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 claims priority to the applications: 63/419,225, and 63/496,105, , with the effective filing dates of 25 October 2022 and 14 April 2023, respectively.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 13 April 2026.
Applicant’s election without traverse of Group I (claims 1-19) in the reply filed on 13 April 2026 is acknowledged.
Claims 20-24 were canceled.
Election was made without traverse in the reply field on 14 April 2026.
Claims 1-19 are pending.
Information Disclosure Statement
The Information Disclosure Statements filed 30 October 2023 and 13 April 2026 and the references cited therein have been considered, unless indicated otherwise.
Claim Objections
Applicant is advised that should claim 18 be found allowable, claim 19 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
2. Claim(s) 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Dillon (WO 2022/256806, filed 1 June 2022, see IDS filed 30 Oct 2023) in view of Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300).
Dillon teaches Type II PRMT inhibitors and specifically teaches the compound,
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(abstract; page 245). Dillon teaches PRMT5 is a type II arginine methyltransferase that regulates essential cellular functions by symmetrically demethylating proteins involved in transcription and signaling (page 1, lines 14-16). Dillon teaches that PRMT5 is competitively inhibited by 5’-methylthioadenosine and that accumulation of MTA caused by MTAP-deletion partially inhibits PRMT5, rendering MTAP-deleted cells selectively sensitive to additional PRMT5 inhibition (page 1, lines 10-11 and 18-20). Dillon further teaches administration of a PRMT-5 inhibitor with a MAT2A inhibitor for treating cancer, in particular, solid tumors, and that selectivity for MTAP-deleted/MTA accumulating cells is increased when using a PRMT5 inhibitor that uncompetitively/cooperatively binds with MTA (page 1, lines 27-28; page 2, lines 11-14).
Regarding claim 1, Dillon fails to teach a crystalline compound of Formula (I).
Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Morissette teaches that multiple forms of active pharmaceutical ingredients exist and that each form displays unique physiochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability, and other performance characteristics of the drug (page 276, column 1, paragraph 1). Morissette further teaches that most active pharmaceutical ingredients are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process and that a large number of factors can influence crystal nucleation and growth during this process, including composition
of the crystallization medium and process(es) used to generate supersaturation and promote crystallization (page 276, column 2, paragraph 2). Morissette then specifies that high throughput crystallization systems have been developed to more rapidly and comprehensively explore the multiparameter space that contributes to solid form diversity (page 278, column 2, paragraph 2). Morissette further teaches the generation of polymorphs of acetaminophen using a 96-well plate system (e.g. Form III of acetaminophen), while previously, the crystal structure of Form III of acetaminophen was proposed 20 years after it was observed in 1982 by thermal microscopy (page 288, column 1, paragraph 2; page 289, column 1, paragraph 3). Further, Morissette teaches utilizing high throughput crystallization experiments to generate polymorphs of MK-996: over 1500 discrete recrystallization trials from a set of 21 solvents or solvent mixtures yielded 186 solids, which were harvested over a period of 7 days, and produced at least 18 distinct forms (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Additionally, Morissette teaches that pharmaceutical companies currently use high throughput screening of polymorphs to save time and reduce costs (page 288, column 1, paragraph 1). Thus, Morissette teaches that high throughput screening produces many polymorphs in a short period of time.
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the compound of Dillon and the method of Morissette to arrive at instant claim 1 (a compound of Formula (I):
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). One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Dillon teaches Type II PRMT inhibitors and specifically teaches the compound,
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,
-Dillon teaches PRMT5 is a type II arginine methyltransferase that regulates essential cellular functions by symmetrically demethylating proteins involved in transcription and signaling,
-Dillon teaches that PRMT5 is competitively inhibited by 5’-methylthioadenosine and that accumulation of MTA caused by MTAP-deletion partially inhibits PRMT5, rendering MTAP-deleted cells selectively sensitive to additional PRMT5 inhibition,
-Dillon teaches administration of a PRMT-5 inhibitor with a MAT2A inhibitor for treating cancer, in particular, solid tumors, and that selectivity for MTAP-deleted/MTA accumulating cells is increased when using a PRMT5 inhibitor that uncompetitively/cooperatively binds with MTA,
-Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients,
-Morissette teaches that multiple forms of active pharmaceutical ingredients exist and that each form displays unique physiochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability, and other performance characteristics of the drug,
-Morissette teaches that most active pharmaceutical ingredients are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process and that a large number of factors can influence crystal nucleation and growth during this process, including composition of the crystallization medium and process(es) used to generate supersaturation and promote crystallization,
-Morissette teaches that high throughput crystallization systems have been developed to more rapidly and comprehensively explore the multiparameter space that contributes to solid form diversity,
-Morissette teaches the generation of polymorphs of acetaminophen using a 96-well plate system (e.g. Form III of acetaminophen), while previously, the crystal structure of Form III of acetaminophen was proposed 20 years after it was observed in 1982 by thermal microscopy,
-Morissette teaches utilizing high throughput crystallization experiments to generate polymorphs of MK-996: over 1500 discrete recrystallization trials from a set of 21 solvents or solvent mixtures yielded 186 solids, which were harvested over a period of 7 days, and produced at least 18 distinct forms,
-Morissette teaches that pharmaceutical companies currently use high throughput screening of polymorphs to save time and reduce costs, and
-Morissette teaches that high throughput screening produces many polymorphs in a short period of time.
