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
This application is a 35 U.S.C. § 371 national stage filing of International Application No. PCT/US2021/046589, filed August 19, 2021, which claims the benefit of the filing date, under 35 U.S.C. § 119(e), of U.S. Provisional Application No. 63/067,727, filed on August 19, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/10/2025 has been considered by the examiner.
Status of Claims
Claims 1-3, 5, 7, 10-14, 16, 19, 21, 23-24, 27-28, 30, 33, and 35 are pending and under examination. Claims 4, 6, 8-9, 15, 17-18, 20, 22, 25-26, 29, 31-32, 34, and 36 are canceled.
Action Summary
Claims 1-3, 5, 7, 10-14, 16, 19, and 21 rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (WO2012/109108 A1), are maintained.
Claims 23-26, 29, 31-32, 34, and 36 rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (WO2012/109108 A1) in view of Zhornitsky et al (Multiple Sclerosis and Related Disorders 5 (2016) 53–65) and American Academy of Family Physicians (Am Fam Physician. 2019;99(9):589-591), are deleted because this rejection was repeated accidentally repeated twice.
Claims 23-26, 29, 31-32, 34, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (WO2012/109108 A1) in view of Zhornitsky et al (Multiple Sclerosis and Related Disorders 5 (2016) 53–65) and American Academy of Family Physicians (Am Fam Physician. 2019;99(9):589-591), are maintained.
Claims 1-3, 5, 7, 10-14, 16, 19, 21, 23-24, 27-28, 30, 33, and 35 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. US9808449B2; claims 1-38 of U.S. Patent No. US9340527B2; claims 1-21 of U.S. Patent No. US10894040B2 in view of Thomas et al (WO2012/109108 A1) in view of Zhornitsky et al (Multiple Sclerosis and Related Disorders 5 (2016) 53–65) and American Academy of Family Physicians (Am Fam Physician. 2019;99(9):589-591), are maintained.
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.
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 1-3, 5, 7, 10-14, 16, 19, and 21 remain rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (WO2012/109108 A1).
Claim interpretation: claim 10 recites the absence of a cholesterol lowering drug, which is defined in the specification as the subject was never taking a cholesterol lowering drug or stopped taking a cholesterol lowering drug before treatment with Compound 1 or a pharmaceutically acceptable salt thereof was initiated or stopped taking a cholesterol lowering drug at the time treatment with Compound1 or a pharmaceutically acceptable salt thereof was initiated. (See second paragraph of page 6.) Therefore, the subject matter of claims 11, 12, and 13 is considered to further limit the absence of a cholesterol lowering drug.
Thomas teaches a method for prevention or treatment of multiple sclerosis, an autoimmune disease, a chronic inflammatory disorder, asthma, an inflammatory neuropathy, arthritis, transplantation rejection, Crohn's disease, ulcerative colitis, lupus erythematosis, psoriasis, an ischemia-reperfusion injury, a solid tumor, a tumor metastasis, a disease associated with angiogenesis, a vascular disease, a pain condition, an acute viral disease, an inflammatory bowel condition, insulin-dependent diabetes, or non-insulin dependent diabetes in a mammal, comprising administering to said mammal an effective amount of compound of example 36, namely 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid
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or a pharmaceutically acceptable salt thereof. (See claims 22, 1 and 17.) Moreover, Thomas teaches the compound of can promote myelination or remyelination and promote oligodendrocyte progenitor cell differentiation. The dose of a compound administered to a subject can be less than 1 mg, less than 2.5 mg, less than 5 mg, less than 10 mg, less than 15 mg, less than 20 mg, less than 50 mg. (See page 30, lines 5-14.) The compound is a selective S1P4 antagonist. (See page 23, lines 31-33.) Thomas also teaches potential uses of an SIP modulating agent include, but are not limited to, prevention or treatment of a pathological condition or symptom in a mammal. For example, the condition can include inhibited cell migration of oligodendrocyte precursor cells (OPCs). Treatment of multiple sclerosis includes treating various forms of the disease including relapsing-remitting, chronic progressive. (See page 24, lines 15-22.) The absence of a cholesterol lowering drug where the cholesterol lowering drug is a stain in the teaching of Thomas implies that the method does contain a cholesterol lowering drug, meeting the absence of a cholesterol lowering drug recited in claims 10-13. Thomas further teaches the compounds can be used in combination with at least one further active ingredient, such as a medicament used in the treatment of multiple sclerosis such as Tysabri®, dimethyl fumarate, an interferon (such as pegylated or non-pegylated interferons, preferably interferon β-la or pegylated interferon β -la), glatiramer acetate. (See page 26, lines 27-33.) Lastly, Thomas teaches the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub- doses per day. (See page 37, lines 5-7.)
