DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I and the species of benzamide, metaxalone, and phenol as the first organic compound, second organic compound, and volatile co-former organic compound, respectively, in the reply filed on June 18, 2025, is acknowledged.
Claims 30 and 39-43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species and invention, there being no allowable generic or linking claim. With respect to species claim 30 it is the Examiner’s understanding that metaxalone does not contain an amide, acid, alcohol, ketone, aldehyde, amine, ester, or halogen and, consequently, claim 30 recites a non-elected species for the second organic compound. Election was made without traverse in the reply filed on June 18, 2025.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 24-29, 31-35, and 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the crystallization of a select number of deep eutectic solvents as shown in Tables 1-3 and Examples 1-26, does not reasonably provide enablement for the formation of any and all possible organic compounds. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? The standard to be applied is set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). See also MPEP 2164. The factors to be considered to determine whether any necessary experimentation is undue, also known as The Wand factors, include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The invention disclosed in the instant application relates to a crystallization method in which a mixture of at least a first organic compound and at least one volatile co-former organic compound is formed, wherein one of the two compounds comprises a hydrogen acceptor moiety and the other comprises a hydrogen donor moiety. The process allows the mixture to stand for a sufficient period of time for it to liquify at a temperature below that of the melting points of the compounds. After evaporation of the co-formed organic compound, a first organic compound is crystallized. As explained in ¶[0002] of the Background section deep eutectic solvents (DES) are known in the art and are typically composed of two or three molecular species which are able to associate through extensive hydrogen bonding. Through an appropriate choice of two components which usually are solid and crystalline, a liquid with a melting point significantly lower than each of the constituents is formed. A number of examples of DES which contain a relatively volatile hydrogen bond donor compound and one or more hydrogen bond acceptor compounds are provided in Examples 1-26 and Tables 1-3. However, claims 24 and 25 do not specifically recite the nature of the organic compounds to be used and instead, merely recites the use of a “first organic compound,” a “second organic compound,” and a ”volatile co-former organic compound.” This therefore suggests that any and all organic compounds with either a hydrogen acceptor moiety or a hydrogen donor moiety can be used in the process to successfully produce a mixture which liquifies at a temperature below the melting points of the components. However, this necessarily is not the reality as only a certain number and type of organic compounds will behave as a DES when mixed together and allowed to stand for a certain period of time. There are a nearly unlimited number of organic compounds that can be formed which fit the definition of an “organic compound” with either a “hydrogen donor moiety” or a “hydrogen acceptor moiety.” Consequently, an unreasonable amount of experimentation would be needed to sort through each and every one of these organic compounds to determine which will behave as a DES in the claimed manner. Accordingly, it is the Examiner’s position that undue experimentation would be required to determine which specific organic compounds that possess a hydrogen acceptor moiety or hydrogen donor moiety may be mixed together along with the experimental parameters such as the mixing process, temperature, pressure, relative concentrations, and the duration of the reaction which will result in liquefication of the mixture at a lower temperature and then produce a first organic compound by evaporation in the manner recited in the context of claims 24-25. As such, the full scope of claims 24-25 is not enabled by the specification as originally filed. Dependent claims 26-29 and 31-38 are similarly rejected due to their direct or indirect dependence on claim 24.
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 24-29, and 31-35 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 pre-AIA the applicant regards as the invention.
The term “volatile co-former organic compound” in claim 24 is a relative term which renders the claim indefinite. The term “volatile” 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. Since neither the claim nor the specification as originally filed teach or suggest how readily vaporizable the compound must be in order to be considered as “volatile,” is recitation in claim 24 is therefore considered to be indefinite. Dependent claims 25-29 and 31-34 are similarly rejected due to their dependence on claim 24.
