DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Priority
The present Application, filed December 12, 2022, claims the benefit of U.S. Provisional Patent Application Nos. 63/422,542 and 63/288,777, November 4, 2022 and December 13, 2021, respectively.
Status of the Claims
In the amendment filed January 5, 2026, claims 21-24 and 26 are canceled; and claims 1, 7, 18, and 41 are amended. Claims 2-3, 16, 19-20, and 27-40 were previously canceled. Claims 1, 4-15, 17-18, 25, and 41 are currently pending.
Previous Rejections and/or Objections
Any objections and/or rejections raised in the previous Office Action but not reiterated below are considered to have been withdrawn.
Claim Rejections - 35 USC § 103 – Modified in View of Amendment; Maintained in Substance
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, 4-10, 15, 17-18, 25, and 41 are obvious over Metcalf:
Claims 1, 4-10, 15, 17-18, 25, and 41 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S. Patent No. 10,584,124 to Metcalf et al. (hereinafter, “Metcalf”).
Response to Applicant’s amendment and arguments:
In Applicant’s Remarks of January 5, 2026, regarding claim 1, Applicant disagrees with the previous rejections, on the basis that the primary reference, Metcalf (and the other references, too) does not teach the newly added features of amended claims 1. In particular, Applicant asserts that Metcalf fails to teach that, in step, b., after addition of water, the slurry is cooled to 0 °C, or that, after filtration of the recrystallized selpercatinib, the crystal is washed with water until less than 0.5 wt% DMSO remains. These arguments have been fully considered, but are not found persuasive.
As noted in the modified rejection below, Metcalf teaches cooling the slurry to 25 °C after addition of water, not to 0 °C as claimed. However, differences in parameters like temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such temperature is critical. In the present case, there is no showing of criticality of the claimed wash temperature relative to the prior art wash temperature. With respect to the limitation that the recrystallized selpercatinib is washed with water until residual DMSO is 0.5 wt% or less, Metcalf teaches that the recrystallized cake was washed three times with water (col. 216, lines 59-60). Metcalf does not specify washing until a given remaining DMSO percentage is achieved, but similar to crystallization temperature, the number of washes by itself does not confer patentability if not shown to be critical.
Applicant further asserts that Metcalf does not teach the recrystallized product contains no more than 10 wt% of Form B, at least because Form B was not known. However, where the procedure of the prior art is the same as the presently claimed procedure, it would produce the same material. Discovering a new property of a known process does not make the process itself new. Finally, Applicant notes that claim 1 requires the recrystallized material to be washed with a solvent selected from heptane and/or MTBE, and asserts that this excludes methanol. This latter assertion is incorrect, as claim instant claim 1 does not exclude washing with methanol. In fact, Metcalf teaches washing with the does teach washing with water 3×, with methanol 2× and then with MTBE 2×. This constitutes washing with water and subsequently washing with MTBE, and the intermediate washing with methanol is not excluded by instant claim 1. It is noted that claim 1 was amended to state that the further washing is with a solvent selected from heptane and/or MTBE rather than comprising heptane and/or MTBE, but this still does not exclude a methanol wash, it merely requires a wash in which the solvent is only heptane or only MTBE but as long as that wash is present, others may be present too.
With respect to claim 18, Applicant again asserts that Metcalf fails to teach a limit to the amount of Form B, because Form B was not known. As above, this by itself does not confer nonobviousness; discovery of a new property in a known method (e.g. maintaining a low percentage of a previously unknown polymorph) does not make the method new. Similarly, Applicant’s assertion that reciting a heptane and/or MTBE wash excludes a methanol wash is incorrect. The recitation merely requires a heptane and/or MTBE wash, it does not exclude any other wash.
Applicant then asserts that it would not be obvious to replace the DMSO/water solvent/antisolvent system of Metcalf with the dichloromethane/heptane of claim 18. However, as noted in the rejection, Metcalf expressly teaches that polymorph Form 1 (Form A) can be prepared by recrystallizing a composition comprising the compound of Formula II to generate polymorph Form 1, where the recrystallizing solvent is selected from the group consisting of (i) a mixture of DMSO and water and (ii) a mixture of dichloromethane and heptane (col 30, lines 58-63). Thus, contrary to Applicant’s assertion, the Office describes exactly why one would be motivated to make this substitution: because Metcalf itself directly teaches the substitution as an acceptable, workable substitution.
