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 .
Status of the Claims
Per Applicant’s amendment to the claims, submitted on 01/14/2023, claims 2-10 are amended, and claims 11-18 are newly added. Currently, claims 1-18 are pending in the instant application.
Priority
The instant application is a 371 of PCT/IB2021/053696, filed on 05/04/2021, and claims foreign priority to Indian Application IN20241019951, filed on 05/12/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/14/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Duplicate Claim Warning
Applicant is advised that should claim 7 be found allowable, claim 13 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Applicant is advised that should claim 8 be found allowable, claim 14 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Applicant is advised that should claim 9 be found allowable, claim 15 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Applicant is advised that should claim 10 be found allowable, claim 16 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Applicant is advised that should claim 11 be found allowable, claim 17 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Applicant is advised that should claim 12 be found allowable, claim 18 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Objections
Claim 1 is objected to because of the following informalities: Spelling Error. The instant claim recites the phrase “at a pre-determined temperate and time” (underlined for emphasis). The claim should read “temperature” rather than “temperate”. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: No claim identifier. Currently, the instant claim does not have an identifier indicating the status of the claim (i.e., Original, Currently Amended, New, etc. ). An identifier should be present to indicate the status of the claim. Appropriate correction is required.
Claim 3 is objected to because of the following informalities: Grammar. Claim 3 recites “the polar protic polar solvents and polar aprotic solvents” (underlined for emphasis). Claim 1 part b. recites “polar protic solvents or polar aprotic solvents” (underlined for emphasis). The “and” in claim 3 should be changed to “or” for consistency with the parent claim. Appropriate correction is required.
Claim 3 is objected to because of the following informalities: Spelling. Claim 3 recites the term “teracholoethane”. The correct term should read “tetrachloroethane”. Appropriate correction is required.
Claims 10-12 and 16-18 are objected to because of the following informalities: Grammar. Each of claims 10-12 and 16-18 recite the phrase “ranging from 0.001 micron to 100 micron through” (underlined for emphasis). The instant claims recite a definitive micron range as a limitation, and the word “through” appears to be added extraneously. Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities: Spelling Error. Specification page 2, line 14 uses the term “teracholoethane”. The correct term should be “tetrachloroethane”. Appropriate correction is required.
The disclosure is objected to because of the following informalities: Syntax Error. Specification page 2, lines 14-15 states the following: “chlorinated solvents (like dichloromethane, teracholoethane or chloroform”. An opening parenthesis has been used; however, no closing parenthesis is present. Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Sixth Paragraph
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Claim Rejections - 35 USC § 112 – Second Paragraph
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 2-5, 7-12, and 16-18 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 2 is indefinite for reciting the phrase “wherein the triazole compounds are posaconazole, voriconazole and itraconazole” because a person of ordinary skill in the art would not reasonably understand the metes and bounds of the claim. The instant claim recites “the triazole compounds” (i.e., multiple triazole compounds), while the parent claim 1 recites “a triazole compound” (i.e., a single triazole compound). Currently, the recitation of claim 2 provides improper antecedence to claim 1. A re-wording of the claim would overcome this rejection (ex. “wherein the triazole compound is selected from…”).
Claim 3 is indefinite for reciting the term “preferably” because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 4 is indefinite for reciting the term “preferably” because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 5 is indefinite for reciting the phrase “wherein, the triazole salt are isolated in the form of amorphous salt, crystalline salt or a combination thereof” because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. With regards to recrystallization processes, it is generally understood that isolated yields from such processes can only exist in three general forms: 1) specific crystal polymorphs, 2) amorphous crystals, and 3) and combinations thereof. The instant claim is considered as not further limiting of the method of claim 1, as the it would encompass any resulting triazole salt form produced by the method. Furthermore, the instant claim is reciting the result of carrying out the method of claim 1, without providing further structure (i.e., steps, processes, etc.) to the method. Without further provided structure to the established method, a person of ordinary skill in the art would not reasonably be able to understand how to arrive at the claimed result.
Claim 7 is indefinite for reciting the phrase “the preparation of dilauryl glyceryl fumarate of posaconazole” because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. Claim 1 to which the instant claim depends upon recites a “process for preparation of triazole salts”, but does not explicitly recite the preparation of dilauryl glyceryl fumarate of posaconazole. Accordingly, the instant claim provides improper antecedence to its parent claim.