Claim 25 recites the limitation "a hydrogen acceptor moiety" in ll. 3-4, “a respective hydrogen donor moiety” in l. 5, and “a hydrogen donor moiety” in l. 6, and “a respective hydrogen acceptor moiety” in l. 7. There is insufficient antecedent basis for these limitations in the claim. Since claim 25 depends from claim 24 which recites “a hydrogen acceptor moiety” and “a hydrogen donor moiety” it is unclear whether their recitation in claim 25 refers to the same or a different hydrogen donor or acceptor moiety. It is assumed applicants intended to recite, for example, “the hydrogen acceptor moiety” and “the hydrogen donor moiety.” Dependent claims 28-29 and 31-34 are similarly rejected due to their dependence on claim 25.
Claim 29 recites the limitation "a respective hydrogen bond acceptor moiety" in ll. 2-3 and “a hydrogen bond donor moiety” in l. 4. There is insufficient antecedent basis for these limitations in the claim.
Claim 31 recites the limitation "a respective hydrogen bond donor moiety" in ll. 2-3 and “a hydrogen bond acceptor moiety” in l. 4. There is insufficient antecedent basis for these limitations in the claim.
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 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 24, 27-28, and 35-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Appl. Publ. No. 2016/0122676 to Patil, et al. (hereinafter “Patil”) in view of a publication to Rodrigues, et al. entitled “Pharmaceutical cocrystallization techniques: Advances and challenges,” International Journal of Pharmaceutics, Vol. 547, pp. 404-420 (2018) (“Rodrigues”).
Regarding claim 24, Patil teaches a solidification or crystallization method (see the Abstract, Figs. 1-8, and entire reference which teach a method of forming an eutectic mixture which is liquid), the method comprising:
forming a mixture of a plurality of components including at least a first organic compound and at least one volatile co-former organic compound (see ¶¶[0031]-[0037], ¶¶[0042]-[0050], and claims 12-18 which teach forming a mixture of a first organic compound such as benzene and a volatile co-former organic compound such as phenol),
wherein either the first organic compound or the volatile co-former organic compound comprises a hydrogen acceptor moiety and the other comprises a hydrogen donor moiety, such that hydrogen bonds between the first organic compound and the volatile co-former organic compound are allowed to form (see ¶¶[0031]-[0037], ¶¶[0042]-[0050], and claims 12-18 as well as elsewhere throughout the entire reference which further teach that one compound acts as a hydrogen bond donor whereas the other acts as a hydrogen bond acceptor such that hydrogen bonds form between the two compounds; moreover, it is noted that although the elected first organic compound of benzamide and the elected volatile co-former organic compound of phenol are listed as a hydrogen bond donor in Patil they may also function as a hydrogen bond acceptor as claimed);
allowing the mixture to stand for a sufficient time for the mixture to liquify at a temperature below that of the melting points of the components, such that a liquid mixture is formed from the mixture (see ¶¶[0051]-[0055] and claims 12-18 which teach that the solid mixture is allowed to stand for a sufficient time such that it liquefies at a temperature below the melting point of the individual components and a liquid mixture is formed from the solid components).
Patil does not teach allowing the volatile co-former organic compound to evaporate, resulting in crystallization of at least the first organic compound. However, it is well-known in the art that the evaporation of one component in an eutectic mixture comprised of a plurality organic compounds results in the crystallization of the other organic compound. This is specifically taught in Section 2.1.1 at pp. 406-407 of Rodrigues which teaches that in order to co-crystallize a solid phase the solvent is removed after dissolution of the active pharmaceutical ingredients (API) and coformer in a solvent or mixture of solvents. In one embodiment the solvent is removed by the process of solvent evaporation in order to produce the resulting cocrystal. Thus, a person of ordinary skill in the art prior to the effective filing date of the invention would look to the teachings of Rodrigues and would be motivated to utilize solvent evaporation to crystallize the desired cocrystal for use as a pharmaceutical ingredient. The combination of prior art elements according to known methods to yield predictable results has been held to support a prima facie determination of obviousness. All the claimed elements are known in the prior art and one skilled in the art could combine the elements as claimed by known methods with no change in their respective functions, with the combination yielding nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. 398, __, 82 USPQ2d 1385, 1395 (2007). See also, MPEP 2143(A).
