DETAILED ACTION
Claims 1-3, 5-15, and 17-19 were pending; claims 2, 5, 15, 17, and 19 have been canceled; claims 1, 6, and 18 have been amended per the reply of 3/25/2026.
Claims 1, 3, 6-14, and 18 are pending.
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
The instant application, filed 1/12/2023 is a National Stage entry of PCT/US21/12594 , International Filing Date: 1/8/2021. PCT/US21/12594 Claims Priority from Provisional Application 63051532 , filed 7/14/2020.
Claim Rejections - 35 USC § 102
(Maintained)
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, 7-9, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Qin et al. US 2012/0010196 published 1/12/2012 with evidence from Giráldez-Pérez et al. “Models of α-synuclein aggregation in Parkinson’s disease,” Acta Neuropathologica Communications 2014, 2:176.
Instant claim 1 requires a method of treating a patient with a proteinopathy-associated condition, comprising administering a therapeutically effective amount of a rho kinase inhibitor to said patient, instant claim 2 refines the patient to one with has Huntington's disease or Parkinson's disease.
Qin teaches in claim 1 a method of treating a neurodegenerative disease, comprising administering a formulation to at least one central nervous system component of a mammal, wherein the formulation comprises an inhibitor of Rho-associated protein kinase (ROCK), and wherein the dosage of the ROCK inhibitor is sufficient to inhibit axonal degradation or growth cone collapse of a neuron. Qin’s claim 4 states, method of claim 1, wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, or Niemann-Pick type C disease.
Instant claims 7-9 require the method according to claim 1 wherein the rho kinase inhibitor is an isoquinoline derivative, 8 wherein the isoquinoline derivative is fasudil, a salt, or a derivative thereof. Instant claim 9 requires the method according to claim 7 wherein said derivative is M3.
Qin teaches in claim 3, the method of claim 1, wherein the ROCK inhibitor is Y-27632 (trans-4-[(1R)-1-Aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride), H 1152 ((S)-(+)-2-Methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-hexahydro-1H-1,4-diazepine dihydrochloride), or Fasudil Hydrochloride. Fasudil when administered is a prodrug of M3, as such claim 9 in inherent to the admin of Fasudil.
Instant claim 15 requires the method according to claim 1, wherein said patient has a proteinopathy associated with Parkinson's disease or Down syndrome. PD is taught by Qin.
Instant claim 17 requires wherein the proteinopathy is characterized by deposits containing one or more of the following in normal or mutant form… including deposits comprising α-synuclein (instant claim 18).
Giráldez-Pérez teaches Parkinson's disease patients have aggregation of α-synuclein. Giráldez-Pérez teaches in the Abstract. Parkinson’s disease (PD) is not only characterized by motor disturbances but also, by cognitive, sensory, psychiatric and autonomic dysfunction. It has been proposed that some of these symptoms might be related to the widespread pathology of α-synuclein (α-syn) aggregation in different nuclei of the central and peripheral nervous system.
Giráldez-Pérez teaches (page 2, column 1) these abnormal protein deposits may provoke LB pathologies that involve the deposition of LBs in cell bodies, or the formation of Lewy neurites (LNs) and Papp-Lantos inclusions. While the presence of LBs is a histological hallmark of PD, they are also associated with disorders such as dementia with LBs, multiple system atrophy, Alzheimer’s disease, Down’s syndrome, neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz disease), progressive autonomic failure, rapid eye movement sleep disorder, parkinsonism-dementia complex of Guam, Gaucher’s disease or Pick’s disease. Thereby one instantly envisions the treatment of the progression to multiple system atrophy in these disease state.
Claims 1, 7-9, and 18 are anticipated by Qin.
Response to Arguments: Applicant argues the Qin reference doesn’t teach treating a human with PD. This argument is not persuasive as claim 4 states, PD as a disease to be treated by the invention. Moreover, a human patient is at once envisaged by the teaching of Qin, as a PHOSITA would understand PD is a human disease.
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, 3, 7-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xiao CN 101612157 A published 12/30/2009.
Instant claim 1 requires a method of treating a patient with a proteinopathy-associated condition, comprising administering a therapeutically effective amount of a rho kinase inhibitor to said patient, instant claim 3 refines the patient wherein the patient has dementia.
Xiao teaches in claim 1, the use of fasudil in preparing drugs for inducing neural stem cells of adult brain to regenerate. Then in claims 7 and 8, wherein said nervous system disease is selected from cerebral ischemia, cerebral injury, Alzheimer's disease, Parkinson disease, dementia or retinal disease. Xiao is teaching senile or dementia of old age, as such instant claim 5 to wherein the patient does not have vascular dementia is also anticipated.
Xiao teaches fasudil, or a salt, including Fasudil Hydrochloride. Fasudil when administered is a prodrug of M3, as such claim 9 in inherent to the admin of Fasudil.
Instant claims 1, 3, 5, 7-9 are anticipated.