Thomas does not specifically teach 10 mg to 60 mg per day in combination with glatiramer acetate for treating relapsing-remitting stage or chronic progressive stage of multiple sclerosis.
However, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use compound of example 36 as a selective S1P4 antagonist in the amount of 10 mg to 60 mg per day in combination with glatiramer acetate for treating relapsing-remitting stage or chronic progressive stage of multiple sclerosis. One would have been motivated to do so, because Thomas suggests compound of example 36 in the amount of 10 mg to 60 mg per day in combination with glatiramer acetate for treating relapsing-remitting stage or chronic progressive stage of multiple sclerosis. One would reasonably expect compound of example 36 in the amount of 10 mg to 60 mg per day in combination with glatiramer acetate for treating relapsing-remitting stage or chronic progressive stage of multiple sclerosis with success.
Claims 23-26, 29, 31-32, 34, and 36 remain rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (WO2012/109108 A1) in view of Zhornitsky et al (Multiple Sclerosis and Related Disorders 5 (2016) 53–65) and American Academy of Family Physicians (Am Fam Physician. 2019;99(9):589-591)
Thomas teaches a method for prevention or treatment of multiple sclerosis, an autoimmune disease, a chronic inflammatory disorder, asthma, an inflammatory neuropathy, arthritis, transplantation rejection, Crohn's disease, ulcerative colitis, lupus erythematosis, psoriasis, an ischemia-reperfusion injury, a solid tumor, a tumor metastasis, a disease associated with angiogenesis, a vascular disease, a pain condition, an acute viral disease, an inflammatory bowel condition, insulin-dependent diabetes, or non-insulin dependent diabetes in a mammal, comprising administering to said mammal an effective amount of compound of example 36, namely 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid
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or a pharmaceutically acceptable salt thereof. (See claims 22, 1 and 17.) Moreover, Thomas teaches the compound of can promote myelination or remyelination and promote oligodendrocyte progenitor cell differentiation. The dose of a compound administered to a subject can be less than 1 mg, less than 2.5 mg, less than 5 mg, less than 10 mg, less than 15 mg, less than 20 mg, less than 50 mg. (See page 30, lines 5-14.) The compound is a selective S1P4 antagonist. (See page 23, lines 31-33.) Thomas also teaches potential uses of an SIP modulating agent include, but are not limited to, prevention or treatment of a pathological condition or symptom in a mammal. For example, the condition can include inhibited cell migration of oligodendrocyte precursor cells (OPCs). Treatment of multiple sclerosis includes treating various forms of the disease including relapsing-remitting, chronic progressive. (See page 24, lines 15-22.) The absence of a cholesterol lowering drug in the teaching of Thomas implies that the method does contain a cholesterol lowering drug. Thomas further teaches the compounds can be used in combination with at least one further active ingredient, such as a medicament used in the treatment of multiple sclerosis such as Tysabri®, dimethyl fumarate, an interferon (such as pegylated or non-pegylated interferons, preferably interferon β-la or pegylated interferon β -l), glatiramer acetate. (See page 26, lines 27-33.) Lastly, Thomas teaches the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub- doses per day. (See page 37, lines 5-7.)
Thomas does not teach the subject being treated with a cholesterol lowering drug and assessing the subject plasma cholesterol level if the subject’s plasma level is outside of a target range, adjusting the amount of cholesterol.
