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
The present Application, filed December 15, 2022, is a Continuation-In-Part of International Patent Application No. PCT/EP2022/051940, filed January 27, 2022. The present Application also claims priority to International Patent Application PCT/IB2021/000033, filed January 28, 2021, and to European Patent Application No. EP21199256, filed September 27, 2021.
Status of the Claims
In the amendment filed June 29, 2026, claims 155, 158-159, 161, and 164-177 are canceled and new claims 178-186 are added. Claims 153, 156-157, and 160 are amended. Claims 153-154, 156-157, 160, 162-163, and 178-186 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 29, 2026 is acknowledged. It is noted that the 30 pages of the Zheng reference that are cited are presumed to correspond to the first 30 pages of the book that were submitted. This consists largely of title pages, table of contents, foreword, preface, list of contributors, etc., and does not encompass a significant proportion of the substance of the book.
Previous Rejections and/or Objections
All objections to, and rejections of, canceled claims are mooted by their cancelation.
Claim Rejections - 35 USC § 103 – Modified in View of Amendment
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 153-154, 156-157, 160, 162-163, 178, and 181-186 are obvious over Kojima, Liu, and Legangneux:
Claims 153-154, 156-157, 160, 162-163, 178, and 181-186 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S Patent No. 8,318,811 to Kojima et al. (hereinafter, “Kojima”), in view of U.S. Patent No. 9,925,138 to Liu (hereinafter, “Liu”) further in view of U.S. Patent Application Publication No. 2017/0027907 to Legangneux et al. (hereinafter, “Legangneux”).
Applicant’s Remarks, filed June 29, 2026, deal substantially with the previous rejection of claim 153, and with the previous obviousness rejections, generally. In summary, Applicant argues that none of the cited references, individually, teaches all components of the composition of instant claim 153; and that in view of the unpredictability of the field, one would not have selected the recited components in the recited proportions with a reasonable expectation of success in producing a formulation having the high stability shown for the select test formulation of the specification.
This reasoning is found unpersuasive first and foremost because the claimed genus of formulations is not commensurate in scope with any showing of stability. Applicant notes that the instant claims are based on blend 17 from the instant specification, which tested relatively favorably for stability. However claim 153 recites ranges of component quantities that correspond to the following weight percentages:
Component
Minimum wt%
Maximum wt%
Mannitol
43.6
92.5
Microcrystalline cellulose
4.6
47.3
Sodium starch glycolate
0.7
12.9
Magnesium stearate
0.02
6.8
Colloidal silicon dioxide
0.08
3.5
mocravimod
0.7
5.3
-For each component, the minimum weight percentage is calculated by setting that component at its minimum amount and all other components at their maximum amount; and the maximum weight percentage is calculated by setting that component at its maximum amount and all others at their minimum amounts.
Claim 179 recites a more specific formulation, identical to Example 6 from the specification, which the specification describes as “derived from” blend 17, although the nature of this derivation is not immediately clear.
Component
Blend 17 (Table 4)
Example 6/Claim 179
Mannitol
45.5
68.23
Microcrystalline cellulose
45
25.19
Sodium starch glycolate
4
4
Magnesium stearate
1
1
Colloidal silicon dioxide
0.3
0.5
Hydroxypropylmethylcellulose
4
N/A
mocravimod
0.2
1.08
Table 5 if the instant specification shows stability data for blend 17 (which is not within the scope of instant claim 153 in all respects), indicating it is more stable than other formulations, although dissimilar blend 16 appears to be at least comparably stable. No data in the specification are shown for the formulation of Example 6/claim 179, nor is it disclosed how Example 6 was “derived from” blend 17, although Applicant’s arguments state that Example 6 is the current clinical formulation and shows desirable stability properties. In any event, the stability data of record do not support enhanced stability, or any particular property, for the genus of formulations of claim 153, particularly in view of Applicant’s assertion of the unpredictability of the art.
Addressing o Applicant’s specific assertions, Applicant first argues that obviousness of the present invention is subject to a “lead-modification” analysis, similar to the lead compound analysis involving novel compounds, citing Unigene Laboratories, Inc. v. Apotex, Inc., 655 F.3d 1352 (Fed. Cir. 2011) – pg. 7, last full paragraph, through paragraph spanning bottom of pg. 7 to top of pg. 8 of Applicant’s Remarks.