Thus, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a crystalline compound of Formula (I):
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having an XRPD pattern comprising one or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 2, Dillon teaches the compound,
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(page 245). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of Dillon and Morissette teaches a polymorph of a compound of Formula (I) having one or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 3, Dillon teaches the compound,
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(page 245). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of Dillon and Morissette teaches a polymorph of a compound of Formula (I) having three or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 4, Dillon teaches the compound,
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(page 245). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of Dillon and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 5, Dillon teaches the compound,
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(page 245). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of Dillon and Morissette teaches a polymorph of a compound of Formula (I) having three or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 6, Dillon teaches the compound,
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(page 245). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of Dillon and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees and additionally having at least one additional peak at 2θ angles selected from 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, and 23.7 ± 0.2.
Regarding claim 7, Dillon teaches the compound,
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(page 245). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of Dillon and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 8, Dillon teaches a pharmaceutical composition (page 9, lines 22-25; page 278, lines 27-29).
Regarding claim 9, Dillon teaches a pharmaceutical composition (page 9, lines 22-25; page 278, lines 27-29).
3. Claim(s) 1-10 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Dillon (WO 2022/256806, filed 1 June 2022, see IDS filed 30 Oct 2023) and Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300) as applied to claim 1-9 above, and further in view of Cottrell (U.S. Patent No. 11,077,101, issued 3 Aug 2021, see IDS filed 30 Oct 2023).
Dillon (WO 2022/256806, filed 1 June 2022, see IDS filed 30 Oct 2023) and Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300) are applied as discussed in the 35 U.S.C. § 103 rejection above.
Regarding claim 10, while the combination of Dillon and Morissette teaches a crystalline composition of the compound of Formula (I), they differ from that of the instantly claimed invention in that they do not explicitly teach the composition having about 10% (w/w) of the crystalline form of a compound of Formula (I).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to exemplify the crystalline compound of Dillon and Morissette with the composition having about 10% (w/w) of the crystalline form of Cottrell to arrive at the instantly claimed invention.
One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because Cottrell teaches PRMT5 inhibitors to treat cancer wherein loss of methylthioadenosine phosphorylase confers vulnerability to PRMT5 inhibition (column 1, lines 45-47; column 2, lines 14-15). Cottrell further teaches that loss of MTAP causes accumulation of its substrate, MTA, which has been demonstrated to function as a SAM-competitive PRMT5 inhibitor (column 1, lines 63-65). Cottrell additionally teaches that PRMT5 is a type II arginine methyltransferase that regulates essential cellular functions by symmetrically demethylating proteins involved in transcription and signaling (column 2, lines 1-5). Cottrell teaches that PRMT5 inhibitors have been developed but that they do not demonstrate selectivity for MATP-deleted cancer cell lines (column 2, lines 13-14). Cottrell additionally teaches PRMT5 inhibitors that leverage accumulation of MTA by binding in an MTA-uncompetitive manner to demonstrate selectivity for MATP-deleted tumor cells (column 2, lines 20-24). Cottrell teaches compositions wherein the active component is typically a minor component, being from about 0.05 to 10% by weight (column 344, lines 10-13; column 343, lines 59-60).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and
70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Cottrell teaches compositions wherein the active component is typically a minor component, being from about 0.05 to 10% by weight (column 344, lines 10-13; column 343, lines 59-60). The range of the claimed invention (about 10%) significantly overlaps with that of Cottrell. The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of active pharmaceutical ingredient (a compound of Formula (I)) that is encompassed by claim 10 is 0-20% (w/w). Further, the range of the claimed invention does not provide an unexpected result in view of Cottrell, who describes PRMT5 inhibitors and compositions thereof for treating cancer (column 1, lines 45-47; column 2, lines 14-15; column 343, lines 23-24). Thus, the combination of Dillon, Morissette, and Cottrell teaches a composition having about 10% (w/w) of the crystalline form of a compound of Formula (I).
Regarding claim 16, Cottrell teaches a dosage form (column 344, lines 32-42).
Regarding claim 17, Cottrell teaches a dosage form of between 1 mg and 1000 mg per dose (column 345, lines 56-62). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Cottrell teaches a dosage form of between 1 mg and 1000 mg per dose (column 345, lines 56-62). The range of the claimed invention (about 100 mg to 500 mg) significantly overlaps with that of Cottrell. Further, the range of the claimed invention does not provide an unexpected result in view of Cottrell, who describes PRMT5 inhibitors and compositions thereof for treating cancer (column 1, lines 45-47; column 2, lines 14-15; column 343, lines 23-24). Thus, the combination of Dillion, Morissette, and Cottrell teaches a composition having about 100 mg to 500 mg of the compound of Formula (I).
Regarding claim 18, Cottrell teaches a dosage form of between 1 mg and 1000 mg per dose (column 345, lines 56-62). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Cottrell teaches a dosage form of between 1 mg and 1000 mg per dose (column 345, lines 56-62). The range of the claimed invention (about 10 mg to 50 mg) significantly overlaps with that of Cottrell. Further, the range of the claimed invention does not provide an unexpected result in view of Cottrell, who describes PRMT5 inhibitors and compositions thereof for treating cancer (column 1, lines 45-47; column 2, lines 14-15; column 343, lines 23-24). Thus, the combination of Dillion, Morissette, and Cottrell teaches a composition having about 10 mg to 50 mg of the compound of Formula (I).