Response to Arguments: Applicant argues the Xiao reference doesn’t teach treating a human with PD/demintia. This argument is not persuasive as claim 7 states, PD/demintia as a disease to be treated by the invention. Moreover, a human patient is at once envisaged by the teaching of Xiao, as a PHOSITA would understand PD is a human disease.
Claim Rejections - 35 USC § 103
Obviousness of the dependent claims.
In regards to claim 6 to monitoring the patient.
Instant claim 6, the method according to claim 1 wherein the patient is administered a mini metal exam and treatment results in a greater-than 3-point improvement on the mini mental state exam.
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.
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 1, 6-9, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Qin et al. US 2012/0010196 published 1/12/2012, Giráldez-Pérez et al. “Models of α-synuclein aggregation in Parkinson’s disease,” Acta Neuropathologica Communications 2014, 2:176, Tatenhorst et al. “Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease,” Acta Neuropathologica Communications (2016) 4:39, and Zadikoff et al. “A Comparison of the Mini Mental State Exam to the Montreal Cognitive Assessment in Identifying Cognitive Deficits in Parkinson’s Disease,” Movement Disorders, Vol. 23, No. 2, 2008.
Instant claim 1 requires a method of treating a patient with a proteinopathy-associated condition, comprising administering a therapeutically effective amount of a rho kinase inhibitor to said patient, instant claim 2 refines the patient to one with has Huntington's disease or Parkinson's disease. The dependent claims indicate Fasudil as a rho kinase inhibitor.
Qin teaches Fasudil for the treatment of Parkinson’s disease, Qin is silent on the disease’s aggregation of α-synuclein.
Giráldez-Pérez teaches that α-synuclein is aggregated in Parkinson’s disease.
Tatenhorst teaches that Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease.
Therefore it is taught (not novel) to use Fasudil in Parkinson’s disease, and it is obvious that the drug, Fasudil, would attenuate aggregation of α-synuclein in the disease characterized by aggregation of α-synuclein. These references do not discuss administering the Mini Mental State Exam (MMSE).
Zadikoff is brought in to show that the MMSE is a standard test used in patients with cognitive decline for neuro-decline. Zadikoff states:
Neuropsychological testing is the gold standard for assessing cognition but it is time consuming and many clinicians lack easy and timely access to such assessments. The use of a rapid and easily applied screening test sensitive to cognitive impairment in PD is a more practical approach as it can guide clinical decision making and triage referral to neuropsychological testing. The mini-mental state examination (MMSE) is widely used because it is quick and easy to administer in a clinical setting.
A person of ordinary skill in the art would treat PD patients with Fasudil because it is taught in the art to treat the disease (Qin). A POSA would also predictably expect the drug to attenuate aggregation of α-synuclein because Tatenhorst notes this property of Fasudil in animal models. Lastly a POSA would look to monitor patients by assessing their cognition and would look to use a standard test like the MMSE because the test is rapid and easily applied for screening patients. Claims 1, 6-9, and 18 are prima facie obvious at the time of filing.
Response to Arguments: Applicant amended the claim to require administration of the MME. This was previously rendered obvious and Applicant did not argue this specifically.
Claim Rejections - 35 USC § 103
Obviousness of the dependent claims.
Instant claims 10-13 to dose and formulation:
Instant claim 10, the method according to claim 1 where said treatment continues for at least 6 months.
Instant claim 11, wherein said isoquinoline derivative is administered in a dose of at least 70 mg per day.
Instant claim 12, wherein said dose is administered in three equal portions throughout the day.
Instant claim 13, the total daily dose is between 70 mg and 180 mg.
Claims 1, 7-13, 15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Qin et al. US 2012/0010196 published 1/12/2012, Giráldez-Pérez et al. “Models of α-synuclein aggregation in Parkinson’s disease,” Acta Neuropathologica Communications 2014, 2:176, Tatenhorst et al. “Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease,” Acta Neuropathologica Communications (2016) 4:39.
Instant claim 1 requires a method of treating a patient with a proteinopathy-associated condition, comprising administering a therapeutically effective amount of a rho kinase inhibitor to said patient, wherein the patient has Parkinson's disease. The dependent claims indicate Fasudil as a rho kinase inhibitor.
Qin teaches (anticipates) Fasudil for the treatment of Parkinson’s disease, Qin is silent on the disease’s aggregation of α-synuclein.
Giráldez-Pérez teaches that α-synuclein is aggregated in Parkinson’s disease.
Tatenhorst teaches that Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease. Tatenhorst states, “[s]ince Fasudil is already approved for clinical human treatment, the repurposing of this drug for the treatment of PD and other synucleinopathies appears therefore highly promising.”
Therefore it is taught (not novel) to use Fasudil in Parkinson’s disease, and it is obvious that the drug, Fasudil, would attenuate aggregation of α-synuclein in the disease characterized by aggregation of α-synuclein. These references do not discuss the specific dose (70 mg and 180 mg) the duration of treatment (at least 6 months), or a sustained release formulation.