Claim 8 is indefinite for reciting the phrase “the preparation of dilauryl glyceryl fumarate of voriconazole” because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. Claim 1 to which the instant claim depends upon recites a “process for preparation of triazole salts”, but does not explicitly recite the preparation of dilauryl glyceryl fumarate of voriconazole. Accordingly, the instant claim provides improper antecedence to its parent claim.
Claim 9 is indefinite for reciting the phrase “the preparation of dilauryl glyceryl fumarate of itraconazole” because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. Claim 1 to which the instant claim depends upon recites a “process for preparation of triazole salts”, but does not explicitly recite the preparation of dilauryl glyceryl fumarate of itraconazole. Accordingly, the instant claim provides improper antecedence to its parent claim.
Claims 10-12 and 16-18 are each indefinite for reciting the phrase “using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron” because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. The instant claims invoke 35 USC 112(f) because the written description fails to disclose the corresponding structure, material, or acts for performing the claimed function to clearly link the structure, material, or acts to the function.
Under broadest reasonable interpretation, the recited “chemical process or physical manipulation” could encompass any number of techniques for adjusting particle size. Such processes may include, but are not limited to, methods such as spray drying, encapsulation, milling, grinding, and others.
Looking towards Applicant’s specification for guidance, page 2 lines 27-28 and page 3 lines 11-13 provide indications of the aforementioned processes. The disclosure on page 2 states a “method of manipulation such as milling or micronisation for producing the desired particle size”, while the page 3 disclosure states an embodiment wherein a triazole salt is “processed to a fine material […] through chemical process or physical manipulation (milling or micronisation)”. It appears that the disclosure indicates that milling or micronisation are forms of physical manipulation. However, any chemical processes for modifying or controlling particle size do not appear to have been described or exemplified. While physical manipulation can be construed as encompassing milling and micronization, the recitation of chemical processes to obtain a particle size would be considered as indefinite. Furthermore, milling and micronization would generally be understood by a person of ordinary skill in the art to solely fall under physical manipulation, as these processes would not alter the chemical makeup of the target compound.
Accordingly, a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the instant claim .
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181. (FP 7.34.23)
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.
Claim(s) 1-8, 13-14 and is/are rejected under 35 U.S.C. 103 as being unpatentable over Kandula (WO 2018/096497 A1) in view of McDaniel (University of Massachusetts, 2020).
Claim 1 recites a process for preparation of triazole salts, comprising:
the salt formation; by dissolving a triazole compound and a dilaurylglyceryl fumarate in a suitable polar solvents for formation of a triazole salt at a pre- determined temperate and time
isolation of: the triazole salt using a non-polar cyclic or acyclic hydrocarbon solvent; wherein the polar solvent for salt formation is selected from polar protic solvents or polar aprotic solvents; further the non-polar solvent for isolation of the triazole salt is selected from cyclic and acyclic hydrocarbons.
Kandula teaches compounds and methods of treating fungal infections, and methods of preparation of said compounds. Of particular interest is the synthesis of the following compound 10 (paragraphs [00128]-[00129]):
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As can be seen from the above, compound 6 is dilauryl glyceryl fumarate, compound 9 is posaconazole (i.e., a triazole), and claim 10 is a posaconazole dilauryl glyceryl fumarate salt. Per the teachings of Kandula, the salt of compound 10 is formed by performing the following (paragraph [00129])1:
Form a solution of compound 9 (dilauryl glyceryl fumarate) in acetonitrile
Add compound 9 (posaconazole) to the solution at ambient temperature
Heat the reaction mixture to 50C for 3 hours
Evaporate the solvent under reduced pressure to yield the final product of compound 10
As can be seen in the method of preparation above, Kandula teaches the step of salt formation of step a of the instant claim wherein a triazole and dilauryl glyceryl fumarate are dissolved in a polar solvent (ACN) for salt formation.
Kandula does not explicitly teach the isolation of triazole salt using a non-polar cyclic or acyclic hydrocarbon solvent. However it would be obvious to carry out such an isolation step because McDaniel teaches recrystallization as a basic technique for the purification of organic solids, while Rubin teaches hexane as a common solvent for such recrystallizations.