Regarding claim 19, Cottrell teaches a dosage form of between 1 mg and 1000 mg per dose (column 345, lines 56-62). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Cottrell teaches a dosage form of between 1 mg and 1000 mg per dose (column 345, lines 56-62). The range of the claimed invention (about 10 mg to 50 mg) significantly overlaps with that of Cottrell. Further, the range of the claimed invention does not provide an unexpected result in view of Cottrell, who describes PRMT5 inhibitors and compositions thereof for treating cancer (column 1, lines 45-47; column 2, lines 14-15; column 343, lines 23-24). Thus, the combination of Dillion, Morissette, and Cottrell teaches a composition having about 10 mg to 50 mg of the compound of Formula (I).
4. Claim(s) 1-12 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Dillon (WO 2022/256806, filed 1 June 2022, see IDS filed 30 Oct 2023) , Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300), and Cottrell (U.S. Patent No. 11,077,101, issued 3 Aug 2021, see IDS filed 30 Oct 2023) as applied to claim 1-10 and 16-19 above, and further in view of Heberlein (WO 2022/013692, filed 15 Jul 2020).
Dillon (WO 2022/256806, filed 1 June 2022, see IDS filed 30 Oct 2023) , Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300), and Cottrell (U.S. Patent No. 11,077,101, issued 3 Aug 2021, see IDS filed 30 Oct 2023) are applied as discussed in the 35 U.S.C. § 103 rejection above.
Regarding claim 11, while the combination of Dillon, Morissette, and Cottrell teaches (a) a crystalline composition of the compound of Formula (I); (c) a glidant (column 344, lines 4-5); (d) a disintegrant (column 344, lines 2-3); and (e) a lubricant (column 344, lines 3-4), they differ from that of the instantly claimed invention in that they do not explicitly teach the composition having about (b) a filler.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to exemplify the crystalline compound of Dillon, Morissette, and Cottrell with a composition having a filler of Heberlein to arrive at the instantly claimed invention.
One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because Heberlein teaches a crystalline small molecule inhibitor of PRMT-5 and therapeutic uses thereof (page 1, lines 5-9; page 5, lines 1-4). Heberlein teaches that a PRMT5 inhibitor is useful in the treatment of abnormal cell growth in mammals, especially humans, for treating cancer (page 3, lines 5-6). Heberlein teaches that PRMT5 is overexpressed in many cancers and has been observed in patient samples and cell lines including B-cell lymphoma and leukemia and solid tumors and that overexpression of PRMT5 is correlated with poor prognosis (page 4, lines 29-30 and 32-33). Heberlein teaches that formulations suitable for oral administration and that liquid formulations include fillers (page 11, lines 18-23). Heberlein additionally teaches formulations of a crystalline PRMT5 inhibitor, wherein the filler is cellulose and dibasic calcium phosphate, which are present in 61.4 and 30.8 w/w%, which combined is 92.2% (page 21, Table 2). Thus, the combination of Dillon, Morissette, Cottrell, and Heberlein teaches (a) a crystalline composition of the compound of Formula (I); (b) a filler, (c) a glidant; (d) a disintegrant; and (e) a lubricant.
Regarding (a) of claim 12, Cottrell teaches compositions wherein the active component is typically a minor component, being from about 0.05 to 10% by weight (column 344, lines 10-13; column 343, lines 59-60). Thus, Cottrell teaches (a) about 10% (w/w) of a crystalline form of the active pharmaceutical ingredient (a compound of Formula (I)).
Regarding (b) of claim 12, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the filler is cellulose and dibasic calcium phosphate, which are present in 61.4 and 30.8 w/w%, which combined is 92.2% (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of filler that is encompassed by claim 12 is 72.5-93.5% (w/w). Thus, Heberlein teaches (b) about 83.5% (w/w) of a filler.
Regarding (c) of claim 12, Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). The range of the claimed invention significantly overlaps with that of Heberlein (0-10%, as the specification defines about to be ±10% variation; [0052]). Further, the range of the claimed invention does not provide an unexpected result in view of Heberlein, who describes a crystalline PRMT5 inhibitor and formulations thereof for treating cancer (page 1, lines 5-9; page 5, lines 1-4; page 3, lines 5-6). Thus, Heberlein teaches (c) about 1.5% (w/w) of a glidant.
Regarding (d) of claim 12, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the disintegrant is sodium starch glycolate, which is present in 3% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of disintegrant that is encompassed by claim 12 is 0-14% (w/w). Thus, Heberlein teaches (d) about 4% (w/w) of a disintegrant.
Regarding (e) of claim 12, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the lubricant is magnesium stearate, which is present in 1% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of lubricant that is encompassed by claim 12 is 0-11% (w/w). Thus, Heberlein teaches (e) about 1% (w/w) of a disintegrant.
Thus, the combination of Dillon, Morissettte, Cottrell, and Heberlein teaches a composition wherein (a) about 10% (w/w) of a crystalline form of the active pharmaceutical ingredient (a compound of Formula (I)), (b) about 83.5% (w/w) of a filler, (c) about 1.5% (w/w) of a glidant, (d) about 4% (w/w) of a disintegrant, and (e) about 1% (w/w) of a disintegrant.
5. Claim(s) 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Dillon (WO 2022/256806, filed 1 June 2022, see IDS filed 30 Oct 2023) , Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300), Cottrell (U.S. Patent No. 11,077,101, issued 3 Aug 2021, see IDS filed 30 Oct 2023), and Heberlein (WO 2022/013692, filed 15 Jul 2020) as applied to claim 1-12 and 16-19 above, and further in view of Shotton (J. Pharm. Sci., 1976, 65(8), 1170-1174).
