DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application, filed September 3, 2024, is a Continuation of U.S. Patent Application No. 17/207,518 (now U.S. Patent No. 12,076,315), filed March 19, 2021, which claims priority to U.S. Provisional Patent Application No. 63/043,382, filed June 24, 2020, and to U.S. Provisional Patent Application No. 62/992,720, filed March 20, 2020. The latter document does not appear to disclose the presently claimed subject matter. As such, the priority date is considered to be June 24, 2020.
Drawings
The replacement drawings filed April 16, 2025 are accepted.
Status of the Claims
Claims 1-18 are currently pending.
Information Disclosure Statement
The three information disclosure statements (IDSs) submitted on April 30, 2025 are acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 recites a method of making a crystal comprising a polymorphic form C of brequinar sodium salt. Claim 1 further recites that the crystallizing step “produce[s] a crystal comprising polymorphic form C of brequinar sodium salt.” As such, it appears intended as a limiting feature of the claimed method that it result in production of “polymorphic form C of brequinar sodium salt.” It would not be possible for a person having ordinary skill in the art to determine the metes and bounds of the claimed invention and, in particular, of this limitation, for the following three reasons:
there is no recited threshold or amount of polymorphic form C of brequinar sodium salt that must be present in the produced crystal,
there is neither any recited method nor any accepted standard method for determining an amount of polymorphic form C of brequinar sodium salt in a produced crystal, and
there is no time recited at which the presence of polymorphic form C of brequinar sodium salt must be determined.
In view of the first two reasons above, a broadest reasonable interpretation of claim 1 could be that the recited method produces a crystals comprising any detectable quantity of polymorphic form C of brequinar sodium salt, as determined by any suitable procedure. However, the instant disclosure indicates that a commercially obtained solid sample of brequinar (PS04375-1-E-P4) contains a mix of polymorphic forms, including form C. As such, it is likely that many, if not all, methods of producing solid brequinar would produce at least some polymorphic form C. Furthermore, it is unclear that there exist in the art any commonly accepted suitable procedures for detecting polymorphic form C of brequinar, although there are procedures presented in the instant specification that purport to detect polymorphic form C.
Regarding the third reason, above, the instant disclosure indicates that, depending on storage conditions, different polymorphs of brequinar spontaneously convert to form C over time. The limitation that the recited method produced brequinar polymorphic form C is therefore further indefinite, as the presence or amount of polymorphic form C would presumably be time dependent, at least under some conditions. For the aforementioned reasons, the limitation that the method of claim 1 produces a crystal comprising polymorphic form C of brequinar sodium salt is indefinite, and cannot be afforded patentable weight.
Claim 1 is further indefinite for reciting “polymorphic C form of brequinar sodium salt” in line 6, because this element lacks antecedent basis. The line 1 preamble of claim 1 recites “polymorphic form C of brequinar sodium salt.” This inversion of “form C” to “C form” in the line 6 recitation of the polymorph causes the line 6 recitation to lack antecedent basis.
Claim 15, depending from claim 11, is further rejected for lack of antecedent basis. Claim 15 recites the limitation "the alkane-containing mixture" in line 2. There is insufficient antecedent basis for this limitation in the claim. In the interest of compact prosecution, claim 15 is examined against the prior art, below, as if claim 15 depended from claim 13 instead of from claim 11.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 5-7, and 9 are unpatentable over Sykes and Wu:
Claims 1, 5-7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over the non-patent publication, Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia, Cell, 167, pgs. 171-186, including additional experimental pgs. e1-e8 (2016) by Sykes et al. (hereinafter, “Sykes”), in view of the non-patent publication, The Impact of Crystallinity on Brequinar Sodium Hygroscopicity, Pharm. Dev. & Tech., 1 pgs. 42-49 (1996) by Wu et al. (hereinafter, “Wu”).
Claim 1 recites a method of making a crystal comprising polymorphic form C of brequinar sodium salt, the method comprising the steps of combining a solid form of brequinar acid, sodium hydroxide (NaOH), and a solvent to produce a solution; and crystallizing brequinar sodium salt from the solution to produce a crystal comprising polymorphic form C of brequinar sodium salt.
