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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/09/2026 has been entered.
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.
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7, 10-14, 16, 19, and 21 rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (WO2012/109108 A1), are withdrawn in light of the claim amendment.
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Related Disorders 5 (2016) 53–65) and American Academy of Family Physicians (Am Fam Physician. 2019;99(9):589-591), are withdrawn in light of the claim amendment.
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Related Disorders 5 (2016) 53–65) and American Academy of Family Physicians (Am Fam Physician. 2019;99(9):589-591), are withdrawn in light of the claim amendment.
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 withdrawn in light of the claim amendment.
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, and 7 rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (WO2012/109108 A1).
Thomas teaches a method for prevention or treatment of multiple sclerosis 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, which corresponds to compound 1 recited in the instant claims. (See claims 22, 1 and 17.) Moreover, Thomas identifies the compound as a selective S1P4 antagonist and teaches that compounds thereof promote myelination or remyelination and promote oligodendrocyte progenitor cell differentiation. (See page 23, lines 31-33; and lines 15-16 of page 24.) The subject includes a human. (See lines 7-8.).
Thomas further teaches administration of the compound at does including 1 mg, less less than 10 mg, less than 15 mg, less than 20 mg, less than 50 mg (see page 30, lines 5-14), thereby teaching dosage amounts overlapping the presently claimed range of 10-60 mg/day in claim 7. Thomas additionally 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 further teaches treatment of various forms of multiple-sclerosis, including relapsing-remitting, chronic progressive (ee page 24, lines 15-22), thereby rendering obvious the subject matter of claim 3. Thomas additionally teaches administration of its compounds with another active agent useful for treatment of multiple sclerosis, expressly including interferon and glatiramer acetate. (See page 26, lines 27-33.)
Thomas does not expressly state administration of compound of 31 according to the above-described MS treatment reduces cholesterol level in the human subject, as newly recited in claim 1.
Nevertheless, Applicant’s own specification provides evidence that reduction of circulating cholesterol is a pharmacodynamic effect of administering the same compound 1 within the presently claimed dosage range. Applicant states that healthy human subjects receiving compound 1 at 10, 30, 60 mg/day exhibited a time-and-dose-dependent reduction in circulating total cholesterol, and Applicant further relies upon those results as demonstrating that compound reduces cholesterol when administered within the claimed range.
Accordingly, to the extent administration of the same compound at the claimed dosage necessarily produces the demonstrated cholesterol-reducing effect, the recitation of “reducing a cholesterol level in the human subject” identifies a pharmacological result of performing the otherwise obvious administration rather than requiring a different drug, route, dosage, or affirmative treatment step.
The prior art need not have recognized an inherent property at the relevant time, provided that the property is necessarily present or is the natural result of performing the prior-art-method. See MPEP 2112. Thus, Thomas provided the reason to administer compound 1 to an MS patient and the claimed cholesterol reduction naturally results from administration of compound 1 within the claimed dosage range, as evidenced by Applicant’s own disclosure.
One of ordinary skill in the art would have had a reasonable expectation of successfully treating MS because Thomas expressly teaches the same compound I for the treatment of MS and teaches its remyelination and oligodendrocyte progenitor-cell differentiation activities.
Alternative rationale regarding the limitation “reducing cholesterol level in the human subject.”
Claims 1-3, 5, and 7 rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (WO2012/109108 A1) and Zhornitsky et al. (Multiple Sclerosis and Related Disorders 5 (2016) 53–65).
Thomas teaches administering compound of example 36 to a human subject having multiple sclerosis at the claimed or overlapping dosage amounts for treatment of MS, as discussed above.
Thomas does not expressly teach that administration of compound of example 36 reduces cholesterol level in the human subject.
Zhornitsky, however, teaches that elevated circulating cholesterol and markers of cholesterol turnover are associated with MS and concludes that cholesterol and markers of cholesterol turnover have the potential to be used clinically as biomarkers of disease activity and may even be implicated in the pathogenesis of MS. (See Abstract.) Zhornitsky does not merely identify cholesterol as an unrelated laboratory parameter, but teaches a relationship between circulating cholesterol/cholesterol turnover and MS disease activity and potentially MS pathogenesis.
In view of Zhornitksy, one of ordinary skill in the art would have been motivated, when treating a human subject having multiple sclerosis according to Thomas, to achieve a reduction in elevated circulating cholesterol and cholesterol turnover as associated with MS disease activity and potentially implicated in MS pathogenesis. A reduction of cholesterol would therefore have been understood as a desirable therapeutic and/or disease-associated outcome in an MS human subject.
One or ordinary skill in the art would have also have had a reasonable expectation of success because Zhornitsky teaches a relationship between circulating cholesterol/cholesterol turnover and MS disease activity and potential pathogenesis, while Thomas expressly teaches compound 36 as effective for treating MS. Accordingly, the skilled artisan would have reasonably expected that successful treatment of MS disease process could favorably affect a disease-associated cholesterol parameter, including circulating cholesterol. Applicant’s own clinical data confirm that administration of compound 1 (compound 36 of Thomas) within the claimed dosage range in fact produces a reduction in circulating cholesterol.
Claims 10-14, 16, 19, 21 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, cited as “AAFP”).
Thomas does not expressly teach the subject is being treated with a cholesterol lowering drug, and treatment with cholesterol-lowering drug, including a statin.
Zhornitsky teaches that circulating cholesterol and cholesterol-related markers are clinically relevant in MS. In particular, Zhornitsky reports associations between elevated LDL cholesterol, total cholesterol, ApB and oxidized LDL, and adverse clinical and MRI outcomes in MS. Zhornitsky further discusses cholesterol-lowering drug in MS and reports that statins substantially reduce LDL and ApoB. (Abstract; and second paragraph of the left column of page 63.) Zhornitsky additionally recognizes a competing consideration particularly relevant to MS: cholesterol is an essential component of myelin, and prolonged CNS-penetrating statin treatment may adversely affect remyelination, including reducing mature oligodendrocytes, blocking oligodendrocytes progenitor-cell differentiation, and inhibiting remyelination. (See Abstract; and second paragraph of the left column of page 63.)
