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 .
Election/Restrictions
Applicant's election with traverse of Group III (i.e., claims 6-12, 14, 16, 18-22, 24-25, and 27 drawn to a method for purifying an echinocandin drug impurity of a structure represented by Formula I) in the reply filed on December 1, 2025, is acknowledged. Additionally, Applicant's election with traverse of Species B (i.e., a single and specific macroporous adsorptive resin purification as HP20SS for the macroporous adsorptive resin and methyl alcohol for the organic solvent; and a single and specific silica gel purification as Click Xion silica gel for the silica gel, acetic acid for the acidic solution, and acetonitrile for the organic solvent) in the reply filed on December 1, 2025, is acknowledged. The traversal is on the grounds that the Groups have the same or corresponding technical feature over the prior arts, and thus relate to a single general inventive concept under PCT Rule 13.1 (See Applicant’s Response received on 12/1/25, pg. 6). Furthermore, Applicants assert that any prior art searched for the elected Group III would be applicable to the non-elected Groups (See Applicant’s Response received on 12/1/25, pg. 6).
This is not found persuasive because the shared technical feature between Groups I-III lacks unity of invention as stated in the Restriction mailed on 10/2/25. As stated in the Restriction, the shared technical feature is an echinocandin drug impurity of a structure represented by Formula I (See Restriction, pg. 5). This technical feature does not make a contribution over the prior art, as asserted by Applicant, in light of the teachings of Liu et al. US 2015/0065417 A1 (See Restriction, pg. 5). Thus, contrary to Applicant’s argument, the shared technical feature between Groups I-III lacks unity of invention for the reasons set forth in the Restriction.
Furthermore, in response to Applicant’s argument that there is no search burden in examining the Groups together, it is noted that undue search burden is not a criteria for election/restriction purposes under 35 USC §121 and 35 USC § 372. As stated in the Restriction, according to PCT Rule 13.1, unity of invention exists only when there is a technical relationship among the claimed inventions involving one or more of the same or corresponding special technical features. PCT Rule 13.2 has clearly stated that ‘Where a group of inventions is claimed in one and the same international application, the requirement of unity of invention referred to in Rule 13.1 shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art’. Please refer MPEP 1850 for details. In the instant case, as stated in supra, the shared technical feature does not make a contribution over the prior art in light of the teachings of Liu et al. Thus, Groups I-III lack unity of invention.
The requirement is still deemed proper and is therefore made FINAL.
Please note that the single and specific acidic solution in Species B is hereby withdrawn. However, please note that the remaining elements of Species B are maintained.
Status of Claims
Claims 1-28 were originally filed on January 19, 2023.
The amendment received on January 19, 2023, canceled claims 13, 15, 17, 23, and 26; and amended claims 12, 14, 16, 22, 25, and 28. The amendment received on December 1, 2025, amended claim 6.
Claims 1-12, 14, 16, 18-22, 24-25, and 27-28 are currently pending and claims 6-12, 14, 16, 18-22, 24-25, and 27 are under consideration as claims 1-5 and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on December 1, 2025.
Priority
The present application claims status as a 371 (National Stage) of PCT/CN2022/099564 filed June 17, 2022, and claims priority under 119(a)-(d) to Chinese Application No. 202111057760.2 filed on September 9, 2021.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for Chinese Application No. 202111057760.2, which papers have been placed of record in the file. Please note that the Chinese application is not in English and therefore cannot be verified.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on April 17, 2023; and November 28, 2025, are being considered by the examiner.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 6, regarding a “high purity echinocandin drug impurity”, it is noted that the instant specification does not define what constitutes a high purity echinocandin drug impurity. As discussed in the 112(b) rejection below, the instant specification provides an example where the HPLC purity of the echinocandin drug impurity in the reaction liquid is further increased and reaches up to 90% or more, and states that a requirement that a purity of a drug impurity reference substance needs to reach 90% or more is well known to the field (See instant, [0010]). However, it is noted that a purity percentage of at least 90% does not correspond to the percent of the impurity in the sample, i.e., the total yield. A low yield of the echinocandin drug impurity of instant Formula I, e.g., less than 1% total yield obtained from a purification method, does not correspond to the purity percentage of the drug impurity. In other words, a purification method can result in a low yield of the drug impurity, but where the drug impurity is highly pure.