As noted above in the rejection of claim 1 under 35 U.S.C. § 112(b), the recited feature in which the method produces a crystal comprising a polymorphic form C of brequinar sodium salt cannot be given patentable weight due to the absence of any threshold amount of form C, method for determining the presence or amount of form C beyond the amount apparently present in a commercial sample, among other reasons. As such, claim 1 is examined against the prior art as reciting a method of making a crystal comprising brequinar sodium salt, comprising combining a solid form of brequinar acid, NaOH, and a solvent to produce a solution; and crystallizing brequinar sodium salt from the solution.
Sykes teaches synthesis of 2-(2'-Fluoro-1,1'-biphenyl-4-yl)-6-fluoro-3-methyl-4-quinolinecarboxylic acid (brequinar free acid, BSQ) via Pfitzinger reaction. Of note, Sykes further teaches that the BSQ product is recrystallized in dimethyl formamide followed by conversion of the recrystallized BSQ into brequinar sodium via reaction with sodium hydroxide in a subsequent step (referred to hereinafter as the ionization step) under unspecified conditions. As such, Sykes teaches a method of making a crystal comprising brequinar and reacting brequinar with NaOH to form brequinar sodium. Sykes further teaches that the method comprises combining brequinar with a solvent (DMF) to produce a solution, and crystallizing brequinar from the solution
[AltContent: textbox (ionization step)][AltContent: textbox (Pfitzinger reaction)]
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Above: modified scheme of the synthesis of brequinar sodium salt, from Sykes. This scheme does not show the recrystallization in DMF, which is performed after initial brequinar formation, and before conversion to brequinar sodium salt.
Sykes does not explicitly teach the conditions of the ionization reaction, nor whether the product of the ionization reaction is a crystal or a solution. As such, Sykes does not explicitly teach combining brequinar free acid and brequinar sodium in solution to crystallize brequinar sodium. This would have been obvious to one of ordinary skill in the art, however, in order to reduce steps and because brequinar sodium was known in the art as a material to be stored in crystalline form. See for example, Wu.
Wu describes a study of the stability of different lots of brequinar sodium crystals, teaching that brequinar sodium was used in clinical trials (Introduction, first paragraph). Wu further teaches that impurities and crystal lattice imperfections can affect crystalline properties like stability and polymorphic transitions (pg. 43, right column, final paragraph, onto pg. 44 left column, first paragraph). Because Wu teaches that brequinar sodium crystals are a useful storage vehicle, it would have been obvious to one of ordinary skill in the art to combine sodium hydroxide with brequinar free acid, as in the crystallization of Sykes, to directly produce brequinar sodium crystals.
Claims 5-7 and 9 recite ratios of NaOH to brequinar in the ionization/crystallization solution (claims 5 and 6) or ranges of temperature at which the solution is set (claims 7 and 9). Sykes as modified by Wu and Mullin teaches recrystallization of brequinar in isopropanol/water, with NaOH present to ionize the free acid to sodium salt, but does not explicitly teach a specific ratio of isopropanol:water, a specific ratio of NaOH to brequinar, or a specific ionization/solubilization temperature. It would have been obvious, however to optimize these ratios and temperatures through routine experimentation, to improve yield. “[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. Thus, it would have been obvious to optimize NaOH to brequinar molar ratio to drive the ionization of brequinar free acid to completion, and to optimize temperature to allow ionization and maximum solubilization of the ionized brequinar.
This is particularly so in a chemical preparation where no particular yield, purity, or threshold amount of the desired product (polymorphic form C of brequinar) is claimed and where there is no showing of criticality of the recited ranges of NaOH:brequinar ratio, or of temperature.
Claims 2-4, 11-12, and 16 are unpatentable over Sykes, Wu, and Mullin:
Claims 2-4, 11-12, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Sykes, in view of Wu, further in view of the non-patent publication, Crystallization (Fourth Edition), published by Butterworth-Heinemann (2001) by Mullin (hereinafter, “Mullin”).
Claim 2 recites the method of claim 1 wherein the solvent (i.e. the solvent in which brequinar acid and NaOH are co-dissolved in prior to recrystallization) is isopropanol and water. Claims 3 recites that the ratio of isopropanol:water is from about 95:5 to about 98.2, while claim 4 recites that this ratio is about 97:3. Neither Sykes nor Wu expressly teaches crystallization of brequinar sodium from a solution comprising an isopropanol/water mixed solvent system, it would have been obvious to try this solvent system during routine crystallization optimization, as the use of water/alcohol solvent systems for crystallization was very common in the art, particularly for polar or ionized organic molecules, such as brequinar/brequinar sodium. See, for example, Mullin.