Thomas in contrast, teaches that compound of example 36 promotes myelination/remyelination and oligodendrocyte progenitor-cell differentiation.
Accordingly, the combined teachings would have provided one of ordinary skill in the art with reason to use Thomas’s compound of example 36 in an MS patient to its remyelination-[promoting activity while managing the patient’s cholesterol-lowering therapy in view of the known relationship between cholesterol and MS and the recognized potential effects of prolong statin treatment on remyelination.
Claim 10
With respect to claims 10, Thomas teaches compound of example 36, treatment of MS, treatment of relapse-remitting, chronic progressive MS, the overlapping dosages, and combination treatment with interferon and glatiramer acetate for the reasons discussed above
Thomas does not expressly teach that compound of example 36 (claimed compound 1) is administered “in the absence of a cholesterol lowering drug” as presently claimed.
Zhornitsky teaches although cholesterol-lowering therapy, particularly statin therapy, has been investigated in multiple schlerosis, cholesterol is an essential component of myelin and prolonged statin treatment may adversely affect myelination/remyelination. In particular, Zhornitsky teaches that statin treatment may reduce mature oligodendrocytes, block differentiation of oligodendrocyte progenitor cells, and inhibit remyelination. (See Abstract; second paragraph of the left column of page 63.)
Thomas conversely, teaches that compound 1 (example 36) promotes oligodendrocyte progenitor-cell differentiation and myelination/remyelination. Accordingly, one of ordinary skill in the art, considering the teachings of Thomas and Zhornitsky together, would have had reason to administer Thomas’s compound for treatment of MS in the absence of a cholesterol-lowering drug, particularly a statin, so as to obtain the remyelination-promoting effect the compound of example 36 without potentially countervailing effect of cholesterol-lowering statin therapy on oligodendrocyte differentiation and remyelination.
One of ordinary skill in the art would have had a reasonable expectation of success because Thomas expressly teaches compound of example 36 as useful for treating MS and promoting oligodendrocyte progenitor-cell differentiation and myelination/remyelination, while Zhornitsky provides a reason for avoiding concomitant statin treatment when promotion of remyelination is desired.
Claim 11
With respect to claim 11, Thomas does not expressly teach that the subject has previously been treated with a cholesterol-lowering drug and the such treatment is terminated before initiation of treatment with compound of example 36, as recited in claim 11.
However, Zhornitsky teaches both the potential benefit of cholesterol reduction in MS and the potential disadvantage associated with prolonged CNS-penetrating statin therapy, including inhibition of oligodendrocyte differentiation and remyelination. (See second paragraph of the left column of page 63.)
In view thereof, one of ordinary skill in the art would have had reason to discontinue a statin before initiating a remyelination-promoting treatment such as Thomas’s compound of example 36 where continued statin therapy was considered undesirable, thereby permitting treatment with Thomas’s compound to promote oligodendrocyte differentiation and remyelination without the potentially countervailing remyelination-inhibiting effects associated with continued statin therapy.
One of ordinary skill would reasonably have expected success because Thomas expressly teaches that compound of example 36 promotes remyelination/myelination and OPC differentiation, whereas Zhornitsky identifies prolonged statin treatment as potentially interfering with those same biological processes.
Claim 12
With respect to claim 12, Zhornitsky and Thomas render obvious terminating treatment with cholesterol-lowering drug prior to initiation of treatment with compound 36 for the reasons discussed above with respect to claim 11. Claim 12 further requires that the treatment with the cholesterol-lowering drug be terminated “at least 6 days prior” to initiation of treatment of compound of example 36. AAFP teaches clinical management of cholesterol-lowering therapy over extended time periods, including repeating lipid measurements every three to twelve months as needed. (See first paragraph of the right column of page 590.)
Thus, the prior art establishes that the timing associated with management of cholesterol-lowering therapy was not limited to short or immediate intervals, but was routinely managed over periods substantially exceeding six days. In view of Zhornitsky ‘s teaching providing reason to discontinue statin treatment and Thoma’s teaching providing reason thereafter to administer compound of example 36 (claimed compound 1) to promote myelination/remyelination and OPC differentiation, selection of an interval of at least six days between termination of at least six days between termination of the cholesterol-lowering drug and initiation of compound of example 36, would have been within the ordinary skill in the art.
One of ordinary skill in the art would have been motivated to provide an interval between discontinuation of the stain and initiation of compound of example 36 so to permit cessation of the potentially countervailing effects associated with prolonged statin therapy before initiating a treatment intended to promote OPC differentiation and remyelination. Because the claimed interval is open-ended and encompassed any interval of six days or longer, including intervals extending “at least 6 days” does not represent a narrowly defined six-day washout period.
One of ordinary skill in the art would have reasonably expected success because Zhornitsky identifies the potentially adverse effect of prolonged stating treatment on remyelination, Thomas expressly teaches compound of example 36 as promoting OPC differentiation, and AAFP demonstrates that cholesterol-lowering therapy was conventionally managed and monitored over time periods substantially exceeding the claimed minimum six-day interval.
Claim 13
Claim 13 recites that the cholesterol-lowering drug is a statin, PCSK9 inhibitor, selective cholesterol absorption inhibitor, bile acid sequestrant, fibrate, or lipid-lowering therapy.
Zhornitsky expressly teaches statin therapy in MS and additionally identifies other lipid-regulating agents, including gemfibrozil and ezetimibe, as possible alternatives to statins. (See last paragraph of left column of page 63.) Accordingly, at least the statin species expressly encompasses by claim 13 would have been obvious from Zhornitsky.
Claims 14 and 16
The dosage limitations of claims 14 and 16 are rendered obvious for substantially the reasons discussed with respect to claim 1 and 7. Thomas teaches overlapping dosage amounts and administration of effective amounts of compound of example 36, Selection of therapeutically useful doses within the disclosed overlapping range would have been within the ordinary skill in the art.
Claim 19
Thomas expressly identifies relapsing-remitting and chronic progressive MS. Thus, selection of relapsing-remitting MS as recited in claim 16 would have been expressly suggested by Thomas.