Claim Objections
Claim 27 is objected to because of the following informalities: claim 27 recites in line 1, “performing absorption by using…” It is respectfully requested that claim 27 recites, “performing adsorption by using…” in order to be grammatically correct. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 6-12, 14, 16, 18-22, and 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 6 includes a method for purifying an echinocandin drug impurity of a structure represented by Formula I (hereinafter referred to as “the echinocandin drug impurity”) by producing a “high purity” echinocandin drug impurity through column chromatography purification. As discussed in the 112(b) rejection below, “high purity” is being interpreted as a purity level of at least 90% (hereinafter referred to as “high purity”). As such, the claimed purification must result in the echinocandin drug impurity that exhibits the property of a purity level of at least 90%. The scope of claim 6 broadly encompasses any column chromatography process that is performed under any conditions in order to achieve the high purity echinocandin drug impurity. Thus, there is no critical method parameters required in order to produce the echinocandin drug impurity exhibiting the claimed property.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Liu et al. US 2015/0065417 A1 teaches that it is very difficult to separate structural analogs of compound of formula I (See Liu, [0030]). As discussed in the 103(a) rejection below, there are two structural stereochemical differences between the active sodium micafungin compound (i.e., Liu’s formula II) and the instantly claimed sodium micafungin impurity compound, i.e., a hydroxyl group in the S configuration in the impurity compound whereas it is in the R configuration in the active compound and another hydroxyl group where the stereochemistry is not indicated (note: it is presumed that the second hydroxyl group where the stereochemistry is not indicated is a typo given that the hydrogen atom attached to the same carbon atom is in the S configuration). As such, separating the echinocandin drug impurity from the active sodium micafungin would be very difficult thereby rendering a high purity echinocandin drug impurity very difficult to achieve, especially without any critical parameters and/or process steps needed to produce a high purity echinocandin drug impurity. Thus, the claims are directed to a purification method that produces an echinocandin drug impurity with a certain property but no correlated process parameters and/or steps needed to produce such an echinocandin drug impurity. Without recitation of critical parameters and/or process steps, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches four related embodiments where the purity of the echinocandin impurity is 92%, 90%, 91%, and 91%, respectively. Embodiment 5 describes producing a high purity echinocandin drug impurity by performing macroporous adsorption purification by using 20 ml of HP20SS resin, washing with 40 ml of 50% methanol, elution with 60 ml of 90% methanol; then collection, reduced pressure distillation and concentration to obtain a collected liquid containing the impurity components; and performing a silica gel chromatography by using Click XIon silica gel (i.e., a zwitterionic stationary phase), elution with 60% acetonitrile aqueous solution with a pH of about 4.0 (See instant, [0072]). Embodiment 6 describes a similar purification process compared to embodiment 5 using macroporous adsorption purification and silica gel purification, but the conditions are slightly different with respect to the volume percent of methanol in the macroporous adsorption purification is 30% and 85%, and a different silica gel with 70% acetonitrile aqueous solution with a pH of about 6.0 in the silica gel purification (See instant, [0075]). Embodiment 7 describes a similar purification process compared to embodiment 5 using macroporous adsorption purification and silica gel purification, but the conditions are slightly different with respect to the macroporous resin being SP207, the organic solvent is ethanol in a volume percent of 1% to wash and 95% to elute in the macroporous adsorption purification, and a different silica gel with 60% acetonitrile aqueous solution with a pH of about 3.0 in the silica gel purification (See instant, [0077]). Moreover, embodiment 8 describes a similar purification process compared to embodiment 5 using macroporous adsorption purification and silica gel purification, but the conditions are slightly different with respect to the organic solvent is methanol in a volume percent of 50% to wash and ethanol in a volume percent of 95% to elute in the macroporous adsorption purification, and a different silica gel with 60% acetonitrile aqueous solution with a pH of about 3.0 in the silica gel purification (See instant, [0077]). Although there are four embodiments demonstrating the production of an echinocandin drug impurity with a purity of 90-92%, these embodiments do not constitute a representative number of column chromatography processes including a representative number of parameters that can extend to the scope of the claimed genus of column chromatography processes and parameters. These embodiments demonstrate possession of a small subgenus of column chromatography steps utilizing specific parameters. Thus, the specification is not sufficient for the skilled artisan to envisage what purification process steps and/or parameters are critical in order to produce a high purity echinocandin drug impurity.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, what is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides which preserve the required function, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 6-12, 14, 16, 18-22, and 24-25 do not meet the written description requirement.
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 6-12, 14, 16, 18-22, 24-25, and 27 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. The term “high” in claim 6 is a relative term which renders the claim indefinite. The term “high” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is noted that claim 6 recites the manipulative step of “producing a high-purity echinocandin drug impurity through column chromatography purification,…” As such, “high” is in relation to the purity of the echinocandin drug impurity. The instant specification provides an example where the HPLC purity of the echinocandin drug impurity in the reaction liquid is further increased and reaches up to 90% or more, and states that a requirement that a purity of a drug impurity reference substance needs to reach 90% or more is well known to the field (See instant, [0010]). However, there is no indication that a purity amount of at least 90% is considered “high”. Plus, this purity amount is limited to a specific type of column chromatography purification, i.e., HPLC, whereas the instant purification method encompasses any column chromatography purification. Thus, it is unclear what constitutes a “high” purity echinocandin drug impurity.
Please note that the Examiner is interpreting that a “high” purity echinocandin drug impurity corresponds to where the purity of the echinocandin drug impurity is at least 90% in order to advance prosecution.
Claims 12, 14, 16, 22, and 25 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. Regarding claims 12, 14, 16, 22, and 25, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Please note that the Examiner is interpreting the scope of each claim such that the limitations following “preferably” are not required, but rather optional in order to advance prosecution. For example, claim 12 is being interpreted as “…wherein, in step b), a volume percent of the organic solvent is 0% to 50% of a total volume of an eluant, optionally 0% to 40%.
Claims 20 and 27 contain the trademarks/trade names “UniSil®”, “Chromatorex”, “Click “XIon” and “Inertsil”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the silica gel being utilized in the purification method and, accordingly, the identification/description is indefinite.
Please note that since claim 20 only recites trademarks, registered marks or trade names, the scope of claim 20 cannot be interpreted in order to advance prosecution. Thus, claim 20 cannot be examined for prior art purposes. However, for claim 27, please note that the Examiner is interpreting that the silica gel is any silica gel in order to advance prosecution.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 6-7 are rejected under pre-AIA 35 U.S.C. 102 (a) as anticipated by or, in the alternative, under pre-AIA 35 U.S.C. 103(a) as obvious over Liu et al. US 2015/0065417 A1 published on March 5, 2015.
Liu et al. discloses a micafungin impurity compound with the structure VIIa depicted as impurity 9a (See Liu, [0019]). The compound is identical to the instant echinocandin drug impurity of the structure of Formula I as recited in instant claim 6 (note: it is presumed that the a hydroxyl group where the stereochemistry is not indicated is a typo given that the hydrogen atom attached to the same carbon atom is in the S configuration):
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. This micafungin compound is an impurity of sodium micafungin (i.e., FK463) as a structural analog of micafungin (See Liu, [0004]). When analyzing a FK463 formulation by HPLC, there are 5 impurities found including the instantly claimed impurity compound (See Liu, [0006], [0029]). In this formulation, the amount of impurity 9a is greater than 0.2% (See Liu, [0027]). Liu et al. discloses that a variety of purification process conventionally used in the at including ion exchange resin, macroporous absorption resin, and reverse-phase preparative chromatography bonded with C18 silica gel and normal preparative chromatography with spherical silica gel are used by Liu et al. to purify the base sodium micafungin through chromatography (See Liu, [0031]). As such, Liu et al. discloses using a column chromatography purification comprises macroporous adsorptive resin purification and silica gel purification in order to produce sodium micafungin, which necessarily produces an echinocandin drug impurity of a structure represented by instant Formula I. Thus, the teachings of Liu et al. satisfy the claim limitation with respect to purifying an echinocandin drug impurity of a structure represented by Formula I by producing an echinocandin drug impurity through column chromatography purification where the column chromatography purification comprises macroporous adsorptive resin purification and silica gel purification as recited in instant claims 6-7.
