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: PCT/CN2021/127945, 63/280,972, and PCT/US2022/078962 with effective filing dates of 1 Nov 2021, 18 Nov 2021, and 31 Oct 2022.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 5 August 2026.
Applicant’s election without traverse of Group I (claims 1-4, 6-7, 9, 11, 14-15, 17) and a crystalline form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyll-1H-indole-2-carboxamide having Free Base Form II as the species in the reply filed on 5 August 2026 is acknowledged.
Claim 3-4, 6-7, 9, and 71-75 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected species, there being no allowable generic or linking claim. Claim 3 recites Free Base Form III, which does not read on the elected species. Claim 4 recites Free Base Form IV, which does not read on the elected species. Claim 6 recites HCl Form I, which does not read on the elected species. Claim 7 recites HCl Form II, which does not read on the elected species. Claim 9 recites HBr Form I, which does not read on the elected species. Claim 71 depends upon claim 3, which recites Free Base Form III, which does not read on the elected species. Claim 72 depends upon claim 4, which recites Free Base Form IV, which does not read on the elected species. Claim 73 depends upon claim 6, which recites HCl Form I, which does not read on the elected species. Claim 74 depends upon claim 7, which recites HCl Form II, which does not read on the elected species. Claim 75 depends upon claim 9, which recites HBr Form I, which does not read on the elected species.
Claims 1-2, 11, 14-15, 17, 70, and 76-78 are under consideration in the instant office action.
Information Disclosure Statement
The Information Disclosure Statement filed 25 April 2025 and 5 August 2026 and the references cited therein have been considered, unless indicated otherwise.
The reference, Fahey (Cold Spring Harbor Perspective in Medicine, 2017, 7(5): a026468, 1-15), is lined through, because a copy of the reference was not provided.
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.
1. Claim(s) 1-2 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Lampe (WO 2020/037079, published 20 Feb 2020; of record, see PTO-892 mailed 7 May 2026) in view of Morissette (Adv. Drug Delivery Rev., 2004, 56, 275-300).
Lampe teaches substituted indole compounds that are SETD2 protein inhibitors (abstract; [0001]). Lampe teaches that the selective addition of methyl groups to specific amino acid sites on histones is controlled by the action of a family of enzymes known as histone methyltransferases and that the level of expression of a particular gene is influenced by the presence or absence of one or more methyl groups at a relevant histone site ([0002]). Lampe teaches that that special effect of a methyl group at a particular histone site persists until the methyl group is removed by a histone demethylase or until the modified histone is replaced through nucleosome turnover ([0002]). Lampe teaches that SETD2 is a human histone methyltransferase, which has been shown to have tumor suppressor functionality ([0003]; [0004]). Lampe teaches the despite its known functionality as a tumor suppressor, inhibition of SETD2 can be used to treat cancer ([0005]). Lampe teaches that Compound 15:
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, which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyll-1H-indole-2-carboxamide (page 53, Table 1; Example 1, [0632]). Lampe teaches pharmaceutical compositions of the compounds therein ([0405]).
Regarding claim 1, Lampe fails to teach a crystalline form of Form II having an XRPD of 7.0, 14.0, 18.0, and 20.2 degrees 2θ ± 0.2 °2θ.
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 modify the compound of Lampe with the method of Morissette to arrive at instant claim 1 (a crystalline form of
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having Free Base Form II). One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Lampe teaches substituted indole compounds that are SETD2 protein inhibitors,
-Lampe teaches that the selective addition of methyl groups to specific amino acid sites on histones is controlled by the action of a family of enzymes known as histone methyltransferases and that the level of expression of a particular gene is influenced by the presence or absence of one or more methyl groups at a relevant histone site,
-Lampe teaches that that special effect of a methyl group at a particular histone site persists until the methyl group is removed by a histone demethylase or until the modified histone is replaced through nucleosome turnover,
-Lampe teaches that SETD2 is a human histone methyltransferase, which has been shown to have tumor suppressor functionality,
-Lampe teaches the despite its known functionality as a tumor suppressor, inhibition of SETD2 can be used to treat cancer,
-Lampe teaches that Compound 15:
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, which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyll-1H-indole-2-carboxamide,
-Lampe teaches pharmaceutical compositions of the compounds therein,
-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 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,
-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,
-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,
-Morissette teaches that 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.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a crystalline form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyll-1H-indole-2-carboxamide (
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) having Free Base Form II with an XRPD of 7.0, 14.0, 18.0, and 20.2 degrees 2θ ± 0.2 °2θ.