Claim 21
Thomas expressly teaches combination treatment with another agent useful for MS, including interferon and glatiramer acetate. Claim 21 therefore would have been obvious for the reason discussed with respect to claim 5.
Claims 23, 24, 27, 28, 30, 33, and 35 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), American Academy of Family Physicians (Am Fam Physician. 2019;99(9):589-591).
Thomas teaches treating MS using compound of example 36 for the reasons set forth above, including its ability to promote myelination/remyelination and OPC differentiation.
Thomas does not expressly teach administering compound of example 36 to an MS patient already received cholesterol-lowering therapy, assessing plasma cholesterol, and adjusting the amount of cholesterol-lowering drug when the cholesterol falls outside a target range.
Zhornitksy teaches that elevated LDL, total cholesterol, and related lipid markers are associated with adverse clinical and MRI outcomes in MS and teaches the use and cholesterol-lowering effects of stains. Zhornitksy further reports clinical use of simvastatin in MS and discusses other lipid-regulating agents. (See Abstract; and second paragraph of the left column of page 63.) Thus, Zhornitsky would have provided one of ordinary skill with reason to manage elevated cholesterol in MS patient, including through administration of cholesterol-lowering therapy.
At the same time, Zhornitksy teaches that excessive or prolonged CNS-penetrating statin treatment may interfere with myelination/remyelination. (See last paragraph of left column of page 63.) This teaching would have discouraged use of Thomas’s compound. Rather, it provides additional reason for employing Thomas’ compound because Thomas expressly teaches that compound of example 36 promotes myelination and remyelination and OPC differentiation-the biological processes Zhornitsky identifies as potentially adversely affected by prolonged statin treatment.
Accordingly, one of ordinary skill in the art would have had reason to administer Thomas’ compound to an MS patient receiving cholesterol-lowering therapy in order to obtain the respective benefits of treating MS/promoting remyelination and managing circulating cholesterol.
AAFP further teaches that following initiation of adjustment of statin therapy, fasting lipid measurements should be repeated to assess adherence and response to LDL-C-lowering medication, with subsequent measurements performed as clinically appropriate. (See first paragraph of the right column of page 590.)
Therefore, one of ordinary skill in the art would have been motivated to monitor the cholesterol level in MS patient receiving cholesterol-lowering medication and to adjust the amount of the cholesterol-lowering drug in response to the measured cholesterol level. This represents the ordinary clinical management of cholesterol-lowering pharmacotherapy taught by AAFP.
One of ordinary skill in the art would have had a reasonable expectation of success because each component was being employed for its known function. Thomas’ compound for treatment of MS and promotion of remyelination/OPC differentiation, cholesterol-lowering medication for control cholesterol, and periodic lipid measurements and dosage adjustment for monitoring and controlling the patient’s response to lipid-lowering treatment.
Furthermore, Applicant’s specification established that compound 1 (Thomas’s compound 36) lowers circulating cholesterol within the claimed dosage range. Thus, when the obvious combination results in administration of compound 1 is a pharmacodynamic consequence of administering the compound. The prior art need not have recognized an inherent property where the property necessarily results from the otherwise-obvious combination.
Claim 24
With respect to claim 24, Zhornitsky teaches studies evaluating cholesterol and markers of cholesterol turnover in MS subject and expressly reports clinically evaluated cholesterol threshold including LDL-C greater than 100 mg/dl and total cholesterol greater than 200 mg/ml. See Table 1.) Thus, Zhornitsky establishes that circulating cholesterol values of 100 mg/dl and 200 mg/dl were recognized and clinically evaluated cholesterol threshold in subjects having risk of developing MS.
AAFP teaches that lipid measurements should be repeated after initiation or adjustment of cholesterol-lowering therapy to assess response to the medication and therefore repeated as clinically appropriate.
In view of these teachings, it would have been obvious to one of ordinary skill in the art to repeatedly assess the cholesterol level of an MS patient receiving cholesterol-lowering therapy and adjust such therapy as necessary to maintain the patient’s cholesterol within a desired range defined by clinically recognized cholesterol values. Accordingly, selection of a target range having endpoints corresponding to the clinically recognized cholesterol values taught Zhornitsky, including a range extending from 100 mg/dl to 200 mg/dl, would have been within the ordinary skill in the art. One would have reasonably expected success because AAFP teaches repeated lipid monitoring for determining response to cholesterol-lowering medication, while Zhornitsky identifies cholesterol values relevant to assessment of cholesterol-associated outcomes in MS patients.
Because claim 24 recites the target ranges in the alternatives, i.e., between 100 mg/dL and 200 mg/dL or between 125 mg/dL and 200 mg/dL,” rendering obvious the recited 100-200 mg/dL alternative is sufficient to render the scope of claim 24 obvious.
Claims 27, 28, and 30
Claim 27 is rendered obvious at least by Zhornitsky’s express use of statins and discussion of other lipid-regulating agents. Claims 28 and 30 are rendered obvious by Thomas’s overlapping dose teachings for compound 36for the reasons discussed above.
Claim 33
Thomas expressly teaches relapsing-remitting MS and therefore renders obvious the disease-stage limitation.
Claim 35
Thomas expressly teaches combining its compounds with other MS-active agent, including interferon and glatiramer acetate, thereby rendering obvious the additional therapy.
Response to Applicant’s arguments
Applicant’s arguments have been considered but are not persuasive of patentability for the reasons discussed below.
Claims 1-3, 5, and 7
Applicant argues that Thomas does not teach or suggest using compound 1 to both treat MS and reduce cholesterol level in a human subject. Applicant further argues that Thomas is silent regarding any effect of compound 1 on cholesterol and. Therefore, that one of ordinary skill in the art would have lacked both a motivation and a reasonable expectation of success in arriving at the claimed method.
In response, Applicant’s argument is not persuasive. Specifically, Thomas expressly teaches the administration of the same compound 1 recited in the instant claims for treatment of MS and teaches dosage amounts encompassing or overlapping the presently claimed dosage range. Thomas further teaches that compound 36 (compound 1 claimed) promotes myelination and remyelination and OPC differentiation and identifies treatment of various forms of MS, including relapsing-remitting and chronic progressive MS. The Examiner acknowledges that Thomas does not expressly state that administration of the compound reduces a cholesterol level in the treated patient. However, the absence of that express statement in Thomas does not establish that the newly recited cholesterol reduction limitation renders the claimed method nonobvious.
