 (LRRK2) has emerged as a promising therapeutic target for the treatment of Parkinson’s disease (PD). See page 407 column 1 paragraph 1. Atashrazm et. al. teach that in vitro LRRK2 activity assays demonstrated that the most common pathogenic missense mutation, G2019S, increased the enzyme’s catalytic kinase activity. See page 407 column 1 paragraph 2. Additionally, Atashrazm et. al. teach that the most robust LRRK2 substrate is Rab10, which is phosphorylated on threonine 73, a residue in the switch II region of Rab10 that appears important for regulating Rab10 protein interactions and subcellular localization. See page 407 column 1 paragraph 3. Furthermore, Atashrazm et. al. teach that Rab10 is expressed in peripheral blood cells including B-lymphocytes, monocytes, and neutrophils, and in healthy controls, Rab10 phosphorylation is decreased in these cell types by ex vivo LRRK2 inhibitor treatment. See page 407 column 1 paragraph 3. See claim 18. Moreover, Atashrazm et. al. teach that the current gold standard readout of LRRK2 inhibitor target engagement is to monitor reduced phosphorylation of serine 935, a residue on the LRRK2 protein that is required for interaction with 14-3-3 protein family members. See page 407 column 1 paragraph 4. See claim 17.
Atashrazm et. al. teach that the use of LRRK2 serine 935 as a peripheral readout of LRRK2 inhibitor target engagement has been further validated in PD cohorts. See page 407 column 1 paragraph 4. Atashrazm et. al. teach that phosphorylation on this residue is complexly regulated, including phosphorylation by other kinases and counter-regulation by phosphatases. See page 407 column 1 paragraph 4. Hence, Atashrazm et. al. teach that for a clinical trial of LRRK2 inhibitors, it would therefore be prudent to include a second readout of inhibitor target engagement. See page 407 column 2 paragraph 1.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the method of Estrada’206 for treating Parkinson’s disease using prior art compound 78 in view of Atashrazm et. al., that is to monitor for a reduction of phosphorylated S935 LRRK2 (pS935) and a reduction in phosphorylated ras-related protein Rab 10 (pRab 10). One of ordinary skill in the art would have been motivated to make this modification because phosphorylation on the S935 LRRK2 is complexly regulated, including through phosphorylation by other kinases and counter-regulation by phosphatases. Moreover, one of ordinary skill in the art would have had reasonable expectation of success because Rab10 phosphorylation is decreased in these cell types by ex vivo LRRK2 inhibitor treatment.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication US 2017/0362206 A1 to Estrada et. al. (Estrada’206; cited on the ISR form) in view of Alcalay et. al. ((2019), Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development, Movement Disorder, 35, 134 – 141; cited on the ISR).
The teachings of Estrada’206 as they relate to claim 1, from which claim 19 depends, are given previously in this office action and are fully incorporated here.
However, Estrada’206 fail to teach a method for treating Parkinson’s disease where the method results in a reduction of lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine of the subject. See claim 19.
