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 August 7, 2026, in response to the Office Action of May 8, 2026, are acknowledged.
Response to Arguments
Applicant argues that the salt and salt formation claimed Is not obvious.
The examiner refers to Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) as well as the pKa rule set forth by He and the teachings of Gupta to refute these arguments. Allegations of unexpected results have been considered and are addressed below.
The examiner notes that even though it may be true that properties of the specific salt form may not be predicted with absolute certainty, finding the optimal salt form among a finite number of known options represents routine optimization rather than true invention – especially when that particular salt was already used in other FDA-approved drugs. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007). In this particular instance, the tosylate salt form is known form among a finite listed.
Similarly, as stated by the Pfizer Court,
However, irrefutable evidence shows that a skilled chemist at the time would simply make known pharmaceutically-acceptable salts of whatever active ingredient with which he or she was working at the time.
The genus of approved salts is small and the salts taught by the prior art are approximately 14 salts. He teaches a tosylate salt is one of a few known counteranion forms and teaches a method that includes evaluating the p-toluenesulfonic acid salt as one to screen at the initial stage. Selection of a proper counterion is based on the functional groups in the molecule and “when the pKa difference between and acid and base is greater than 2 or 3, salt formation is expected.” See He et al., p3, 2nd par.
It would appear that tosylate has a pKa of about -2.8 and this when forming a salt with a basic nitrogen of opevesostat, the pKa is well above 3. As described above, this means that the salt form is expected. This basis described by the prior art provides more than a reasonable expectation of success.
With respect to Applicant’s allegations of unexpected results, Applicant argues that the melting point is 255°C for the tosylate salt form. The Table shows salts with higher, lower, and the same melting point. Further, 6 of the 13 salts have a melting point at about 200°C or above. Applicant argues that the melting point would not have been predicted. Similarly, Applicant argues that the percent change in degradation after 5 years ius 0.07 for the tosylate salt form. The Table shows salts with higher, lower, and similar degradation percentages. Further, 9 of the 13 salts have a percent degradation of less than 1.0 after 5 years.
As such, even if having a 255 degree melting point were of practical significance, it does not appear unexpectedly and statistically superior to other salt forms. Moreover, even if have a salt form with a degradation rate that is less than 1% better than numerous other salts forms were advantageous, it is also not clear that this constitutes an advantage of statistical significance.
Here, the prior art teaches crystalline forms of the claimed compound. The formation of a salt of a limited genus as explained by the Pfizer Court and independently as described by the pKa rule each appear to concludes on distinct bases that a tosylate form is expected. As such, a prima facie showing is established and unexpected results have not been shown for the record.
The DP over 12,030,871, is maintained because the claims are directed to a method that requires the claimed compound and pharmaceutically acceptable salts thereof. A co-applicant of that patent is an inventor of the primary reference below wherein the claimed agent and salts thereof are taught in crystalline form. As pointed out above, the use of a tosylate salt form is predictable and among a finite list of acceptable pharmaceutical salts. As such, this rejection is maintained over claims 2 and 21-24.
The DP over 11,098,032, is maintained because the claims are directed to a claimed compound and pharmaceutically acceptable salts thereof. A co-applicant of that patent is an inventor of the primary reference below wherein the claimed agent and salts thereof are taught in crystalline form. As pointed out above, the use of a tosylate salt form is predictable and among a finite list of acceptable pharmaceutical salts. As such, this rejection is maintained over claims 2 and 21-24.
The DP over 10,717,726, is maintained because the claims are directed to a claimed compound and pharmaceutically acceptable salts thereof. A co-applicant of that patent is an inventor of the primary reference below wherein the claimed agent and salts thereof are taught in crystalline form. As pointed out above, the use of a tosylate salt form is predictable and among a finite list of acceptable pharmaceutical salts. As such, this rejection is maintained over claims 2 and 21-24.