As set forth in the rejection, Zhornitksy teaches that elevated circulating cholesterol and makers of cholesterol turnover are associated with MS and further concludes that cholesterol and makers of cholesterol turnover have the potential to be used clinically as biomarkers of MS disease activity and may even be implicated in the pathogenesis of MS. Thus, Zhornitsky does not identify circulating cholesterol as an unrelated laboratory measurement, but instead teaches a relationship between circulating cholesterol/cholesterol turnover and MS disease activity and potentially MS pathogenesis. In view of this teaching, one of ordinary skill in the art would have recognized reduction of elevated circulating cholesterol as a desirable outcome in the treatment and management of and MS patient. Accordingly, when administering Thomas’s compound to treat MS, the skilled artisan would have had reason to obtain a reduction in elevated circulating cholesterol because the art had identified cholesterol/cholesterol turnover as associated with MS disease activity, and potentially implicated in the disease process. The skilled artisan would have had a reasonable expectation of success. Thomas expressly teach compound 36 for treatment of MS, while Zhornitsky establishes a relationship between circulating cholesterol/cholesterol turnover and MS disease activity and potential pathogenesis. The combined teachings therefore provide a scientifically reasonable basis for expecting that treatment directed to the MS disease process could favorably affect a disease-associated cholesterol parameter.
Applicant’s argument that Thomas itself does not identify compound 1 as a cholesterol-lowering drug does not address the rejection as a whole. The obviousness inquiry does not require that a single reference expressly articulate every reason supporting the claimed method. Thomas provides the teaching to administer the claimed compound for the treatment of the claimed disease (MS), while Zhornitsky provides the additional teaching concerning the relationship between circulating cholesterol/cholesterol turnover and MS disease activity and potential pathogenesis. Moreover, Applicant’s own disclosure demonstrates that the administration of compound 1 within the presently claimed dosage range does, in fact, result in reduction of circulating cholesterol. Thus, the experimental evidence is consistent with, rather than contrary to, the direction suggested the prior-art relationship between cholesterol/cholesterol turnover and MS disease activity.
Accordingly, Applicant’s argument that the claimed cholesterol reduction could not reasonably have been expected merely because Thomas does not expressly disclose that property is not persuasive.
Applicant’s alleged unexpected reduction in cholesterol
Applicant further argues that the observed dose-dependent reduction in cholesterol constitutes an unexpected result sufficient to overcome the rejection.
In response, Applicant’s argument is not persuasive. The fact that Thomas does not expressly report the cholesterol-lowering effect of compound 36 does not, by itself, establish that the result is unexpected for purposed of obviousness. Zhornitsky had already identified circulating cholesterol and cholesterol-tunover markers as associated with MS disease activity and potentially implicated in MS pathogenesis. Thus, a favorable effect upon a cholesterol-related parameter in connection with treatment of the MS disease process was not whole disconnected from what was known in the art.
Further, Applicant’s data demonstrate a pharmacodynamic effect resulting from administration of compound 1. Applicant has not established that the claimed method produces unexpected superior result relative to the closest prior art treatment with compound 1 sufficient to outweigh the evidence of obviousness. The objective has been considered together with the prior art as a whole, but does not outweigh the teachings discussed above.
Alleged Criticality of the 10-60 mg/day dosage range and neutropenia
Applicant additionally relies upon Example 7 and argues that the claimed dosage range provides efficacy while minimizing the risk of neutropenia.
In response, the evidence has been considered but is not persuasive. Although Applicant has tested doses both inside and outside the claimed range, the evidence has not been shown to be commensurate in scope with the full breadth of the claimed 10-60 mg/day range. Additionally, the evidence is not commensurate in scope with the claim as well because reduction in neutropenia risk is not recited in the claim. The claims encompass administration at any dosage throughout the continuous range from 10 though 60 mg/day. Whereas Applicant relies upon results obtained at only 10, 30, and 60 mg/day within that range.
Moreover, Applicant’s own evidence indicates that neutrophil response is not uniform throughout the claimed range. Applicant states that the decline in neutrophil count at doses below 30 mg/day was indistinguishable from placebo, whereas a dose-dependent decline in absolute neutrophil count was observed at doses 30 mg/day or greater. Thus, the evidence itself demonstrates differing responses within the claimed range and does not provide an adequate basis for reasonably concluding that the asserted safety advantage extends throughout the entire claimed range of 10-60 mg/day.
Applicant’s evidence also does not establish criticality of the claimed lower boundary of 10 mg/day. Applicant reports that doses below 30 mg/day exhibited a neutrophil-count decline indistinguishable from placebo, which includes the tested doses of 10 and 3 mg/day falling outside the claimed range as well as the claimed dose of 10 mg/day. Thus, the evidence does not demonstrate a difference in the asserted neutrophil-related effect at the claimed 10 mg/day lower boundary relative to the tested immediately outside the claimed range.
Furthermore, the relied-upon neutropenia data were obtained from healthy human subjects, whereas the presently claimed method require administration to a human subject having MS. Applicant has not provided evidence stablishing that the asserted neutropenia-related advantage demonstrated in healthy subjects would extend throughout the claimed 10-60 mg/day in the claimed MS patient papulation. Accordingly, the evidence is not commensurate in scope with the claimed subject population.
Although the results at disease above 60 mg/day may indicate an increased risk of neutropenia at higher doses, these results do not establish that the entire claimed range of 10-60 mg/day, when administered to the claimed MS patient population possesses the asserted unexpected safety advantage or constitutes a critical range as a whole. Accordingly, Applicant’s evidence is insufficient to outweigh the evidence supporting the prima facie case of obviousness.