McDaniel teaches a general overview of the technique of recrystallization. In particular, McDaniel indicates recrystallization as a purification method for organic solids. The general crystallization scheme taught by McDaniel for the removal of soluble impurities generally includes the following steps (pages 1-2)2:
A solubility test is conducted on known compounds in order to find a suitable recrystallization solvent
The target compound is dissolved in the chosen solvent at near or boiling temperature to a saturated concentration
The mixture is allowed to cool slowly, wherein crystals of the target compound are formed, and impurities are left behind in the solvent
The solvent is removed from the formed crystals
The resulting crystals are rinsed with cold solvent to remove residual impurities
McDaniel further provides exemplary lab procedures for determining solvent choice for given compounds. The provided solvents include, water, methanol, ethanol, hexanes, and toluene (page 4)3. Hexanes would be considered as an acyclic hydrocarbon.
Given the teachings of Kandula which provides a method of forming dilauryl glyceryl salts of posaconazole, and the teachings of McDaniel which provides commonly used recrystallization techniques for purification, it would have been prima facie obvious for a person of ordinary skill in the art to modify the method of Kandula by applying the purification technique of McDaniel because there would have been a reasonable expectation of success in providing a higher purity yield of the triazole salt of Kandula.
Claim 2 further limits the method of claim 1 wherein the triazole compounds are posaconazole, voriconazole, and itraconazole.
Kandula teaches the use of posaconazole.
Claim 3 further limits the method of claim 1 wherein the polar protic solvents and polar aprotic solvents for salt formation comprises methanol, ethanol, isopropanol, water, acetonitrile, methyl tertiary butyl ether (MTBE), tetrahydrofuran, chlorinated solvent, dichloromethane, teracholoethane or chloroform preferably acetonitrile and dichloromethane.
Kandula teaches the use of ACN as a solvent in salt formation.
Claim 4 further limits the method of claim 1 wherein the non-polar cyclic or acyclic hydrocarbon solvent for isolation comprises cyclohexane, hexane or heptane preferably hexane.
McDaniel teaches the use of hexane solvent for recrystallization.
Claim 5 further limits the method of claim 1 wherein the triazole salt are isolated in the form of amorphous salt, crystalline salt or a combination.
Kandula indicates that their method for forming triazole salt results in an off white solid. As the method of Kandula is essentially an evaporation crystallization, it would be expected that the resulting off white solid would contain crystals of triazole salt either in amorphous or crystalline form.
Claim 6 further limits the method of claim 1 wherein the triazole salts are dilauryl glyceryl fumarate of posaconazole, dilauryl glyceryl fumarate of voriconazole and dilauryl glyceryl fumarate of itraconazole.
Kandula teaches the formation of dilauryl glyceryl fumarate of posaconazole.
Claim 7 further limits the method of claim 1 wherein the preparation of dilauryl glyceryl fumarate of posaconazole comprises of:
a. dissolving posaconazole and dilaurylglyceryl fumarate in the acetonitrile and heating the reaction mixture to a temperature about 50-55°C for 180 minutes with continuous stirring to obtain a clear solution ;
b. acetonitrile is distilled off from the reaction mixture at temperature not exceeding 40°C to obtain a solid having the dilauryl glyceryl fumarate of posaconazole; and
c. dilauryl glyceryl fumarate of posaconazole is isolated from the solid by washing and filtering the solid in hexane to yield above 97.3 % dilauryl glyceryl fumarate of posaconazole as solid.