Regarding claim 2, Lampe teaches
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and pharmaceutical compositions thereof (Table 1, page 53; [0405]). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of Lampe and Morissette teaches the crystalline form of
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having Free Base Form II.
Regarding claim 11, Lampe teaches
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and pharmaceutical compositions thereof (Table 1, page 53; [0405]). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of Lampe and Morissette teaches the crystalline form of
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having Free Base Form II.
2. Claim(s) 1-2, 11, 14-15, 17, 70, and 76-78 are rejected under 35 U.S.C. 103 as being unpatentable over Lampe (WO 2020/037079, published 20 Feb 2020; of record, see PTO-892 mailed 7 May 2026) in view of Morissette (Adv. Drug Delivery Rev., 2004, 56, 275-300) as applied to claims 1-2 and 11 above, and further in view of Keilhack (U.S. Patent No. 10,786,511, issued 29 Sept 2020).
Lampe (WO 2020/037079, published 20 Feb 2020; of record, see PTO-892 mailed 7 May 2026) in view of Morissette (Adv. Drug Delivery Rev., 2004, 56, 275-300) are applied as discussed in the 35 U.S.C. 103 rejection above.
The Examiner notes the relevant teachings with respect to claims 1-2 and 11 set forth above and are incorporated herein by reference.
Additional relevant teachings are set forth below.
Regarding claim 14, while Lampe and Morissette teaches a crystalline form of
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having Free Base Form II, the combination of Lampe and Morissette differs from that of the instantly claimed invention in that the combination of Lampe and Morissette does not explicitly teach a pharmaceutical composition have 35% w/w microcrystalline cellulose, 35% w/w lactose, and 3% w/w croscarmellose sodium.
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 Lampe and Morissette with the formulation as taught by Keilhack 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 Keilhack teaches formulations of the small molecule:
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for inhibiting EZH2, a histone methyltransferase, which has been associated with various kinds of cancers, such as leukemia (column 1, lines 16-21; column 1, lines 35-50). Keilhack teaches solid pharmaceutical formulations of a therapeutic agent and one or more pharmaceutically acceptable excipients for oral administration to a subject (column 3, lines 4-12; column 4, lines 21-27). Keilhack teaches that the concentration of the therapeutic agent is about 35-65 wt% in the formulation (column 4, lines 25-27) and that the term, “about” is defined to be that a collection or ranger of values is included and includes ±10% (column 20, lines 21-24). Accordingly, Keilhack teaches that the concentration of the therapeutic agent in the formulation is 25-75 wt%. Additionally, Keilhack teaches that the formulation has pharmaceutically acceptable excipients, such as a lubricant, a binder, a filler, and a disintegrant, which are useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable (column 24, lines 38-52). Keilhack teaches that microcrystalline cellulose is a binder and a disintegrant (column 24, line 67; column 25, lines 1; column 25, lines 13-14). Keilhack teaches that the composition has about 20 wt% (10-30 wt%) disintegrant (column 14, lines 58-64; column 25, lines 13-20). Additionally, Keilhack teaches an anhydrous lactose (a diluent) and that the lactose is present in the formulation in about 10-20 wt% (0-30 wt%; column 14, lines 58-64; column 25, line 8). Keilhack also teaches that the formulation is about 1-3 wt% (0-13%) magnesium stearate (column 14, lines 58-64). Keilhack teaches that the formulation is about 10-30% (0-40%) sodium croscarmellose (column 14, lines 58-64; column 25, line 15).