Mullin provides a general overview of crystallization, including optimization of crystallization conditions. Mullin teaches that water is used whenever possible as a crystallization solvent, even for organic compounds, for various reasons including availability, cheapness, and innocuousness (pg. 86, final full paragraph). Mullin further teaches that, particularly in industrial applications, the list of solvents used in organic crystallization can be reduced to a few dozen solvents selected from a small number of groups; one of the groups being lower alcohols (e.g. isopropanol – bottom of pg. 86 to top of pg. 86). Mullin further teaches that binary solvent systems are often useful for crystallization, and presents a short list of the most common binary solvent systems for crystallization, including alcohols with water. Further, Mullin teaches that solvents can be divided into 3 categories: polar protic (such as water and methanol), dipolar aprotic, and non-polar aprotic, and that a solute capable of H-bonding (such as the carboxylate group of brequinar acid) will tend to make a polar protic solvent a good choice for crystallization (pg. 87, bottom, to pg. 88, top). Wu teaches that brequinar sodium is soluble in water (pg. 49, left column, second full paragraph). It would have been obvious to try a solvent comprising isopropanol and water, as a common binary solvent system for crystallization, particularly of polar solutes as taught by Mullin, and further given the known solubility of brequinar sodium in water as taught by Wu, in order to optimize purity and obtain crystals with few imperfections, as motivated by Wu. As such, claim 2 is obvious.
Claims 3-4, as noted, recite ranges of isopropanol:water in the ionization/crystallization solvent. Sykes as modified by Wu and Mullin teaches recrystallization of brequinar in isopropanol/water, with NaOH present to ionize the free acid to sodium salt, but does not explicitly teach a specific ratio of isopropanol:water. As discussed above with respect to NaOH:brequinar ratio, it would have been obvious, to optimize the isopropanol/water ratio through routine experimentation, to improve yield. “[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. Thus, it would have been obvious to optimize the isopropanol:water ratio to enhance solubility of the ionized brequinar relative to the free acid.
This is particularly so in a chemical preparation where no particular yield, purity, or threshold amount of the desired product (polymorphic form C of brequinar) is claimed and where there is no showing of criticality of the recited ranges of solvent ratio.
With respect to claim 11, claim 11 recites that the crystallizing step comprises adding a seed crystal of polymorphic form C of brequinar sodium salt to the solution to produce a seeded mixture. Mullin teaches that supersaturation or supercooling are not sufficient to cause a system to begin to crystallize, and that there must exist in the solution a number of minute solid bodies, embryos, nuclei or seeds. Mullin further teaches that this crystallization initiation, i.e. nucleation, can occur spontaneously (via particles resident in the system) or can be induced (pg. 181, first paragraph). Mullin further teaches that a supersaturated solution nucleates much more readily, i.e. at a lower supersaturation, when crystals of the solute are already present or deliberately added (pg. 195, Section 5.2 Secondary nucleation, first paragraph).
With respect to claim 12, as noted, Mullin teaches the well-known method of cooling a crystallization solution to facilitate depositing the solute from solution as a desired crystal. Also as discussed above, the precise temperature ranges are a matter of routine experimentation and optimization, particularly absent any showing of criticality, such as a critical temperature to obtain a specified percentage of the desired polymorphic form.
With respect to claim 16, Mullin teaches filtering the product crystals after crystallization, e.g. removing the solvent from the product crystals (pg. 96, section 3.5, discussing undesirable retention of mother liquor after filtration).
Claims 8 and 10 are unpatentable over Sykes, Wu, and Romão:
Claims 8 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Sykes, in view of Wu, and further in view of the non-patent publication, An Efficient and Inexpensive Apparatus for Hot Filtration, J. Chem. Ed., 78, pg. 65 (2001) by Romão et al. (hereinafter, “Romão”).
Claim 8 recites the method of claim 1, wherein the combining step comprises removing insoluble material from the solution. Sykes and Wu are applied to claim 8 as to claim 1, above, but neither explicitly teaches removing insoluble material from the solution during the combining step. It would have been obvious to one of ordinary skill in the art to remove insoluble material during the combining step, because it was well-known in the art to remove insoluble impurities from the crystallization solution during recrystallization, e.g. by hot filtration. See, for example, Romão.