As discussed previously, Kandula teaches a method of formation of dilauryl glyceryl fumarate of posaconazole wherein posaconazole and posaconazole and dilaurylglyceryl fumarate are dissolved in ACN and heated to 50 C for 3 hours (corresponds to step a). Kandula further teaches the evaporation of ACN (corresponds to step b). McDaniel teaches filtration and washing in hexane as a recrystallization and isolation technique (corresponds to step c). Kandula does not explicitly teach the distilling of ACN at a temperature not to exceed 40C. However, it would be obvious for a person of ordinary skill in the art to utilize such a temperature per the principle of routine optimization. The method of Kandula essentially teaches steps a and b of the instant claim, only differing in the evaporation temperature of ACN. A person of ordinary skill in the art would be readily motivated to find the optimum temperature for the removal of ACN from the mixture as it may affect the formation or yield of target triazole salts. See MPEP 2144.05(II)(A):
“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.");”
Claim 8 further limits the method of claim 1 wherein the preparation of dilauryl glyceryl fumarate of voriconazole comprises of:
a. dissolving voriconazole and dilaurylglyceryl fumarate in the acetonitrile and heating the reaction mixture to a temperature about 50-55°C for 180 minutes with continuous stirring to obtain a clear solution ;
b. acetonitrile is distilled off from the reaction mixture at temperature not exceeding 40°C to obtain a solid mixture having the dilauryl glyceryl fumarate of voriconazole; and
c. dilauryl glyceryl fumarate of voriconazole is isolated from the solid mixture by washing, filtering drying the solid mixture in hexane to yield above 98.8 % dilauryl glyceryl fumarate of voriconazole as solid.
As discussed previously, Kandula teaches a method of formation of dilauryl glyceryl fumarate of posaconazole. Kandula further teaches the application of essentially the same process in formation of dilauryl glyceryl fumarate salt of voriconazole, represented by the following synthesis (page 73):
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The method of Kandula comprises combining voriconazole (compound 11) and dilauryl glyceryl fumarate (compound 6) in ACN, heating the mixture to 50C for 3 hours, and evaporating the ACN to yield the target salt (compound 12).
McDaniel teaches filtration and washing in hexane as a recrystallization and isolation technique. Kandula does not explicitly teach the distilling of ACN at a temperature not to exceed 40C. However, it would be obvious for a person of ordinary skill in the art to utilize such a temperature per the principle of routine optimization. The method of Kandula essentially teaches steps a and b of the instant claim, only differing in the evaporation temperature of ACN. A person of ordinary skill in the art would be readily motivated to find the optimum temperature for the removal of ACN from the mixture as it may affect the formation or yield of target triazole salts. See MPEP 2144.05(II)(A).
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kandula in view of McDaniel, and further in view of Sharpe (WO 02/080678 A1).
Claim 10 further limits the method of claim 7 wherein the triazole salts are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron.
As discussed above, the teachings of Kandula in view of McDaniel obviate a method of preparing dilauryl glyceryl fumarate of posaconazole, as recited in claim 7.
Neither of Kandula or McDaniel explicitly teach the manipulation of the resulting dilauryl glyceryl fumarate of posaconazole to obtain a particle size in the stated range.
However, it would be obvious for a person of ordinary skill in the art to be able to carry out such a manipulation because Sharpe teaches the micronization of posaconazole for use in pharmaceutical formulations.
Sharpe teaches pharmaceutical compositions comprising micronized posaconazole. Along with compositions, Sharpe further teaches the micronization of posaconazole by microfluidization in order to obtain a particle size in the range of 1200 nm (1.2 micron) to 1600 nm (1.6 microns) (page 7)4. Furthermore, Sharpe indicates that the micronization of posaconazole can be applied after the use of crystallization techniques (page 7)5. A person of ordinary skill in the art would readily be motivated to apply such micronization techniques to the triazole salts of Kandula as there would be a reasonable expectation that the micronized triazole salts such as dilauryl glyceryl fumarate of posaconazole would be effective and readily usable in pharmaceutical compositions such as in antifungal compositions.
In summary, the combined teachings of Kandula and McDaniel obviate a method of preparing dilauryl glyceryl fumarate of posaconazole, while Sharpe teaches the micronization of posaconazole either before or after the application of crystallization techniques. It would have been prima facie obvious at the time of invention for a person of ordinary skill in the art to apply micronization to the teachings of Kandula and McDaniel as there would have been reasonable expectation of success in creating a triazole salt readily usable in pharmaceutical anti-fungal compositions.
Claim 11 further limits the method of claim 8 wherein the triazole salts are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron.
As discussed above, the teachings of Kandula in view of McDaniel obviate a method of preparing dilauryl glyceryl fumarate of voriconazole, as recited in claim 7.
Neither of Kandula or McDaniel explicitly teach the manipulation of the resulting dilauryl glyceryl fumarate of voriconazole to obtain a particle size in the stated range.