Nevertheless, Alcalay et. al. teach that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are among the most common genetic causes of Parkinson’s disease (PD). See page 135 column 1 paragraph 1. Alcalay et. al. teach that bis(monoacylglycerol) phosphate (BMP) isoforms are localized within the inner membranes of late endosomes (multivesicular bodies) and lysosomes, where they contribute to the multivesicular/lamellar morphology of the Endo lysosomal network. See page 135 column 1 paragraph 3. Moreover, Alcalay et. al. teach that didocosahexaenoyl(22:6)-BMP (di-22:6-BMP), a specific species of BMP, is decreased in the urine of LRRK2-knockout mice and in non-human primates treated with chemically distinct LRRK2 kinase inhibitors (PFE-360, MLi-2, and GNE-7915), directly implicating its utility as a biomarker of LRRK2 activity. See page 135 column 1 paragraph 3. Alcalay et. al. teach that there was a correlational analyses indicated that total di-18:1-BMP and total di-22:6-BMP most strongly discriminated the LRRK2 mutation carriers from non-carriers. See page 136 column 2 paragraph 4. Moreover, Alcalay et. al. teach that among PD patients, higher di- 22:6-BMP (total levels and 2,20 isoform levels) were associated with worse cognitive performance on the Montreal Cognitive Assessment (MoCA) suggesting that BMP isoforms may be biomarkers of pathophysiology of PD. See page 138 column 1 paragraph 3. Additionally, Alcalay et. al. teach that the utility of urinary BMP as a biomarker to monitor disease progression and as a pharmacodynamic biomarker to demonstrate LRRK2 kinase modulation by drug candidates. See page 140 column 2 paragraph 2.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the method of Estrada’206 for treating Parkinson’s disease using prior art compound 78 in view of Alcalay et. al., that is to monitor for a reduction of lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine. One of ordinary skill in the art would have been motivated to make this modification because higher di- 22:6-BMP in the subjects urine was associated with worse cognitive performance on the Montreal Cognitive Assessment (MoCA). Moreover, one of ordinary skill in the art would have had reasonable expectation of success because di-22:6-BMP most strongly discriminated the LRRK2 mutation carriers from non-carriers.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication US 2017/0362206 A1 to Estrada et. al. (Estrada’206; cited on the ISR form) in view of Kluss et. al. ((2019), LRRK2 links genetic and sporadic Parkinson’s disease, Biochemical Society Transactions, 47, 651 – 661).
The teachings of Estrada’206 as they relate to claim 1, from which claim 31 depend, are given previously in this office action and are fully incorporated here.
However, Estrada’206 fail to teach a method for treating Parkinson’s disease where the Parkinson's disease is familial, or sporadic. See claim 31.
Nevertheless, Kluss et. al. teach that Parkinson’s disease (PD) is a neurodegenerative disorder affecting over 4 million people over the age of 50 within the world’s top 15 most populated countries, and that number is expected to double by 2030. See page 651 paragraph 1. Kluss et.al. teach that although ∼90% of PD cases are sporadic (sPD), that is having no clearly defined single cause, the remaining 10% show a clear family history and are thus considered monogenic PD, that is familial. See page 651 paragraph 1. Kluss et. al. teach that patients carrying mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene, one of the most common genetic contributors of PD, manifest clinical features which are almost indistinguishable from the sporadic form. See page 651 paragraph 2. Moreover, Kluss et. al. teach that both forms, have similar patterns of motor symptoms which include the hallmark bradykinesia, tremor, rigidity, and postural instability have been reported. See page 651 paragraph 2. Furthermore, Kluss et. al. teach that nonmotor symptoms which include hallucinations, depression, anxiety, cognitive impairment, and pain also appear in both familial and sporadic PD. See page 651 paragraph 2. Thus Kluss et. al. teach that there are convergent pathways that drive neuropathology in both familial and sporadic PD with a potential common cellular pathway of dysfunction. See page 651 paragraph 2.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the method of Estrada’206 for treating Parkinson’s disease using prior art compound 78 in view of Kluss et. al., that is to treat either familial or sporadic Parkinson’s disease. One of ordinary skill in the art would have been motivated to make this modification because either form has similar patterns of motor symptoms which include the hallmark bradykinesia, tremor, rigidity, and postural instability. Moreover, one of ordinary skill in the art would have had reasonable expectation of success because the prior art suggest that familial and sporadic PD have convergent pathways that drive neuropathology with a potential common cellular pathway of dysfunction.
Claims 24 – 25 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication US 2017/0362206 A1 to Estrada et. al. (Estrada’206; cited on the ISR form) in view of Alcalay et. al. ((2019), Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development, Movement Disorder, 35, 134 – 141; cited on the ISR).
