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
Claims 1-23 do not have support from the disclosures of provisional applications 63/325,705 (filed 03/21/2022) or 63/318,041 (filed 03/09/2022). The disclosures of these provisional applications make no mention of Tolebrutinib: succinic acid or succinate salts. Therefore, have not been granted the priority date of these provisional applications.
Instant claims have been granted the benefit of provisional applications 63/391,342 (filing date 07/22/2022) and 63/413,644 (filing date 10/06/2022).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/04/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The use of the term Eudragit®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
While the Examiner has made every attempt to check the Specification for trade mark compliance, Applicant is required to carefully check the entire Specification for any and all issues regarding trade mark use compliance. – several other trademarks used in [0107]-[0109] for example.
Status of the Claims
Claims 1-23 are pending in this application.
Examiner Notes
Claimed embodiments drawn to the co-crystals of Tolebrutinib: succinic acid are free of the prior art, however, embodiments drawn to salts of Tolebrutinib succinate are obvious in view of the prior art of record.
Claim Objections
Claim 2 is objected because it reads: “…which is a co-crystal of Tolebrutinib and succinic acid or a salt of Tolebrutinib and succinic acid, or a co-crystal of Tolebrutinib and succinic acid.” [emphasis added] – please delete repeated limitations.
Claim 13 is objected because the claim should read: “…wherein the molar ratio of Tolebrutinib: succinic acid is about…” or something to that effect.
Claim 17 reads:
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The claim should be reworded for clarity. The Examiner suggests amending as follows: “A method of preparing crystalline polymorphs of Tolebrutinib, Tolebrutinib salts, Tolebrutinib cocrystals, or solid-state forms thereof from the crystalline Tolebrutinib: succinic acid according to claim 1” – or something to that effect. See also 112(b) section.
Claim 18 reads:
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The claim should be redrafted for clarity. The Examiner suggests amending as follows: “A method of preparing pharmaceutical compositions comprising Tolebrutinib, Tolebrutinib salts, Tolebrutinib cocrystals, and/or crystalline polymorphs thereof using the crystalline Tolebrutinib: succinic acid according to claim 1” – or something to that effect. See also 112(b) section.
Appropriate correction is required.
Claims 4-12 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.
Claim Interpretation
When the pharmaceutical composition of claim 19 comprises co-crystals Tolebrutinib: succinic acid, the “pharmaceutically acceptable excipients” will be interpreted as encompassing only solid state “pharmaceutically acceptable excipients” which do not destroy the polymorphic structure of the co-crystal, as required by the instant claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 15-19 and 21-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 is indefinite because it reads: The crystalline Tolebrutinib: succinic acid according to claim 1, which is polymorphically pure; wherein the Tolebrutinib: succinic acid contains: about 20% (w/w) or less …of any other forms of Tolibrutinib: succinic acid.” Examiner believes Applicant intended for the claim to read: “… which is polymorphically pure, or wherein the Tolebrutinib: succinic acid contains: about 20% (w/w) or less …” – Otherwise the claim contains conflicting limitations which are not separated by the conjunction “or” to list the contradicting limitations as alternatives. Claim will be interpreted as such for the purposes of applying art.
Claim 16 reads:
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It is unclear if applicant intended for the crystalline tolebrutinib: succinic acid to be enantiomerically pure and substantially free of (S) enantiomer and less than about 0-20% (w/w) (S) enantiomer; or if Applicant intended for the crystalline tolebrutinib: succinic acid to be enantiomerically pure or substantially free of (S) enantiomer or less than about 0-20% (w/w) (S) enantiomer.
Claims 17-18 are unclear because they relate to a process without setting forth any steps involved in the process – See MPEP 2173.05(q), which states: “Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness. For example, a claim which read: "[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon" was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986). See claim objections for help with rewording claims 17-18 for clarity. Include active steps required in for the claimed processes in accordance what the present disclosure.
Claim 19 reads: “…and at least one pharmaceutically acceptable excipient, optionally in the form of a solid dosage form, a capsule or a tablet.” It is unclear from the claim language if applicant intended for the “at least one pharmaceutically acceptable excipient” to be “optionally in the form of a solid dosage form, a capsule or a tablet” or if Applicant intended for the “pharmaceutical composition or formulation” itself to be “optionally in the form of a solid dosage form, a capsule or a tablet”. Examiner suggests amending the claim to read: “wherein the pharmaceutical composition or formulation is optionally in the form . . .” or something to that effect.