Applicant’s reliance of MPEP 2107.03 does not alter this conclusion. The Examiner is not requiring Applicant to provide evidence demonstrating the safety of compound 1 in human subjects with MS, nor is the Examiner questioning the asserted therapeutic utility of compound 1. Rather, Applicant has affirmatively relied upon results obtained in heathy subjects as objective evidence of unexpected results to rebut the prima facie case of obviousness. Accordingly, it is appropriate to consider whether the relied-upon evidence is reasonably commensurate in scope with the claimed invention, including MS patient population. The utility principles cited by Applicant do not establish that unexpected results demonstrated in one subject population necessarily constitutes unexpected results commensurate with a claim directed to a different subject population.
Claim 10- “in the absence of a cholesterol lowering drug”
Applicant argues that Thomas does not teach administration of compound 1 “in the absence of a cholesterol lowering drug.” Applicant further relies upon in re Strongbridge Dublin Ltd. For the proposition that silence in a prior-art reference, standing alone, does not establish the absence of an unmentioned treatment.
In response, Applicant’s argument is not percussive. Thomas is relied upon for teaching treatment of MS with compound 1 and for teaching that compound 1 promotes OPC differentiation, myelination/remyelination. Zhornitsky additionally teaches that, although statin reduces circulating cholesterol and have been investigated in MS, cholesterol is an essential component of myelin and prolonged statin treatment may have deleterious effects relevant to MS, including reducing the number of mature oligodendrocytes, blocking differentiation of OPC, and inhibiting myelination. These teachings provide an affirmative reason for the claimed absence. Thomas teaches compound 1 for promoting the very processes that Zhornitsky teaches may be adversely affected by prolonged statin treatment. Thus, one of ordinary skill in the art would have had a reason to administer compound 36 of Thomas for treatment of MS without concomitant cholesterol-lowering statin therapy, thereby obtaining the remyelination/OPC differentiation benefits taught by Thomas without the potentially countervailing effects associated with prolonged statin therapy. One of ordinary skill in the art would have reasonably expected success because Thomas expressly teaches compound 36 as useful for MS treatment and promoting myelination/remyelination and OPC differentiation while Zhornitsky expressly identifies the potential adverse effects of prolonged statin therapy upon those same biological processes.
Accordingly, unlike a rejection based solely upon a reference’s failure to mention a concomitant medication, the present rejection relies upon an affirmative teaching providing a reason to practice Thomas’s MS treatment without concomitant cholesterol lowering statin therapy. Applicant’s reliance on Strongbridge therefore does not overcome the rejection.
Claims 11 and 12 – Termination of cholesterol-lowering therapy
Applicant’s argument concerning the absence of a cholesterol-lowering drug likewise do not render claims 11 and 12 patentable.
Claim 11 requires that the subject previously be treated with a cholesterol-lowering drug and that treatment with that drug be terminated before initiation of compound 1. As discussed above, Zhornitsky teaches that prolong statin treatment may reduce mature OPC, block differentiation, and inhibit remyelination, whereas Thomas teaches compound 1 as promoting OPC differentiation and myelination/remyelination. One of ordinary skill in the art would have discontinued statin treatment before initiating Thomas’s compound in order to avoid the potentially countervailing effects of continued statin treatment upon OPC differentiation and remyelination while obtaining the remyelination-promoting effects taught by Thomas. One of ordinary skill in the art would have reasonably expected success because the references expressly describe relevant biological effects underlying the proposed sequential treatment.
Claim 12 further requires that the treatment with the cholesterol-lowering drug be terminated “at least 6 days prior” to initiation of compound 1. The claim does not require termination precisely at 6 days before compound 1 treatment. Rather, its open-ended limitation encompasses any interval of six days or longer.
AAFP teaches clinical management and monitoring of cholesterol-lowering therapy over extended periods, including repeated lipid measurement at intervals of three to twelve months as needed. Such intervals substantially exceed the minimum six-day interval recited in claim 12 and demonstrate that cholesterol-lowering therapy was conventionally managed over extended periods.
In view of Zhornitsky’s reason for discontinuing prolonged statin treatment before employing a remyelination-promoting treatment, Thomas’s reason for subsequently administering compound 36, and AAFP’s teaching that cholesterol-lowering therapy is clinically managed over periods substantially exceeding six days, selection of an interval of at least six days between termination of the cholesterol-lowering drug and initiation of compound 36 would have been within the level of ordinary skill in the art. The skilled artisan would reasonably have expected success because the claimed minimum interval doses does not require a narrowly defined or critical six-day washout, but encompasses the substantially larger treatment-management periods conventionally employed in the art.
Claim 23- Dependent claims- Combination with cholesterol-lowering therapy
Applicant argues that Thomas, Zhornitsky, and AAFP do not teach or suggest that compound 1 itself lowers cholesterol and therefore do not render obvious the monitoring and adjustment method of claim 23.
In response to applicant's arguments against the references individually, one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the present case, Thomas teaches claimed compound 1for treatment of MS and promotion of myelination/remyelination and OPC differentiation. Zhornitsky teaches that elevated circulating cholesterol and cholesterol-related markers are associated with adverse MS disease activity and that cholesterol and markers of cholesterol turnover may be useful biomarkers of disease activity and potentially implicated in MS pathogenesis. Zhornitsky additionally teaches cholesterol-lowering therapy, including stain therapy in MS. Thus, one of ordinary skill in the art would have had reason to treat MS patient with Thomas’s compound 1 while also managing clinically relevant circulating cholesterol.
AAFP teaches that lipid levels should be measured following initiation or adjustment of cholesterol-lowering therapy in order to assess response and that lipid measurements should thereafter be repeated as clinically appropriate. Accordingly, monitoring the subject’s cholesterol and adjusting the cholesterol-lowering medication in response to measured cholesterol represents the expected clinical management of such therapy. The references also provide a reasonable expectation of success because each component of the proposed method performs its known function: Thomas’s compound 1 treats MS and promotes remyelination/OPC differentiation; the cholesterol-lowering medication reduces circulating cholesterol; and monitoring and adjustment cholesterol=lowering therapy permits control of the patient’s cholesterol response.