Applicant asserts that the wherein clauses, found in the previous rejection to be mere intended results devoid of patentable weight, should be given patentable weight. Applicant’s rationale appears to be that they should be given patentable weight because they are the purpose of the method (“[t]he washing and drying methods described in the specification are directed to minimizing the formation of Form B…[t]hus, the Office’s position that the “wherein” clauses carry no weight cannot be agreed to”). This argument has been fully considered, but is not found persuasive. Applicant’s position is seemingly that because the intended result is intended, it must be given patentable weight. However, as described in the rejection, it is established that intended results on their own, when they do not require any change in the manner in which a claimed method is performed, do not carry patentable weight. In the present case, the method is described by its positively recited steps and, for the reasons described, those steps are described by Metcalf, with only minor variations of crystallization temperature (now recited at 0 °C vs. the 25 °C of Metcalf), and amount of water washing (to a given low DMSO residual vs. the 3× wash of Metcalf). As discussed above, these minor differences are not sufficient to confer patentability, in the absence of any evidence that they are critical to obtaining the desired result of quantified low Form B percentage. The mere assertion of low Form B percentage (less than 10%) by itself does not change this.
Applicant’s arguments with respect to the Metcalf/Beckman combination rely on the arguments above, and therefore require no separate response.
For the reasons addressed above, the rejections, modified in view of the amendments, are maintained.
Modified but Substantially Reiterated rejection:
Amended claim 1 recites a method for converting selpercatinib to selpercatinib Form A. The instant specification states that selpercatinib has a structure shown by the following line drawing (paragraph [0001]):
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and that the claimed “Form A” is a crystalline polymorphic form of this compound (paragraph [0003]). Claim 1 further recites that the method for converting selpercatinib to selpercatinib Form A includes steps of:
(a) dissolving selpercatinib in a solvent comprising DMSO and thereby forming a selpercatinib DMSO solution wherein about 1 gram of selpercatinib is dissolved in about 10-15 mL of DMSO;
(b) adding water to the selpercatinib DMSO solution to form a slurry, wherein after the addition of water, the solution is cooled to 0 °C; and
(c) isolating the crystallized selpercatinib Form A from the slurry, wherein the Form A has XRPD peaks at about 4.9, 9.7, and 15.5° 2θ, and wherein the Form A contains less than 10 wt% of selpercatinib Form B;
wherein step a comprises heating the DMSO and selpercatinib to a temperature of about 50 to 70 °C; and wherein the method comprises washing the isolated selpercatinib Form A from step c with water such that the residual amount of DMSO is 0.5 wt% or less, and further washing with a solvent selected from heptane and/or MTBE, and drying the selpercatinib Form A at a temperature of 40°C to 60°C.
Regarding the first two “wherein” clauses of step (c) (wherein the product has the recited XRPD peaks; and wherein the product contains less than a given amount of undesired forms), these are intended results that cannot be given patentable weight in this instance.
“A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Minton v. Nat'l Ass'n. of Sec. Dealers, 336 F.3d 1373, 1381 (Fed. Cir. 2003 – emphasis added to quotation). See also MPEP § 2111.04(I), which makes clear that this rule of claim construction is not limited to clauses marked off by the term “whereby,” but is applicable to functionally equivalent clauses having terms such as “wherein” or other functionally equivalent terms. As such, any prior art methods having method steps indistinguishable from those of instant claim 1 will be understood to produce the same product, with the same XRPD peaks and the same purity. Thus, for examination against the prior art, step (c) is effectively isolating the crystallized selpercatinib Form A from the slurry.
Metcalf teaches polymorphic Form 1 of a composition of Formula II:
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(col. 2, lines 16-25 and 58-62). The compound of Formula II of Metcalf is referred to hereinafter as selpercatinib. Metcalf teaches that polymorph Form 1 of selpercatinib can be formed by recrystallizing selpercatinib in a recrystallizing solvent consisting of a mixture of DMSO and water col. 30, lines 58-63). Metcalf specifically teaches that recrystallization of selpercatinib is performed by first charging a flask with selpercatinib and DMSO and heating until all solid is in solution (dissolving selpercatinib in a solvent comprising DMSO and thereby forming a selpercatinib DMSO solution; col. 216, lines 48-52). Metcalf further teaches that after the solution is cooled and polish filtered, water is added in two steps, first forming a seed bed and then a slurry (adding water to the selpercatinib DMSO solution to form a slurry; col 216, lines 52-59). Metcalf further teaches cooling the slurry to 25 °C after water addition, and subsequent filtration of the slurry to form a cake (isolating the crystallized selpercatinib Form A from the slurry). While Metcalf teaches cooling to 25 °C rather than to 0 °C after water addition, such a difference in temperature does not confer patentability unless such difference is shown to be 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, (CCPA 1955).
With respect to the limitation that step (a) comprises heating the DMSO and selpercatinib to a temperature of about 50 to 70 °C, Metcalf teaches heating the selpercatinib/DMSO mixture to 50 °C to ensure all solids are in solution (col. 216, lines 48-52; heating the DMSO and selpercatinib to a temperature of about 50 to 70 °C).