The previous and present obviousness rejects are not made under a pseudo-lead compound analysis. Unigene is understood to state that obviousness of a formulation can be formulated under a lead compound-type analysis, in circumstances when the subject composition was demonstrably derived as a workaround of a prior art composition, as was the case in Unigene where the subject invention was an intentional design-around of a prior art composition, Miacalcin. That fact pattern does not apply in the present case.
Applicant notes that Kojima does not expressly teach all excipient of the claimed invention in combination with mocravimod., noting for example that the composition of Kojima includes several components of instant claim 1 (e.g. the API mocravimod, mannitol, and magnesium stearate). Applicant further asserts that the secondary references fail to cure this alleged deficiency of Kojima, presumably because none of the secondary references teaches, by itself, all of the recited excipients in combination with mocravimod (pg. 7, last full paragraph, through paragraph spanning bottom of pg. 7 to top of pg. 8 of Applicant’s Remarks).
Further to this point, Applicant argues that In re Wertheim is not applicable because it involves the obviousness of a single claimed range over a single prior art range for a “known parameter,”, while the instant claims require the prior art first to motivate the selection and combination of multiple distinct excipients before any amount (quantity) optimization analysis becomes relevant (paragraph spanning the bottom of pg. 8 to the top of pg. 9 of Applicant’s Remarks). This argument is not persuasive because the combination of the recited excipients is separately and independently supported under the KSR “combination of known elements” rationale, as discussed above. The Wertheim overlapping-range analysis is applied only after that combination has already been rendered obvious, to address the specific quantities of each already-selected excipient — precisely the posture in which Wertheim and its progeny are properly applied. See MPEP § 2144.05.
Applicant further argues that the art of pharmaceutical formulation stability is unpredictable, citing Narang, and further citing the Examiner's own discussion of unpredictability in the withdrawn 35 U.S.C. § 112(a) rejection of former claim 161 in the non-final Office action, and that this unpredictability precludes a reasonable expectation of success in combining the recited excipients. This argument is not persuasive. Unpredictability in the art does not, by itself, preclude an obviousness determination; it speaks to how much can be inferred from an established combination with confidence, not on whether a person of ordinary skill would have had reason to try a combination of art-recognized elements each performing its known function. See MPEP § 2143.02. The unpredictability discussed in the withdrawn § 112(a) rejection of former claim 161 concerned the difficulty of predicting, without experimentation, whether a given formulation within the broad genus of claim 153 would satisfy a specific, numerically demanding, 24-month stability specification — not whether a person of ordinary skill would have had reason to combine conventional, art-recognized excipients, each performing its known pharmaceutical function, into a solid oral dosage form of a known API. A reasonable expectation of success does not require certainty or a guarantee that the resulting formulation will meet every conceivable performance specification; it requires only a reasonable expectation, based on what was known in the art, that the combination would work for its intended, conventional purpose. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Here, each recited excipient was already known, both generally and in Liu specifically, to be compatible with, and to perform its conventional function in, solid oral dosage forms of this class of S1P receptor agonist API, providing the required reasonable expectation of success.
Related to this, Applicant argues that the stability data of Examples 4-6 of the specification (Tables 4-7), and in particular the selection of “Blend 17” and the resulting formulation of Table 6, demonstrate unexpected results establishing the nonobviousness of the claimed formulation.
As noted above, however, these data do not support favorable stability of the genus of claim 153. It is debatable the extent to which they support stability of Example 6/claim 179, given the significant difference between blend 17 and Example 6. It is furthermore noted that blend 16 is quite different from blend 17 and exhibits reasonably favorable stability, drawing into question whether blend 17 is indeed particularly stable. This question is accentuated by the fact that stability data are presented for a relatively small number of combinations of excipients and concentrations.
For the aforementioned reasons, the rejection of claims 153-154, 156-157, 160, 162-163 are reiterated in substance, with slight modification in view of the amendments. For substantially the same reasons, new claims 178 and 181-186 are rejected.
Modified, but largely reiterated rejection:
Amended claim 153 recites a pharmaceutical composition comprising (i) an S1P receptor modulator of formula (II) (or one of two alternative S1P receptor modulators):
PNG
media_image1.png
130
390
media_image1.png
Greyscale
(ii) mannitol at a content from 48 to 88 mg/unit; (iii) microcrystalline cellulose at a content from 5 to 45 mg/unit; (iv) sodium starch glycolate at a content from 1 to 8 mg/unit; (v) magnesium stearate at a content from 0.025 to 4 mg/unit; and (vi) colloidal silicon dioxide at a content from 0.125 to 2 mg/unit. Claim 1 further recites that the composition is a solid dosage, having a dosage strength of the S1P receptor modulator of about 1 mg/unit or about 3 mg/unit. The compound of formula (II) is referred to hereinafter as mocravimod.