Zhornitsky teaches statins have been shown to reduce LDL and ApoB by as much as 55% and 45%, respectively and increased HDL and ApoA1 by as much as 10% and 9%, respectively (Jones et al., 2003, 2004). In addition to reduction of cholesterol, statins can promote other mechanisms that could be beneficial in MS, including inhibition of LDL oxidation, scavenger receptor expression, metalloproteinase secretion, superoxide generation and growth of macrophages induced by oxidized LDL. These benefits could extend to the CNS because some statins are able to cross the BBB (simvastatin and atorvastatin). On the other hand, CNS penetrating statins could exert deleterious effects because cholesterol synthesis is necessary for remyelination. Indeed, there is evidence that prolonged simvastatin treatment can induce demyelination, reduce the number of mature oligodendrocytes, block differentiation of oligodendrocyte progenitor cells and inhibit remyelination in the cuprizone model. (See second paragraph of the left column of page 63.) Moreover, Zhornitsky teaches in a random controlled trial for the treatment of MS, simvastatin was used at a dose of 40-80 mg. (See first paragraph of the left column of page 63.)
American Academy of Family Physicians teaches based on high-quality RCTs, fasting lipid measurement should be repeated four to 12 weeks after starting the statin or making a dose adjustment to assess adherence and response to LDL-C–lowering medications and lifestyle changes. Following that, lipid measurement should be repeated every three to 12 months as needed. (See first paragraph of the right column of page 590.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use compound of example 36 as a selective S1P4 antagonist in the amount of 10 mg to 60 mg per day in combination with glatiramer in a subject being treated with and effective amount of simvastatin (a cholesterol lowering drug) for treating relapsing-remitting stage or chronic progressive stage of multiple sclerosis by promoting myelination or remyelination and promoting oligodendrocyte progenitor cell differentiation in the MS patient and to modify said method to include the steps of ii) assessing the subject's plasma cholesterol level and iii) if the subject's plasma cholesterol level is outside of a target range, adjusting the amount of cholesterol lowering drug administered to the subject to bring the subject's plasma cholesterol level within the target range to give Applicant’s claimed invention. One would have been motivated to do so, because Thomas suggests compound of example 36 in the amount of 10 mg to 60 mg per day in combination with glatiramer for treating relapsing-remitting stage or chronic progressive stage of multiple sclerosis and because Zhornitsky teaches prolonged simvastatin treatment in the amount of 40-80 mg, which can drastically lower cholesterol, can induce demyelination, reduce the number of mature oligodendrocytes, block differentiation of oligodendrocyte progenitor cells and inhibit remyelination in the cuprizone model, and also because American Academy of Family Physicians teaches based on high-quality RCTs, fasting lipid measurement should be repeated four to 12 weeks after starting the statin or making a dose adjustment to assess adherence and response to LDL-C–lowering medications and lifestyle changes. One would reasonably expect compound of example 36 in the amount of 10 mg to 60 mg per day in a subject being treated with an effective amount of simvastatin to treat relapsing-remitting stage or chronic progressive stage of multiple sclerosis, assessing the subject's plasma cholesterol level and if the subject's plasma cholesterol level is outside of a target range, adjusting the amount of cholesterol lowering drug administered to the subject to bring the subject's plasma cholesterol level within the target range, with success.
With respect to steps ii) and iii) are repeated until the subject's plasma cholesterol level is within the target range, wherein the target range is between 100 mg/dL and 200 mg/dL or between 125 mg/dL and 200 mg/dL as claimed in claim 24, it would have been prima facie obvious to repeat steps II (assessing the subject’s plasma cholesterol level and III (if the subject's plasma cholesterol level is outside of a target range, adjusting the amount of cholesterol lowering drug administered to the subject to bring the subject's plasma cholesterol level within the target range) in order to improve patient compliance. The motivation to do so, would be because lowering cholesterol levels can impair brain function, since cholesterol is essential for synapse formation and maturation, and myelin membranes and plays an important role in the regulation of signal transduction through its function as a component of the cell membrane. One would reasonably expect success of maintaining plasma cholesterol within the target range by repeating steps I and II in order to prevent damage low cholesterol can do to the body and the brain.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on October 10, 2025.