With regard to the provisional DP Rejection over 18/674,603, Applicant claims the claimed compound and any pharmaceutically acceptable salt in claims 59-66. The secondary references make clear that a tosylate salt is among those limited salt forms. Even being a “rare” salt form is not a disqualifier. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007).
As such, rejections are set forth below.
Status of the Claims
Claims 2, 5-7, and 21-26 are pending. Claims 25 and 26 are withdrawn. Claims 2, 5-7, and 21-24 are examined.
Allowable Subject Matter
Claims 5-7 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. The specific polymorphic forms of p-toluenesulfonic acid salt is free of the art and non-obvious in light thereof.
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 2 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Din Belle et al., (WO2018/115591) (cited in ISR), in view of Gupta et al., “Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations,” Molecules 2018, 23, 1719, and in view of He et al., “The Selection of a Pharmaceutical Salt- The Effect of the Acidity of the Counter ion on Its Solubility and Potential Biopharmaceutical Performance,” Journal of Pharmaceutical Sciences 107 (2018) 419-425.
Din Belle teaches compound 185 and teaches salt forms of the same. See prior art claim 28, e.g. Pharmaceutical salts are also taught, which are useful for CYP11A1 inhibitors. Salts are well known in the field and can be in the form of chlorides, bromides, sulfates, nitrates, sulfates, sulfonates, and others. Crystallization is also taught as a conventional method for isomer separation and purification, among others. Excipients can be used in the form of a tablet, granules, capsule, suspensions, and solutions, e.g.
Din Belle does not explicitly teach p-toluenesulfonic acid salt form.
Gupta teaches currently available salts in the form of a counter anion or cation. In this case, an anion would form a salt. Of the known and available anions, bromide, chloride, and tosylate are among those known. See Table 1. Salt formation provides benefits of increasing solubility and dissolution rate of a drug. The most common counterions used to form salts are hydrochloride, hydrobromide, mesylate, acetate, and fumarate. See p5, last par.
Similarly, He teaches a roadmap for selecting a pharmaceutical salt form during development. The overall procedure entailed an initial screening method that screened candidate salt forms including the following: “hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, lactic acid, citric acid, L-(þ)-tartaric acid, L-malic acid, succinic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and glutamic acid.” See p420, 3rd par. New salts were identified of the particular drugs for crystalline salt hits and they included tosylate salts. See p421, 5th par. While the examiner acknowledges that for each particular API, different salts will yield different advantages and disadvantages. However, a tosylate salt is one of a few known counteranion forms and He teaches a method that includes evaluating the p-toluenesulfonic acid salt as one to screen at the initial stage. In view of He, a POSA would have considered and presumable arrived at an optimized salt form of claimed compound.
It would have been prima facie obvious for a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed products in view of Din Belle, Gupta, and He. One would be motivated to do so because the claimed API is known to be used in numerous and non-limiting salt forms and multiple reasons for crystallizing the same compound are known to include isomer selection and purification. Further, claimed salt forms are known to be commonly employed as counteranions and improve the solubility of pharmaceutical active agents. Tosylate and other claimed salt forms are known for this. Even further, He teaches a method of salt form selection that entails starting with a limited number of salt forms and deciding based on various factors (i.e., optimization) to yield the most advantageous salt form for any particular API. Among the limited list of salt forms used in an initial salt selection phase is the p-toluenesulfonic acid salt. This is used by He in an initial salt screening stage of the process. The tosylate salt form is also described by Gupta. As such, a POSA would have arrived at a crystalline tablet formulation of claimed API as taught by Din Belle and would have been able to optimize to the claimed salt polymorphic form in view of Gupta and He.
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.