Romão teaches an apparatus for use in college chemistry labs for hot filtration during recrystallization. Romão teaches that hot filtration, which allows removing insoluble impurities, is particularly important in recrystallization processes (pg. 65, left column, first paragraph). It would have been obvious to incorporate the removal of insoluble impurities via hot filtration (removal of insoluble material) into the method of Sykes and Wu, in order to ensure a higher purity product. With respect to claim 10, claim 10 combines the features of claims 1 and 7-9, and is thus obvious for the reasons described above with respect to claims 1, 7, 8, and 9.
Claims 13-15 and 17-18 are rejected as unpatentable over Sykes, Wu, Mullin, and De la Rosa:
Claims 13-15 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Sykes, Wu, and Mullin, and further in view of the non-patent publication, non-patent publication, Solubility Determination and Correlation of Warfarin Sodium 2-Propanol Solvate in Pure, Binary, and Ternary Solvent Mixtures, J. Chem. Eng. Data, 64, pgs. 1399-1413 (2019) by De la Rosa et al. (hereinafter, “De la Rosa”).
Claim 13 recites the method of claim 11 (having the step of adding a seed crystal) wherein the crystallizing step comprises adding an alkane to the solution to produce an alkane-containing mixture. Sykes, Wu, and Mullin are applied to claim 13 as to claims 1 and 11, above. Sykes, Wu, and Mullin do not explicitly teach adding an alkane to produce an alkane-containing mixture, however it would have been obvious to one of ordinary skill in the art to add an antisolvent such as an alkane to the crystallization solution in order to facilitate crystallization of organic APIs. See, for example, De la Rosa.
De la Rosa teaches crystallization of warfarin from various mixed (e.g. binary and ternary) solvent systems, including isopropanol/water, isopropanol/water/hexane, and isopropanol/water/heptane (Abstract). De la Rosa teaches that hexane and heptane act as antisolvents in these systems (Abstract) and that hexane is commonly used as an antisolvent in pharmaceutical crystallization processes (pg. 1400, left column, first full paragraph). De la Rosa teaches that, with hexane and heptane functioning as antisolvents in this system, the solubility of the solute decreases with increasing heptane or hexane concentration in the solvent (pg. 1410, left column, first full paragraph), thereby facilitating deposition of the solute into a desire crystalline form. Given the similarity of the solvent systems and the common usage of hexane as an antisolvent as taught by De la Rosa, it would have been obvious to try the commonly used hexane as an antisolvent to lower solubility of the solute (brequinar) in the method of Sykes, Wu, and Mullin and facilitate crystallization.
With respect to claim 14, De la Rosa teaches heptane as an antisolvent similar to hexane. With respect to claim 15, Mullin teaches that crystal growth predominates during desupersaturation of a crystal growth solution and that the system can approach equilibrium (with concomitant crystal growth) during period of hours or days (pg. 207, third paragraph). As such, Mullin teaches the utility of allowing a crystallization system to incubate for a period of hours or days, depending on conditions and components. Similar to the molar ratios and temperatures of claims 3-7 and 9, above, it would have been a matter of routine experimentation, and therefore obvious to optimize the period of hours and days of Mullin to the 6 to 24 hours of claim 15.
Claim 17 combines the features of claims 11-13 and is obvious for the reasons applied to claims 11-13. Claim 18 combines the features of claims 15-17 and is obvious for the reasons applied to claims 15-17.
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.
Claims 1-18 are rejected for nonstatutory double patenting over the ’315 patent:
Claims 1-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,076,315 to Tadayon et al. (hereinafter, “the ’315 patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite a more generalized version of the method recited in claims 1-12 and 14 of the ’315 patent.
Claim 1 of the ’315 patent recites a method of making a crystal comprising at least 80% polymorphic form C of brequinar sodium salt. The method includes the steps of instant claims 1-2 and 11-14, with an overlapping but slightly different incubation temperature range, and further recites that the method produces a crystal having at least 80% polymorphic form C as determined by XRD. As such, aside from minor possible incubation temperature difference, any performance of the method of the ’315 patent will necessarily also be a performance of the method of the instant claims. Claims 2-14 of the ’315 patent are substantially the same as instant claims 3-9 and 15-18. In short, the instant claims are directed to a highly similar method to that of the ’315 patent with considerable overlap in scope. And while the method of the ’315 patent is not necessarily an obvious variant of the method of the instant claims, as the former requires formation of the crystal having 80% polymorphic form C, the method of the instant claims is an obvious variant of the method of the ’315 patent.
Conclusion
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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