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). Keilhack teaches formulations for inhibiting EZH2, a histone methyltransferase, which has been associated with various kinds of cancers, such as leukemia (column 1, lines 16-21; column 1, lines 35-50) and particularly including microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate (column 14, lines 58-64; column 24, lines 38-52; column 25, lines 8, 13-20, 15). The ranges of the claimed invention (± 10%) significantly overlap with that of Keilhack. The specification of the claimed invention defines the term “about” to be a ±10% variation ([0182]). Accordingly, the pharmaceutical composition of claim 14 comprises: 15-35% crystalline form, 25-45% microcrystalline cellulose, 25-45% anhydrous lactose, 0-13% croscarmellose sodium, and 0-11.5% magnesium stearate (all w/w). Further, the range of the claimed invention does not provide an unexpected result in view of Keilhack, who teaches formulations of another histone methyltransferase for treating cancer (e.g. leukemia) via pharmaceutically acceptable excipients, which are useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable (column 1, lines 16-21; column 24, lines 38-52).
Thus, one of ordinary skill in the art would have substituted one known element for another, and the results would be predictable. As such, an artisan having ordinary skill in the art would have been motivated to make such a selection, to predictably arrive at instant claim 14: pharmaceutical composition of claim 14 comprises: 15-35% w/w crystalline form, 25-45% w/w microcrystalline cellulose, 25-45% w/w anhydrous lactose, 0-13% w/w croscarmellose sodium, and 0-11.5% w/w magnesium stearate.
Regarding claim 15, Keilhack teaches film-coated tablets (column 17, line 6).
Regarding claim 17, Keilhack teaches film-coated tablets (column 17, line 6).
Regarding claim 70, Keilhack teaches that the oral formulation is a stable formulation of the active compound and is at least 95% the desired formulation (column 14, lines 7-15).
Regarding claim 76, Keilhack teaches that the formulation has pharmaceutically acceptable excipients, such as a lubricant, a binder, a filler, and a disintegrant (column 24, lines 38-52).
Regarding claim 77, Keilhack teaches that the formulation has microcrystalline cellulose, pregelantinized corn starch, anhydrous lactose , mannitol, croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, and stearic acid (column 24, lines 38-52; column 24, line 67; column 25, line 1; column 26, line 26; column 25, line 6; column 25, lines 15; column 25, line 16; column 25, line 15; column 24; lines 67; column 25, line 36; column 25, line 22; column 25, line 24).
Regarding claim 78, Keilhack teaches the coating comprises hypromellose, titanium dioxide or macrogol (column 12, lines 64-65; column 13, lines 1-5).
3. Claim(s) 1-2 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Lampe (WO 2020/037079, published 20 Feb 2020; of record, see PTO-892 mailed 7 May 2026) in view of Carlson (US 2003/0124028) and Gardner (Computers and Chemical Engineering, 2004, 28, 943-953).
Lampe teaches substituted indole compounds that are SETD2 protein inhibitors (abstract; [0001]). Lampe teaches that the selective addition of methyl groups to specific amino acid sites on histones is controlled by the action of a family of enzymes known as histone methyltransferases and that the level of expression of a particular gene is influenced by the presence or absence of one or more methyl groups at a relevant histone site ([0002]). Lampe teaches that that special effect of a methyl group at a particular histone site persists until the methyl group is removed by a histone demethylase or until the modified histone is replaced through nucleosome turnover ([0002]). Lampe teaches that SETD2 is a human histone methyltransferase, which has been shown to have tumor suppressor functionality ([0003]; [0004]). Lampe teaches the despite its known functionality as a tumor suppressor, inhibition of SETD2 can be used to treat cancer ([0005]). Lampe teaches that Compound 15:
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, which is N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyll-1H-indole-2-carboxamide (page 53, Table 1; Example 1, [0632]). Lampe teaches pharmaceutical compositions of the compounds therein ([0405]).
Regarding claim 1, Lampe fails to teach a crystalline form of Form II having an XRPD of 7.0, 14.0, 18.0, and 20.2 degrees 2θ ± 0.2 °2θ.