With respect to the step of washing the isolated selpercatinib Form A from step c with water until residual DMSO is 0.5 wt% or less, Metcalf teaches washing the isolated selpercatinib with water 3x (col. 216, lines 59-60). Metcalf does not specify washing until a given remaining DMSO percentage is achieved, but similar to crystallization temperature, the number of washes by itself does not confer patentability if not shown to be critical.
With respect to the steps of washing the isolated selpercatinib Form A from step c with a solvent comprising heptane and/or MTBE, and drying the selpercatinib Form A at a temperature of 40°C to 60°C, it is noted that Metcalf expressly teaches, in a working example, washing recrystallized compound of Formula II (selpercatinib) with MTBE (col. 216, lines 59-61), or with heptane (col. 216, lines 44-46). Metcalf further teaches that in some embodiments, the disclosed method of forming selpercatinib Form 1 (i.e. instant Form A) includes, after recrystallization, drying the residual solid (crystallized Form A) at a temperature of between about 30 °C and about 50 °C (overlapping the 40 to 60 °C of claim 1, col. 30, lines 30-34). While this specific teaching of drying in Metcalf is in the context of a slightly different Form 1 production process (slurrying and collecting the selpercatinib, rather than completely dissolving the selpercatinib and crystallizing it via subsequent addition of antisolvent), it would have been obvious to utilize this drying condition in any selpercatinib crystal drying regimen of Metcalf.
With respect to the limitation that in step (a), 1 gram of selpercatinib is dissolved in 10-15 mL of DMSO, strictly construed, this appears to recite an absolute amount of material, rather than merely a concentration; i.e. the method is performed with only 1 g of selpercatinib. Metcalf does not teach this absolute amount of material, and there does not appear to be any significance to the absolute amount of material utilized. This element may be intended to be directed toward a ratio of solute to solvent, rather than to absolute amounts. In any event, Metcalf teaches a ratio of selpercatinib to DMSO (10 mg of selpercatinib initially dissolved in 110 mL of DMSO) that is within the concentration range corresponding to the amounts recited in amended claim 1. Given this, the absolute amounts of selpercatinib and DMSO in step (a) are, at minimum, obvious over Metcalf.
Metcalf thus teaches the method steps of instant claim 1, other than the absolute amounts of selpercatinib and solvent used in step (a), and with a slight difference in the temperature to which the slurry is cooled and a slightly different way in which the amount of water washing of the filtered cake is described. As discussed, Metcalf at minimum renders these amounts obvious, and the minor differences of temperature and cake washing description are obvious variations unless shown to be critical to a desired result. The method of amended claim 1 is therefore obvious over Metcalf.
With respect to claim 4, Metcalf teaches that after initial heating of the selpercatinib DMSO solution, 5 mL of water is added and the mixture is stirred for 35 min to form a seed bed mixture, then 25 mL of water is added and the mixture is aged for an additional hour (adding a first batch of water and a second batch of water; col. 216, lines 52-59). With respect to claim 5, Metcalf teaches in an example addition of a first 5 mL batch of water (5 mL) to a selpercatinib DMSO solution of about 120 mL (a ratio of DMSO to water of about 96:4 by volume; col. 216, lines 51-55).
With respect to claim 6, Metcalf teaches cooling to 25 °C before addition of the first batch of water and then setting the temperature to 45 °C before adding the second batch (col. 216, lines 52-55). While the temperature taught by Metcalf is not identical to that recited in claim 6, 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 (Fed. Cir. 1985). See also MPEP 2144.03(I).
With respect to claim 7, Metcalf teaches in an example, addition of a second portion of water of 25 mL so that 30 mL of water total have been added to about 120 mL of selpercatinib DMSO solution (a ratio of DMSO to water of about 80:20 by volume; col. 216, lines 50-57).
With respect to claim 8, Metcalf teaches cooling the DMSO:water to 25 °C. With respect to claims 9 and 10, Metcalf teaches that the first water addition (5 mL in the real example) is at about 0.5 mL per gram of selpercatinib in the mixture. While these teachings of temperature (claim 8) and concentrations (claims 9-10) in the teachings of Metcalf are not identical to those claimed, the recited values are similar to and obvious over those taught in the example of Metcalf as a matter of routine optimization. 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).
With respect to claim 15, Metcalf teaches isolating the recrystallized selpercatinib via filtration (col. 216, line 59), but does not explicitly state that a vacuum was used to pull solvent through the filter. However, Metcalf elsewhere explicitly states that vacuum filtration is used in the isolation of solids from a slurry to produce a cake, e.g. in the synthesis of an active compound (col. 206, lines 1-2). It would have been obvious to use the vacuum filtration as explicitly taught in Metcalf for other synthetic procedures, to the preparation of selpercatinib Form 1.
Claim 17 combines the features of claims 4 and 6, and is therefore obvious for the reasons described above for claims 4 and 6.