Dillon (WO 2022/256806, filed 1 June 2022, see IDS filed 30 Oct 2023) , Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300), Cottrell (U.S. Patent No. 11,077,101, issued 3 Aug 2021, see IDS filed 30 Oct 2023), and Heberlein (WO 2022/013692, filed 15 Jul 2020) are applied as discussed in the 35 U.S.C. § 103 rejection above.
Regarding claim 13, while the combination of Dillon, Morissette, Cottrell, and Heberlein teaches (a) a crystalline composition of the compound of Formula (I); (b) a filler; (c) a glidant; (d) a disintegrant; and (e) a lubricant, they differ from that of the instantly claimed invention in that they do not explicitly teach the composition having intragranular or extragranular agents.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to exemplify the crystalline compound of Dillon, Morissette, Cottrell, and Heberlein with a composition having intragranular and extragranular agents as taught by Shotton to arrive at the instantly claimed invention.
One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because Shotton teaches methods of incorporating granularity into formulations via intragranular addition, extragranular addition, and both intragranular and extragranular addition (abstract). Shotton teaches intragranular agents give smaller particle size than extragranular formulations (page 1174, column 1, paragraph 1). Shotton teaches that extragranular agent only cause the tablet to break up rapidly to aggregates, many of which were comparable in size to the original granule (page 1173, column 2, paragraph 1). Shotton teaches that intragranular agent only causes erosion of the tablet from the outside since penetration was slow, but the mean aggregate size was much smaller (page 1173, column 2, paragraph 1). Shotton teaches that a combination of intra- and extragranular agents gave the best compromise (abstract). Shotton teaches that by using different ratios of intra-and extragranular agents or different agents intra- and extragranularly, a tablet with improved properties can be formulated (page 1173, column 2, paragraph 7; page 1174, column 1, paragraph 2). Thus, the combination of Dillon, Morissette, Cottrell, Heberlein, and Shotton teaches (a) a crystalline composition of the compound of Formula (I); (b) an intragranular filler; (c) an intragranular glidant; (d) an intragranular disintegrant; (e) an intragranular lubricant; (f) an extragranular glidant; (g) an extragranular disintegrant; and (h) an extragranular lubricant.
Regarding (a) of claim 14, Cottrell teaches compositions for oral administration from about 0.1 to 40% by weight (column 343, lines 59-60; column 344, lines 10-13). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Cottrell teaches compositions for oral administration from about 0.1 to 40% by weight (column 343, lines 59-60; column 344, lines 10-13). The range of the claimed invention (about 2-20%) significantly overlaps with that of Cottrell. The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of active pharmaceutical ingredient (a compound of Formula (I)) that is encompassed by claim 14 is 0-40% (w/w). Further, the range of the claimed invention does not provide an unexpected result in view of Cottrell, who describes PRMT5 inhibitors and compositions thereof for treating cancer (column 1, lines 45-47; column 2, lines 14-15; column 343, lines 23-24). Thus, Cottrell teaches (a) about 2% to about 20% (w/w) of a crystalline form of the active pharmaceutical ingredient (a compound of Formula (I)).
Regarding (b) of claim 14, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the filler is cellulose and dibasic calcium phosphate, which are present in 61.4 and 30.8 w/w%, which combined is 92.2% (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of filler that is encompassed by claim 14 is 30-100% (w/w). Thus, Heberlein teaches (b) about 50% to about 90% (w/w) of a filler. Shotton then teaches that an intragranular agent produces a finer particle than an extragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (b) about 50% to about 90% (w/w) of an intragranular filler.
Regarding (c) of claim 14, Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). The range of the claimed invention significantly overlaps with that of Heberlein (0-11.25%, as the specification defines about to be ±10% variation; [0052]). Further, the range of the claimed invention does not provide an unexpected result in view of Heberlein, who describes a crystalline PRMT5 inhibitor and formulations thereof for treating cancer (page 1, lines 5-9; page 5, lines 1-4; page 3, lines 5-6). Thus, Heberlein teaches (c) about 0.75% to about 1.25% (w/w) of a glidant. Shotton then teaches that an intragranular agent produces a finer particle than an extragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (c) about 0.75% to about 1.25% (w/w) of an intragranular glidant.
Regarding (d) of claim 14, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the disintegrant is sodium starch glycolate, which is present in 3% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of disintegrant that is encompassed by claim 14 is 0-13% (w/w). Thus, Heberlein teaches (d) about 1% to about 3% (w/w) of a disintegrant. Shotton then teaches that an intragranular agent produces a finer particle than an extragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (d) about 1% to about 3% (w/w) of an intragranular disintegrant.
Regarding (e) of claim 14, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the lubricant is magnesium stearate, which is present in 1% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of lubricant that is encompassed by claim 14 is 0-10.75% (w/w). Thus, Heberlein teaches (e) about 0.25% to about 0.75% (w/w) of a disintegrant. Shotton then teaches that an intragranular agent produces a finer particle than an extragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (e) about 0.25% to about 0.75% (w/w) of an intragranular disintegrant.
Regarding (f) of claim 14, Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). The range of the claimed invention significantly overlaps with that of Heberlein (0-11.25%, as the specification defines about to be ±10% variation; [0052]). Further, the range of the claimed invention does not provide an unexpected result in view of Heberlein, who describes a crystalline PRMT5 inhibitor and formulations thereof for treating cancer (page 1, lines 5-9; page 5, lines 1-4; page 3, lines 5-6). Thus, Heberlein teaches (c) about 0.25% to about 0.75% (w/w) of a glidant. Shotton then teaches that an extragranular agent disintegrates more rapidly than an intragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (f) about 0.25% to about 0.75% (w/w) of an extragranular glidant.