Regarding claims 24 – 25, Estrada’206 teach novel heteroaryl-substituted pyrimidines and their use as therapeutic agents as inhibitors of LRRK2. See page 1 paragraph 0002. Additionally, Estrada’206 teach pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds of the present disclosure. See page 1 paragraph 0006. See claim 24. Estrada’206 teach compounds of formula I of structure
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. See page 1 paragraph 0007. Specifically, Estrada’206 teach compound No. 78 of structure
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. See page 34 Table 1B-contitnued 1st column 2nd row. See claim 24. Furthermore, Estrada’206 teach that the disease or condition mediated, at least in part by LRRK2 is a neurodegenerative disease which includes Parkinson's disease (PD), Alzheimer's disease (AD), dementia (including Lewy body dementia and cascular dementia), amyotrophic lateral sclerosis (ALS). See page 54 paragraph 0285. See claim 24. Moreover, Estrada’206 teach that the disease or condition mediated, at least in part by LRRK2 also include cancers such as those of the thyroid, renal (including papillary renal), breast, lung, blood, and prostate cancers (e.g. solid tumor), leukemias (including acute myelogenous leukemia (AML)), or lymphomas. See page 55 paragraph 0286. Estrada’206 teach that pharmaceutical compositions comprising compound no. 78 can be administered in either single or multiple doses. See page 56 paragraph 0299.
Furthermore, Estrada’206 teach that pharmaceutical composition comprising compound 78 can administered orally. See page 56 paragraph 0299. Additionally, Estrada’206 teach that pharmaceutical composition comprising compound 78 include the active ingredient diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. See page 56 paragraph 0301. Estrada’206 teach that when compositions comprising compound 78 are administered orally, the total daily dosage for a human subject can be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day. See page 57 paragraph 0309. See claim 24. Moreover, Estrada’206 teach that compounds of the present application or the compositions thereof can be administered once, twice, three, four, or more times daily. See page 57 paragraph 0310.
However, Estrada’206 fail to teach a method of (i) reducing phosphorylated S935 LRRK2 (pS935) in whole blood of a subject suffering from Parkinson's disease, (ii) reducing phosphorylated ras-related protein Rab 10 (pRab 10) in peripheral blood mononuclear cells (PBMC) of a subject suffering from Parkinson's disease, or (iii) reducing lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine comprising administering about 70 to 800 mg/day of the above compound (claims 24 – 25).
Nevertheless, Alcalay et. al. teach that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are among the most common genetic causes of Parkinson’s disease (PD). See page 135 column 1 paragraph 1. Alcalay et. al. teach that bis(monoacylglycerol) phosphate (BMP) isoforms are localized within the inner membranes of late endosomes (multivesicular bodies) and lysosomes, where they contribute to the multivesicular/lamellar morphology of the Endo lysosomal network. See page 135 column 1 paragraph 3. Moreover, Alcalay et. al. teach that didocosahexaenoyl(22:6)-BMP (di-22:6-BMP), a specific species of BMP, is decreased in the urine of LRRK2-knockout mice and in non-human primates treated with chemically distinct LRRK2 kinase inhibitors (PFE-360, MLi-2, and GNE-7915), directly implicating its utility as a biomarker of LRRK2 activity. See page 135 column 1 paragraph 3. Alcalay et. al. teach that there was a correlational analyses indicated that total di-18:1-BMP and total di-22:6-BMP most strongly discriminated the LRRK2 mutation carriers from non-carriers. See page 136 column 2 paragraph 4. Moreover, Alcalay et. al. teach that among PD patients, higher di- 22:6-BMP (total levels and 2,20 isoform levels) were associated with worse cognitive performance on the Montreal Cognitive Assessment (MoCA) suggesting that BMP isoforms may be biomarkers of pathophysiology of PD. See page 138 column 1 paragraph 3. Additionally, Alcalay et. al. teach that the utility of urinary BMP as a biomarker to monitor disease progression and as a pharmacodynamic biomarker to demonstrate LRRK2 kinase modulation by drug candidates. See page 140 column 2 paragraph 2.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the method of Estrada’206 for treating Parkinson’s disease using prior art compound 78 in view of Alcalay et. al., that is to monitor for a reduction of lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine. One of ordinary skill in the art would have been motivated to make this modification because higher di- 22:6-BMP in the subjects urine was associated with worse cognitive performance on the Montreal Cognitive Assessment (MoCA). Moreover, one of ordinary skill in the art would have had reasonable expectation of success because di-22:6-BMP most strongly discriminated the LRRK2 mutation carriers from non-carriers.
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.