Applicant’s newly asserted cholesterol-lowering effect of compound 1 does not negate this rationale. Rather, Applicant’s own evidence demonstrates that compound 1 provides an additional cholesterol-lowering effect when administered within the claimed dosage range. In a patient already receiving cholesterol-lowering medication, this additional effect provides further reason-not less reason-to monitor the patient’s cholesterol and adjust the amount of cholesterol-lowering medication as necessary to maintain the desired level.
Accordingly, the combined teachings support both the motivation for the claimed monitoring/adjustment method and a reasonable expectation of successfully carrying it out.
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 and for reducing cholesterol level in the subject.
Thomas teaches a method for prevention or treatment of multiple sclerosis 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, which corresponds to compound 1 recited in the instant claims. (See claims 22, 1 and 17.) Moreover, Thomas identifies the compound as a selective S1P4 antagonist and teaches that compounds thereof promote myelination or remyelination and promote oligodendrocyte progenitor cell differentiation. (See page 23, lines 31-33; and lines 15-16 of page 24.) The subject includes a human. (See lines 7-8.).
Thomas further teaches administration of the compound at does including 1 mg, less less than 10 mg, less than 15 mg, less than 20 mg, less than 50 mg (see page 30, lines 5-14), thereby teaching dosage amounts overlapping the presently claimed range of 10-60 mg/day in claim 7. Thomas additionally 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 further teaches treatment of various forms of multiple-sclerosis, including relapsing-remitting, chronic progressive (ee page 24, lines 15-22), thereby rendering obvious the subject matter of claim 3. Thomas additionally teaches administration of its compounds with another active agent useful for treatment of multiple sclerosis, expressly including interferon and glatiramer acetate. (See page 26, lines 27-33.)
Nevertheless, Applicant’s own specification provides evidence that reduction of circulating cholesterol is a pharmacodynamic effect of administering the same compound 1 within the presently claimed dosage range. Applicant states that healthy human subjects receiving compound 1 at 10, 30, 60 mg/day exhibited a time-and-dose-dependent reduction in circulating total cholesterol, and Applicant further relies upon those results as demonstrating that compound reduces cholesterol when administered within the claimed range.
Accordingly, to the extent administration of the same compound at the claimed dosage necessarily produces the demonstrated cholesterol-reducing effect, the recitation of “reducing a cholesterol level in the human subject” identifies a pharmacological result of performing the otherwise obvious administration rather than requiring a different drug, route, dosage, or affirmative treatment step.
The prior art need not have recognized an inherent property at the relevant time, provided that the property is necessarily present or is the natural result of performing the prior-art-method. See MPEP 2112. Thus, Thomas provided the reason to administer compound 1 in the overlapping amount claimed to an MS patient and the claimed cholesterol reduction naturally results from administration of compound 1 within the claimed dosage range, as evidenced by Applicant’s own disclosure.
One of ordinary skill in the art would have had a reasonable expectation of successfully treating MS because both the patent claims and Thomas expressly teaches the same compound I for the treatment of MS and Thomas teach its remyelination and oligodendrocyte progenitor-cell differentiation activities.
Alternative rationale regarding the limitation “reducing cholesterol level in the human subject.”
Claims 1-3, 5, and 7 rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (WO2012/109108 A1) and Zhornitsky et al. (Multiple Sclerosis and Related Disorders 5 (2016) 53–65).
The patent claims and Thomas teach administering compound of example 36 to a human subject having multiple sclerosis and Thomas teach the overlapping dosage amounts for treatment of MS, as discussed above.
The patent claims do not expressly teach that administration of compound of example 36 reduces cholesterol level in the human subject.
Zhornitsky, however, teaches that elevated circulating cholesterol and markers of cholesterol turnover are associated with MS and concludes that cholesterol and markers of cholesterol turnover have the potential to be used clinically as biomarkers of disease activity and may even be implicated in the pathogenesis of MS. (See Abstract.) Zhornitsky does not merely identify cholesterol as an unrelated laboratory parameter, but teaches a relationship between circulating cholesterol/cholesterol turnover and MS disease activity and potentially MS pathogenesis.
In view of Zhornitksy, one of ordinary skill in the art would have been motivated, when treating a human subject having multiple sclerosis according to the patent claims and Thomas, to achieve a reduction in elevated circulating cholesterol and cholesterol turnover as associated with MS disease activity and potentially implicated in MS pathogenesis. A reduction of cholesterol would therefore have been understood as a desirable therapeutic and/or disease-associated outcome in an MS human subject.
One or ordinary skill in the art would have also have had a reasonable expectation of success because Zhornitsky teaches a relationship between circulating cholesterol/cholesterol turnover and MS disease activity and potential pathogenesis, while the patent claims and the patent claims and Thomas expressly teach compound 36 as effective for treating MS. Accordingly, the skilled artisan would have reasonably expected that successful treatment of MS disease process could favorably affect a disease-associated cholesterol parameter, including circulating cholesterol. Applicant’s own clinical data confirm that administration of compound 1 (compound 36 of Thomas) within the claimed dosage range in fact produces a reduction in circulating cholesterol.
With respect to Claims 10-14, 16, 19, 21.
The patent claims do not expressly teach the subject is being treated with a cholesterol lowering drug, and treatment with cholesterol-lowering drug, including a statin.
Zhornitsky teaches that circulating cholesterol and cholesterol-related markers are clinically relevant in MS. In particular, Zhornitsky reports associations between elevated LDL cholesterol, total cholesterol, ApB and oxidized LDL, and adverse clinical and MRI outcomes in MS. Zhornitsky further discusses cholesterol-lowering drug in MS and reports that statins substantially reduce LDL and ApoB. (Abstract; and second paragraph of the left column of page 63.) Zhornitsky additionally recognizes a competing consideration particularly relevant to MS: cholesterol is an essential component of myelin, and prolonged CNS-penetrating statin treatment may adversely affect remyelination, including reducing mature oligodendrocytes, blocking oligodendrocytes progenitor-cell differentiation, and inhibiting remyelination. (See Abstract; and second paragraph of the left column of page 63.)
Thomas in contrast, teaches that compound of example 36 promotes myelination/remyelination and oligodendrocyte progenitor-cell differentiation.