Carlson teaches well-known systems for automated high-throughput preparation and screening of salts and polymorphs of drug candidates (abstract). Carlson teaches processes that determine suitable salts and processes that discover substantially every polymorph that can form from a particular drug candidate and a system that screens for crystalline forms of drug candidates or salts thereof (abstract; [0023]). Carlson teaches crystallization in ethanol and water ([0157]; [0165]; [0168]) under heat such as how Free Base Form II is generated ([0285]). Carlson also teaches cooling the mixture ([0264]). Carlson teaches filtering the mixture and drying under vacuum (abstract; [0124]; [0132]). Carlson teaches birefringence testing of crystals to determine the crystallinity of the sample: the quantity, size, and shape of crystals ([0195]). Additionally, Carlson teaches that different salts and polymorphs have characteristics that are desirable for a drug candidate and have different physical characteristics ([0004]-[0005]). Carlson also teaches that the polymorphic state of an active pharmaceutical ingredient can change the biological profile of the drug ([0005]).
Gardner teaches a commercially available system that is a similar system to Carlson: CrystalMax™ (page 948). Gardner teaches that CrystalMax™ is a high throughput platform for selection of forms and formulations of pharmaceutical candidates and products (page 947, column 2, paragraph 3). Gardner teaches success of CrystalMax™ in determining all polymorphs (even those previously unknown, such as Form III) in the known drug, ritonavir (page 949, column 2, paragraphs 2-3). Gardner teaches that previously drug discovery only paid a limited amount of attention to the physical/chemical properties and instead relied on solubilizing agents or pH control to force the compound into animal models or pharmacokinetic studies (page 944, column 2, paragraph 2). Gardner additionally teaches that that the consequences of ignoring these characteristics as lead candidates fall by the way-side due to the inability to administer them at appropriate doses in toxicology studies and in humans (page 945, column 1, paragraph 1). Additionally, Gardner teaches that the comprehensive investigation of the options for physical forms of drug candidates has two significant benefits: optimization of performance (e.g. oral bioavailability, suitable intravenous formulation, maximum chemical stability) and avoiding the risk of developing a metastable form which could later convert to a more stable form with physical properties that adversely affect the pharmaceutical performance of the formulation of the drug (page 945, column 2, paragraph 4).
Given the high level of skill in the art as evidenced by Carlson and Gardner, one of ordinary skill in the art would have considered the application of Carlson’s technique using a commercially available system as taught by Gardner to generate the Free Base Form II of
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of Lampe as “routine optimization,” because it was well-known, commercially available, and was a routine part of drug discovery as taught by Gardner (page 944, Figure 2; page 945, Figure 3).
One of ordinary skill in the art would have had a reasonable expectation of success in producing a polymorph having Free Base Form II of
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, because Lampe teaches
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and Carlson teaches the same process using ethanol and water, varying temperature, and filtering the crystals ([0006]; [0165]; [0124]; [0132]). “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.” KSR International Co. v Teleflex Inc., 550 U.S. 380 82 USPQ2d 1385 (2007). One of ordinary skill in the art would have known about the need to select the optimal form of the drug identified in Lampe, including the specific polymorphic forms which were known to be predictably discoverable by application of Carlson’s technique and were also within one of ordinary skill in the art’s technical grasp as evidenced by the commercially available system taught by Gardner. Thus, it would have been obvious to try and one of ordinary skill in the art would have anticipated success in the endeavor.