Applicant’s argument
Applicant argues that although Thomas discloses Compound 1 of present claim 1 specifically, it does not disclose any specific daily dosage range for Compound 1, let alone the specific daily dosage range of 10 mg to 60 mg as required in claim 1. Firstly, the skilled person reading Thomas would learn nothing about the importance of the ability of Compound 1 to engage the cholesterol biosynthesis pathway. As explained on page 3 of the present application, it was believed that Compound 1's effects on the S1P4 receptor could contribute to re-myelination but the Applicant has now found that S1P4 has little if any expression in human CNS and it is now believed that the remyelinating effects of Compound 1 are at least in
part due to its ability to engage the cholesterol biosynthesis pathway. As stated in the application, "based on these discoveries, it is expected that Compound 1 can achieve OPC differentiation and re- myelination" in humans at low doses. In contrast, Thomas fails to provide any such teaching.
Examiner’s response
In response, Applicant’s argument is not persuasive. It may well be true that Thomas does not disclose the specific daily dosage range of 10 mg to 60 mg as required by the claims. However, Thomas clearly teaches the compound can be conveniently administered in unit dosage form; for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form. (See lines 29-31.) Thomas also teaches the dose of a compound of formula (I) or (II) administered to a subject can be less than 10 μg, less than 25 μg, less than 50 μg, less than 75 μg, less than 0.10 mg, less than 0.25 mg, less than 0.5 mg, less than 1 mg, less than 2.5 mg, less than 5 mg, less than 10 mg, less than 15 mg, less than 20 mg, less than 50 mg, less than 75 mg, less than 100 mg, or less than 500 mg. (See page 30, lines 5-14.) Although Thomas teaches a broad range of doses, Thomas clearly contemplates or prefers a dose of 0.01 to 10 mg. Moreover, Thomas teaches the compound of can promote myelination or remyelination and promote oligodendrocyte progenitor cell differentiation. (See lines 5-8 of page 30.)
Applicant’s argument
Applicant argues that the present application has demonstrated that Compound 1 in the claimed range (10 mg - 60 mg) reduces the risk of neutropenia, which cannot be reasonably predicted by a person skilled in the art in view of Thomas. Specifically, Example 7 of the present application describes the effect of compound 1 dosage on neutrophil count and risk of neutropenia in a clinical trial study with healthy volunteers. The data shows the extent of neutrophil count decline at low doses (< 30 mg) was indistinguishable from placebo control, suggesting minimal effect of Compound 1 on neutrophil count. A dose-dependent decline in absolute neutrophil count from baseline was observed for subjects that received doses > 30 mg. With the exception of 1 patient who discontinued treatment due to grade 3 neutropenia, all subjects in the 60 mg per day dose remained throughout the study in the normal range for absolute monocyte counts. This data suggests that a dose higher than 60 mg per day could significantly increase the risk of neutropenia, which cannot be predicted or reasonably expected based on the teaching of Thomas.
Examiner’s response
In response, Applicant’s argument is not persuasive. Example 7 of the present application may well demonstrate that Compound 1 in the claimed range (10 mg - 60 mg) reduces the risk of neutropenia in healthy individuals. However, the Examiner contends that such unexpected results are not commensurate in scope with the claims. Specifically, the subject population in Example 7 which uses the dosage regimen in Example 1, is healthy subject. Second, neutropenia is not recited in the claims. Claims 1, 10, and 23 recite a human subject with multiple sclerosis and not healthy human subject. 30-60 mg dose of compound 1 is not recited in claims 10 and 23. As such, the asserted unexpected result is not commensurate in scope with claims 1.