Regarding where the echinocandin drug impurity is produced at a purity percentage of at least 90% (note: as being interpreted in the 112(b) rejection supra), it is noted that Liu et al. does not expressly teach the purity percentage of each impurity including impurity 9a. Although Liu et al.’s purification method is to obtain a high purity of sodium micafungin instead of one the impurity compounds including impurity 9a where the amount of the impurity compounds obtained from the purification is low, as stated in the “Claim Interpretation” section supra, the scope of claim 6 does not limit the amount or yield percentage of the produced echinocandin drug impurity thereby encompassing low yield percentages, but rather limits the purity percentage of the impurity produced.
MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, Liu et al. teaches purifying an micafungin composition that contains 5 related impurity compounds including an echinocandin drug impurity having a structure represented by instant Formula I by producing the drug impurity through column chromatography purification such as macroporous absorption purification and reverse-phase preparative chromatography bonded with C18 silica gel. Thus, the teachings of Liu et al. expressly teach the claimed manipulative step in instant claim 6 of producing an echinocandin drug impurity represented by Formula I through column chromatography purification.
The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants’ echinocandin drug impurity differs, and if so to what extent, from the echinocandin drug impurity disclosed in Liu et al. The cited art taken as a whole demonstrates a reasonable probability that the echinocandin drug impurity of Liu et al. is either identical or sufficiently similar to the claimed echinocandin drug impurity that whatever differences exist are not patentably significant. Therefore, with the showing of the reference, the burden of establishing novelty or non-obviousness by objective evidence is shifted to the Applicants.
Merely because a property of an echinocandin drug impurity is not expressly disclosed in a reference does not make the known echinocandin drug impurity patentable. The new echinocandin drug impurity possesses inherent properties which might not be displayed in the tests used in Liu et al. Accordingly, the disclosure of Liu et al. is a sufficient basis that the echinocandin drug impurity has a purity percentage of at least 90%.
In the alternative, even if the claimed echinocandin drug impurity is not identical to the Liu echinocandin drug impurity with regard to some unidentified properties, the differences between that which is disclosed and that which is claimed are considered to be so slight that the Liu echinocandin drug impurity is likely to inherently possess the same properties of the claimed echinocandin drug impurity particularly in view of the same manipulative step being performed. Thus, the claimed echinocandin drug impurity would have been obvious to those of ordinary skill in the art under the meaning of USC 103. Accordingly, the claimed invention as a whole was at least prima facie obvious, if not anticipated by the reference, especially in the absence of sufficient, clear, and convincing evidence to the contrary.
Accordingly, the disclosure of Liu et al. anticipates or, in the alternative, renders obvious the instant claims 6-7.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 6-12, 14, 18, 21-22, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. US 2015/0065417 A1 published on March 5, 2015 as applied to claims 6-7 above, and further in view of Aassveen et al. US Publication No. 2014/0371423 A1 published on December 18, 2014, alone or as evidenced by, Dolan, J., “A Guide to HPLC and LC-MS Buffer Selection,” available online at https://www.hplc.eu/Downloads/ACE_Guide_BufferSelection.pdf, 20 pages (first available 2014), as applied to claims 8-12, 14, 18, 21-22, and 24-25.
For claims 6-12, 14, 18, 21-22, and 24-25, please see discussion of Liu supra. In particular, it is noted that Liu et al. teaches that a variety of purification process conventionally used in the at including ion exchange resin, macroporous absorption resin, and reverse-phase preparative chromatography bonded with C18 silica gel and normal preparative chromatography with spherical silica gel are used by Liu et al. to purify the base sodium micafungin through chromatography (See Liu, [0031]). Although Liu et al. teaches that the purity of sodium micafungin (i.e., the desired active compound) cannot reach over 99% utilizing these purification methods, it is noted that the purity of sodium micafungin is not relevant to the claimed invention, and thus, does not teach away from utilizing the taught purification methods to achieve a purity percentage of the instantly claimed sodium micafungin impurity with a structure of Formula I of at least 90%. Rather, Liu et al. demonstrates that an ordinary skilled artisan would be well-aware of multiple purification methods that are known to be used to purify a sodium micafungin compound where such purification methods necessarily result in purification of the sodium micafungin impurity compound as instantly claimed. It is further noted that there are two structural stereochemical differences between the active sodium micafungin compound and the instantly claimed sodium micafungin impurity compound, i.e., a hydroxyl group in the S configuration in the impurity compound whereas it is in the R configuration in the active compound and another hydroxyl group where the stereochemistry is not indicated (note: it is presumed that the second hydroxyl group where the stereochemistry is not indicated is a typo given that the hydrogen atom attached to the same carbon atom is in the S configuration):
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(i.e., active compound) compared to
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(i.e., impurity compound). Therefore, the teachings of Liu et al. demonstrate that purification methods such as macroporous absorption purification and purification using a silica gel are known to purify sodium micafungin and its impurity compounds including the instant impurity compound of Formula I.
More specifically, Liu et al. utilized HPLC to purify the sodium micafungin compound (See Liu, [0045]-[0055], [0173]-[0183]). This HPLC purification method uses a silica gel column, i.e., YMC-ODS 250*4.6 mm, 5 µm and acetonitrile at volume percent of 70% in a phosphate buffer, but this HPLC method does not elute the collected liquid with an acidic aqueous solution. Furthermore, Liu et al. does not expressly teach the specific steps involved in macroporous absorption purification.