Qin teaches “wherein the dosage of the ROCK inhibitor is sufficient to inhibit axonal degradation or growth cone collapse of a neuron,” claim 1. Qin teaches, “[t]ypically, one of skill in the art also solubilizes test compounds, and decides on their initial dosage ranges according to protocols and knowledge in the art.”
Tatenhorst states, “Treatment with Fasudil, beginning 24 h before transfection, reduced the number of transfected H4 cells with inclusions in a dose-dependent manner within 24 h (Fig. 1a, b).”
Tatenhorst states, “After mice displayed clinical symptoms, long-term Fasudil treatment significantly improved gait performance of α-SynA53T mice as compared to untreated controls. In detail, run average speed was improved dose-dependently as compared to α-SynA53T control, with high Fasudil dosage reaching significance (wt ctrl: 28.6 ± 2.11 cm/s; A53T ctrl: 13.6 ± 1.20 cm/s, p = 7.05x10-6, T-test; A53T Fas10: 19.7 ±1.85 cm/s; A53T Fas30: 21.7 ± 3.24 cm/s, p = 0.03, ANOVA with Dunnett post-hoc test; Fig. 5d). Step sequence regularity index (a fractional measure of interpaw coordination) was significantly improved dose dependently after Fasudil treatment.”
From the MPEP, 2141.02, after KSR, the presence of a known result-effective variable would be one, but not necessarily the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. See MPEP § 2144.05, subsection II.B. See also In re Papesch, 315 F.2d 381, 391, 137 USPQ 43, 51 (CCPA 1963) ("From the standpoint of patent law, a compound and all its properties are inseparable.").
The art is clearly recognizing the dose as result effective in treating aggregation of α-synuclein.
Moreover, Tatenhorst doses Fasudil at 10 mg/kg and 30 mg/kg, giving a POSA a starting point to dose the drug in humans for Parkinson’s disease.
The Supreme Court has clarified that an "obvious to try" line of reasoning may properly support an obviousness rejection. In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because "obvious to try" is not a valid rationale for an obviousness finding. However, in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421, 82 USPQ2d at 1397 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.
As such the claimed doses and duration of dose is obvious as the art teaches the dose as result effective variable for aggregation of α-synuclein. The variable is dose dependent for effect in aggregation. Therefore a POSA would optimize the dose for effect. The art also teaches “long term” treatment and that one would treat as long as improvement was being made. Therefore the duration of at least 6 months is obvious, as duration will be optimized by the doctor.
As such claims 1, 7-13, 15, and 18 are obvious based on the teaching in the art.
Response to Arguments: Applicant argues the Qin reference doesn’t teach human, this was previously discussed. Applicant then argues the Giraldez-Perez reference provides doubt to the effect on the model used and the treatment to be effective. While this is a resonalbe area of research and the Giraldez-Perez reference does provide some hesitation, this doesn’t overcome the fact that Qin states in claims 1 and 4 to use the same drug in patients with PD. As such this doesn’t overcome this clear teaching in the art. As such this is not persuasive.
Claim Rejections - 35 USC § 103
Obviousness of the dependent claims.
Instant claim 14 to dose and sustained release formulation:
Instant claim 14, total daily dose exceeds 70 mg and is administered in a sustained release formulation.
Claims 1, 7-14, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Qin et al. US 2012/0010196 published 1/12/2012, Giráldez-Pérez et al. “Models of α-synuclein aggregation in Parkinson’s disease,” Acta Neuropathologica Communications 2014, 2:176, Tatenhorst et al. “Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease,” Acta Neuropathologica Communications (2016) 4:39 as applied to claims 1-2, 7-13, 15, and 17-19 above in further view of Kranz WO 2005117896 A1 published 12/15/2005.
Instant claim 14, total daily dose exceeds 70 mg and is administered in a sustained release formulation.
Qin, Giráldez-Pérez, and Tatenhorst render obvious the treatment of PD with Fasudil and optimization of the dose and duration of treatment. These references do not discuss the actual formulation of Fasudil in a “sustained release” formulation.
Kranz teaches solving the problem of needing multiple daily doses of Fasudil by formulatin the drug in a matrix body and an envelope surrounding the matrix body. The matrix body and envelope comprise poly vinyl pyrrolidone and poly vinyl acetate. Release occurs according to zero order reaction kinetics.
A POSA would use the formulation of Kranz because it provides daily dosing instead of multiple doses a day, thereby increasing patient compliance and convenience in patients with PD needing Fasudil as taught by Qin, Giráldez-Pérez, and Tatenhorst.
Response to Arguments: Applicant argues the Qin reference doesn’t teach human, this was previously discussed. Applicant then argues the Giraldez-Perez reference provides doubt to the effect on the model used and the treatment to be effective. While this is a resonalbe area of research and the Giraldez-Perez reference does provide some hesitation, this doesn’t overcome the fact that Qin states in claims 1 and 4 to use the same drug in patients with PD. As such this doesn’t overcome this clear teaching in the art. As such this is not persuasive.
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.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL J SCHMITT whose telephone number is (571)270-7047. The examiner can normally be reached M-F 8-6 MidDay Flex.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/MICHAEL J SCHMITT/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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