Accordingly, the combined teachings would have provided one of ordinary skill in the art with reason to use the patent claims and Thomas’s compound of example 36 in an MS patient to Thomas’s remyelination-promoting activity in combination treatment with interferon and glatiramer acetate, while managing the patient’s cholesterol-lowering therapy in view of the known relationship between cholesterol and MS and the recognized potential effects of prolong statin treatment on remyelination. Thomas teaches the overlapping dosages, and combination treatment with interferon and glatiramer acetate.
Claim 10
With respect to claims 10, the patent claims and Thomas teach compound of example 36, treatment of MS, treatment of relapse-remitting, chronic progressive MS, while Thomas teaches the overlapping dosages, and combination treatment with interferon and glatiramer acetate for the reasons discussed above
The patent claims do not expressly teach that compound of example 36 (claimed compound 1) is administered “in the absence of a cholesterol lowering drug” as presently claimed.
Zhornitsky teaches although cholesterol-lowering therapy, particularly statin therapy, has been investigated in multiple schlerosis, cholesterol is an essential component of myelin and prolonged statin treatment may adversely affect myelination/remyelination. In particular, Zhornitsky teaches that statin treatment may reduce mature oligodendrocytes, block differentiation of oligodendrocyte progenitor cells, and inhibit remyelination. (See Abstract; second paragraph of the left column of page 63.)
Thomas conversely, teaches that compound 1 (example 36) promotes oligodendrocyte progenitor-cell differentiation and myelination/remyelination. Accordingly, one of ordinary skill in the art, considering the teachings of the patent claims, Thomas and Zhornitsky together, would have had reason to administer Thomas’s compound for treatment of MS in the absence of a cholesterol-lowering drug, particularly a statin, so as to obtain the remyelination-promoting effect the compound of example 36 without potentially countervailing effect of cholesterol-lowering statin therapy on oligodendrocyte differentiation and remyelination.
One of ordinary skill in the art would have had a reasonable expectation of success because the patent claims and Thomas expressly teach compound of example 36 as useful for treating MS, while Thomas teaches promoting oligodendrocyte progenitor-cell differentiation and myelination/remyelination, while Zhornitsky provides a reason for avoiding concomitant statin treatment when promotion of remyelination is desired.
Claim 11
With respect to claim 11, the patent claims do not expressly teach that the subject has previously been treated with a cholesterol-lowering drug and the such treatment is terminated before initiation of treatment with compound of example 36, as recited in claim 11.
However, Zhornitsky teaches both the potential benefit of cholesterol reduction in MS and the potential disadvantage associated with prolonged CNS-penetrating statin therapy, including inhibition of oligodendrocyte differentiation and remyelination. (See second paragraph of the left column of page 63.)
In view thereof, one of ordinary skill in the art would have had reason to discontinue a statin before initiating a remyelination-promoting treatment such as the patent claims and Thomas’s compound of example 36 where continued statin therapy was considered undesirable, thereby permitting treatment with Thomas’s compound to promote oligodendrocyte differentiation and remyelination without the potentially countervailing remyelination-inhibiting effects associated with continued statin therapy.
One of ordinary skill would reasonably have expected success because Thomas expressly teaches that compound of example 36 promotes remyelination/myelination and OPC differentiation, whereas Zhornitsky identifies prolonged statin treatment as potentially interfering with those same biological processes.
Claim 12
With respect to claim 12, the patent claims, Zhornitsky and Thomas render obvious terminating treatment with cholesterol-lowering drug prior to initiation of treatment with compound 36 for the reasons discussed above with respect to claim 11. Claim 12 further requires that the treatment with the cholesterol-lowering drug be terminated “at least 6 days prior” to initiation of treatment of compound of example 36. AAFP teaches clinical management of cholesterol-lowering therapy over extended time periods, including repeating lipid measurements every three to twelve months as needed. (See first paragraph of the right column of page 590.)
Thus, the prior art establishes that the timing associated with management of cholesterol-lowering therapy was not limited to short or immediate intervals, but was routinely managed over periods substantially exceeding six days. In view of Zhornitsky ‘s teaching providing reason to discontinue statin treatment and the patent claims and Thomas’s teaching providing reason thereafter to administer compound of example 36 (claimed compound 1) where Thomas teaches to promote myelination/remyelination and OPC differentiation, selection of an interval of at least six days between termination of at least six days between termination of the cholesterol-lowering drug and initiation of compound of example 36, would have been within the ordinary skill in the art.
One of ordinary skill in the art would have been motivated to provide an interval between discontinuation of the stain and initiation of compound of example 36 so to permit cessation of the potentially countervailing effects associated with prolonged statin therapy before initiating a treatment intended to promote OPC differentiation and remyelination. Because the claimed interval is open-ended and encompassed any interval of six days or longer, including intervals extending “at least 6 days” does not represent a narrowly defined six-day washout period.
One of ordinary skill in the art would have reasonably expected success because Zhornitsky identifies the potentially adverse effect of prolonged stating treatment on remyelination, Thomas expressly teaches compound of example 36 as promoting OPC differentiation, and AAFP demonstrates that cholesterol-lowering therapy was conventionally managed and monitored over time periods substantially exceeding the claimed minimum six-day interval.
Claim 13
Claim 13 recites that the cholesterol-lowering drug is a statin, PCSK9 inhibitor, selective cholesterol absorption inhibitor, bile acid sequestrant, fibrate, or lipid-lowering therapy.
Zhornitsky expressly teaches statin therapy in MS and additionally identifies other lipid-regulating agents, including gemfibrozil and ezetimibe, as possible alternatives to statins. (See last paragraph of left column of page 63.) Accordingly, at least the statin species expressly encompasses by claim 13 would have been obvious from Zhornitsky.
Claims 14 and 16
The dosage limitations of claims 14 and 16 are rendered obvious for substantially the reasons discussed with respect to claim 1 and 7. Thomas teaches overlapping dosage amounts and administration of effective amounts of compound of example 36, Selection of therapeutically useful doses within the disclosed overlapping range would have been within the ordinary skill in the art.
Claim 19
The patent claims and Thomas expressly identifies relapsing-remitting and chronic progressive MS. Thus, selection of relapsing-remitting MS as recited in claim 16 would have been expressly suggested by Thomas.