Aassveen et al. teaches a one step purification method of a salt of micafungin such as micafungin sodium in order to avoid a “salt swap” on an ion-exchange resin (See Aassveen, [0007], [0009]). It is noted that Aassveen et al. does not teach away from utilizing two purification steps in general, but advantageously found a one step purification process to eliminate the “salt swap” step. This one step purification process comprises (a) applying a micafungin starting material such as micafungin DIPEA to a hydrophobic adsorbent resin support such as HP20SS, (b) exposing the bound micafungin to an aqueous solution of a dissolved pharmaceutically acceptable salt, (c) eluting the dissolved pharmaceutically acceptable salt of micafungin with a solution comprising a water miscible organic solvent such as methanol, provided that at least one of (i) the starting material in step (a) or (ii) the aqueous solution in step (b) comprises a water miscible organic solvent (See Aassveen, [0011]-[0013], [0020]-[0023], [0026], [0029]-[0031], [0034], [0036], [0045], [0076], [0082]). Aassveen et al. further teaches an optional step where the bound micafungin in step (b) is exposed to an aqueous solution comprising a water miscible organic solvent one or more times for the removal of impurities (See Aassveen, [0014], [0026]) (note: the type of impurities are not specified). As such, Aassveen’s purification method constitutes a macroporous adsorption purification as recited in instant claim 7 where Aassveen’s steps (a) and (b) constitutes instant step (a), i.e., performing adsorption on a reaction product through a macroporous adsorptive resin, as recited in instant claim 8 where the macroporous adsorptive resin comprises styrene-divinylbenzene as a basic skeleton such as HP20SS as recited in instant claims 9-10. Moreover, Aassveen’s step (c) constitutes instant step (b), i.e., performing elution by using an organic solvent to obtain a collected liquid, as recited in instant claim 8 where the organic solvent is methyl alcohol (i.e., same as methanol) as recited in instant claim 11. The volume percent of the methanol as the water miscible organic solvent in Aassveen’s step (c), i.e., the elution step, can vary including a range of 30-50% v/v or at least 70% v/v (See Aassveen, [0024], [0029], [0078], [0088]). As such, the volume percent of the organic solvent overlaps with the instantly claimed volume percent ranges of 0-50% and 70-100% as recited in instant claims 12 and 14. MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses 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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed volume percent range of methanol would have been obvious to one of ordinary skill in the art since the claimed range (i.e., 0-50% v/v as recited in instant claim 12 and 70-100% v/v as recited in instant claim 14) overlaps with the prior art volume percent range of methanol (i.e., 30-50% v/v or at least 70% v/v).
Following the macroporous adsorption purification, the collected purified micafungin material is subjected to a HPLC assay in order to ensure that the cation of the micafungin starting material, e.g., DIPEA, has been properly switched to another cation, e.g., sodium (See Aassveen, [0049], [0072]-[0073]). The HPLC assay is performed in hopes that the micafungin starting material cation is not detectable (See Aassveen, [0049]). The HPLC system parameters include a column Kinetex C18, 2.6µ, 100 mm x 2.1 mm, 100 A, which is a silica gel with two mobile phases where the first mobile phase utilizes 99% MilliQ water, 1% acetonitrile, and 0.1% v/v TFA (i.e., trifluoroacetic acid), and the second mobile phase utilizes 1% MilliQ water, 99% acetonitrile, and 0.1% v/v TFA (See Aassveen, [0049]-[0070]). Although not expressly taught by Aassveen et al., the pH of the each mobile phase would be 2.0 as evidenced by Dolan. Dolan teaches that TFA generates a mobile phase pH of ~ 2.0 at 0.1% v/v (See Dolan, pg. 7, 2nd paragraph; Table 2). As such, the pH of the acidic solution comprising MilliQ water, acetonitrile and TFA is 2.0, which is a specific pH value that lies within the claimed pH range of 2.0-7.0 as recited in instant claim 25. Thus, the purification process taught by Aassveen et al. constitutes where a silica gel purification (i.e., HPLC that using a silica gel as the column material) is performed such that absorption on the collected purified micafungin liquid of the macroporous adsorption purification occurs through a silica gel column, and then the liquid is eluted through two mobile phases that include an acidic solution such as TFA of an organic solvent such as acetonitrile as recited in instant claims 18, 21, and 24. Moreover, the organic solvent being 99% in the second mobile phase would constitute the volume percent of the organic solvent (See Aassveen, [0059]). Although Aassveen et al. does not specify that the unit is 99% v/v since the acetonitrile is in liquid form being a component of an eluant, it would necessarily follow that acetonitrile is present in a volume percent of 99%. As such, acetonitrile being present in the second mobile phase in a volume percent of 99% lies within the claimed range of 20-100% as recited in instant claim 22. MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses 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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed volume percent range of acetonitrile would have been obvious to one of ordinary skill in the art since the claimed range (i.e., 20-100% v/v as recited in instant claim 22) overlaps with the prior art volume percent range of acetonitrile (i.e., 99%).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Liu et al. and purify a sodium micafungin composition thereby necessarily purifying a micafungin impurity compound with a structure of instant Formula I and a purity percent of at least 90% by performing a macroporous adsorption purification process and a HPLC purification process that uses a silica gel as the column material where the macroporous adsorption purification comprises (a) applying a micafungin starting material such as micafungin DIPEA to a hydrophobic adsorbent resin support such as HP20SS, (b) exposing the bound micafungin to an aqueous solution of a dissolved pharmaceutically acceptable salt, (c) eluting the dissolved pharmaceutically acceptable salt of micafungin with a solution comprising a water miscible organic solvent such as methanol, provided that at least one of (i) the starting material in step (a) or (ii) the aqueous solution in step (b) comprises a water miscible organic solvent, and optionally repeating steps (b) and (c) to remove impurities, and where the HPLC purification process uses a column Kinetex C18, 2.6µ, 100 mm x 2.1 mm, 100 A as a silica gel with two mobile phases where the first mobile phase utilizes 99% MilliQ water, 1% acetonitrile, and 0.1% v/v TFA, and the second mobile phase utilizes 1% MilliQ water, 99% acetonitrile, and 0.1% v/v TFA in order to purify sodium micafungin. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because sodium micafungin and its impurities were known to be purified by using a macroporous adsorption purification process comprising (a) applying a micafungin starting material such as micafungin DIPEA to a hydrophobic adsorbent resin support such as HP20SS, (b) exposing the bound micafungin to an aqueous solution of a dissolved pharmaceutically acceptable salt, (c) eluting the dissolved pharmaceutically acceptable salt of micafungin with a solution comprising a water miscible organic solvent such as methanol, provided that at least one of (i) the starting material in step (a) or (ii) the aqueous solution in step (b) comprises a water miscible organic solvent, and optionally repeating steps (b) and (c) to remove impurities, and a HPLC purification process comprising a column Kinetex C18, 2.6µ, 100 mm x 2.1 mm, 100 A as a silica gel with two mobile phases where the first mobile phase utilizes 99% MilliQ water, 1% acetonitrile, and 0.1% v/v TFA, and the second mobile phase utilizes 1% MilliQ water, 99% acetonitrile, and 0.1% v/v TFA as taught by Aassveen et al.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because the sodium micafungin and its impurities including an impurity with a structure of instant Formula I of Liu et al. was purified via conventional purification processes such as macroporous adsorption and HPLC with a silica gel, and therefore, purifying sodium micafungin and its impurities including an impurity with a structure of instant Formula I via a combination of a macroporous adsorption process comprising (a) applying a micafungin starting material such as micafungin DIPEA to a hydrophobic adsorbent resin support such as HP20SS, (b) exposing the bound micafungin to an aqueous solution of a dissolved pharmaceutically acceptable salt, (c) eluting the dissolved pharmaceutically acceptable salt of micafungin with a solution comprising a water miscible organic solvent such as methanol, provided that at least one of (i) the starting material in step (a) or (ii) the aqueous solution in step (b) comprises a water miscible organic solvent, and optionally repeating steps (b) and (c), and a HPLC purification process comprising a column Kinetex C18, 2.6µ, 100 mm x 2.1 mm, 100 A as a silica gel with two mobile phases where the first mobile phase utilizes 99% MilliQ water, 1% acetonitrile, and 0.1% v/v TFA, and the second mobile phase utilizes 1% MilliQ water, 99% acetonitrile, and 0.1% v/v TFA would support the production of a sodium micafungin impurity compound with a structure of instant Formula I and having a purity percentage of at least 90% by constituting the use of a known technique to improve similar devices (methods, or products) in the same way; the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results; the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claims 6-8 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. US 2015/0065417 A1 published on March 5, 2015, in view of Aassveen et al. US Publication No. 2014/0371423 A1 published on December 18, 2014, as applied to claims 6-8 above, and further in view of Zou et al., J. Chromatography B 978-979:111-117 (2015), as applied to claim 16 herewith.
For claims 6-8, please see discussion of Liu et al. and Aassveen et al. supra.
For claim 16, with respect to the temperature during macroporous adsorption purification:
Liu et al. and Aassveen et al. do not expressly teach the temperature at which the macroporous adsorption purification process is maintained at.
Zou et al. utilized a separation strategy involving one-step macroporous resin adsorption chromatography for echinocandin B (ECB) purification (See Zou, abstract). Zou et al. tested nine macroporous resin adsorbents and found that the non-polar resin, HP-20, had the best adsorption and desorption performance (See Zou, abstract). Zou et al. also performed kinetic and thermodynamic studies and theat temperatures of 288, 298 and 308 K (i.e., 14.85°C, 24.85°C, and 34.85°C, respectively) (See Zou, pg. 113, col. 2, last paragraph to pg. 113, col. 1, 1st paragraph; pg. 114, col. 2, 3rd paragraph). Zou et al. found that the amount of ECB adsorbed at equilibrium (i.e., qe) was higher at the lower temperature of 14.85°C indicating an exothermic process of ECB adsorption on HP20 resin (See Zou, pg. 113, col. 1, 1st paragraph). Thus, Zou et al. demonstrates that a temperature of 14.85°C, which lies within the claimed temperature range of 10-30°C as recited in instant claim 16, is an ideal temperature to purify echinocandin compounds. MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses 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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed temperature range would have been obvious to one of ordinary skill in the art since the claimed range (i.e., 10-30°C as recited in instant claim 16) overlaps with the prior art temperature (i.e., 14.85°C).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Liu et al. and purify a sodium micafungin composition thereby necessarily purifying a micafungin impurity compound with a structure of instant Formula I and a purity percent of at least 90% by performing a macroporous adsorption purification process where the temperature is maintained at 14.85°C. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because purifying an echinocandin compound was known to be performed using a one-step macroporous resin adsorption chromatography comprising HP-20 as the macroporous adsorptive resin and maintaining the temperature at 14.85°C thereby resulting in increased purity and recovery yield as taught by Zou et al. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because the sodium micafungin and its impurities including an impurity with a structure of instant Formula I of Liu et al. was purified via conventional purification processes such as macroporous adsorption and HPLC with a silica gel, and therefore, purifying sodium micafungin and its impurities including an impurity with a structure of instant Formula I such that the macroporous adsorption purification process is carried out at a temperature of 14.85°C would support the production of a sodium micafungin impurity compound with a structure of instant Formula I and having a purity percentage of at least 90% by constituting the use of a known technique to improve similar devices (methods, or products) in the same way; the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results; the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claims 6-8 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. US 2015/0065417 A1 published on March 5, 2015, in view of Aassveen et al. US Publication No. 2014/0371423 A1 published on December 18, 2014, as applied to claims 6-8 and 18 above, and further in view of Agilent, “Hydrophilic Interaction Chromatography Method Development and Troubleshooting, available online at https://www.agilent.com/cs/library/technicaloverviews/public/5991-9271EN_HILIC_method_development_TechOverview.pdf?srsltid=AfmBOopaDvF2Xgko5EN-xBvRatmRgp9fCqTVc3yyeSokVbzvYBdrHw5i, 14 pages (2018), as applied to claim 19 herewith.