At the time of invention, there was an art recognized need to identify the optimal solid forms of a pharmaceutical. Carlson teaches that different salts and polymorphs have characteristics that are desirable for a drug candidate and have different physical characteristics ([0004]-[0005]). Carlson also teaches that the polymorphic state of an active pharmaceutical ingredient can change the biological profile of the drug ([0005]). Gardner teaches that previously drug discovery only paid a limited amount of attention to the physical/chemical properties and instead relied on solubilizing agents or pH control to force the compound into animal models or pharmacokinetic studies (page 944, column 2, paragraph 2). Gardner additionally teaches that that the consequences of ignoring these characteristics as lead candidates fall by the way-side due to inability to administer them at appropriate doses in toxicology studies and in humans (page 945, column 1, paragraph 1). Additionally, Gardner teaches that comprehensive investigation of the options for physical forms of drug candidates has two significant benefits: optimization of performance (e.g. oral bioavailability, suitable intravenous formulation, maximum chemical stability) and avoiding the risk of developing a metastable form which could later convert to a more stable form with physical properties that adversely affect the pharmaceutical performance of the formulation of the drug (page 945, column 2, paragraph 4). Accordingly, one of ordinary skill in the art would have pursued the commercially available system with a reasonable expectation of success, because the systems were known to identify substantially every polymorph (Carlson: abstract) and further Gardner demonstrated success with a commercial system (page 949, column 2, paragraphs 2-3). Similarly, one of ordinary skill in the art would have applied the known technique of pharmaceutical solid form optimization as taught by Carlson and Gardner to the known compound of Lampe:
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, which would have yielded the predictable result of the optimal pharmaceutical solid form. Alternatively, one of ordinary skill in the art would have used the known technique that successfully identified the optimal form of other pharmaceuticals demonstrated by Gardner and the polymorphic forms of ritonavir and applied the known optimization technique in the same way to the compound of Lampe where the result would have been predictable due to the explicit teaching of Carlson that the technique was known to identify ‘substantially every polymorph’ and ‘suitable salt.’ Moreover, products of identical chemical composition cannot have mutually exclusive properties. In re Spada, 911 F.2d 705, 709 15 USPQ2d 1655m, 1658 (Fed. Cir. 1990). A compound composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present. See MPEP 2112.01 (I)-(II).
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a crystalline form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyll-1H-indole-2-carboxamide (
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) having Free Base Form II with an XRPD of 7.0, 14.0, 18.0, and 20.2 degrees 2θ ± 0.2 °2θ.
Regarding claim 2, Lampe teaches
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and pharmaceutical compositions thereof (Table 1, page 53; [0405]). Carlson teaches a method of generating a polymorph via the same process using ethanol and water, varying temperature, and filtering the crystals ([0006]; [0165]; [0124]; [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of Lampe, Carlson, and Gardner teaches the crystalline form of
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having Free Base Form II.
Regarding claim 11, Lampe teaches
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and pharmaceutical compositions thereof (Table 1, page 53; [0405]). Carlson teaches a method of generating a polymorph via the same process using ethanol and water, varying temperature, and filtering the crystals ([0006]; [0165]; [0124]; [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of Lampe, Carlon, and Gardner teaches the crystalline form of
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having Free Base Form II.
4. Claim(s) 1-2, 11, 14-15, 17, 70, and 76-78 are rejected under 35 U.S.C. 103 as being unpatentable over Lampe (WO 2020/037079, published 20 Feb 2020; of record, see PTO-892 mailed 7 May 2026) in view of Carlson (US 2003/0124028) and Gardner (Computers and Chemical Engineering, 2004, 28, 943-953) as applied to claims 1-2 and 11 above, and further in view of Keilhack (U.S. Patent No. 10,786,511, issued 29 Sept 2020).
Lampe (WO 2020/037079, published 20 Feb 2020; of record, see PTO-892 mailed 7 May 2026) in view of Carlson (US 2003/0124028) and Gardner (Computers and Chemical Engineering, 2004, 28, 943-953) are applied as discussed in the 35 U.S.C. 103 rejection above.
The Examiner notes the relevant teachings with respect to claims 1-2 and 11 set forth above and are incorporated herein by reference.
Additional relevant teachings are set forth below.
Regarding claim 14, while Lampe, Carlson, and Gardner teaches a crystalline form of
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having Free Base Form II, the combination of Lampe, Carlson, and Gardner differs from that of the instantly claimed invention in that the combination of Lampe, Carlson, and Gardner does not explicitly teach a pharmaceutical composition have 35% w/w microcrystalline cellulose, 35% w/w lactose, and 3% w/w croscarmellose sodium.
