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 .
Response to Amendments
Applicant’s amendments to the claims of October 1, 2025, in response to the Office Action of July 2, 2025, are acknowledged.
Response to Arguments
Applicant’s arguments and allegations of unexpected results have been thoroughly considered in their entirety. The prior art is cited for all that is teaches and the teachings of each of the references are as a whole.
The instant claims require preventing pruritus while preventing or reducing lymphopenia by administering the claimed compound, which modulates an S1P receptor. Thus, a subject being treated does not need to have pruritus or lymphopenia according to claim 1. The active step claimed is administering the claimed compound to a subject at a dose that remains within 25% of the initiation dose or initial daily dose. The results of this administration include preventing pruritic and lymphopenia and decreasing a subject’s heart rate by less than 5 beats per minutes daily. These results are considered secondary to the active steps, absent evidence to the contrary.
Applicant alleges unexpected results which include reducing side effects, such as bradycardia when dose titration is less than 25% from the initial to standard daily dose. The examiner notes that the instant claims do not require an initial dose to differ at all from a standard daily dose. This means that if a subject takes a daily dose and remains on that daily dose, this could meet the dosage limitation claimed. Further, the instant claims also include dose titration wherein the higher dose is 25% higher than the initial dose. The instant claims do not exclude dose titration, but rather include a less extreme increase in dosage.
Gill teaches the claimed compound prevents lymphopenia and pruritus. Gill2 teaches the same. Gill3 teaches the claimed S1P modulator compound can comprise only 0.001% to 3% of a composition, or up to 25%. See prior art claims 16 and 18, respectively. Targeted dosing is taught to be advantageous in some instances over systemic exposure. It is not clear that targeted dosing would be expected to alter a subject’s heart rate. Also, slow release formulations are also taught and can limit systemic exposure. This can limit the side effects that may occur. See par. 53. Filler can include lactose monohydrate, lubricants include magnesium stearate, sodium starch glycolate (disintegrant), povidone (binder), maize starch (filler), and others. See par. 64. The dosage of API can be from 1 to 200 mg up to about three or more times daily. See par. 73.
Schmouder is cited to show that standard dosages fall within the narrowest claimed range of 0.5 mg to 12 mg. Schmouder does use dose titration and Gill3 does not. However, the methods taught by Gill also treat the claimed subject population. The standard dose taught by Schmouder falls within/overlaps the range of 1 mg to 200 mg taught by Gill3.
Unexpected Results are not presently shown because a critical dosage is not shown; Applicant did not control for route of administration; and the claims are not commensurate in scope with dosage nor route of administration.
To constitute unexpected results, Applicant must show: (1) the claimed method provides an unexpected advantage; (2) as compared to the closest prior art; and (3) the showing must be commensurate in scope with the breadth of the claims. In this case, the closest prior art is Gill. Gill teaches administration of 0.1 to 200 mg of the claimed API to a subject with pruritus. Gill also teaches target dosing rather than systemic dosing and teaches topical and slow release administration.
The claimed compound claimed is alleged to not induce bradycardia at a dose of 0.5 mg to 12 mg, as evidenced by Figure 4 data. In light of this allegation, the only claim that can be considered commensurate in scope with this allegation, if established, is claim 10. Thus, the claims as a whole are not commensurate in scope with the dosage alleged to yield the unexpected result.
Further, Applicant argues that systemic exposure does not increase heart rate even though it results in a dose-proportional increase in concentration in a human. The examiner notes that the claims do not require a systemic administration. The claims provide for a slow release formulation and a topical administration in instant claim 22, which depends from independent claim 1. Further, Gill teaches targeted dosing to be preferable to systemic exposure. It is not clear that even if systemic adverse events result from a systemic administration that a slow release and/or a topical targeted administration would result in a decrease in heart rate that exceeds 5 beats per minute. A slow release formulation, e.g., can be equivalent to administration of a much lower dose than a dose-equivalent immediate release form. Similarly, a low dose of a topical formulation may have low systemic effect. The claims do not control for route of administration as a whole.