In claims 22-23, the term “particularly” is a relative term which renders the claim indefinite. The term “particularly” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 21-23 recites the limitation "or a pharmaceutical composition or formulation including the crystalline Tolebrutinib: succinic acid". There is insufficient antecedent basis for this limitation in the claims or in claim 1, from which the claims depend. Applicant may reference claim 19 as it pertains to the pharmaceutical composition or formulation, since claims are being referenced in the alternative – see MPEP 608.01(i), which states: “Any dependent claim which refers to more than one other claim ("multiple dependent claim") shall refer to such other claims in the alternative only.”
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 1-3, 13-16, and 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Goldstein et al. (WO 2016/196840 A1 – cited in IDS) (“Goldstein”); and Bastin et al. (Organic Process Research & Development 2000, 4, 427-435) (“Bastin”).
To the extent that these claims are drawn to salts of Tolebrutinib succinate, these rejections apply – see claim interpretation below, as read in light of the specification.
The specification [0074] states ‘crystalline Tolebrutinib: succinic acid may be a co-crystal of Tolebrutinib and succinic acid, or it may be a salt, i.e. Tolebrutinib succinate.’
Therefore, for the purposes of applying art, crystalline Tolebrutinib: succinic acid (as claimed in claim 1 will be interpreted as encompassing both crystal forms of Tolebruinib: succinic acid and salts of Tolebrutinib succinate. See MPEP 2173.05(a)(I), which states: “During patent examination, the pending claims must be given the broadest reasonable interpretation consistent with the specification. In re Morris, 127 F.3d 1048, 1054, 44 USPQ2d 1023, 1027 (Fed. Cir. 1997); In re Prater, 415 F.2d 1393, 162 USPQ 541 (CCPA 1969). See also MPEP § 2111 - § 2111.01. When the specification states the meaning that a term in the claim is intended to have, the claim is examined using that meaning, in order to achieve a complete exploration of the applicant’s invention and its relation to the prior art. In re Zletz, 893 F.2d 319, 13 USPQ2d 1320 (Fed. Cir. 1989).”
Regarding claims 1-2 and 21-22, Goldstein discloses their compounds of Formula I (page 2), and specifically discloses Tolebrutibib, which they call Example 3 (page 83, top; Goldstein’s claims 1 and 44 – top page 116) and salts thereof. Goldstein teaches ‘pharmaceutically acceptable salts’ include salts resulting from the addition of acids, such as succinic acid (page 17, lines 7-8) – thus reading on Tolebrutinib succinate salts – see claim interpretation above.
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Bastin teaches selection of an appropriate salt form for a new chemical entity provides the pharmaceutical chemist and formulation scientist with the opportunity to modify the characteristics of the potential drug substance and to permit the development of dosage forms with good bioavailability, stability, manufacturability, and patient compliance (abstract). Bastin teaches succinic acid as a common class of salts in pharmaceuticals (Table 1, page 428).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to prepare succinate salts of Tolebrutinib, as taught by Goldstein and Bastin. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Goldstein discloses Tolebrutinib (Example 3 in their disclosure) which has a free base amino group and teaches pharmaceutically acceptable salts include salts of their compounds include succinate salts; further because Bastin teaches selection of an appropriate salt form for a new chemical entity provides the pharmaceutical chemist and formulation scientist with the opportunity to modify the characteristics of the potential drug substance and to permit the development of dosage forms with good bioavailability, stability, manufacturability, and patient compliance and further discloses succinate salts as common in pharmaceuticals.
Therefore, regarding claims 1-2 and 21-22, to the extent that the claims are drawn to Tolebrutinib and succinic acid salts, the claims are obvious.
Further regarding claims 21-22, Goldstein discloses their Tolebrutinib succinate salts as medicaments for the treatment of MS (Goldstein’s claim 48, for example). Furthermore, Applicant is advised, a recitation of the intended use of the claimed invention, such as the use of the crystalline Tolebrutinib: succinic acid of claim 1 as a medicament in the instant application, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02.
Regarding claims 3 and 13, Goldstein discloses Tolebrutinib succinate salts, and teaches salts are formed when an acidic proton present in the parent compound coordinates with an organic base (page 17, lines 16-18). Therefore, one of ordinary skill would have had a reasonable expectation of success in determining the ratio of Tolebrutinib to succinic acid to be between 2: 1 and 1:1, since succinic acid has two acidic centers, each of which would be expected to coordinate with a different Tolebrutinib to arrive at the claimed ranges.