Regarding claim 27, Patil teaches that the sufficient time is a time period of 8 hours to 10 days (see at least ¶[0055] which teaches that the reaction time may be from 0.5 to 72 hours).
Regarding claim 28, Patil teaches that allowing the mixture to stand for the sufficient time further comprises heating the mixture (see at least ¶[0055] which teaches that the reaction temperature may be between 25 to 150 °C which, when above 25 °C which is at room temperature, would necessarily involve heating the mixture).
Regarding claim 35, Patil teaches that the volatile co-former organic compound has a boiling point of 289 °C or lower (see ¶¶[0042]-[0050], and claims 12-18 which teach, inter alia, the use of an organic compound such as phenol which has a boiling point of approximately 181.7 °C).
Regarding claim 36, Patil teaches that the volatile co- former organic compound is selected from the group consisting of cyclohexanol and a hydroxy-functionalised aromatic compound (see ¶¶[0042]-[0050], and claims 12-18 which teach, inter alia, the use of an organic compound such as phenol).
Regarding claim 37, Patil teaches that the volatile co- former organic compound is a hydroxy-functionalized aromatic compound of formula:
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130
231
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Greyscale
Wherein, independently n is 0 or 1 and m is 0, 1, or 2 (see ¶¶[0042]-[0050], and claims 12-18 which teach, inter alia, the use of an organic compound such as phenol in which m = 0 and n = 0).
Regarding claim 38, Patil teaches that the volatile co-former organic compound is selected either from the group consisting of phenol, hydroquinone, resorcinol, catechol, a cresol, a xylenol, and cyclohexanol, or from a mixture of two or more of phenol, hydroquinone, resorcinol, catechol, a cresol, a xylenol or cyclohexanol (see ¶¶[0042]-[0050], and claims 12-18 which teach, inter alia, the use of an organic compound such as phenol).
Claims 25, 29, and 31-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patil in view of Rodrigues and further in view of U.S. Patent Appl. Publ. No. 2013/0158083 to Holland, et al. (“Holland”).
Regarding claim 25, Patil teaches that the mixture of the plurality of components further includes a second organic compound, and wherein either: A) the volatile co-former organic compound comprises a hydrogen acceptor moiety and the first organic compound and the second organic compound each comprise a respective hydrogen donor moiety, or B) the volatile co-former organic compound comprises a hydrogen donor moiety and the first organic compound and the second organic compound each comprise a respective hydrogen acceptor moiety, such that forming the mixture allows the formation of hydrogen bonds between the first organic compound and the volatile co-former organic compound and between the second organic compound and the volatile co-former organic compound, such that allowing the volatile co-former organic compound to evaporate results in co-crystallization of at least the first and second organic compounds (See ¶¶[0042]-[0050], and claims 12-18 which teach the use of an organic compound such as phenol as a hydrogen bond donor (¶[0047) together with a first component as a hydrogen bond acceptor which may include a first and second organic compound (¶[0044]) as claimed. It is noted that although the elected first organic compound of benzamide is listed as a hydrogen bond donor in Patil it may also function as a hydrogen bond acceptor as claimed.)
Patil does not teach the use of the elected compound metaxalone as the second organic compound which comprises either a hydrogen acceptor moiety or a hydrogen donor moiety. However, in ¶¶[0003]-[0007] Holland teaches that metaxalone is a known compound that is used as a muscle relaxant which is a solid white powder which melts at 121.5 to 123 °C. Metaxalone is not water soluble and has less bioavailability, but that this may be altered through the use of a crystalline form of the active pharmaceutical ingredient. In ¶¶[0047]-[0053] Holland further teaches that Metaxalone may be formed as a cocrystal with phenol as an additive while specific examples in which metaxalone is mixed in, for example, a 1:1 ratio with another organic compound are provided in the Examples. Thus, a person of ordinary skill in the art prior to the effective filing date of the invention would look to the teachings of Holland and would be motivated to utilize metaxalone as a first or second organic compound which functions as a hydrogen bond donor or a hydrogen bond acceptor as claimed in combination with benzamide and phenol as taught by Patil and Rodrigues in order to produce an eutectic mixture with a lower melting point which may be formed into crystals which possess a higher bioavailability.
