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/CN2021/108776 and PCT/CN2022/108128, with the effective filing dates of 28 July 2021 and 27 July 2022.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 6 May 2026.
Applicant’s election with traverse of Group I (claims 36-49 and 51-57) and the species of polymorph form I in the reply filed 6 May 2026 is acknowledged. The traversal is on the ground(s) that the Examiner incorrectly asserting lack of unity a priori and that the Examiner did not assert lack of unity a posteriori as the Examiner did not assert prior art.
However, this is not found persuasive, because Applicant incorrectly states that the Examiner relied on an a priori assertion that the claims did not possess common subject matter. Additionally, the Applicant states that the Examiner did not assert lack of unity a posteriori and did not cite prior art. The Examiner asserted lack of unity via showing that the special technical feature of Groups I-III and the species did not make a contribution over the prior art in view of Henry (U.S. Patent No. 9,637,474, issued 2 May 2017; of record; see PTO-892 mailed 11 Mar 2026) and Sugimoto (U.S. Patent No. 9,346,787, issued 24 May 2017; of record; see PTO-892 mailed 11 Mar 2026). Additionally, Applicant has not established that the claimed invention provides a contribution over the cited prior art in the Restriction Requirement mailed 11 March 2026. Thus, the requirement is still deemed proper and is therefore made FINAL.
Claims 50 and 58-60 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected group (Group II: 50; Group III: 58-60), there being no allowable generic or linking claim.
Claims 36 and 42-47 were canceled.
Claims 37-41, 47-49, and 51-57 read on the elected species.
Information Disclosure Statement
The Information Disclosure Statement filed 26 January 2024 and the references cited therein have been considered, unless indicated otherwise.
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. Claims 37-41 and 51-54 are rejected under 35 U.S.C. 103 as being unpatentable over Henry (U.S. Patent No. 9,637,474, issued 2 May 2017; of record; see PTO-892 mailed 11 Mar 2026) in view of Sugimoto (U.S. Patent No. 9,346,787, issued 24 May 2017; of record; see PTO-892 mailed 11 Mar 2026) and Morissette (Adv. Drug Delivery Rev., 2004, 56, 275-300).
Henry teaches aminopyridine compounds and salts thereof that inhibit Aurora A for treating cancer (abstract; column 1, lines 29-32;
lines 37-44). Henry specifically teaches the compound,
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, and a pharmaceutically acceptable salt thereof (column 2, lines 24-46). Additionally, Henry teaches that a number of inorganic and organic acids and bases are competent for generating a pharmaceutically acceptable salt of the compounds (column 5, lines 6-15). Further, Henry teaches it is important to provide selective Aurora A inhibitors that reduce or avoid Aurora B or Aurora A/B dual inhibition, because Aurora B inhibition induces endo-reduplication and subsequent polyploidy, which is a major pathway for genomic instability (column 1, lines 38-44; lines 13-15). Additionally, Henry teaches that Example 1 shows excellent selectivity for Aurora A over Aurora B (column 19, lines 30-35; column 20, lines 28-30).
Regarding claim 37, Henry fails to teach the eastern fragment,
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Sugimoto teaches Aurora A inhibitors and salts thereof with core scaffold:
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(abstract; column 3, lines 5-15). Sugimoto specifically teaches the compound,
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(column 43, Example 13). Additionally, Sugimoto teaches examples of base addition salt include an alkali metal salt such as sodium salt and a potassium salt (column 17, lines 48-49). Sugimoto also teaches that the compounds therein are crystals that are solvates or hydrates (column 17, lines 34-36). Sugimoto further teaches compounds with excellent selectivity for Aurora A, which are orally bioavailable (column 2, lines 44-51). Sugimoto teaches that specific substitution on the pyridine ring of the eastern fragment shows excellent Aurora A selectivity (column 2, lines 56-59). Sugimoto also teaches that Example 13 has excellent selectivity for Aurora A over Aurora B (Table 19, column 56, line 38).