Applicant’s argument
Applicant argues that the method in claim 10 is based on the surprising finding that Compound 1 reduces cholesterol levels in healthy human volunteers in a dose dependent manner. Specifically, Example 1 of the present application describes a clinical trial that tested total cholesterol levels in healthy volunteers when they received Compound 1 in various once daily doses ranging from 1 mg to 100 mg. Figure 1 of the present application shows the total cholesterol levels in the healthy volunteers tested in the clinical trial, specifically those administered placebo, 10 mg, 30 mg or 60 mg per day of Compound 1 over a 28-day period. Based on a PK/PD model, the concentration of circulating cholesterol in this model is reduced at all daily doses higher than 10 mg. The model also predicts that circulating cholesterol could decrease by approximately 35% at a dose level of 60 mg per day. See the first paragraph on page 13 of the specification as filed. Based on the cholesterol lowering effect observed for Compound 1, the claimed method of treatment for MS comprising administering Compound 1 requires that the compound is administered in the absence of a cholesterol lowering drug.
Examiner’s response
In response, Applicant’s argument is not persuasive. It may well be true that a PK/PD model predicts that circulating cholesterol could decrease by approximately 35% at a dose level of 60 mg per day and based on said cholesterol lowering effect observed for Compound 1 on healthy human volunteers the claimed method of treatment for MS comprising administering Compound 1 requires that the compound is administered in the absence of a cholesterol lowering drug. However, again, the Examiner contends that healthy human volunteers are not claimed. The subject of claim 10 is a human subject with multiple sclerosis. Under MPEP 716.02(d), to prove "unexpected results" overcome an obviousness rejection, an applicant must compare their claimed invention's results directly against the closest prior art, showing a significant, practical improvement (difference in kind, not just degree) across the entire claimed scope, often by testing points inside and outside the claimed range to demonstrate criticality. This evidence must be objective, not argument, demonstrating results greater than expected from the prior art to rebut the prima facie case of obviousness. Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See in re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). In the present case, the asserted showing of the reduction of total cholesterol levels in human volunteers does not appear to be a true comparison as said asserted unexpected result did not compare the claimed invention with the prior art. Assuming arguendo, a person of ordinary skill in the art would expect the teaching of the same compound at overlapping dose to decrease circulating cholesterol since Example 1 of the instant specification teaches compound 1 could result in greater reduction of circulating cholesterol levels at doses higher than 60 mg. Additionally, the absence of a cholesterol lowering drug where the cholesterol lowering drug is a stain in the teaching of Thomas implies that the method does contain a cholesterol lowering drug, meeting the absence of a cholesterol lowering drug recited in claims 23-26, 29, 31-32, 34, and 36. Lastly, Applicant has not demonstrated that the PK/PD model for the healthy individuals can be extrapolated to the MS treatment. Specifically, extrapolation data from healthy individuals often fail to predict treatment outcome because disease states significantly alter the body's physiological and biochemical environment. Key factors causing this discrepancy include:
Altered Pharmacokinetics (PK): Diseases can change how a drug is absorbed, distributed, metabolized, and excreted (ADME). For example, renal or hepatic impairment can reduce drug clearance, and chronic inflammation (common in cancer) can modulate the enzymes and transporters responsible for metabolism.
Target Site Differences: In healthy individuals, drug concentrations in the blood may correlate well with the target site. However, in disease states, barriers—such as tumor architecture or impaired tissue penetration (e.g., in septic shock)—can prevent the drug from reaching its site of action effectively.
Pharmacodynamic (PD) Sensitivity: The disease itself can change receptor expression, immune responses, or the target burden. A patient's system may already be in an "inhibited" or "adapted" state, making them more or less sensitive to the drug's intended effect compared to a healthy volunteer.
Co-morbidities and Polypharmacy: Patients often suffer from multiple conditions and take concomitant medications, which introduces drug-drug interactions (DDIs) rarely present in healthy volunteer studies.
Lack of Efficacy Biomarkers: Healthy volunteers do not express the disease-specific biomarkers or clinical endpoints (such as tumor shrinkage or pain relief) that are essential for validating a PD model’s efficacy component.
Inter-individual Variability: Patient populations are inherently more heterogeneous in age, genetics, and disease severity than the highly screened, homogeneous groups used in Phase 1 healthy volunteer trials.