Regarding claim 29, Patil teaches that the first organic compound and the second organic compound each comprise a respective hydrogen bond acceptor moiety and the volatile co-former organic compound comprises a hydrogen bond donor moiety (See ¶¶[0042]-[0050], and claims 12-18 which teach, inter alia, the use of a first and second organic compound as a hydrogen bond acceptor and specifically lists benzamide along with an organic compound such as phenol as a hydrogen bond donor. It is noted that although the elected first organic compound of benzamide is listed as a hydrogen bond donor it may also function as a hydrogen bond acceptor as claimed.).
Patil and Rodrigues do not teach the use of the elected compound metaxalone as the second organic compound which comprises a hydrogen bond acceptor moiety. However, as noted supra with respect to the rejection of claim 25, in ¶¶[0003]-[0007] Holland teaches that metaxalone is a known compound that is used as a muscle relaxant which is a solid white powder which melts at 121.5 to 123 °C. Metaxalone is not water soluble and has less bioavailability, but that this may be altered through the use of a crystalline form of the active pharmaceutical ingredient. In ¶¶[0047]-[0053] Holland further teaches that Metaxalone may be formed as a cocrystal with phenol as an additive while specific examples in which metaxalone is mixed in, for example, a 1:1 ratio with another organic compound are provided in the Examples. Thus, a person of ordinary skill in the art prior to the effective filing date of the invention would look to the teachings of Holland and would be motivated to utilize metaxalone as a first or second organic compound which functions as a hydrogen bond acceptor as claimed in combination with benzamide and phenol as taught by Patil and Rodrigues in order to produce an eutectic mixture with a lower melting point which may be formed into crystals which possess a higher bioavailability.
Regarding claim 31, Patil teaches that the first and second organic compounds each comprise a respective hydrogen bond donor moiety and the volatile co-former organic compound comprises a hydrogen bond acceptor moiety (See ¶¶[0042]-[0050], and claims 12-18 which teach, inter alia, the use of a first and second organic compound as a hydrogen bond donor and specifically lists benzamide along with an organic compound such as phenol. It is noted that although the elected volatile co-former organic compound of phenol is listed as a hydrogen bond donor in Patil it may also function as a hydrogen bond acceptor as claimed.).
Patil and Rodrigues do not teach the use of the elected compound metaxalone as the second organic compound which comprises a hydrogen bond donor moiety. However, as noted supra with respect to the rejection of claim 25, in ¶¶[0003]-[0007] Holland teaches that metaxalone is a known compound that is used as a muscle relaxant which is a solid white powder which melts at 121.5 to 123 °C. Metaxalone is not water soluble and has less bioavailability, but that this may be altered through the use of a crystalline form of the active pharmaceutical ingredient. In ¶¶[0047]-[0053] Holland further teaches that Metaxalone may be formed as a cocrystal with phenol as an additive while specific examples in which metaxalone is mixed in, for example, a 1:1 ratio with another organic compound are provided in the Examples. Thus, a person of ordinary skill in the art prior to the effective filing date of the invention would look to the teachings of Holland and would be motivated to utilize metaxalone as a first or second organic compound which functions as a hydrogen bond donor as claimed in combination with benzamide and phenol as taught by Patil and Rodrigues in order to produce an eutectic mixture with a lower melting point which may be formed into crystals which possess a higher bioavailability.