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 Lampe, Carlson, and Gardner with the formulation as taught by Keilhack 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 Keilhack teaches formulations of the small molecule:
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for inhibiting EZH2, a histone methyltransferase, which has been associated with various kinds of cancers, such as leukemia (column 1, lines 16-21; column 1, lines 35-50). Keilhack teaches solid pharmaceutical formulations of a therapeutic agent and one or more pharmaceutically acceptable excipients for oral administration to a subject (column 3, lines 4-12; column 4, lines 21-27). Keilhack teaches that the concentration of the therapeutic agent is about 35-65 wt% in the formulation (column 4, lines 25-27) and that the term, “about” is defined to be that a collection or ranger of values is included and includes ±10% (column 20, lines 21-24). Accordingly, Keilhack teaches that the concentration of the therapeutic agent in the formulation is 25-75 wt%. Additionally, Keilhack teaches that the formulation has pharmaceutically acceptable excipients, such as a lubricant, a binder, a filler, and a disintegrant, which are useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable (column 24, lines 38-52). Keilhack teaches that microcrystalline cellulose is a binder and a disintegrant (column 24, line 67; column 25, lines 1; column 25, lines 13-14). Keilhack teaches that the composition has about 20 wt% (10-30 wt%) disintegrant (column 14, lines 58-64; column 25, lines 13-20). Additionally, Keilhack teaches an anhydrous lactose (a diluent) and that the lactose is present in the formulation in about 10-20 wt% (0-30 wt%; column 14, lines 58-64; column 25, line 8). Keilhack also teaches that the formulation is about 1-3 wt% (0-13%) magnesium stearate (column 14, lines 58-64). Keilhack teaches that the formulation is about 10-30% (0-40%) sodium croscarmellose (column 14, lines 58-64; column 25, line 15).
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). Keilhack teaches formulations for inhibiting EZH2, a histone methyltransferase, which has been associated with various kinds of cancers, such as leukemia (column 1, lines 16-21; column 1, lines 35-50) and particularly including microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate (column 14, lines 58-64; column 24, lines 38-52; column 25, lines 8, 13-20, 15). The ranges of the claimed invention (± 10%) significantly overlap with that of Keilhack. The specification of the claimed invention defines the term “about” to be a ±10% variation ([0182]). Accordingly, the pharmaceutical composition of claim 14 comprises: 15-35% crystalline form, 25-45% microcrystalline cellulose, 25-45% anhydrous lactose, 0-13% croscarmellose sodium, and 0-11.5% magnesium stearate (all w/w). Further, the range of the claimed invention does not provide an unexpected result in view of Keilhack, who teaches formulations of another histone methyltransferase for treating cancer (e.g. leukemia) via pharmaceutically acceptable excipients, which are useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable (column 1, lines 16-21; column 24, lines 38-52).
Thus, one of ordinary skill in the art would have substituted one known element for another, and the results would be predictable. As such, an artisan having ordinary skill in the art would have been motivated to make such a selection, to predictably arrive at instant claim 14: pharmaceutical composition of claim 14 comprises: 15-35% w/w crystalline form, 25-45% w/w microcrystalline cellulose, 25-45% w/w anhydrous lactose, 0-13% w/w croscarmellose sodium, and 0-11.5% w/w magnesium stearate.
Regarding claim 15, Keilhack teaches film-coated tablets (column 17, line 6).
Regarding claim 17, Keilhack teaches film-coated tablets (column 17, line 6).
Regarding claim 70, Keilhack teaches that the oral formulation is a stable formulation of the active compound and is at least 95% the desired formulation (column 14, lines 7-15).
Regarding claim 76, Keilhack teaches that the formulation has pharmaceutically acceptable excipients, such as a lubricant, a binder, a filler, and a disintegrant (column 24, lines 38-52).
Regarding claim 77, Keilhack teaches that the formulation has microcrystalline cellulose, pregelantinized corn starch, anhydrous lactose , mannitol, croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, and stearic acid (column 24, lines 38-52; column 24, line 67; column 25, line 1; column 26, line 26; column 25, line 6; column 25, lines 15; column 25, line 16; column 25, line 15; column 24; lines 67; column 25, line 36; column 25, line 22; column 25, line 24).
Regarding claim 78, Keilhack teaches the coating comprises Hypromellose, titanium dioxide or macrogol (column 12, lines 64-65; column 13, lines 1-5).
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.
5. Claim 1-2 and 11 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 12-13 and 17-20 of U.S. Patent No.12,116,358 in view of Morissette (Adv. Drug Delivery Rev., 2004, 56, 275-300).