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 Henry with the compound of eastern fragment of Sugimoto and the method of Morissette to arrive at instant claim 37 (a polymorph form I of
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). One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Henry teaches aminopyridine compounds and salts thereof that inhibit Aurora A for treating cancer,
-Henry teaches the compound,
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, and a pharmaceutically acceptable salt thereof,
-Henry teaches that a number of inorganic and organic acids and bases are competent for generating a pharmaceutically acceptable salt of the compounds,
-Henry teaches it is important to provide selective Aurora A inhibitors that reduce or avoid Aurora B or Aurora A/B dual inhibition, because Aurora B inhibition induces endo-reduplication and subsequent polyploidy, which is a major pathway for genomic instability,
-Henry teaches that Example 1 shows excellent selectivity for Aurora A over Aurora B,
-Sugimoto teaches Aurora A inhibitors and salts thereof with core scaffold:
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,
-Sugimoto specifically teaches the compound,
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,
-Sugimoto teaches examples of base addition salt include an alkali metal salt such as sodium salt and a potassium salt,
-Sugimoto also teaches that the compounds therein are crystals that are solvates or hydrates,
-Sugimoto teaches compounds with excellent selectivity for Aurora A, which are orally bioavailable,
-Sugimoto teaches that specific substitution on the pyridine ring of the eastern fragment shows excellent Aurora A selectivity,
-Sugimoto also teaches that Example 13 has excellent selectivity for Aurora A over Aurora B,
-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.
Additionally, while neither Henry nor Sugimoto teach a methyl para to the nitrogen of the pyridinyl ring, 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 compounds of Henry and Sugimoto differ from a compound of Formula I in the change from hydrogen to methyl at the para-position of the pyridine ring, a person of ordinary skill in the art would expect the compounds to have similar properties and thus would contemplate making them to try and obtain compounds with improved properties. Thus, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a compound having the structure:
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.
Accordingly, the combination of Henry, Sugimoto, and Morissette teaches a pharmaceutical composition of a solvate of polymorph form I of
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having XRPD peaks at diffraction angles 2θ of 4.7° ± 0.2, 9.3° ± 0.2, and 14.1° ± 0.2.
Regarding claim 38, Morissette teaches that high throughput screening produces many polymorphs in a short period of time (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Thus, one of ordinary skill in the art would use the high throughput screening technology as described by Morissette to access a solvate of polymorph form I of Formula (I):
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, wherein the XRPD has peaks at diffraction angles 2θ of 4.7° ± 0.2, 9.3° ± 0.2, 14.1° ± 0.2, 22.1° ± 0.2, and 26.4° ± 0.2.
Regarding claim 39, Morissette teaches that high throughput screening produces many polymorphs in a short period of time (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Thus, one of ordinary skill in the art would use the high throughput screening technology as described by Morissette to access a solvate of polymorph form I of Formula (I):
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, wherein the XRPD has peaks at diffraction angles 2θ of 4.7° ± 0.2, 9.3° ± 0.2, 14.1° ± 0.2, 15.9° ± 0.2, 17.9° ± 0.2, 22.1° ± 0.2, 26.4° ± 0.2, 32.2° ± 0.2, and 38.0° ± 0.2.
Regarding claim 40, Morissette teaches that high throughput screening produces many polymorphs in a short period of time (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Thus, one of ordinary skill in the art would use the high throughput screening technology as described by Morissette to access a solvate of polymorph form I of Formula (I):
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, wherein the XRPD has peaks at diffraction angles 2θ of 4.7° ± 0.2, 9.3° ± 0.2, 14.1° ± 0.2, 15.9° ± 0.2, 17.9° ± 0.2, 19.5° ± 0.2, 22.1° ± 0.2, 23.5° ± 0.2, 24.6° ± 0.2, 25.0° ± 0.2, 26.4° ± 0.2, 32.2° ± 0.2, 35.6° ± 0.2, and 38.0° ± 0.2.
Regarding claim 41, Morissette teaches that high throughput screening produces many polymorphs in a short period of time (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Thus, one of ordinary skill in the art would use the high throughput screening technology as described by Morissette to access a solvate of polymorph form I of Formula (I):
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, wherein the XRPD is as shown in Figure 1.
Regarding claim 51, Henry teaches that the compound is formulated using a pharmaceutically acceptable carrier (column 5, lines 16-19; column 26, lines 1-21).
Regarding claim 52, Sugimoto teaches a composition comprising at least one additional active ingredient: paclitaxel (column 58, lines 28-38; Text Example 4; Groups 4 and 5).