Regarding (g) of claim 14, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the disintegrant is sodium starch glycolate, which is present in 3% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of disintegrant that is encompassed by claim 14 is 0-13% (w/w). Thus, Heberlein teaches (d) about 1% to about 3% (w/w) of a disintegrant. Shotton then teaches that an extragranular agent disintegrates more rapidly than an intragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (g) about 1% to about 3% (w/w) of an extragranular disintegrant.
Regarding (h) of claim 14, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the lubricant is magnesium stearate, which is present in 1% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of lubricant that is encompassed by claim 14 is 0-10.75% (w/w). Thus, Heberlein teaches (e) about 0.25% to about 0.75% (w/w) of a disintegrant. Shotton then teaches that an extragranular agent disintegrates more rapidly than an intragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (h) about 0.25% to about 0.75% (w/w) of an extragranular disintegrant.
Thus, the combination of Dillon, Morissettte, Cottrell, Heberlein, and Shotton teaches a composition wherein (a) about 2% to about 20% (w/w) of a crystalline form of the active pharmaceutical ingredient (a compound of Formula (I)); (b) about 50% to about 90% (w/w) of an intragranular filler; (c) about 0.75% to about 1.25% (w/w) of an intragranular glidant; (d) about 1% to about 3% (w/w) of an intragranular disintegrant; (e) about 0.25% to about 0.75% (w/w) of an intragranular disintegrant; (f) about 0.25% to about 0.75% (w/w) of an extragranular glidant; (g) about 1% to about 3% (w/w) of an extragranular disintegrant; and (h) about 0.25% to about 0.75% (w/w) of an extragranular disintegrant.
Regarding (a) of claim 15, Cottrell teaches compositions for oral administration from about 0.1 to 40% by weight (column 343, lines 59-60; column 344, lines 10-13). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Cottrell teaches compositions for oral administration from about 0.1 to 40% by weight (column 343, lines 59-60; column 344, lines 10-13). The range of the claimed invention (about 10%) significantly overlaps with that of Cottrell. The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of active pharmaceutical ingredient (a compound of Formula (I)) that is encompassed by claim 15 is 0-20% (w/w). Further, the range of the claimed invention does not provide an unexpected result in view of Cottrell, who describes PRMT5 inhibitors and compositions thereof for treating cancer (column 1, lines 45-47; column 2, lines 14-15; column 343, lines 23-24). Thus, Cottrell teaches (a) about 10% (w/w) of a crystalline form of the active pharmaceutical ingredient (a compound of Formula (I)).
Regarding (b) of claim 15, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the filler is cellulose and dibasic calcium phosphate, which are present in 61.4 and 30.8 w/w%, which combined is 92.2% (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of filler that is encompassed by claim 15 is 73.5-93.5% (w/w). Thus, Heberlein teaches (b) about 83.5% (w/w) of a filler. Shotton then teaches that an intragranular agent produces a finer particle than an extragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (b) about 83.5% (w/w) of an intragranular filler.
Regarding (c) of claim 15, Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). The range of the claimed invention significantly overlaps with that of Heberlein (0-11%, as the specification defines about to be ±10% variation; [0052]). Further, the range of the claimed invention does not provide an unexpected result in view of Heberlein, who describes a crystalline PRMT5 inhibitor and formulations thereof for treating cancer (page 1, lines 5-9; page 5, lines 1-4; page 3, lines 5-6). Thus, Heberlein teaches (c) about 1% (w/w) of a glidant. Shotton then teaches that an intragranular agent produces a finer particle than an extragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (c) about 1% (w/w) of an intragranular glidant.
Regarding (d) of claim 15, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the disintegrant is sodium starch glycolate, which is present in 3% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of disintegrant that is encompassed by claim 15 is 0-12% (w/w). Thus, Heberlein teaches (d) about 2% (w/w) of a disintegrant. Shotton then teaches that an intragranular agent produces a finer particle than an extragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (d) about 2% (w/w) of an intragranular disintegrant.
Regarding (e) of claim 15, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the lubricant is magnesium stearate, which is present in 1% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of lubricant that is encompassed by claim 15 is 0-10.5% (w/w). Thus, Heberlein teaches (e) about 0.5% (w/w) of a disintegrant. Shotton then teaches that an intragranular agent produces a finer particle than an extragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (e) about 0.5% (w/w) of an intragranular disintegrant.
Regarding (f) of claim 15, Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Heberlein also teaches that the glidant is 0.2-1 wt% (page 12, lines 11-12). The range of the claimed invention significantly overlaps with that of Heberlein (0-10.5%, as the specification defines about to be ±10% variation; [0052]). Further, the range of the claimed invention does not provide an unexpected result in view of Heberlein, who describes a crystalline PRMT5 inhibitor and formulations thereof for treating cancer (page 1, lines 5-9; page 5, lines 1-4; page 3, lines 5-6). Thus, Heberlein teaches (c) about 0.5% (w/w) of a glidant. Shotton then teaches that an extragranular agent disintegrates more rapidly than an intragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (f) about 0.5% (w/w) of an extragranular glidant.
Regarding (g) of claim 15, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the disintegrant is sodium starch glycolate, which is present in 3% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of disintegrant that is encompassed by claim 15 is 0-12% (w/w). Thus, Heberlein teaches (d) about 2% (w/w) of a disintegrant. Shotton then teaches that an extragranular agent disintegrates more rapidly than an intragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (g) about 2% (w/w) of an extragranular disintegrant.