Applicant is advised that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that where 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. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II. Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claims 14-16, Goldstein teaches their compounds may be isolated in optically active or racemic forms (page 17, 2nd to last para.) – thus reading on claim 14 (where the salt is isolated – see also end of page 33 where Goldstein states compounds may be isolated and purified by crystallization or filtration, which are common methods of purification of salts), claim 15 (where the salt may contain 0% of other forms), and claim 16 (where the form may be enantiomerically pure or a mixture of enantiomers).
Further regarding claim 16, with respect to stereoisomerism, it is noted that in Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293 (Fed. Cir. 2007), the court also relied on the settled principle that in chemical cases, structural similarity can provide the necessary reason to modify prior art teachings. The Federal Circuit also addressed the kind of teaching that would be sufficient in the absence of an explicitly stated prior art-based motivation, explaining that an expectation of similar properties in light of the prior art can be sufficient, even without an explicit teaching that the compound will have a particular utility. The Federal Circuit cautioned that requiring such a clearly stated motivation in the prior art to isolate 5(S) ramipril ran counter to the Supreme Court' s decision in KSR. The court stated: [r]equiring an explicit teaching to purify the 5(S)-stereoisomer from a mixture in which it is the active ingredient is precisely the sort of rigid application of the TSM test that was criticized in KSR. Id. at 1301 (See MPEP 2143).
Regarding claims 18-20, Goldstein discloses pharmaceutical compositions and formulations comprising their compounds or salts thereof and excipients (page 46, para. 2).
Further regarding the methods of claims 18 and 20, Goldstein discloses Tolebrutinib (Example 3), and discloses salts thereof may be prepared with succinic acid. Goldstein also discloses pharmaceutical compositions comprising their compounds or salts thereof. Therefore, it follows that Goldstein was in possession of a method for preparing pharmaceutical compositions comprising Tolebrutinib succinate salts. Furthermore, combining a known compound with a pharmaceutical excipient to obtain a pharmaceutical composition is a routine step, which one of ordinary skill in the art would have had a reasonable expectation of success in performing.
Regarding claim 23, Goldstein claims a method of treating diseases, such as multiple sclerosis (MS), comprising administration of their compounds, salts thereof, or pharmaceutical compositions thereof (Goldstein’s claim 48). Therefore, the instant method of treatment is obvious in view of the cited art.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Goldstein et al. (WO 2016/196840 A1 – cited in IDS) (“Goldstein”); and Bastin et al. (Organic Process Research & Development 2000, 4, 427-435) (“Bastin”); as applied to claims 1-3, 13-16, and 18-23; in view of Mithu et al. (Cryst. Growth Des., 2021, 21, 1358−1374) (“Mithu”).
The teachings of Goldstein and Bastin are disclosed above and incorporated herein.
While Goldstein and Bastin do not specifically teach a method of preparing other forms of Tolebrutinib with their Tolebrutinib succinate salts, the teachings of Mithu are relied upon for these disclosures.
Mithu teaches pharmaceutical salt formation is the most preferred and effective method to enhance the physicochemical properties of an active pharmaceutical ingredient (API) (abstract). Mithu teaches salt formation depends on the basicity of the API and the safety of the counterion (page 1360, col. 2, last 2 para.) – and discloses hydrochloride salts have been commonly used to develop salts of weakly basic drug substances, however, the use of HCl is restricted due to the high acidity of formulations, risk of corrosion, and poor stability of acid labile and hygroscopic drugs. Mithu lists counterions which may be used for salt formation, among which is succinic acid, specifically stating that succinates etc. have gained increasing acceptability (Table 1, col. 1, page 1361).
Therefore, regarding claim 17, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to prepare Tolebrutinib or salts thereof (other than succinates) from Goldstein and Bastin’s Tolebrutinib succinate salts, in view of Mithu. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Goldstein and Bastin disclose Tolebrutinib succinate; and Mithu teaches pharmaceutical salt formation is the most preferred and effective method to enhance the physicochemical properties of an API, and teaches operational principles of commonly employed salt manufacturing (see pages 1365-end). Furthermore, because Mithu teaches HCl salts have been used to develop other salts, however, Mithu discourages the use of HCl salts due to high acidity of formulations, risk of corrosion, and potentially poor stability of acid labile and hygroscopic drugs. Thus, one of ordinary skill would have been motivated to, with a reasonable expectation of success, use Goldstein and Bastin’s succinate salt to make other salts. Applicant is advised, a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2143(E) KSR,550 U.S. at 421, 82 USPQ2d at 1397.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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