Regarding claim 32, Patil teaches that a molar ratio of the volatile co-former organic compound and either the first organic compound or the second organic compound is in the range 20:1 to 1:1 (see ¶[0035] which teaches that the ratio of constituents may be adjusted to obtain the desired properties with ¶[0129] specifically teaching an embodiment where a molar ratio of 1:1 to 5:1 is used; accordingly it would have been within the capabilities of a person of ordinary skill in the art prior to the effective filing date of the invention to utilize routine experimentation to determine the optimal ratio of the organic compounds, including within the claimed range of 20:1 to 1:1, that is necessary to obtain the desired properties).
Regarding claim 33, Patil teaches that a molar ratio of the first organic compound and the second organic compound is in the range 1:5 to 5:1 (see ¶[0035] which teaches that the ratio of constituents may be adjusted to obtain the desired properties with ¶[0129] specifically teaching an embodiment where a molar ratio of 1:1 to 5:1 is used; accordingly it would have been within the capabilities of a person of ordinary skill in the art prior to the effective filing date of the invention to utilize routine experimentation to determine the optimal ratio of the organic compounds, including within the claimed range of 1:1 to 5:1, that is necessary to obtain the desired properties).
Regarding claim 34, Patil teaches that the hydrogen bond acceptor or donor moiety of the first organic compound and the second organic compound is not so sterically hindered that it is unable to interact with the hydrogen bond donor or acceptor moiety of the volatile co-former compound (see ¶¶[0042]-[0050], and claims 12-18 which teach, inter alia, the use of a first and second organic compound as a hydrogen bond donor or a hydrogen bond acceptor and specifically lists benzamide along with an organic compound such as phenol; moreover, the first and second organic compounds of Patil necessarily are not sterically hindered from interacting with phenol).
Patil and Rodrigues do not teach the use of the elected compound metaxalone as the second organic compound which is not sterically hindered from interacting with phenol. However, as noted supra with respect to the rejection of claim 25, in ¶¶[0003]-[0007] Holland teaches that metaxalone is a known compound that is used as a muscle relaxant which is a solid white powder which melts at 121.5 to 123 °C. Metaxalone is not water soluble and has less bioavailability, but that this may be altered through the use of a crystalline form of the active pharmaceutical ingredient. In ¶¶[0047]-[0053] Holland further teaches that Metaxalone may be formed as a cocrystal with phenol as an additive while specific examples in which metaxalone is mixed in, for example, a 1:1 ratio with another organic compound are provided in the Examples. Thus, a person of ordinary skill in the art prior to the effective filing date of the invention would look to the teachings of Holland and would be motivated to utilize metaxalone as a first or second organic compound in combination with benzamide and phenol as taught by Patil and Rodrigues in order to produce an eutectic mixture with a lower melting point which may be formed into crystals which possess a higher bioavailability. Moreover, since the combination of Patil, Rodrigues, and Holland teach each and every step of the claimed process, the metaxalone and benzamide organic compounds necessarily are not sterically hindered from interacting with phenol as claimed.
Claim 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patil in view of Rodrigues and further in view of U.S. Patent Appl. Publ. No. 2007/0134803 to Blatter, et al. (“Blatter”).
Regarding claim 26, Patil and Rodrigues do not teach that allowing the mixture to stand comprises sealing the mixture in a vessel and allowing the mixture to stand in the vessel. However, in ¶¶[0010]-[0018] as well as elsewhere throughout the entire reference Blatter teaches an analogous system and method for the formation of cocrystalline compounds via evaporation of a solvent. In ¶¶[0011]-[0012] Blatter specifically teaches the use of a vessel with a flow-through seal or an air-tight connection in order to facilitate reaction of the constituents and the formation of the desired cocrystalline compound. Thus, a person of ordinary skill in the art prior to the effective filing date of the invention would look to the teachings of Blatter and would be motivated to utilize a sealed vessel to contain and isolate the mixture in the method of Patil and Rodrigues such that the desired reaction(s) may occur in a controlled environment.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENNETH A BRATLAND JR whose telephone number is (571)270-1604. The examiner can normally be reached Monday- Friday, 7:30 am to 4:30 pm EST.
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/KENNETH A BRATLAND JR/Primary Examiner, Art Unit 1714