Kojima teaches a series of closely related compounds for the treatment of inflammatory bowel disease and having chemical formula 1 (Abstract)
PNG
media_image2.png
121
367
media_image2.png
Greyscale
Kojima teaches these compounds are sphingosine-1-phosphate receptor agonists (col. 1, lines 9-12). In a real example, Kojima teaches 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol and hydrochloride salts thereof (col. 6, lines 6-9 and 43-47). This compound, referred to as KRP-203 in Kojima, is mocravimod. Kojima further teaches a real example of a mocravimod capsule (Col. 9, lines 1-17), having 0.1 mg mocravimod, 247.5 mg mannitol, and 2.5 mg magnesium stearate. Kojima also teaches more generally that the disclosed compounds (e.g. mocravimod) are preferably administered in a single dose of 0.1 to 5 mg/patient, encompassing the recited mocravimod amounts per unit (dose). Kojima thus teaches a capsule (pharmaceutical composition) having an S1P receptor modulator of formula (II) present within a range that encompasses 1 or 3 mg, magnesium stearate, and mannitol, but does not expressly teach that the composition includes microcrystalline cellulose, sodium starch glycolate, or colloidal silicon dioxide, nor does it expressly teach the recited amounts of excipients. It would have been obvious to incorporate these components into the composition of Kojima, however, because these were well-known in the art as conventional excipients for solid pharmaceutical formulations of S1P receptor agonists. See, for example, Liu.
Liu teaches pharmaceutical dosage forms (pharmaceutical compositions) containing fingolimod (Abstract), which is a S1P receptor agonist (col. 2, lines 10-24):
PNG
media_image3.png
79
243
media_image3.png
Greyscale
Liu teaches the composition can include one or more sugar alcohols, such as mannitol (col. 10, lines 4-15); and may further include conventional pharmaceutically acceptable excipients such as lubricants, fillers, binders, disintegrants, and glidants (col. 10, lines 65 through col. 11, line 1). Liu teaches an exemplary suitable lubricant is magnesium stearate (col. 11, lines 8-10), an exemplary suitable filler is microcrystalline cellulose (col. 11, lines 19-21)an exemplary suitable disintegrant is sodium starch glycolate (col. 12, lines 17-20), and an exemplary suitable glidant is colloidal silicon dioxide (col. 12, lines 25-27). It would have been obvious to incorporate the conventional disintegrant; sodium starch glycolate, the conventional filler, microcrystalline cellulose; and the conventional glidant, colloidal silicon dioxide, as taught for the stable S1P receptor agonist pharmaceutical composition of Liu, into the mocravimod pharmaceutical composition of Kojima.
With respect to the specific quantities recited in claim 153, Liu teaches ~200 mg tablets (e.g. Examples 1, 2, 7, and 8) and teaches that the tablets can have 20-95% sugar alcohol (e.g. ~40-190 mg mannitol, col. 10, lines 45-48), 0.5 to 5 wt% lubricant (e.g. 1-10% magnesium stearate, col. 11, lines 14-18); (0-20% filler, Examples 4-6). With respect to disintegrants and glidants, Liu does not expressly state amount ranges, but states that the amount of these (and all) excipients present in the solid dosage forms will vary depending upon the specific and desired properties of the solid dosage form, and that ranges and amounts of these excipients are known and reported in the literature (col. 11, lines 3-7). It would have been obvious to utilize amounts of filler (e.g. microcrystalline cellulose) and glidant (e.g. colloidal silicon dioxide) in amounts within the recited ranges, because these amounts were known in the art as suitable for pharmaceutical compositions, see, for example, Legangneux.
Legangneux teaches formulations of the S1P receptor modulator, Siponimod (Abstract), that can include excipients such as a disintegrant and a glidant. Legangneux teaches the glidant can be present at 1-3 wt% (paragraph [0553]) and the disintegrant can be present 2-8 wt% (paragraph [0055]). In the capsule or tablet of Kojima and Liu, this would correspond to 2-6 mg of colloidal silicon dioxide and 4-16 mg of sodium starch glycolate. These amount ranges are not identical to the ranges recited in instant claim 153, but substantially overlap with them, and 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 (CCPA 1976), particularly where, as here, there is no showing of criticality of the recited ranges.