Claims 1 – 2, 4, 14 – 21, 24 – 25, 30 – 31, 35 – 37, and 49 – 50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 5, 9, 11 – 14, 16 – 17, 19 – 20, and 25 – 26, of U.S. Patent No. US 9932325 B2 to Estrada et. al. (Estrada’325; cited on the IDS) in view of US Patent Application Publication US 2017/0362206 A1 to Estrada et. al. (Estrada’206; cited on the ISR form), Atashrazm et. al. ((2018), LRRK2-Mediated Rab10 Phosphorylation in Immune Cells From Parkinson’s Disease Patients, Movement Disorder, 34, 406 – 415; cited on the ISR), Alcalay et. al. ((2019), Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development, Movement Disorder, 35, 134 – 141; cited on the ISR), and Kluss et. al. ((2019), LRRK2 links genetic and sporadic Parkinson’s disease, Biochemical Society Transactions, 47, 651 – 661).
Estrada’325 recite a compound of formula Ia: compound of formula Ia:
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. See reference claim 1. Specifically, Estrada’114 recite the compound
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. See reference claims 1 – 5, 9, 11 – 14, 16 – 17, and 19. See instant claim 1, and 35. Additionally, Estrada’114 recite a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier, diluent, or excipient. See reference claims 20, and 25 – 26. See instant claim 35.
However, Estrada’325 fail to recite a method of treating Parkinson’s disease comprising administering about 70 to 800 mg/day of the above compound. See instant claim 1. Moreover, Estrada’325 fail to recite a method of (i) reducing phosphorylated S935 LRRK2 (pS935) in whole blood of a subject suffering from Parkinson's disease, (ii) reducing phosphorylated ras-related protein Rab 10 (pRab 10) in peripheral blood mononuclear cells (PBMC) of a subject suffering from Parkinson's disease, or (iii) reducing lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine comprising administering about 70 to 800 mg/day of the above compound. See instant claim 24. Furthermore, Estrada’325 fail to recite a pharmaceutical composition comprising 70 - 800 mg of the above compound. See instant claim 35.
The teachings of Estrada’206, Atashrazm et. al., Alcalay et. al., and Kluss et. al. as they relate to the prior art rejection of instant claims 1 – 2, 4, 14 – 21, 24 – 25, 30 – 31, 35 – 37, and 49 – 50, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the invention of Estrada’325 a compound of formula Ia in view of Estrada’206, that is for a method comprising administering about 70 to 800 mg/day of the above compound in view of Atashrazm et. al., that is to monitor for a reduction of phosphorylated S935 LRRK2 (pS935) and a reduction in phosphorylated ras-related protein Rab 10 (pRab 10); in view of Alcalay et. al., that is to monitor for a reduction of lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine; and further in view of Kluss et. al., that is to treat either familial or sporadic Parkinson’s disease.
One of ordinary skill in the art would have been motivated to make this modification because phosphorylation on the S935 LRRK2 is complexly regulated, including through phosphorylation by other kinases and counter-regulation by phosphatases. Moreover, one of ordinary skill in the art would have had reasonable expectation of success because Rab10 phosphorylation is decreased in these cell types by ex vivo LRRK2 inhibitor treatment. One of ordinary skill in the art would have been motivated to make this modification because higher di- 22:6-BMP in the subjects urine was associated with worse cognitive performance on the Montreal Cognitive Assessment (MoCA). Moreover, one of ordinary skill in the art would have had reasonable expectation of success because di-22:6-BMP most strongly discriminated the LRRK2 mutation carriers from non-carriers. One of ordinary skill in the art would have been motivated to make this modification because either form has similar patterns of motor symptoms which include the hallmark bradykinesia, tremor, rigidity, and postural instability. Moreover, one of ordinary skill in the art would have had reasonable expectation of success because the prior art suggest that familial and sporadic PD have convergent pathways that drive neuropathology with a potential common cellular pathway of dysfunction.