However, it would be obvious for a person of ordinary skill in the art to be able to carry out such a manipulation because Sharpe teaches the micronization of posaconazole for use in pharmaceutical formulations.
Sharpe teaches pharmaceutical compositions comprising micronized posaconazole. Along with compositions, Sharpe further teaches the micronization of posaconazole by microfluidization in order to obtain a particle size in the range of 1200 nm (1.2 micron) to 1600 nm (1.6 microns) (page 7)6. Furthermore, Sharpe indicates that the micronization of posaconazole can be applied after the use of crystallization techniques (page 7)7. A person of ordinary skill in the art would readily be motivated to apply such micronization techniques to the triazole salts of Kandula as there would be a reasonable expectation that the micronized triazole salts such as dilauryl glyceryl fumarate of voriconazole would be effective and readily usable in pharmaceutical compositions such as in antifungal compositions. While posaconazole and voriconazole, are not identical compounds, it would be reasonable to believe, without evidence of the contrary, that micronization would still have similar effects on both compounds. The reasons being that both compounds are the same class of compounds (i.e., triazoles with anti-fungal function), and that micronization operates on the principle of increasing surface area of active pharmaceutical compound.
In summary, the combined teachings of Kandula and McDaniel obviate a method of preparing dilauryl glyceryl fumarate of voriconazole, while Sharpe teaches the micronization of posaconazole either before or after the application of crystallization techniques. It would have been prima facie obvious at the time of invention for a person of ordinary skill in the art to apply micronization to the teachings of Kandula and McDaniel as there would have been reasonable expectation of success in creating a triazole salt readily usable in pharmaceutical anti-fungal compositions.
Claim(s) 13-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kandula in view of McDaniel.
Claim 13 further limits the method of claim 6 wherein the preparation of dilauryl glyceryl fumarate of posaconazole comprises of:
a. dissolving posaconazole and dilaurylglyceryl fumarate in the acetonitrile and heating the reaction mixture to a temperature about 50-55°C for 180 minutes with continuous stirring to obtain a clear solution ;
b. acetonitrile is distilled off from the reaction mixture at temperature not exceeding 40°C to obtain a solid having the dilauryl glyceryl fumarate of posaconazole; and
c. dilauryl glyceryl fumarate of posaconazole is isolated from the solid by washing and filtering the solid in hexane to yield above 97.3 % dilauryl glyceryl fumarate of posaconazole as solid.
The instant claim is essentially a duplicate of claim 7, as both claims appear to have identical limitations and breadth. Accordingly, the instant claim is rejected as being obvious over Kandula in view of McDaniel for the same obviousness reasons as claim 7 above.
Claim 14 further limits the method of claim 6 wherein the preparation of dilauryl glyceryl fumarate of voriconazole comprises of:
a. dissolving voriconazole and dilaurylglyceryl fumarate in the acetonitrile and heating the reaction mixture to a temperature about 50-55°C for 180 minutes with continuous stirring to obtain a clear solution ;
b. acetonitrile is distilled off from the reaction mixture at temperature not exceeding 40°C to obtain a solid mixture having the dilauryl glyceryl fumarate of voriconazole; and
c. dilauryl glyceryl fumarate of voriconazole is isolated from the solid mixture by washing, filtering drying the solid mixture in hexane to yield above 98.8 % dilauryl glyceryl fumarate of voriconazole as solid.
The instant claim is essentially a duplicate of claim 8, as both claims appear to have identical limitations and breadth. Accordingly, the instant claim is rejected as being obvious over Kandula in view of McDaniel for the same obviousness reasons as claim 8 above.
Claim(s) 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kandula in view of McDaniel, and further in view of Sharpe.
Claim 16 further limits the method of claim 13 wherein the triazole salts are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron through.
The instant claim is essentially a duplicate of claim 10, as both claims appear to have identical limitations and breadth. Accordingly, the instant claim is rejected as being obvious over Kandula in view of McDaniel, and further in view of Sharpe for the same obviousness reasons as claim 10 above.
Claim 17 further limits the method of claim 14 wherein the triazole salts are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron through.
The instant claim is essentially a duplicate of claim 11, as both claims appear to have identical limitations and breadth. Accordingly, the instant claim is rejected as being obvious over Kandula in view of McDaniel, and further in view of Sharpe for the same obviousness reasons as claim 11 above.