Non-provisional:
Claims 2 and 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,030,871, in view of Din Belle et al., (WO2018/115591), in view of Gupta et al., “Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations,” Molecules 2018, 23, 1719, and in view of He et al., “The Selection of a Pharmaceutical Salt- The Effect of the Acidity of the Counter ion on Its Solubility and Potential Biopharmaceutical Performance,” Journal of Pharmaceutical Sciences 107 (2018) 419-425.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘871 patent include the claimed compound and pharmaceutically acceptable salts thereof. Although the claims at issue are not identical, they are not patentably distinct from each other because the ’871 patent is directed to methods and compositions comprising the claimed API or a salt thereof. The Specification supports the use of any salt and in view of Gupta and He, a POSA would understand that a tosylate salt is one of a few counteranion salt forms and He teaches a method that screens for appropriate salt forms and starts with p-toluenesulfonic acid as one of only a few to screen. Crystallization and tablet formulations are taught, as noted above. As such, there is a reasonable and predictable expectation of success in arriving at the claimed salt form of compound described in the ‘871 patent in view of Gupta and He.
Claims 2 and 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,098,032, in view of Din Belle et al., (WO2018/115591), in view of Gupta et al., “Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations,” Molecules 2018, 23, 1719, and in view of He et al., “The Selection of a Pharmaceutical Salt- The Effect of the Acidity of the Counter ion on Its Solubility and Potential Biopharmaceutical Performance,” Journal of Pharmaceutical Sciences 107 (2018) 419-425.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘032 patent include the claimed compound and pharmaceutically acceptable salts thereof. Although the claims at issue are not identical, they are not patentably distinct from each other because the ’032 patent is directed to methods and compositions comprising the claimed API or a salt thereof. The Specification supports the use of any salt and in view of Gupta and He, a POSA would understand that a tosylate salt is one of a few counteranion salt forms and He teaches a method that screens for appropriate salt forms and starts with p-toluenesulfonic acid as one of only a few to screen. Crystallization and tablet formulations are taught, as noted above. As such, there is a reasonable and predictable expectation of success in arriving at the claimed salt form of compound described in the ‘032 patent in view of Gupta and He.
Claims 2 and 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 10,717,726, in view of Din Belle et al., (WO2018/115591), in view of Gupta et al., “Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations,” Molecules 2018, 23, 1719, and in view of He et al., “The Selection of a Pharmaceutical Salt- The Effect of the Acidity of the Counter ion on Its Solubility and Potential Biopharmaceutical Performance,” Journal of Pharmaceutical Sciences 107 (2018) 419-425.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘726 patent include the claimed compound and pharmaceutically acceptable salts thereof. Although the claims at issue are not identical, they are not patentably distinct from each other because the ’726 patent is directed to methods and compositions comprising the claimed API or a salt thereof. The Specification supports the use of any salt and in view of Gupta and He, a POSA would understand that a tosylate salt is one of a few counteranion salt forms and He teaches a method that screens for appropriate salt forms and starts with p-toluenesulfonic acid as one of only a few to screen. Crystallization and tablet formulations are taught, as noted above. As such, there is a reasonable and predictable expectation of success in arriving at the claimed salt form of compound described in the ‘726 patent in view of Gupta and He.
Provisional:
Claims 2 and 21-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 59-66 of copending Application No. 18/674,603, in view of Din Belle et al., (WO2018/115591), in view of Gupta et al., “Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations,” Molecules 2018, 23, 1719, and in view of He et al., “The Selection of a Pharmaceutical Salt- The Effect of the Acidity of the Counter ion on Its Solubility and Potential Biopharmaceutical Performance,” Journal of Pharmaceutical Sciences 107 (2018) 419-425.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ’603 application is directed to methods and compositions comprising the claimed API or a salt thereof. The Specification supports the use of any salt and in view of Gupta and He, a POSA would understand that a tosylate salt is one of a few counteranion salt forms and He teaches a method that screens for appropriate salt forms and starts with p-toluenesulfonic acid as one of only a few to screen. Crystallization and tablet formulations are taught, as noted above. As such, there is a reasonable and predictable expectation of success in arriving at the claimed salt form of compound described in the ’603 application in view of Gupta and He.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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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