Regarding (h) of claim 15, Heberlein teaches a crystalline PRMT5 inhibitor formulation wherein the lubricant is magnesium stearate, which is present in 1% (w/w) (page 21, Table 2). The specification of the claimed invention defines the term “about” to be a ±10% variation ([0052]). Accordingly, the amount of lubricant that is encompassed by claim 15 is 0-10.5% (w/w). Thus, Heberlein teaches (e) about 00.5% (w/w) of a disintegrant. Shotton then teaches that an extragranular agent disintegrates more rapidly than an intragranular agent (abstract). Thus, the combination of Heberlein and Shotton teaches (h) about 0.5% (w/w) of an extragranular disintegrant.
Thus, the combination of Dillon, Morissettte, Cottrell, Heberlein, and Shotton teaches a composition wherein (a) about 10% (w/w) of a crystalline form of the active pharmaceutical ingredient (a compound of Formula (I)); (b) about 83.5% (w/w) of an intragranular filler; (c) about 1% (w/w) of an intragranular glidant; (d) about 2% (w/w) of an intragranular disintegrant; (e) about 0.5% (w/w) of an intragranular disintegrant; (f) about 0.5% (w/w) of an extragranular glidant; (g) about 2% (w/w) of an extragranular disintegrant; and (h) about 0.5% (w/w) of an extragranular disintegrant.
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.
6. Claims 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 24-25 of U.S. Patent No. 11,999,727 in view of Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300).
U.S. Patent No. 11,999,727 teaches the general formula,
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, and specifically teaches the compound,
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(claims 1 and 24). Additionally, ‘727 teaches a pharmaceutical composition of the compounds therein (claim 25).
Regarding claim 1, ‘727 fails to teach a crystalline compound of Formula (I).
Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Morissette teaches that multiple forms of active pharmaceutical ingredients exist and that each form displays unique physiochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability, and other performance characteristics of the drug (page 276, column 1, paragraph 1). Morissette further teaches that most active pharmaceutical ingredients are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process and that a large number of factors can influence crystal nucleation and growth during this process, including composition
of the crystallization medium and process(es) used to generate supersaturation and promote crystallization (page 276, column 2, paragraph 2). Morissette then specifies that high throughput crystallization systems have been developed to more rapidly and comprehensively explore the multiparameter space that contributes to solid form diversity (page 278, column 2, paragraph 2). Morissette further teaches the generation of polymorphs of acetaminophen using a 96-well plate system (e.g. Form III of acetaminophen), while previously, the crystal structure of Form III of acetaminophen was proposed 20 years after it was observed in 1982 by thermal microscopy (page 288, column 1, paragraph 2; page 289, column 1, paragraph 3). Further, Morissette teaches utilizing high throughput crystallization experiments to generate polymorphs of MK-996: over 1500 discrete recrystallization trials from a set of 21 solvents or solvent mixtures yielded 186 solids, which were harvested over a period of 7 days, and produced at least 18 distinct forms (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Additionally, Morissette teaches that pharmaceutical companies currently use high throughput screening of polymorphs to save time and reduce costs (page 288, column 1, paragraph 1). Thus, Morissette teaches that high throughput screening produces many polymorphs in a short period of time.
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the compound of ‘727 and the method of Morissette to arrive at instant claim 1 (a compound of Formula (I):
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). One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘727 teaches the general formula,
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, and specifically teaches the compound,
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-‘727 teaches pharmaceutical compositions thereof,
-Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients,
-Morissette teaches that multiple forms of active pharmaceutical ingredients exist and that each form displays unique physiochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability, and other performance characteristics of the drug,
-Morissette teaches that most active pharmaceutical ingredients are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process and that a large number of factors can influence crystal nucleation and growth during this process, including composition of the crystallization medium and process(es) used to generate supersaturation and promote crystallization,
-Morissette teaches that high throughput crystallization systems have been developed to more rapidly and comprehensively explore the multiparameter space that contributes to solid form diversity,
-Morissette teaches the generation of polymorphs of acetaminophen using a 96-well plate system (e.g. Form III of acetaminophen), while previously, the crystal structure of Form III of acetaminophen was proposed 20 years after it was observed in 1982 by thermal microscopy,
-Morissette teaches utilizing high throughput crystallization experiments to generate polymorphs of MK-996: over 1500 discrete recrystallization trials from a set of 21 solvents or solvent mixtures yielded 186 solids, which were harvested over a period of 7 days, and produced at least 18 distinct forms,
-Morissette teaches that pharmaceutical companies currently use high throughput screening of polymorphs to save time and reduce costs, and
-Morissette teaches that high throughput screening produces many polymorphs in a short period of time.
Thus, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a crystalline compound of Formula (I):
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having an XRPD pattern comprising one or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 2, ‘727 teaches the compound,
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(claims 1 and 24). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘727 and Morissette teaches a polymorph of a compound of Formula (I) having one or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 3, ‘727 teaches the compound,
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(claims 1 and 24). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘727 and Morissette teaches a polymorph of a compound of Formula (I) having three or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 4, ‘727 teaches the compound,
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(claims 1 and 24). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘727 and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 5, ‘727 teaches the compound,
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(claims 1 and 24). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘727 and Morissette teaches a polymorph of a compound of Formula (I) having three or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 6, ‘727 teaches the compound,
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(claims 1 and 24). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘727 and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees and additionally having at least one additional peak at 2θ angles selected from 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, and 23.7 ± 0.2.