Claims 1 – 2, 4, 14 – 21, 24 – 25, 30 – 31, 35 – 37, and 49 – 50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 5, 9, 11 – 14, 17, 19, and 22 of U.S. Patent No. US 10590114 B2 to Estrada et. al. (Estrada’114; cited on the IDS) in view of US Patent Application Publication US 2017/0362206 A1 to Estrada et. al. (Estrada’206; cited on the ISR form), Atashrazm et. al. ((2018), LRRK2-Mediated Rab10 Phosphorylation in Immune Cells From Parkinson’s Disease Patients, Movement Disorder, 34, 406 – 415; cited on the ISR), Alcalay et. al. ((2019), Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development, Movement Disorder, 35, 134 – 141; cited on the ISR), and Kluss et. al. ((2019), LRRK2 links genetic and sporadic Parkinson’s disease, Biochemical Society Transactions, 47, 651 – 661).
Estrada’114 recite a method for treating a disease or condition mediated, at least in part, by LRRK2, wherein the disease or condition is selected from the group consisting of Parkinson's disease, dementia, Alzheimer' s disease, L-Dopa induced dyskinesia, and amyotrophic lateral sclerosis, the method comprising administering to a subject in need thereof an effective amount of a compound of formula Ia:
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. See reference claim 1. See instant claim 1. Specifically, Estrada’114 recite a method where the compound is
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. See reference claims 1 – 5, 9, 11 – 14, 17, 19, and 22. See instant claim 1, 24, and 35.
However, Estrada’114 fail to recite a method comprising administering about 70 to 800 mg/day of the above compound. See instant claim 1. Moreover, Estrada’114 fail to recite a method of (i) reducing phosphorylated S935 LRRK2 (pS935) in whole blood of a subject suffering from Parkinson's disease, (ii) reducing phosphorylated ras-related protein Rab 10 (pRab 10) in peripheral blood mononuclear cells (PBMC) of a subject suffering from Parkinson's disease, or (iii) reducing lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine comprising administering about 70 to 800 mg/day of the above compound. See instant claim 24. Furthermore, Estrada’114 fail to recite a pharmaceutical composition comprising 70 - 800 mg of the above compound. See instant claim 35.
The teachings of Estrada’206, Atashrazm et. al., Alcalay et. al., and Kluss et. al. as they relate to the prior art rejection of instant claims 1 – 2, 4, 14 – 21, 24 – 25, 30 – 31, 35 – 37, and 49 – 50, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the invention of Estrada’114 for a method for treating a disease or condition mediated, at least in part, by LRRK2, which is Parkinson’s disease in view of Estrada’206, that is for a method comprising administering about 70 to 800 mg/day of the above compound in view of Atashrazm et. al., that is to monitor for a reduction of phosphorylated S935 LRRK2 (pS935) and a reduction in phosphorylated ras-related protein Rab 10 (pRab 10); in view of Alcalay et. al., that is to monitor for a reduction of lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine; and further in view of Kluss et. al., that is to treat either familial or sporadic Parkinson’s disease.
One of ordinary skill in the art would have been motivated to make this modification because phosphorylation on the S935 LRRK2 is complexly regulated, including through phosphorylation by other kinases and counter-regulation by phosphatases. Moreover, one of ordinary skill in the art would have had reasonable expectation of success because Rab10 phosphorylation is decreased in these cell types by ex vivo LRRK2 inhibitor treatment. One of ordinary skill in the art would have been motivated to make this modification because higher di- 22:6-BMP in the subjects urine was associated with worse cognitive performance on the Montreal Cognitive Assessment (MoCA). Moreover, one of ordinary skill in the art would have had reasonable expectation of success because di-22:6-BMP most strongly discriminated the LRRK2 mutation carriers from non-carriers. One of ordinary skill in the art would have been motivated to make this modification because either form has similar patterns of motor symptoms which include the hallmark bradykinesia, tremor, rigidity, and postural instability. Moreover, one of ordinary skill in the art would have had reasonable expectation of success because the prior art suggest that familial and sporadic PD have convergent pathways that drive neuropathology with a potential common cellular pathway of dysfunction.