For claims 6-8 and 18, please see discussion of Liu et al. and Aassveen et al. supra.
For claim 19, with respect to where the silica gel is a silica gel having a hydrophilic interaction chromatography mode such as Click Xion:
As discussed supra, Aassveen et al. teaches that the collected purified micafungin material is subjected to a HPLC assay in order to ensure that the cation of the micafungin starting material, e.g., DIPEA, has been properly switched to another cation, e.g., sodium (See Aassveen, [0049], [0072]-[0073]). The HPLC assay is performed in hopes that the micafungin starting material cation is not detectable (See Aassveen, [0049]). The HPLC system parameters include a column Kinetex C18, 2.6µ, 100 mm x 2.1 mm, 100 A, which is a silica gel with two mobile phases where the first mobile phase utilizes 99% MilliQ water, 1% acetonitrile, and 0.1% v/v TFA (i.e., trifluoroacetic acid), and the second mobile phase utilizes 1% MilliQ water, 99% acetonitrile, and 0.1% v/v TFA (See Aassveen, [0049]-[0070]). However, Aassveen et al. does not expressly teach utilizing hydrophilic interaction chromatography (HILIC) as the silica gel purification where the silica gel is Click Xion.
Agilent teaches that HILIC is a rapidly growing technique within the field of HPLC (See pg. 1, 1st paragraph). The most polar compounds can be separated with HILIC using the same system and solvents as reversed-phase HPLC (See Agilent, pg. 1, 1st paragraph). HILIC eliminates much of the cost and labor for polar analysis compared to older techniques such as normal-phase HPLC (See Agilent, pg. 1, 2nd paragraph). Columns operating in HILIC mode retain moderate to highly polar compounds where this range of compounds overlaps slightly with C18 in reversed-phase HPLC, which retains moderate to nonpolar compounds (See Agilent, pg. 2, col. 1, 1st paragraph). Acetonitrile is the recommended weak solvent, while alcohols can be added to increase solubility of buffers or to alter selectivity slightly (See Agilent, pg. 1, col. 2, 1st paragraph). Tables 1 and 2 describe advantages and disadvantages of types of HPLCs along with HILIC (See Agilent, pg. 2, Tables 1 and 2). HILIC provides fast analysis, uses the same system and solvents as reversed-phase HPLC, separates cations, anions and polar neutrals in a single run, and has equal or superior MS performance to reversed-phase HPLC (See Agilent, pg. 2, Table 2). Although Agilent teaches a few disadvantages of using HILIC (See Agilent, pg. 2, Table 2), these disadvantages would not teach away from substituting HILIC as the HPLC in Aassveen et al. because the disadvantages do not pertain to ensuring that the salt associated with the purified micafungin compound is sodium. Thus, Agilent teaches that HILIC is a robust and reliable choice for analysis of even the most polar compounds, and it is easily implemented in any lab currently using reversed-phase HPLC (See Agilent, pg. 14, col. 1, 1st paragraph). Therefore, Agilent suggests that HILIC can be substituted as a HPLC purification method offering several advantages of fast analysis, uses the same system and solvents as reversed-phase HPLC, separates cations, anions and polar neutrals in a single run, and has equal or superior MS performance to reversed-phase HPLC.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Liu et al. and purify a sodium micafungin composition thereby necessarily purifying a micafungin impurity compound with a structure of instant Formula I and a purity percent of at least 90% by performing a macroporous adsorption purification process and a HILIC purification process instead of a conventional HPLC purification process given that HILIC offers several advantages over conventional HPLC purification processes such as fast analysis, uses the same system and solvents as reversed-phase HPLC, separates cations, anions and polar neutrals in a single run, and has equal or superior MS performance to reversed-phase HPLC. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because HILIC was known to be a rapidly growing technique within the field of HPLC offering several advantages over conventional HPLC purification processes such as fast analysis, uses the same system and solvents as reversed-phase HPLC, separates cations, anions and polar neutrals in a single run, and has equal or superior MS performance to reversed-phase HPLC. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because the sodium micafungin and its impurities including an impurity with a structure of instant Formula I of Liu et al. was purified via conventional purification processes such as macroporous adsorption and HPLC with a silica gel, and therefore, purifying sodium micafungin and its impurities including an impurity with a structure of instant Formula I via a combination of a macroporous adsorption process and HILIC instead of a conventional HPLC would support the production of a sodium micafungin impurity compound with a structure of instant Formula I and having a purity percentage of at least 90% by constituting the use of a known technique to improve similar devices (methods, or products) in the same way; the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results; the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claims 6-7 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. US 2015/0065417 A1 published on March 5, 2015, in view of Aassveen et al. US Publication No. 2014/0371423 A1 published on December 18, 2014, as applied to claims 6-7 above, and further in view of Bionity, “Vacuum distillation,” Bionity.com, available online at https://www.bionity.com/en/encyclopedia/Vacuum_distillation.html, 3 pages (first available 2013), and Dolan, J., “A Guide to HPLC and LC-MS Buffer Selection,” available online at https://www.hplc.eu/Downloads/ACE_Guide_BufferSelection.pdf, 20 pages (first available 2014), as applied to claim 27 herewith.
For claims 6-7, please see discussion of Liu et al. and Aassveen et al. supra.