U.S. Patent No. 12,116,358 claims
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and compositions thereof (claims 12-13 and 17-20).
Regarding claim 1, ‘358 fails to teach a crystalline compound of
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having polymorph form: Free Base Form II.
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 modify the compound of ‘358 with the method of Morissette to arrive at instant claim 1 (a crystalline form of
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having Free Base Form II). One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘358 claims
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and 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 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,
-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,
-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,
-Morissette teaches that 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.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a crystalline form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyll-1H-indole-2-carboxamide (
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) having Free Base Form II with an XRPD of 7.0, 14.0, 18.0, and 20.2 degrees 2θ ± 0.2 °2θ.
Regarding claim 2, ‘358 claims
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and pharmaceutical compositions thereof (claims 12-13 and 17-20). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘358 and Morissette teaches the crystalline form of
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having Free Base Form II.
Regarding claim 11, ‘358 teaches
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and pharmaceutical compositions thereof (claims 12-13 and 17-20). Morissette teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Accordingly, the combination of ‘358 and Morissette teaches the crystalline form of
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having Free Base Form II.
6. Claim 1-2 and 11 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 12-13 and 17-20 of U.S. Patent No.12,116,358 in view of Carlson (US 2003/0124028) and Gardner (Computers and Chemical Engineering, 2004, 28, 943-953).
U.S. Patent No. 12,116,358 claims
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and compositions thereof (claims 12-13 and 17-20).
Regarding claim 1, ‘358 fails to teach a crystalline compound of
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having polymorph form: Free Base Form II.
Carlson teaches well-known systems for automated high-throughput preparation and screening of salts and polymorphs of drug candidates (abstract). Carlson teaches processes that determine suitable salts and processes that discover substantially every polymorph that can form from a particular drug candidate (abstract). Carlson teaches a system that screens for crystalline forms of drug candidates or salts thereof ([0023]). Carlson teaches crystallization in ethanol and water ([0157]; [0165]; [0168]) under heat such as how Free Base Form II is generated ([0285]). Carlson also teaches cooling the mixture ([0264]). Carlson teaches filtering the mixture and drying under vacuum (abstract; [0124]; [0132]). Carlson teaches birefringence testing of crystals to determine the crystallinity of the sample: the quantity, size, and shape of crystals ([0195]). Additionally, Carlson teaches that different salts and polymorphs have characteristics that are desirable for a drug candidate and have different physical characteristics ([0004]-[0005]). Carlson also teaches that the polymorphic state of an active pharmaceutical ingredient can change the biological profile of the drug ([0005]).
Gardner teaches a commercially available system that is similar system to Carlson: CrystalMax™ (page 948). Gardner teaches that CrystalMax™ is a high throughput platform for selection of forms and formulations of pharmaceutical candidates and products (page 947, column 2, paragraph 3). Gardner teaches success of CrystalMax™ in determining all polymorphs (even those previously unknown) in the known drug, ritonavir (page 949, column 2, paragraphs 2-3). Gardner teaches that previously drug discovery only paid a limited amount of attention to the physical/chemical properties and instead relied on solubilizing agents or pH control to force the compound into animal models or pharmacokinetic studies (page 944, column 2, paragraph 2). Gardner additionally teaches that that the consequences of ignoring these characteristics as lead candidates fall by the way-side due to inability to administer them at appropriate doses in toxicology studies and in humans (page 945, column 1, paragraph 1). Additionally, Gardner teaches that comprehensive investigation of the options for physical forms of drug candidates has two significant benefits: optimization of performance (e.g. oral bioavailability, suitable intravenous formulation, maximum chemical stability) and avoiding the risk of developing a metastable form which could later convert to a more stable form with physical properties that adversely affect the pharmaceutical performance of the formulation of the drug (page 945, column 2, paragraph 4).
Given the high level of skill in the art as evidenced by Carlson and Gardner, one of ordinary skill in the art would have considered the application of Carlson’s technique using a commercially available system as taught by Gardner to generate the Free Base Form II of
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of ‘358 as “routine optimization,” because it was well-known, commercially available, and was a routine part of drug discovery as taught by Gardner (page 944, Figure 2; page 945, Figure 3).