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 1-3, 5, 7, 10-14, 16, 19, 21, 23-24, 27-28, 30, 33, and 35 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. US9808449B2; claims 1-38 of U.S. Patent No. US9340527B2; claims 1-21 of U.S. Patent No. US10894040B2 in view of Thomas et al (WO2012/109108 A1) in view of Zhornitsky et al (Multiple Sclerosis and Related Disorders 5 (2016) 53–65) and American Academy of Family Physicians (Am Fam Physician. 2019;99(9):589-591).
The U.S. patent claims teach a method for treating relapsing-remitting or chronic progressive multiple sclerosis in a mammal, comprising administering to said mammal an effective amount of 1-((6-(cis-4-ethylcyclohexyloxy) naphthalen-2-yl) methyl) piperidine-4-carboxylic acid
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or a pharmaceutically acceptable salt thereof.
The U.S. patent claims do not teach 10 mg to 60 mg per day in combination with glatiramer acetate for treating relapsing-remitting stage or chronic progressive stage of multiple sclerosis. Moreover, the U.S. patent claims do not teach the subject being treated with a cholesterol lowering drug and assessing the subject plasma cholesterol level if the subject’s plasma level is outside of a target range, adjusting the amount of cholesterol.
Thomas teaches a method for prevention or treatment of multiple sclerosis, an autoimmune disease, a chronic inflammatory disorder, asthma, an inflammatory neuropathy, arthritis, transplantation rejection, Crohn's disease, ulcerative colitis, lupus erythematosis, psoriasis, an ischemia-reperfusion injury, a solid tumor, a tumor metastasis, a disease associated with angiogenesis, a vascular disease, a pain condition, an acute viral disease, an inflammatory bowel condition, insulin-dependent diabetes, or non-insulin dependent diabetes in a mammal, comprising administering to said mammal an effective amount of compound of example 36, namely 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid
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or a pharmaceutically acceptable salt thereof. (See claims 22, 1 and 17.) Moreover, Thomas teaches the compound of can promote myelination or remyelination and promote oligodendrocyte progenitor cell differentiation. The dose of a compound administered to a subject can be less than 1 mg, less than 2.5 mg, less than 5 mg, less than 10 mg, less than 15 mg, less than 20 mg, less than 50 mg. (See page 30, lines 5-14.) The compound is a selective S1P4 antagonist. (See page 23, lines 31-33.) Thomas also teaches potential uses of an SIP modulating agent include, but are not limited to, prevention or treatment of a pathological condition or symptom in a mammal. For example, the condition can include inhibited cell migration of oligodendrocyte precursor cells (OPCs). Treatment of multiple sclerosis includes treating various forms of the disease including relapsing-remitting, chronic progressive. (See page 24, lines 15-22.) The absence of a cholesterol lowering drug in the teaching of Thomas implies that the method does contain a cholesterol lowering drug. Thomas further teaches the compounds can be used in combination with at least one further active ingredient, such as a medicament used in the treatment of multiple sclerosis such as Tysabri®, dimethyl fumarate, an interferon (such as pegylated or non-pegylated interferons, preferably interferon β-la or pegylated interferon β -la), glatiramer acetate. (See page 26, lines 27-33.) Lastly, Thomas teaches the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub- doses per day. (See page 37, lines 5-7.)
Zhornitsky teaches statins have been shown to reduce LDL and ApoB by as much as 55% and 45%, respectively and increased HDL and ApoA1 by as much as 10% and 9%, respectively (Jones et al., 2003, 2004). In addition to reduction of cholesterol, statins can promote other mechanisms that could be beneficial in MS, including inhibition of LDL oxidation, scavenger receptor expression, metalloproteinase secretion, superoxide generation and growth of macrophages induced by oxidized LDL. These benefits could extend to the CNS because some statins are able to cross the BBB (simvastatin and atorvastatin). On the other hand, CNS penetrating statins could exert deleterious effects because cholesterol synthesis is necessary for remyelination. Indeed, there is evidence that prolonged simvastatin treatment can induce demyelination, reduce the number of mature oligodendrocytes, block differentiation of oligodendrocyte progenitor cells and inhibit remyelination in the cuprizone model. (See second paragraph of the left column of page 63.) Moreover, Zhornitsky teaches in a random controlled trial for the treatment of MS, simvastatin was used at a dose of 40-80 mg. (See first paragraph of the left column of page 63.)