For claim 27, with respect to the macroporous adsorption by using an HP20SS resin, performing washing with 50% methyl alcohol, performing elution with 90% methyl alcohol:
As discussed supra, Liu et al. teaches that a variety of purification process conventionally used in the at including ion exchange resin, macroporous absorption resin, and reverse-phase preparative chromatography bonded with C18 silica gel and normal preparative chromatography with spherical silica gel are used by Liu et al. to purify the base sodium micafungin through chromatography (See Liu, [0031]). More specifically, Liu et al. utilized HPLC to purify the sodium micafungin compound (See Liu, [0045]-[0055], [0173]-[0183]). This HPLC purification method uses a silica gel column, i.e., YMC-ODS 250*4.6 mm, 5 µm and acetonitrile at volume percent of 70% in aqueous phosphate buffer (See Liu, [0045]-[0055], [0173]-[0183]) thereby constituting using chromatographic separation using a silica gel as recited in instant claim 27. However, this HPLC method does not elute the collected liquid using 60% acetonitrile at a pH of 4.0. Furthermore, Liu et al. does not expressly teach the specific steps involved in macroporous absorption purification or performing reduced pressure distillation and concentration to obtain a collected liquid containing echinocandin drug impurity.
Regarding the steps involved in macroporous absorption purification, as discussed supra, Aassveen et al. teaches a one-step purification process of a sodium micafungin composition where this one step purification process comprises (a) applying a micafungin starting material such as micafungin DIPEA to a hydrophobic adsorbent resin support such as HP20SS, (b) exposing the bound micafungin to an aqueous solution of a dissolved pharmaceutically acceptable salt, (c) eluting the dissolved pharmaceutically acceptable salt of micafungin with a solution comprising a water miscible organic solvent such as methanol, provided that at least one of (i) the starting material in step (a) or (ii) the aqueous solution in step (b) comprises a water miscible organic solvent (See Aassveen, [0011]-[0013], [0020]-[0023], [0026], [0029]-[0031], [0034], [0036], [0045], [0076], [0082]). As such, Aassveen’s purification method constitutes performing adsorption by using an HP20SS resin, washing the bound micafungin with an aqueous solution that contains a water miscible organic solvent such as methanol (i.e., exposing the bound micafungin), eluting with methanol, and collection the eluted micafungin as recited in instant claim 27.
Regarding the volume percentages of methanol, Aassveen et al. teaches that the volume percent of the methanol in step (b) (i.e., corresponds to the instant washing step) can range from 0-40% v/v (See Aassveen, [0018]), and the volume percent of the methanol as the water miscible organic solvent in Aassveen’s step (c), i.e., the elution step, can vary including a range of 30-50% v/v or at least 70% v/v (See Aassveen, [0024], [0029], [0078], [0088]).
Regarding the volume percent of the organic solvent during the washing step, the volume percentage of methanol during the washing step is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal volume percentage of methanol during the washing step needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to modify the volume percentage of methanol during the washing step in light of the teachings of Aassveen et al. varying the volume percentage of methanol between the washing and elution steps, because an ordinary skilled artisan would have been able to utilize the teachings of Aassveen et al. to obtain various volume percentage parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the volume percentage of methanol during the washing step would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
Regarding the volume percent of methanol during the elution step of the macroporous adsorption process, it is noted that the taught methanol volume percent overlaps with the instantly claimed volume percent ranges of 90%. MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses 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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed volume percent of methanol would have been obvious to one of ordinary skill in the art since the claimed percentage (i.e., 90% as recited in instant claim 27) lies within with the prior art volume percent range of methanol (i.e., 30-50% v/v or at least 70% v/v).
Regarding performing reduced pressure distillation and concentration following the macroporous adsorption purification to obtain a collected containing the echinocandin drug impurity, Bionity teaches that vacuum distillation is a method of distillation whereby the pressure above the liquid mixture to be distilled is reduced to less than its vapor pressure causing evaporation of the most volatile liquid(s) (those with the lowest boiling points) (See Bionity, pg. 1, 1st paragraph). As such, vacuum distillation is a form of reduced pressure distillation. This distillation method works on the principle that boiling occurs when the vapor pressure of a liquid exceeds the ambient pressure (See Bionity, pg. 1, 1st paragraph). Temperature sensitive materials require vacuum distillation to remove solvents from the mixture without damaging the product (See Bionity, pg. 1, last paragraph). Industrial-scale vacuum distillation offers several advantages including increasing the relative volatility thereby allowing for components to be separated in fewer stages, reducing potential product degradation by using lower temperatures and reduced mean residence time, and increasing capacity, yield and purity (See Bionity, pg. 2, 1st to 4th paragraph). By removing the solvent, the resulting micafungin impurity compound would necessarily be concentrated. Thus, the teachings of Bionity suggest advantages of utilizing vacuum distillation.
Regarding the volume percentages of acetonitrile during the elution step, the volume percentage of acetonitrile during the HPLC elution step is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal volume percentage of acetonitrile during the HPLC elution step needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to adjust the volume percentage of acetonitrile during the HPLC elution step in light of the teachings of Liu et al. and Aassveen et al. varying the volume percentage of acetonitrile, because an ordinary skilled artisan would have been able to utilize the teachings of Liu et al. and Aassveen et al. to obtain various volume percentage parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the volume percentage of acetonitrile during the HPLC elution step would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
Regarding the pH of the eluant solution being 4.0, as discussed supra, following the macroporous adsorption purification, Liu et al. teaches utilizing aqueous phosphate buffer, which as evidenced by Dolan results in a pH from 1.1-3.1, 6.2-8.2, or 11.3-13.3 depending on the pK value utilized (See Dolan, pg. 6, Table 2). Aassveen et al. teaches that the collected purified micafungin material is subjected to a HPLC assay in order to ensure that the cation of the micafungin starting material, e.g., DIPEA, has been properly switched to another cation, e.g., sodium (See Aassveen, [0049], [0072]-[0073]). The HPLC assay is performed in hopes that the micafungin starting material cation is not detectable (See Aassveen, [0049]). The HPLC system parameters include a column Kinetex C18, 2.6µ, 100 mm x 2.1 mm, 100 A, which is a silica gel with two mobile phases where the first mobile phase utilizes 99% MilliQ water, 1% acetonitrile, and 0.1% v/v TFA (i.e., trifluoroacetic acid), and the second mobile phase utilizes 1% MilliQ water, 99% acetonitrile, and 0.1% v/v TFA (See Aassveen, [0049]-[0070]). Although not expressly taught by Aassveen et al., the pH of the each mobile phase would be 2.0 as evidenced by Dolan. Dolan teaches that TFA generates a mobile phase pH of ~ 2.0 at 0.1% v/v (See Dolan, pg. 7, 2nd paragraph; Table 2). As such, Aassveen et al. teaches utilizing an aqueous solution with a pH of about 2.0 when it contains TFA.