Claim 21
Thomas expressly teaches combination treatment with another agent useful for MS, including interferon and glatiramer acetate. Claim 21 therefore would have been obvious for the reason discussed with respect to claim 5.
With respect to claims 23, 24, 27, 28, 30, 33, and 35
The patent claims and Thomas teach treating MS using compound of example 36 for the reasons set forth above, including its ability to promote myelination/remyelination and OPC differentiation.
The patent claims do not expressly teach administering compound of example 36 to an MS patient already received cholesterol-lowering therapy, assessing plasma cholesterol, and adjusting the amount of cholesterol-lowering drug when the cholesterol falls outside a target range.
Zhornitksy teaches that elevated LDL, total cholesterol, and related lipid markers are associated with adverse clinical and MRI outcomes in MS and teaches the use and cholesterol-lowering effects of stains. Zhornitksy further reports clinical use of simvastatin in MS and discusses other lipid-regulating agents. (See Abstract; and second paragraph of the left column of page 63.) Thus, Zhornitsky would have provided one of ordinary skill with reason to manage elevated cholesterol in MS patient, including through administration of cholesterol-lowering therapy.
At the same time, Zhornitksy teaches that excessive or prolonged CNS-penetrating statin treatment may interfere with myelination/remyelination. (See last paragraph of left column of page 63.) This teaching would have discouraged use of the patent claims Thomas’s compound. Rather, it provides additional reason for employing the patent claims and Thomas’ compound because Thomas expressly teaches that compound of example 36 promotes myelination and remyelination and OPC differentiation-the biological processes Zhornitsky identifies as potentially adversely affected by prolonged statin treatment.
Accordingly, one of ordinary skill in the art would have had reason to administer the patent claims and Thomas’ compound to an MS patient receiving cholesterol-lowering therapy in order to obtain the respective benefits of treating MS/promoting remyelination and managing circulating cholesterol.
AAFP further teaches that following initiation of adjustment of statin therapy, fasting lipid measurements should be repeated to assess adherence and response to LDL-C-lowering medication, with subsequent measurements performed as clinically appropriate. (See first paragraph of the right column of page 590.)
Therefore, one of ordinary skill in the art would have been motivated to monitor the cholesterol level in MS patient receiving cholesterol-lowering medication and to adjust the amount of the cholesterol-lowering drug in response to the measured cholesterol level. This represents the ordinary clinical management of cholesterol-lowering pharmacotherapy taught by AAFP.
One of ordinary skill in the art would have had a reasonable expectation of success because each component was being employed for its known function. Thomas’ compound for treatment of MS and promotion of remyelination/OPC differentiation, cholesterol-lowering medication for control cholesterol, and periodic lipid measurements and dosage adjustment for monitoring and controlling the patient’s response to lipid-lowering treatment.
Furthermore, Applicant’s specification established that compound 1 (Thomas’s compound 36) lowers circulating cholesterol within the claimed dosage range. Thus, when the obvious combination results in administration of compound 1 is a pharmacodynamic consequence of administering the compound. The prior art need not have recognized an inherent property where the property necessarily results from the otherwise-obvious combination.
Claim 24
With respect to claim 24, Zhornitsky teaches studies evaluating cholesterol and markers of cholesterol turnover in MS subject and expressly reports clinically evaluated cholesterol threshold including LDL-C greater than 100 mg/dl and total cholesterol greater than 200 mg/ml. See Table 1.) Thus, Zhornitsky establishes that circulating cholesterol values of 100 mg/dl and 200 mg/dl were recognized and clinically evaluated cholesterol threshold in subjects having risk of developing MS.
AAFP teaches that lipid measurements should be repeated after initiation or adjustment of cholesterol-lowering therapy to assess response to the medication and therefore repeated as clinically appropriate.
In view of these teachings, it would have been obvious to one of ordinary skill in the art to repeatedly assess the cholesterol level of an MS patient receiving cholesterol-lowering therapy and adjust such therapy as necessary to maintain the patient’s cholesterol within a desired range defined by clinically recognized cholesterol values. Accordingly, selection of a target range having endpoints corresponding to the clinically recognized cholesterol values taught Zhornitsky, including a range extending from 100 mg/dl to 200 mg/dl, would have been within the ordinary skill in the art. One would have reasonably expected success because AAFP teaches repeated lipid monitoring for determining response to cholesterol-lowering medication, while Zhornitsky identifies cholesterol values relevant to assessment of cholesterol-associated outcomes in MS patients.
Because claim 24 recites the target ranges in the alternatives, i.e., between 100 mg/dL and 200 mg/dL or between 125 mg/dL and 200 mg/dL,” rendering obvious the recited 100-200 mg/dL alternative is sufficient to render the scope of claim 24 obvious.
Claims 27, 28, and 30
Claim 27 is rendered obvious at least by Zhornitsky’s express use of statins and discussion of other lipid-regulating agents. Claims 28 and 30 are rendered obvious by Thomas’s overlapping dose teachings for compound 36for the reasons discussed above.
Claim 33
The patent claims and Thomas expressly teach relapsing-remitting MS and therefore renders obvious the disease-stage limitation.
Claim 35
The patent claims and Thomas expressly teach combining its compounds with other MS-active agent, including interferon and glatiramer acetate, thereby rendering obvious the additional therapy.
Applicant argues that the claims of U.S. Patent Nos 9,808,449, 9,340,527, and 10,894,040 are based on Thomas or continuations thereof and, for the same reasons advanced against the 103 rejections, the presently claimed subject matter is patentably distinct.
In response, Applicant’s arguments have been considered but are not persuasive. Because Applicant relies on the same substantive arguments addressed above with respect to Thomas, Zhornitsky, and AAFP, the Examiner’s responses thereto are incorporated herein by reference and are equally applicable the non-statutory double patenting rejections. Accordingly, the non-statutory double patenting rejections are maintained.
Conclusion
Claims 1-3, 5, 7, 10-14, 16, 19, 21, 23-24, 27-28, 30, 33, and 35 are not allowed.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628
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