Allowable Subject Matter
The method of claims 9 and 15 contains subject matter which appears to be free of the art. As iterated above, claims 9 and 15 are considered as duplicate claims, as they contain identical limitations and breadth of subject matter. The closest prior art to the aforementioned claims is Kandula.
Claims 9 and 15 recite a method of preparing a dilauryl glyceryl fumarate salt of itraconazole by dissolving dilauryl glyceryl fumarate and itraconazole in DCM, heating the mixture to 35-38C for 120 minutes, with continuous stirring, carbon treatment for 60 minutes, and filtration through a hyflo bed washed with DCM. The DCM is subsequently distilled off, and the resulting solid is washed and filtered in hexane.
Kandula teaches a method for the formation of dilauryl glyceryl fumarate salt of itraconazole, the synthesis being represented by the following (page 72):
PNG
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406
1071
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Greyscale
The process for the above synthesis is as follows:
Dilauryl glyceryl fumarate and itraconazole are dissolved in acetonitrile
The mixture is heated to 50C for 3 hours
The acetonitrile is evaporated under reduced pressure to yield a solid of compound 8
The method taught by Kandula does not teach or suggest a process such as recited in claim 9. While the above synthesis essentially describes a recrystallization of a dilauryl glyceryl fumarate of itraconazole, the process is carried out solely using acetonitrile as a solvent.
Conclusion
Claims 1-18 are rejected.
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/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “To a solution of (E)-4-((l,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid 6 (100 mg, 0.18 mmol) in acetonitrile (5 mL) was added 4-(4-(4-(4-(((3R,5R)-5-((lHl,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl) piperazin-l-yl)phenyl)-2-((2S,3S)-2-hydroxypentan-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one 9 (126 mg, 0.18 mmol) at ambient temperature. The resulting reaction mixture was heated up to 50°C for next 3h followed by the evaporation of solvent under reduced pressure to get the desired product 10 as off-white solid (M.P. 78.6°C), yield: 225 mg, quant.”
2 “To remove soluble impurities, the following strategy can be utilized: first, by doing solubility tests, a suitable solvent is chosen (high solubility in hot solvent, low solubility in cold solvent). The soluble impurities are then removed as follows: the desired compound along with the soluble impurities are dissolved in a MINIMUM of near or at BOILING solvent. The solution is then allowed to cool slowly and without interruption. As the solution cools, the solubility of the compound (and of the soluble impurities) decreases, the solution becomes saturated with the desired compound, and the compound begins to crystallize. Because formation of crystals is a highly selective process that usually excludes foreign molecules, only crystals of the desired compound form. Because the soluble impurities are present in smaller amounts, the solution never becomes saturated with the impurities, so the impurities remain in solution even after the solution has cooled. Removing the solution from the crystals thus removes the solvent and the soluble impurities from the desired crystals. A final rinse with a MINIMUM of ICE-COLD solvent, followed by removal of this solvent, cleans off any residual soluble impurities clinging to the surface of the desired crystals.”
3 “Available solvents are water, methanol, pure ethanol, 70% ethanol in water, hexanes or toluene.”
4 “The preferred micronizing technique that is employed to micronize the posaconazole to the desired mean particle size range is microfluidization. Microfluidization is an alternative to traditional homogenization that utilizes the collision of two product streams at high pressures to produce a much more uniform particle size distribution (according to Microfluidics International Co.) and smaller
average particle size of about 1200 nm to 1600 nm.”
5 “This particle size can be obtained either by the final step during the manufacture of the antifungal compound of formula I or by the use of conventional micronizing techniques after the conventional crystallization procedure(s).”
6 “The preferred micronizing technique that is employed to micronize the posaconazole to the desired mean particle size range is microfluidization. Microfluidization is an alternative to traditional homogenization that utilizes the collision of two product streams at high pressures to produce a much more uniform particle size distribution (according to Microfluidics International Co.) and smaller
average particle size of about 1200 nm to 1600 nm.”
7 “This particle size can be obtained either by the final step during the manufacture of the antifungal compound of formula I or by the use of conventional micronizing techniques after the conventional crystallization procedure(s).”