Claims 1 – 2, 4, 14 – 21, 24 – 25, 30 – 31, 35 – 37, and 49 – 50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 5, 9, 11, 13 – 14, 16, 19, and 22 of U.S. Patent No. US 11111235 B2 to de Vicente Fildalgo et. al. (de Vicente Fildalgo’235; cited on the IDS) in view of US Patent Application Publication US 2017/0362206 A1 to Estrada et. al. (Estrada’206; cited on the ISR form), Atashrazm et. al. ((2018), LRRK2-Mediated Rab10 Phosphorylation in Immune Cells From Parkinson’s Disease Patients, Movement Disorder, 34, 406 – 415; cited on the ISR), Alcalay et. al. ((2019), Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development, Movement Disorder, 35, 134 – 141; cited on the ISR), and Kluss et. al. ((2019), LRRK2 links genetic and sporadic Parkinson’s disease, Biochemical Society Transactions, 47, 651 – 661).
de Vicente Fildalgo’235 recite a method for treating a disease or condition mediated, at least in part, by LRRK2, wherein the disease or condition is selected from the group consisting of kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, and ankylosing spondylitis, the method comprising administering to a subject in need thereof an effective amount of a compound of formula Ia
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. See reference claim 1. Specifically, de Vicente Fildalgo’235 recite a method where the compound is
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. See reference claims 1 – 5, 9, 11, 13 – 14, 16, 19, and 22. See instant claim 1, 24, and 35.
However, de Vicente Fildalgo’235 fail to recite a method of treating Parkinson’s disease comprising administering about 70 to 800 mg/day of the above compound. See instant claim 1. Moreover, de Vicente Fildalgo’235 fail to recite a method of (i) reducing phosphorylated S935 LRRK2 (pS935) in whole blood of a subject suffering from Parkinson's disease, (ii) reducing phosphorylated ras-related protein Rab 10 (pRab 10) in peripheral blood mononuclear cells (PBMC) of a subject suffering from Parkinson's disease, or (iii) reducing lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine comprising administering about 70 to 800 mg/day of the above compound. See instant claim 24. Furthermore, de Vicente Fildalgo’235 fail to recite a pharmaceutical composition comprising 70 - 800 mg of the above compound. See instant claim 35.
The teachings of Estrada’206, Atashrazm et. al., Alcalay et. al., and Kluss et. al. as they relate to the prior art rejection of instant claims 1 – 2, 4, 14 – 21, 24 – 25, 30 – 31, 35 – 37, and 49 – 50, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the invention of Estrada’325 for a method for treating a disease or condition mediated, at least in part, by mediated LRRK2, in view of Estrada’206, that is where the disease or condition mediated, at least in part, by mediated LRRK2 is Parkinson Disease further comprising administering about 70 to 800 mg/day of the above compound in view of Atashrazm et. al., that is to monitor for a reduction of phosphorylated S935 LRRK2 (pS935) and a reduction in phosphorylated ras-related protein Rab 10 (pRab 10); in view of Alcalay et. al., that is to monitor for a reduction of lysosomal lipid 22:6-bis[monoacylglycerol]phosphate (BMP) in urine; and further in view of Kluss et. al., that is to treat either familial or sporadic Parkinson’s disease.
One of ordinary skill in the art would have been motivated to make this modification because phosphorylation on the S935 LRRK2 is complexly regulated, including through phosphorylation by other kinases and counter-regulation by phosphatases. Moreover, one of ordinary skill in the art would have had reasonable expectation of success because Rab10 phosphorylation is decreased in these cell types by ex vivo LRRK2 inhibitor treatment. One of ordinary skill in the art would have been motivated to make this modification because higher di- 22:6-BMP in the subjects urine was associated with worse cognitive performance on the Montreal Cognitive Assessment (MoCA). Moreover, one of ordinary skill in the art would have had reasonable expectation of success because di-22:6-BMP most strongly discriminated the LRRK2 mutation carriers from non-carriers. One of ordinary skill in the art would have been motivated to make this modification because either form has similar patterns of motor symptoms which include the hallmark bradykinesia, tremor, rigidity, and postural instability. Moreover, one of ordinary skill in the art would have had reasonable expectation of success because the prior art suggest that familial and sporadic PD have convergent pathways that drive neuropathology with a potential common cellular pathway of dysfunction.
Conclusion
Claims 1 – 2, 4, 14 – 21, 24 – 25, 30 – 31, 35 – 37, and 49 – 50 are rejected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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