Regarding claim 53, Sugimoto teaches oral administration of the compound (column 58, lines 24-25 and 28-38; Test Example 4, Groups 2, 4, and 5).
Regarding claim 54, Sugimoto teaches the oral solid preparation is a tablet (column 19, lines 45-50).
2. Claim(s) 37-41, 47-49, and 51-57 are rejected under 35 U.S.C. 103 as being unpatentable over Henry (U.S. Patent No. 9,637,474, issued 2 May 2017; of record; see PTO-892 mailed 11 Mar 2026) in view of Sugimoto (U.S. Patent No. 9,346,787, issued 24 May 2017; of record; see PTO-892 mailed 11 Mar 2026) and Morissette (Adv. Drug Delivery Rev., 2004, 56, 275-300) as applied to claim 37-41 and 51-54 above, and further in view of Mitsuya (U.S. Patent Publication 2020/087282, published 19 Mar 2020).
Henry (U.S. Patent No. 9,637,474, issued 2 May 2017; of record; see PTO-892 mailed 11 Mar 2026) in view of Sugimoto (U.S. Patent No. 9,346,787, issued 24 May 2017; of record; see PTO-892 mailed 11 Mar 2026) and Morissette (Adv. Drug Delivery Rev., 2004, 56, 275-300) are applied as discussed in the 35 U.S.C. 103 rejection above.
Regarding claim 47, while the combination of Henry, Sugimoto, and Morissette teaches a solvate of polymorph form I of
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, they differ from that of the instantly claimed invention in that they do not explicitly teach that the polymorph as a purity of ≥95%.
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 polymorph of Henry, Sugimoto, and Morissette with the polymorph of Mitsuya 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 Mitsuya teaches polymorphs of the hydrochloride and potassium salts of 1-(2,3-dichlorobenzoyl)-4-((5-fluoro-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid, which is
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(abstract; [0001]; [0023]-[0024]). Additionally, Mitsuya teaches that the compound of interest (Compound 1) is an Aurora A inhibitor with excellent activity and that the free form of Compound 1 has low solubility and oral absorption ([0004]; [0008]). Mitsuya further teaches that oral administration has few burdens for patients and thus improvement of oral absorption is an important issue for the formulation of Compound 1 ([0008]). Additionally, Mitsuya teaches assessment of various salts of Compound 1 and that the HCl salt is particularly excellent in solubility, stability, and oral absorption ([0010]). Mitsuya specifically teaches the potassium salt of Compound 1 has a purity of 99.8% (Table 3, Example 1-1; [0160]-[0161]). Accordingly, Mitsuya teaches polymorph form I of
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in purity ≥95%.
Regarding claim 48, Mitsuya teaches the potassium salt has purity of 99.8% (Table 3, Example 1-1; [0160]-[0161]), which is a purity of ≥99%.
Regarding claim 49, Mitsuya teaches the potassium salt has purity of 99.8% (Table 3, Example 1-1; [0160]-[0161]), which is a purity of ≥99.5%.
Regarding claim 55, Mitsuya teaches a composition of the crystal of Compound 1 are obtained at a weight percent of 50% or more ([0084]-[0085]).
Regarding claim 56, Mitsuya teaches a composition of the crystal of Compound 1 are obtained at a weight percent of 50% or more ([0084]-[0085]).
Regarding claim 57, Mitsuya teaches a composition of the crystal of Compound 1 are obtained at a weight percent of 50% or more ([0084]-[0085]). 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). Mitsuya teaches compositions of a crystal of Compound 1 wherein the weight percent is 50% or more ([0084]-[0085]). Mitsuya additionally teaches that the potassium salt suffered from weight change of 14% in humid conditions and thus is susceptible to ambient humidity, which may decrease stability ([0166]). The specification of the claimed invention defines the term “about” to be a ±10% variation (page 16, paragraph 1). Accordingly, the amount of polymorph form I of
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is 0-40 wt.%. While the range of the claimed invention does not overlap with the range of Mitsuya, the range of the claimed invention does not provide an unexpected result in view of Mitsuya, who describes compositions and their respective weight percents of the polymorph of Compound 1 ([0084]-[0085]) as well as the motivation to make an oral composition having 40 wt.% of a polymorph of Compound 1 to reduce weight change via decreasing the active pharmaceutical ingredient and increasing the pharmaceutically acceptable carrier ([0089]-[0091]; [0166]). Additionally, Mitsuya teaches a composition wherein the seed crystal is 0.1-10% by weight of the salt of Compound 1 to start the crystallization ([0075]), which overlaps with the range of the claimed invention. The range of the claimed invention does not provide an unexpected result in view of Mitsuya, who describe polymorphs of the Aurora A inhibitor, Compound 1, with better solubility, stability, and oral absorption (abstract; [0001]; [0010]; [0023]-[0024]).