Claim 153 is accordingly rejected as obvious over Kojima, in view of Liu, further in view of Legangneux.
With respect to claim 154, Kojima teaches that the composition can have a pharmaceutically acceptable salt of mocravimod (Abstract), such as a hydrochloride salt (e.g. col. 6, lines 1-3). With respect to claim 156, as noted, the real example of Kojima is in the form of a capsule (col. 9, lines 1-17).
With respect to claim 157, neither Kojima nor Liu discloses any coating, matrix, or other release-modifying excipient or structure; Kojima’s real example is a simple powder blend filled into a capsule shell (col. 9, lines 1-17), and Liu’s tablets are conventional compressed tablets. Absent any disclosed mechanism for delaying, targeting, or extending release, the compositions of Kojima and Liu would be understood by a person of ordinary skill in the art to be immediate release dosage forms, that being the default behavior of an uncoated capsule or simple compressed tablet. It therefore would have been obvious that the composition of Kojima as modified by Liu and Legangneux, discussed above with respect to claim 153, is an immediate release dosage form. Because, as noted above, claim 157 fails to further limit the base claim from which it depends, claim 157 is obvious for the same reason as is claim 153. Furthermore, the dosage forms of Legangneux are expressly disclosed as immediate release dosage forms (e.g. claim 1).
With respect to claim 160, Liu teaches that in some embodiments, the fingolimod should be micronized and exhibit a mean particle size preferably less than 20 microns. While this is not identical to the less than 8 µm of instant claim 160, it substantially overlaps, and 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 (CCPA 1976).
With respect to claims 162-163, claim 162 recites a process of preparing the pharmaceutical composition of claim 153, wherein the process comprises adding and blending the components discussed above in a particular order. As discussed, Kojima, as modified by Liu, discloses a process of preparing a capsule, comprising adding and blending the components of S1P receptor modulator, microcrystalline cellulose, colloidal silicon dioxide, mannitol, sodium starch glycolate, and magnesium stearate, and then collecting (recovering) the blend, filling a capsule with it, and possessing (recovering) the filled capsule. Neither Kojima nor Liu discloses the precise sequence of adding and blending the components as recited in claim 162 (and by extension, claim 163), but selection of an order of mixing ingredients is prima facie obvious, particularly in the absence of any showing of new or unexpected results, or any particular benefit to the recited order. In re Gibson 39 F.2d 975 (CCPA 1930); see also MPEP 2144.04(IV)C. In the instant case, no evidence of unexpected results or any particular benefit to the recited order is shown, and so the order of addition and mixing of the formulation ingredients is prima facie obvious.
With respect to claim 178, the ranges recited are, while narrower than those of claim 153, within the conventional ranges shown by Kojima, Liu, and Legangneux, as discussed above with respect to claim 153. Moreover, as discussed above with respect to claim 153, the data of record do not support that formulae of claim 178 broadly have any particular stability property.
With respect to claim 181, Kojima teaches that the composition can be incorporated in capsules (col. 9, lines 1-17) and Liu teaches the composition can be incorporated in tablets (e.g. Abstract). With respect to claims 182 and 183, as discussed above with respect to claim 160, Liu teaches that the S1P receptor modulator should be micronized to a mean particle size (D50) of less than 20 microns, teaching that a smaller average particle size improves dissolution and bioavailability (specification, p. 18). While this is not identical to the less than or equal to 6 or 5 µm of instant claims 182-183, it substantially overlaps, and 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 (CCPA 1976). Furthermore, the overlapping instant range is obvious particularly where there is no showing of criticality of the recited range.
With respect to claims 184-186, D90 particle size is closely related to and would predictably decrease together with, the D50 (average) particle size of a micronized drug substance produced by a given milling or micronization process. As such, a person of ordinary skill in the art practicing Liu 's teaching of micronizing the S1P receptor modulator to a mean particle size (D50) below 20 microns would necessarily and predictably also reduce the D90 of the resulting powder. As such the D90 particle size ranges of claims 184-186 overlap with the D50 less than 20 um of Liu, and are obvious for the same reason as are claims 182-183, again, particularly given the lack of a showing of criticality of the recited particle size ranges.
Allowable Subject Matter
Claims 179-180 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
Prosecution Insights