Dolan teaches a number of common HPLC buffers (See Dolan, pg. 6, Table 2) that can be substituted with phosphate or TFA in the eluant aqueous solution containing acetonitrile. These buffers include several that would result in the eluant solution being 4.0 such as acetate (i.e., range of 3.8 to 5.8) and citrate depending on the pK value (See Dolan, pg. 6, Table 2). Thus, the pH of the eluant aqueous solution containing acetonitrile is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal pH of the eluant aqueous solution during the HPLC elution needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to adjust the pH of the eluant aqueous solution during HPLC in light of the teachings of Liu et al., Aassveen et al. and Dolan demonstrating that the pH varies depending on the buffer used, because an ordinary skilled artisan would have been able to utilize these combined teachings to obtain various eluant pH parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the eluant aqueous solution containing acetonitrile during the HPLC elution would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
Additionally, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Liu et al. and purify a sodium micafungin starting material thereby necessarily purifying a micafungin impurity compound with a structure of instant Formula I and a purity percent of at least 90% by performing a macroporous adsorption purification process, vacuum distillation and concentration, and a HPLC purification process that uses a silica gel as the column material where the macroporous adsorption purification comprises (a) applying a micafungin starting material such as micafungin DIPEA to a hydrophobic adsorbent resin support such as HP20SS, (b) exposing the bound micafungin to an aqueous solution of a dissolved pharmaceutically acceptable salt and a miscible organic solvent such as methanol in a volume percent that is optimized to 50% v/v, (c) eluting the dissolved pharmaceutically acceptable salt of micafungin with a solution comprising a water miscible organic solvent such as methanol in a volume percent that is at least 70% v/v thereby encompassing 90% v/v, provided that at least one of (i) the starting material in step (a) or (ii) the aqueous solution in step (b) comprises a water miscible organic solvent, and where the HPLC purification process uses YMC-ODS 250*4.6 mm, 5 µm as a silica gel with a mobile phase that includes acetonitrile at volume percent that is optimized to 60% v/v in an aqueous solution comprising acetate or citrate buffer instead of phosphate buffer at a pH that is optimized to 4.0 in order to purify sodium micafungin thereby necessarily obtaining a sodium micafungin drug impurity with a structure of instant Formula I having a purity of at least 90%.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because sodium micafungin and its impurities were known to be purified by using a macroporous adsorption purification process comprising (a) applying a micafungin starting material such as micafungin DIPEA to a hydrophobic adsorbent resin support such as HP20SS, (b) exposing the bound micafungin to an aqueous solution of a dissolved pharmaceutically acceptable salt and a miscible organic solvent such as 0-40% v/v methanol, (c) eluting the dissolved pharmaceutically acceptable salt of micafungin with a solution comprising a water miscible organic solvent such as methanol at a volume percentage of at least 70% v/v, provided that at least one of (i) the starting material in step (a) or (ii) the aqueous solution in step (b) comprises a water miscible organic solvent, and a HPLC purification process comprising a column Kinetex C18, 2.6µ, 100 mm x 2.1 mm, 100 A as a silica gel with two mobile phases where the first mobile phase utilizes 99% MilliQ water, 1% acetonitrile, and 0.1% v/v TFA, and the second mobile phase utilizes 1% MilliQ water, 99% acetonitrile, and 0.1% v/v TFA as taught by Aassveen et al.; because vacuum distillation was known as a form of reduced pressure distillation to remove solvents from the mixture without damaging the product and was known to offer several advantages including increasing the relative volatility thereby allowing for components to be separated in fewer stages, reducing potential product degradation by using lower temperatures and reduced mean residence time, and increasing capacity, yield and purity as taught by Bionity; and because the pH utilized during HPLC elution was known to be varied depending on the buffer used including buffers that would result in a pH of 4.0 such as acetate or citrate as taught by Dolan.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because the sodium micafungin and its impurities including an impurity with a structure of instant Formula I of Liu et al. was purified via conventional purification processes such as macroporous adsorption and HPLC using YMC-ODS 250*4.6 mm, 5 µm as a silica gel and acetonitrile at volume percent of 70% in aqueous phosphate buffer. Therefore, purifying sodium micafungin and its impurities including an impurity with a structure of instant Formula I via a combination of a macroporous adsorption process comprising (a) applying a micafungin starting material such as micafungin DIPEA to a hydrophobic adsorbent resin support such as HP20SS, (b) exposing the bound micafungin to an aqueous solution of a dissolved pharmaceutically acceptable salt and a miscible organic solvent such as methanol in a volume percent that is optimized to 50% v/v, (c) eluting the dissolved pharmaceutically acceptable salt of micafungin with a solution comprising a water miscible organic solvent such as methanol in a volume percent that is at least 70% v/v thereby encompassing 90% v/v, provided that at least one of (i) the starting material in step (a) or (ii) the aqueous solution in step (b) comprises a water miscible organic solvent, performing vacuum distillation in order to remove extraneous solvent thereby necessarily concentrating a collected liquid containing the micafungin drug impurity, and a HPLC purification process comprising YMC-ODS 250*4.6 mm, 5 µm as a silica gel with a mobile phase that includes acetonitrile at volume percent that is optimized to 60% v/v in an aqueous solution comprising acetate or citrate buffer instead of a phosphate buffer at a pH that is optimized to 4.0 would support the production of a sodium micafungin impurity compound with a structure of instant Formula I and having a purity percentage of at least 90% by constituting the use of a known technique to improve similar devices (methods, or products) in the same way; the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results; the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654