Further, Gill2 provides examples in which a dose of 0.25 mg/kg provided a decreased lymphocyte count of 70.6%. See lymphopenia assay. To show a criticality of a claimed range, Applicant must show that dosages above and below the claimed range provide a statistically significant and non-extrapolatable advantage over dosages within the critical range. In this case, there does not appear to be any showing on the record that 0.5 mg to 12 mg works unexpectedly better than those ranges outside of that range. According to M.P.E.P. 716.02(d), “To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).”
Thus, absent a showing of a criticality of claimed dosage in claim 10 and in a dosage form that can be shown to yield the unexpected benefit, e.g., the active steps taught by Gill- whether or not they were recognized at the time in providing additional benefits, would have yielded a claimed mitigation in heart rate fluctuation while preventing and treating the claimed subject population.
Overall, a prima facie showing is established because the claimed agent at an overlapping dosage is taught to treat the claimed subject population. An additional reference (i.e., Schmouder) shows that a standard dose includes the narrowest dose claimed. The examiner applies Schmouder as strengthening the rejection in view of the prior art as a whole.
Unexpected results are not show because a critical concentration is only shown when ranges outside the claimed range do not have a claimed effect while those inside the claimed range do. No comparison or showing is made to dosages outside the claimed range. Further, such showing should not merely be extrapolatable as a lower dose would be expected to yield lower adverse events.
Unexpected results are also not shown because the claims include topical administration, which is taught by the prior art to limit adverse events and limit systemic exposure. It is not clear that this would not also mitigate a change in heart rate. No route of administration is claimed in the broadest claim.
Additionally, the claims do not prevent dose titration. Rather, as defined by the Specification and shown in dependent claims, they prevent a dose titration that exceeds 25% of an initial dose. It is not clear that some titration would not mitigate some level of AEs. Further, the required prevention or reduction of lymphopenia includes even a minor amelioration.
To show unexpected results, Applicant can provide statistically significant data that the dosage range claimed is required to achieve the unexpected result. Further, such showing should control for route of administration. Finally, the dosage and route limitations must still distinguish over the teachings of the closest prior art. If the API itself is responsible for the unexpected result, this cannot be shown compared to the closest prior art because the claimed API is taught. The examiner is willing to discuss this matter if Applicant is interested in an interview to clarify what showing can be made to obviate the rejections of record.
To show a critical range associated with less AEs, Applicant should provide a showing of a non-extrapolatable distinction of the claimed range. A reason for this is that a lower amount such as 0.5 mg to 12 mg would be expected to yield lower AEs than the broad range of up to 200 mg taught by the prior art.
For the reasons set forth above, the DP rejections are maintained.
Status of the Claims
Claims 1, 6-22, and 24-31 are pending and examined.
Claim Objection
Claim 1 refers to a narrow range within a broader range. The claims provide for a decrease of about 5 beats per minute or less, 4 beats per minute or less…The phrase “or less” means that 5 beats per minute or less encompasses each scenario. While the examiner does not find the metes and bounds unclear, the recitation of multiple ranges is superfluous and should be removed in the event the claims are in condition for allowance. See M.P.E.P. 2173.05.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 6-22, and 24-31 are rejected under 35 U.S.C. 103 as being unpatentable over Gill et al., (US2016/0038455)(“Gill”), in view of Gill et al., (WO2014063199 A1)(“Gill2”), in view of Gill et al., (US2018/0228778)(“Gill3”), and in view of Schmouder et al., (US2010/0160259).
Gill teaches a method of treating or preventing a condition associated with inappropriate S1P receptor modulator activity. See prior art claim 1. Pruritus is listed as a condition that falls within this category. See par. 36. Further, prior art claim 3 lists specific compounds and the claimed compound is included therein. See compound 2 listed. Treatment can include a concentration of 0.01 nM to 1 Molar. See par. 47. Combination therapy can include an antiviral, antibacterial, and others. See par. 49.
Gill2 teaches the claimed compound also as a S1P receptor modulator (prior art claim 8) for administration topically, orally, intravenously, and through other modes of administration. See prior art claim 10. It is also taught to treat and prevent pruritus. The claims compound is first example on page 22. In a lymphopenia assay, the levels of recorded lymphopenia were down approximately 70% and 17%. See Example 66.