Claim 18 is substantially identical to claim 1, with the exception that dichloromethane is in place of DMSO and heptane is in place of water. As such, claim 18 recites a method for converting selpercatinib to selpercatinib Form A, the method comprising: (a) dissolving selpercatinib in a solvent comprising dichloromethane to form a solution; (b) adding heptane to the solution under conditions effective to form a slurry; and (c) isolating the crystallized selpercatinib Form A from the slurry. As with claim 1, the clauses reciting wherein the Form A has recited XRPD peaks and contains less than 10 wt% of other forms of selpercatinib are not afforded patentable weight.
As discussed above with respect to the rejection of claim 1, Metcalf teaches a real example of recrystallizing selpercatinib to produce polymorph Form 1 at col. 216, lines 48-63. Metcalf further teaches that polymorph Form 1 can be prepared by recrystallizing a composition comprising the compound of Formula II to generate polymorph Form 1, where the recrystallizing solvent is selected from the group consisting of (i) a mixture of DMSO and water and (ii) a mixture of dichloromethane and heptane (col 30, lines 58-63). On this basis, it would have been at least obvious to replace the DMSO and water of the real example of col. 216 lines 48-63 with dichloromethane and heptane.
With respect to the changes in amounts and temperature for the method of claim 18 in dichloromethane:heptane vs the method of claim 1 in water:DMSO, as well as the newly added requirement that heptane antisolvent is added in two batches, these are obvious matters of routine optimization coincident with the change in solvent system. Generally, differences in concentration or temperature (or number whether antisolvent is added in two batches or continuously over an hour as in Metcalf) 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)
With respect to claim 25, Metcalf teaches stirring the solution for at least two hours upon water addition (it is silent about additional stirring during water addition). The difference in stirring time for the method in dichloromethane:heptane vs the method in water:DMSO is also a matter of routine optimization, which would be obvious for a person of skill in the art to perform to maximize crystal formation.
Claim 41 is substantially identical to claim 18, but allows for higher drying temperature of the selpercatinib Form A after recrystallization (maximum temperature of 60 °C rather than 45 °C). Claim 41 is therefore obvious over Metcalf for the same reasons as is claim 18. Both drying temperature ranges are obvious over the drying temperature range of 30 °C to 50 °C taught by Metcalf, as both overlap with this range
Claims 11-14 are obvious over Metcalf and Beckman:
Claims 11-14 are rejected under 35 U.S.C. § 103 as being unpatentable over Metcalf, in view of the non-patent publication, Seeding the Desired Polymorph: Background, Possibilities, Limitations, and Case Studies, Org. Proc. Res. Dev., 4, pgs. 372-383 (2000) by Beckmann (hereinafter, “Beckmann”).
Claim 11 recites that the method further comprises adding selpercatinib seed crystals to the DMSO water. Metcalf is applied to claim 11 as to claim 1, above, but does not explicitly teach adding selpercatinib seed crystals to the slurry formed in step (a). It would have been obvious, however, to add selpercatinib seed crystals to the mixture along with water addition, because addition of seed crystals to promote desired crystal formation during a recrystallization process was well-known in the art. See, for example, Beckmann.
Beckmann teaches seeding a desired polymorph during crystallization (Abstract), and further teaches that seeding for polymorphic selection is most easily obtained when producing the stable form (stable polymorph, as in the present case; pg. 383, right column, second full paragraph). It would have been obvious to one of ordinary skill in the art to add selpercatinib to the recrystallization mixture to facilitate crystallization of the desired Form 1.
With respect to claims 12-13, Beckmann teaches that when producing the stable polymorph, the seed crystal should also be the stable polymorph (i.e. selpercatinib Form A seed crystals should be used to seed formation of polymorphic Form A; see pg. 378, left column, first full paragraph of Beckmann). Beckmann further teaches that it is desirable to use the smallest amount of seed possible (pg. 378, left column, 3rd full paragraph), and that the amount should be balanced to the rate of crystallization (pg. 379, left column, third full paragraph). Beckmann further teaches that experiments to optimize the amount of seed are relatively easy, and that the optimized amount of seed is typically ≤10% of the expected crystalline product. While this is not exactly the same as the recited ranges of about 1 to 15 wt% (claim 12) or about 1 wt% (claim 13), the recited ranges are obvious as a matter of routine optimization. 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 Woodruff, 919 F.2d 1575 (Fed. Cir. 1990). This is particularly so when, as in the present case, there is no evidence of criticality of the recited range. See also, MPEP § 2144.05.
With respect to claim 14, Beckmann teaches it is preferable to add seed crystals before substantial nucleation occurs (pg. 379, left column, 3rd paragraph). It therefore would have been obvious to add the selpercatinib seed crystals before the second addition of water.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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