American Academy of Family Physicians teaches based on high-quality RCTs, fasting lipid measurement should be repeated four to 12 weeks after starting the statin or making a dose adjustment to assess adherence and response to LDL-C–lowering medications and lifestyle changes. Following that, lipid measurement should be repeated every three to 12 months as needed. (See first paragraph of the right column of page 590.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the compound of the U.S. patent claims which is the same compound taught by Thomas, as a selective S1P4 antagonist, in the amount of 10 mg to 60 mg per day in combination with glatiramer acetate in a subject being treated with and effective amount of simvastatin (a cholesterol lowering drug) for treating relapsing-remitting stage or chronic progressive stage of multiple sclerosis by promoting myelination or remyelination and promoting oligodendrocyte progenitor cell differentiation in the MS patient and to modify said method to include the steps of ii) assessing the subject's plasma cholesterol level and iii) if the subject's plasma cholesterol level is outside of a target range, adjusting the amount of cholesterol lowering drug administered to the subject to bring the subject's plasma cholesterol level within the target range to give Applicant’s claimed invention. One would have been motivated to do so, because Thomas suggests compound of example 36 in the amount of 10 mg to 60 mg per day for treating relapsing-remitting stage or chronic progressive stage of multiple sclerosis and because Zhornitsky teaches prolonged simvastatin treatment in the amount of 40-80 mg, which can drastically lower cholesterol, can induce demyelination, reduce the number of mature oligodendrocytes, block differentiation of oligodendrocyte progenitor cells and inhibit remyelination in the cuprizone model, and also because American Academy of Family Physicians teaches based on high-quality RCTs, fasting lipid measurement should be repeated four to 12 weeks after starting the statin or making a dose adjustment to assess adherence and response to LDL-C–lowering medications and lifestyle changes. One would reasonably expect compound of the U.S. patent claims in the amount of 10 mg to 60 mg per day in combination with glatiramer acetate in a subject being treated with an effective amount of simvastatin to treat relapsing-remitting stage or chronic progressive stage of multiple sclerosis, assessing the subject's plasma cholesterol level and if the subject's plasma cholesterol level is outside of a target range, adjusting the amount of cholesterol lowering drug administered to the subject to bring the subject's plasma cholesterol level within the target range, with success.
With respect to steps ii) and iii) are repeated until the subject's plasma cholesterol level is within the target range, wherein the target range is between 100 mg/dL and 200 mg/dL or between 125 mg/dL and 200 mg/dL as claimed in claim 24, it would have been prima facie obvious to repeat steps II (assessing the subject’s plasma cholesterol level and III (if the subject's plasma cholesterol level is outside of a target range, adjusting the amount of cholesterol lowering drug administered to the subject to bring the subject's plasma cholesterol level within the target range) in order to improve patient compliance. The motivation to do so, would be because lowering cholesterol levels can impair brain function, since cholesterol is essential for synapse formation and maturation, and myelin membranes and plays an important role in the regulation of signal transduction through its function as a component of the cell membrane. One would reasonably expect success of maintaining plasma cholesterol within the target range by repeating steps I and II in order to prevent damage low cholesterol can do to the body and the brain.
Applicant argues that for the same reasons above, Applicant submits that the present claims are non-obvious over claims 1-21 of U.S. Patent No. 9,808,449; claims 1-38 of U.S. Patent No. 9,340,527; and Claims 1-21 of U.S. Patent No. 10,894,040, in view of Thomas, Zhornitsky and D3.
In response, for the same reasons set forth in the Examiner’s response, the Examiner contends that the present claims are obvious over claims 1-21 of U.S. Patent No. 9,808,449; claims 1-38 of U.S. Patent No. 9,340,527; and Claims 1-21 of U.S. Patent No. 10,894,040, in view of Thomas, Zhornitsky and D3.
Conclusion
Claims 1-3, 5, 7, 10-14, 16, 19, 21, 23-24, 27-28, 30, 33, and 35 are not allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628