Regarding claim 7, ‘727 teaches the compound,
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(claims 1 and 24). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘727 and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 8, ‘727 teaches a pharmaceutical composition (claim 25).
Regarding claim 9, ‘727 teaches a pharmaceutical composition (claim 25).
7. Claims 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Application No. 18/833,486 in view of Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300).
U.S. Application No. 18/833,486 specifically teaches the compound,
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(claim 1). Additionally, ‘486 teaches a pharmaceutical composition of the compounds therein (claim 2).
Regarding claim 1, ‘486 fails to teach a crystalline compound of Formula (I).
Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Morissette teaches that multiple forms of active pharmaceutical ingredients exist and that each form displays unique physiochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability, and other performance characteristics of the drug (page 276, column 1, paragraph 1). Morissette further teaches that most active pharmaceutical ingredients are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process and that a large number of factors can influence crystal nucleation and growth during this process, including composition
of the crystallization medium and process(es) used to generate supersaturation and promote crystallization (page 276, column 2, paragraph 2). Morissette then specifies that high throughput crystallization systems have been developed to more rapidly and comprehensively explore the multiparameter space that contributes to solid form diversity (page 278, column 2, paragraph 2). Morissette further teaches the generation of polymorphs of acetaminophen using a 96-well plate system (e.g. Form III of acetaminophen), while previously, the crystal structure of Form III of acetaminophen was proposed 20 years after it was observed in 1982 by thermal microscopy (page 288, column 1, paragraph 2; page 289, column 1, paragraph 3). Further, Morissette teaches utilizing high throughput crystallization experiments to generate polymorphs of MK-996: over 1500 discrete recrystallization trials from a set of 21 solvents or solvent mixtures yielded 186 solids, which were harvested over a period of 7 days, and produced at least 18 distinct forms (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Additionally, Morissette teaches that pharmaceutical companies currently use high throughput screening of polymorphs to save time and reduce costs (page 288, column 1, paragraph 1). Thus, Morissette teaches that high throughput screening produces many polymorphs in a short period of time.
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the compound of ‘486 and the method of Morissette to arrive at instant claim 1 (a compound of Formula (I):
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). One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘486 specifically teaches the compound,
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,
-‘486 teaches pharmaceutical compositions thereof,
-Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients,
-Morissette teaches that multiple forms of active pharmaceutical ingredients exist and that each form displays unique physiochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability, and other performance characteristics of the drug,
-Morissette teaches that most active pharmaceutical ingredients are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process and that a large number of factors can influence crystal nucleation and growth during this process, including composition of the crystallization medium and process(es) used to generate supersaturation and promote crystallization,
-Morissette teaches that high throughput crystallization systems have been developed to more rapidly and comprehensively explore the multiparameter space that contributes to solid form diversity,
-Morissette teaches the generation of polymorphs of acetaminophen using a 96-well plate system (e.g. Form III of acetaminophen), while previously, the crystal structure of Form III of acetaminophen was proposed 20 years after it was observed in 1982 by thermal microscopy,
-Morissette teaches utilizing high throughput crystallization experiments to generate polymorphs of MK-996: over 1500 discrete recrystallization trials from a set of 21 solvents or solvent mixtures yielded 186 solids, which were harvested over a period of 7 days, and produced at least 18 distinct forms,
-Morissette teaches that pharmaceutical companies currently use high throughput screening of polymorphs to save time and reduce costs, and
-Morissette teaches that high throughput screening produces many polymorphs in a short period of time.
Further, structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties. See, e.g., Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Deuel, 51 F.3d 1552, 1558, 34 USPQ2d 1210, 1214 (Fed. Cir. 1995). Additionally, structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093- 95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the compound of ‘486 differs from Formula (I) of the claimed invention via the saturation (alkene versus alkane) of the piperidine ring. As alkene and alkanes are homologous, ‘486 teaches a compound of Formula (I).
Thus, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a crystalline compound of Formula (I):
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having an XRPD pattern comprising one or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 2, ‘486 teaches the compound,
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(claim 1). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘486 and Morissette teaches a polymorph of a compound of Formula (I) having one or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 3, ‘486 teaches the compound,
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(claim 1). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘486 and Morissette teaches a polymorph of a compound of Formula (I) having three or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 4, ‘486 teaches the compound,
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(claim 1). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘486 and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 5, ‘486 teaches the compound,
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(claim 1). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘486 and Morissette teaches a polymorph of a compound of Formula (I) having three or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 6, ‘486 teaches the compound,
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(claim 1). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘486 and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees and additionally having at least one additional peak at 2θ angles selected from 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, and 23.7 ± 0.2.
Regarding claim 7, ‘486 teaches the compound,
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(claim 1). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘486 and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 8, ‘486 teaches a pharmaceutical composition (claim 2).
Regarding claim 9, ‘486 teaches a pharmaceutical composition (claim 2).
8. Claims 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, and 16 of U.S. Patent No. 11,492,350 in view of Morrissette (Adv. Drug Delivery Rev., 2004, 56, 275-300).
U.S. Patent No. 11,492,350 teaches the general formula,
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, and specifically teaches the compound,
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(claims 1 and 10). Additionally, ‘350 teaches a pharmaceutical composition of the compounds therein (claim 16).
Regarding claim 1, ‘350 fails to teach a crystalline compound of Formula (I).
Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Morissette teaches that multiple forms of active pharmaceutical ingredients exist and that each form displays unique physiochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability, and other performance characteristics of the drug (page 276, column 1, paragraph 1). Morissette further teaches that most active pharmaceutical ingredients are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process and that a large number of factors can influence crystal nucleation and growth during this process, including composition
of the crystallization medium and process(es) used to generate supersaturation and promote crystallization (page 276, column 2, paragraph 2). Morissette then specifies that high throughput crystallization systems have been developed to more rapidly and comprehensively explore the multiparameter space that contributes to solid form diversity (page 278, column 2, paragraph 2). Morissette further teaches the generation of polymorphs of acetaminophen using a 96-well plate system (e.g. Form III of acetaminophen), while previously, the crystal structure of Form III of acetaminophen was proposed 20 years after it was observed in 1982 by thermal microscopy (page 288, column 1, paragraph 2; page 289, column 1, paragraph 3). Further, Morissette teaches utilizing high throughput crystallization experiments to generate polymorphs of MK-996: over 1500 discrete recrystallization trials from a set of 21 solvents or solvent mixtures yielded 186 solids, which were harvested over a period of 7 days, and produced at least 18 distinct forms (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Additionally, Morissette teaches that pharmaceutical companies currently use high throughput screening of polymorphs to save time and reduce costs (page 288, column 1, paragraph 1). Thus, Morissette teaches that high throughput screening produces many polymorphs in a short period of time.
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the compound of ‘350 and the method of Morissette to arrive at instant claim 1 (a compound of Formula (I):
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). One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘350 specifically teaches the compound,
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,
-‘350 teaches pharmaceutical compositions thereof,
-Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients,
-Morissette teaches that multiple forms of active pharmaceutical ingredients exist and that each form displays unique physiochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability, and other performance characteristics of the drug,
-Morissette teaches that most active pharmaceutical ingredients are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process and that a large number of factors can influence crystal nucleation and growth during this process, including composition of the crystallization medium and process(es) used to generate supersaturation and promote crystallization,
-Morissette teaches that high throughput crystallization systems have been developed to more rapidly and comprehensively explore the multiparameter space that contributes to solid form diversity,
-Morissette teaches the generation of polymorphs of acetaminophen using a 96-well plate system (e.g. Form III of acetaminophen), while previously, the crystal structure of Form III of acetaminophen was proposed 20 years after it was observed in 1982 by thermal microscopy,
-Morissette teaches utilizing high throughput crystallization experiments to generate polymorphs of MK-996: over 1500 discrete recrystallization trials from a set of 21 solvents or solvent mixtures yielded 186 solids, which were harvested over a period of 7 days, and produced at least 18 distinct forms,
-Morissette teaches that pharmaceutical companies currently use high throughput screening of polymorphs to save time and reduce costs, and
-Morissette teaches that high throughput screening produces many polymorphs in a short period of time.
Further, structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties. See, e.g., Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Deuel, 51 F.3d 1552, 1558, 34 USPQ2d 1210, 1214 (Fed. Cir. 1995). Additionally, structural similarities have been found to support a prima facie case of obviousness. See, e.g., In re May, 574 F.2d 1082, 1093- 95, 197 USPQ 601, 610-11 (CCPA 1978) (stereoisomers); In re Wilder, 563 F.2d 457, 460, 195 USPQ 426, 429 (CCPA 1977) (adjacent homologs and structural isomers); In re Hoch, 428 F.2d 1341, 1344, 166 USPQ 406, 409 (CCPA 1970) (acid and ethyl ester); In re Druey, 319 F.2d 237, 240, 138 USPQ 39, 41 (CCPA 1963) (omission of methyl group from pyrazole ring). Generally, some teaching of a structural similarity will be necessary to suggest selection of the claimed species or subgenus. The closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See, e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904 (and cases cited therein). See MPEP § 2144.08(II)(A)(4)(c). As the compound of ‘350 differs from Formula (I) of the claimed invention via a methylene unit of the alkyl chain on the piperidine ring. As methyl and ethyl are homologous, ‘350 teaches a compound of Formula (I).
Thus, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a crystalline compound of Formula (I):
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having an XRPD pattern comprising one or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 2, ‘350 teaches the compound,
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(claims 1 and 10). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘350 and Morissette teaches a polymorph of a compound of Formula (I) having one or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 3, ‘350 teaches the compound,
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(claims 1 and 10). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘350 and Morissette teaches a polymorph of a compound of Formula (I) having three or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 4, ‘350 teaches the compound,
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(claims 1 and 10). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘350 and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 5, ‘350 teaches the compound,
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(claims 1 and 10). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘350 and Morissette teaches a polymorph of a compound of Formula (I) having three or more peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 6, ‘350 teaches the compound,
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(claims 1 and 10). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘350 and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, and 24.5 ± 0.2 degrees and additionally having at least one additional peak at 2θ angles selected from 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, and 23.7 ± 0.2.
Regarding claim 7, ‘350 teaches the compound,
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(claims 1 and 10). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘350 and Morissette teaches a polymorph of a compound of Formula (I) having peaks at 2θ angles selected from 4.4 ± 0.2, 9.6 ± 0.2, 16.8± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 24.5 ± 0.2 degrees.
Regarding claim 8, ‘350 teaches a pharmaceutical composition (claim 16).
Regarding claim 9, ‘350 teaches a pharmaceutical composition (claim 16).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Madeline M Dekarske whose telephone number is (571)272-1789. The examiner can normally be reached Monday - Thursday 10am - 4pm.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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