Gill3 teaches the claimed compound as an S1P receptor modulator. See col. 7, last cmpd. It is claimed to treat pruritus. See prior art claim 23. It can be administered topically, orally, transdermally, parenterally, etc. It can be a powder, liquid, solid, and other forms. See prior art claim 27. It can be implanted and administered by injection or slow release device. See prior at claim 28. Coadministration with antivirals, anti-inflammatory agents is also contemplated. See prior art claim 29. The S1P modulator can be 0.001% to 3% of the composition, or up to 25%. See prior art claims 16 and 18, respectively. Targeted dosing is taught to be advantageous in some instances over systemic exposure. Also, slow release can limit systemic exposure. This can limit the side effects that may occur. See par. 53. Filler can include lactose monohydrate, lubricants include magnesium stearate, sodium starch glycolate (disintegrant), povidone (binder), maize starch (filler), and others. See par. 64. The dosage of API can be from 1 to 200 mg up to about three or more times daily. See par. 73.
Schmouder teaches dosage regimen for S1P receptor agonist. See Title. Schmouder teaches an initial dose for days includes a lower dose than the standard dose. See Abstract. The examiner notes that the Specification allows for “substantially the same” to refer to at least a difference of 25%. See par. 41. Treatment can be for various conditions, including inflammatory and autoimmune conditions. See par. 3. Some S1P modulators can reduce cardiac rhythm and induce a higher heart rate. See par. 5. Schmouder teaches a dosage regimen that can reduce or eliminate negative side effects, including a drop in heart rate. See par. 8. It can be favorable to those susceptible to or suffering from arrythmias, e.g., or those taking beta blockers or anti-arrhythmic treatment, or those that have undergone an interruption of treatment for greater than 4-14 days. See par. 10. The regimen can keep a heart rate decrease to less than 4 bpm, 3 bpm, or 2bpm, e.g. See par. 69. The initial dose can be up to 10 fold or less than 4 fold, or less than 2 fold, less than the standard dose. See par. 76. Dosages can be less than 1.25 mg and an example includes a dosage of 0.5 mg. See par.’s 162 and 163. Further, Schmouder explains, “S1P receptor modulators or agonists are typically sphingosine analogues, such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives.” See par. 14.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Thus, whether applied topically or otherwise, the amount required to optimize the concentration of a known result-effective variable taught for treating a claimed condition and through a known mechanism of action would require nothing more than routine experimentation.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods in view of Gill, Gill2, Gill3, and Schmouder. One would have been motivated to do so because the claimed S1P receptor modulator compound is taught by the cited prior art for treating and preventing pruritus, among other conditions. Further, a specific dosage regimen for S1P receptor agonists includes a method that can mitigate a change in heart rate, including for those taking beta blockers or anti-arrhythmic treatment. Even further, the dosage and routes of administration are also taught by the prior art. One manner to mitigate the side effects is to provide for local administration. Moreover, it would appear that, absent evidence to the contrary, administration of a same API at a same dosage and through a same route of administration would provide for a same and/or substantially similar effect. As such, there is a reasonable and predictable expectation of success in arriving at the claimed methods in view of the cited prior art.
As such, no claim is allowed.
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, 6-22, and 24-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 9,193,716, in view of Schmouder et al., (US2010/0160259), in view of Gill et al., (WO2014063199 A1) (“Gill2”), and in view of Gill et al., (US2018/0228778) (“Gill3”), as set forth above. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘716 patent are directed to administration of the claimed S1P receptor modulator with stabilizing agents, carriers and excipients. The administration can be, in light of the disclosure, to treat conditions including pruritus.
Claims 1, 6-22, and 24-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 8,592,399, in view of Schmouder et al., (US2010/0160259), in view of Gill et al., (WO2014063199 A1) (“Gill2”), and in view of Gill et al., (US2018/0228778) (“Gill3”), as set forth above. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘399 patent are directed to compounds, including the claimed S1P receptor modulator with stabilizing agents, carriers and excipients. The administration can be, in light of the disclosure, to treat conditions including pruritus.
As such, no claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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