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.
3. Claims 37-41 and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of U.S. Patent No. 11,384,066 in view of Morissette (Adv. Drug Delivery Rev., 2004, 56, 275-300).
U.S. Patent No. 11,384,066 teaches the compound,
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, and pharmaceutically acceptable salts thereof, which includes a potassium salt (column 83, lines 57-58; column 84, lines 5-9). Thus, ‘066 teaches
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(claim 1) and a composition having
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and at least one pharmaceutically acceptable carrier (claim 3).
Regarding claim 37, ‘066 fails to teach polymorph form I having XRPD peaks at diffraction angles 2θ of 4.7° ± 0.2, 9.3° ± 0.2, and 14.1° ± 0.2.
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 ‘066 and the method of Morissette to arrive at instant claim 37 (a polymorph form I of
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). One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘066 teaches the compound,
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, and pharmaceutically acceptable salts thereof, which includes a potassium salt,
-‘066 teaches
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and a composition having
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and at least one pharmaceutically acceptable carrier,
-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.
Accordingly, the combination of ‘066 and Morissette teaches a pharmaceutical composition of polymorph form I of
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having XRPD peaks at diffraction angles 2θ of 4.7° ± 0.2, 9.3° ± 0.2, and 14.1° ± 0.2.
Regarding claim 38, Morissette teaches that high throughput screening produces many polymorphs in a short period of time (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Thus, one of ordinary skill in the art would use the high throughput screening technology as described by Morissette to access polymorph form I of Formula (I):
PNG
media_image5.png
172
284
media_image5.png
Greyscale
, wherein the XRPD has peaks at diffraction angles 2θ of 4.7° ± 0.2, 9.3° ± 0.2, 14.1° ± 0.2, 22.1° ± 0.2, and 26.4° ± 0.2.
Regarding claim 39, Morissette teaches that high throughput screening produces many polymorphs in a short period of time (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Thus, one of ordinary skill in the art would use the high throughput screening technology as described by Morissette to access polymorph form I of Formula (I):
PNG
media_image5.png
172
284
media_image5.png
Greyscale
, wherein the XRPD has peaks at diffraction angles 2θ of 4.7° ± 0.2, 9.3° ± 0.2, 14.1° ± 0.2, 15.9° ± 0.2, 17.9° ± 0.2, 22.1° ± 0.2, 26.4° ± 0.2, 32.2° ± 0.2, and 38.0° ± 0.2.
Regarding claim 40, Morissette teaches that high throughput screening produces many polymorphs in a short period of time (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Thus, one of ordinary skill in the art would use the high throughput screening technology as described by Morissette to access polymorph form I of Formula (I):
PNG
media_image5.png
172
284
media_image5.png
Greyscale
, wherein the XRPD has peaks at diffraction angles 2θ of 4.7° ± 0.2, 9.3° ± 0.2, 14.1° ± 0.2, 15.9° ± 0.2, 17.9° ± 0.2, 19.5° ± 0.2, 22.1° ± 0.2, 23.5° ± 0.2, 24.6° ± 0.2, 25.0° ± 0.2, 26.4° ± 0.2, 32.2° ± 0.2, 35.6° ± 0.2, and 38.0° ± 0.2.
Regarding claim 41, Morissette teaches that high throughput screening produces many polymorphs in a short period of time (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1). Thus, one of ordinary skill in the art would use the high throughput screening technology as described by Morissette to access polymorph form I of Formula (I):
PNG
media_image5.png
172
284
media_image5.png
Greyscale
, wherein the XRPD is as shown in Figure 1.
Regarding claim 51, ‘066 teaches that the compound is formulated using a pharmaceutically acceptable carrier (claim 3).
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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