One of ordinary skill in the art would have had a reasonable expectation of success in producing a polymorph having Free Base Form II of
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, because ‘358 teaches
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and Carlson teaches the same process using ethanol and water, varying temperature, and filtering the crystals ([0006]; [0165]; [0124]; [0132]). “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.” KSR International Co. v Teleflex Inc., 550 U.S. 380 82 USPQ2d 1385 (2007). One of ordinary skill in the art would have known about the need to select the optimal form of the drug identified in ‘358, including the specific polymorphic forms which were known to be predictably discoverable by application of Carlson’s technique and were also within one of ordinary skill in the art’s technical grasp as evidenced by the commercially available system taught by Gardner. Thus, it would have been obvious to try and one of ordinary skill in the art would have anticipated success in the endeavor.
At the time of invention, there was an art recognized need to identify the optimal solid forms of a pharmaceutical. Carlson teaches that different salts and polymorphs have characteristics that are desirable for a drug candidate and have different physical characteristics ([0004]-[0005]). Carlson also teaches that the polymorphic state of an active pharmaceutical ingredient can change the biological profile of the drug ([0005]). Gardner teaches that previously drug discovery only paid a limited amount of attention to the physical/chemical properties and instead relied on solubilizing agents or pH control to force the compound into animal models or pharmacokinetic studies (page 944, column 2, paragraph 2). Gardner additionally teaches that that the consequences of ignoring these characteristics as lead candidates fall by the way-side due to inability to administer them at appropriate doses in toxicology studies and in humans (page 945, column 1, paragraph 1). Additionally, Gardner teaches that comprehensive investigation of the options for physical forms of drug candidates has two significant benefits: optimization of performance (e.g. oral bioavailability, suitable intravenous formulation, maximum chemical stability) and avoiding the risk of developing a metastable form which could later convert to a more stable form with physical properties that adversely affect the pharmaceutical performance of the formulation of the drug (page 945, column 2, paragraph 4). Accordingly, one of ordinary skill in the art would have pursued the commercially available system with a reasonable expectation of success, because the systems were known to identify substantially every polymorph (Carlson: abstract) and Gardner demonstrated success with a commercial system (page 949, column 2, paragraphs 2-3). Similarly, one of ordinary skill in the art would have applied the known technique of pharmaceutical solid form optimization as taught by Carlson and Gardner to the known compound of ‘358:
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, which would have yielded the predictable result of the optimal pharmaceutical solid form. Alternatively, one of ordinary skill in the art would have used the known technique that successfully identified the optimal form of other pharmaceuticals demonstrated by Gardner and the polymorphic forms of ritonavir and applied the known optimization technique in the same way to the compound of ‘358 where the result would have been predictable due to the explicit teaching of Carlson that the technique was known to identify ‘substantially every polymorph’ and ‘suitable salt.’ Moreover, products of identical chemical composition cannot have mutually exclusive properties. In re Spada, 911 F.2d 705, 709 15 USPQ2d 1655m, 1658 (Fed. Cir. 1990). A compound composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present. See MPEP 2112.01 (I)-(II).
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a crystalline form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyll-1H-indole-2-carboxamide (
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) having Free Base Form II with an XRPD of 7.0, 14.0, 18.0, and 20.2 degrees 2θ ± 0.2 °2θ.
Regarding claim 2, ‘358 claims
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and pharmaceutical compositions thereof (claims 12-13 and 17-20). Carlson teaches a method of generating a polymorph via the same process using ethanol and water, varying temperature, and filtering the crystals ([0006]; [0165]; [0124]; [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘358, Carlson, and Gardner teaches the crystalline form of
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having Free Base Form II.
Regarding claim 11, ‘358 teaches
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and pharmaceutical compositions thereof (claims 12-13 and 17-20). Carlson teaches a method of generating a polymorph via the same process using ethanol and water, varying temperature, and filtering the crystals ([0006]; [0165]; [0124]; [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘358, Carlon, and Gardner teaches the crystalline form of
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having Free Base Form II.
Conclusion
No claim is allowed.
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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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