DETAILED ACTION
STATUS OF THE APPLICATION
Receipt is acknowledged of Applicant’s Amendments and Remarks, filed 3 December 2025, the matter of Application No. 18/190,631. Said documents have been entered onto the record. The Examiner notes the following:
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-11 are pending.
Claims 1-2, 4-9, and 11 have been amended.
No claims have been cancelled.
Thus, claims 1-11 represent all claims currently under consideration.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
Claim Objections
Applicant’s amendments to claims 1-2, 4-9, and 11 are sufficient to overcome the claim objections.
35 U.S.C.§ 112
Applicant’s amendments to the claims have fully overcome the rejections over instant claims 1-6 and 9.
Claim Interpretation
Claim 1 recites the term “Zwitterion”. For the purposes of examination, the term “Zwitterion” be will interpreted as a neutral compound having internal formal unit electrical charges of opposite sign, e.g., H3N+CH2C(=O)O– (glycine), (CH3)3N+-O– (trimethylamine oxide), in a manner consistent with the teachings of the prior art (c.f., IUPAC Compendium of Chemical Terminology; 2014, IUPAC Goldbook). Furthermore, the ionizable functional groups of cyclocreatine phosphate are being interpreted as possessing similar pKa values to that of creatine phosphate, as taught by Zerange et al. at page 4 (US 8,202,852 B2; IDS reference):
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As such, the skilled artisan would recognize that compounds possessing the ionizable functional groups detailed above (i.e., carboxylate, terminal phosphate, and guanidinium ions) would largely exist in a Zwitterionic form over a broad range of pH (from about 2 to about 13).
Claim 5 be will interpreted as further limiting claim 1, wherein R6 is selected from Na and K.
Claim 9 be will interpreted as further limiting claim 7, wherein R6 is selected from Na, K, and combinations thereof.
REJECTIONS MAINTAINED
MAINTAINED Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-5 remain rejected under 35 U.S.C. 103 as being unpatentable over Ahmed et al. (US 2008/0242639 A1; PTO-892 of 10-02-2025; hereinafter “Ahmed”), in view of Guidi et al. (Chem. Soc. Rev. 2020, 49, 8910-8932; hereinafter “Guidi”) and Kaddurah-Daouk et al. (WO 94/16712; PTO-892 of 10-02-2025; hereinafter “Kaddurah-Daouk”).
Regarding claim 1, Ahmed teaches that cyclocreatine phosphate can be prepared in large quantities from inexpensive starting materials to afford a stable product (Ahmed; Abstract). Ahmed further teaches that cyclocreatine phosphate can be prepared by reacting cyclocreatine with phosphorous oxychloride under basic conditions (Ahmed; paragraph [0042]; Scheme 2):
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The cyclocreatine structure (Ahmed; Scheme 2, left) taught by Ahmed reads directly on formula (III) of instant claim 1 when R1 is H and R2 is CH2CO2H, and the cyclocreatine phosphate structure (Ahmed; Scheme 2, right) taught by Ahmed reads directly on formula (IV) of instant claim 1 when R5 is Li+ (i.e., R5 is a mono-valent cation) and R6 is H, respectively. In one embodiment, Ahmed teaches the preparation of cyclocreatine phosphate (1-carboxymethyl-3-phosphono-2-iminoimidazoline, dilithium salt, dihydrate), wherein a solution of 0.5 g (3.5 mmol) of cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) in 0.5 mL of 3.7 N lithium hydroxide and 5 mL water was cooled in an ice-salt bath; a freshly distilled portion of POCl3 (1.6 mL, 17.5 mmol) in 32 mL of 3.7 N lithium hydroxide was added very cautiously portionwise (e.g., 16-20 portions) over a period of 2 hours, with mechanical stirring and cooling; after a further 2 hours, the pH of the solution was adjusted to 7.2 using 6 N HCl; solids were removed by filtration or centrifugation and then washed with 30% methanol/water v/v; the filtrate or supernatant was combined with the washings, and subjected to vacuum at room temperature to reduce the volume to about 5 mL; the resulting slightly turbid solution was filtered through a fine-grade sintered glass funnel to give a clear filtrate; absolute ethanol was added to the filtrate, which was then allowed to stand overnight; the resulting crystals were collected by filtration and recrystallized from water-ethanol; an additional crop was obtained by addition of ethanol to the mother liquor until it became turbid, allowing it to stand overnight, and filtering (Ahmed; paragraphs [0056] and [0061]; Scheme 4, step G). The skilled artisan could reasonably ascertain from the teachings of Ahmed that the pH of the initial reaction mixture prior to POCl3 addition is about 11.3 (i.e., 0.5 mL of 3.7 N LiOH = 1.85 mmol corresponds to OH–, corresponding to a pH of approximately 11.3), and the pH of the reaction mixture after all of the components are added must be less than 13 (i.e., 32.5 mL of 3.7 N LiOH = 120.25 mmol OH–; 17.5 mmol of POCl3 would generate 52.5 mmol of HCl in an aqueous solution to be neutralized, such that at maximum 64.75 mmol OH– is remaining, corresponding to a pH of approximately 12.8). Therefore, one of ordinary skill in the art would recognize that the in situ formed cyclocreatine phosphate (i.e., cyclocreatine phosphate dilithium) described in the method of Ahmed would exist as a Zwitterion complex in a manner consistent with the instant claim, because at any point during the course of the reaction it resides within the pH range of about 2 to about 13 in the reaction mixture (see Claim Interpretation for further details regarding the claimed ionizable functional groups). Finally, Ahmed teaches that the pH of the reaction mixture can be controlled (i.e.; Ahmed adjusts pH to 7.2; paragraph [0061]) to generate an aqueous solution of cyclocreatine phosphate dilithium, in manner analogous to the instant claim.
Ahmed fails to teach (1) using a continuous flow reactor (CFR) system including at least two flow cells; (2) a first flow cell to generate an aqueous solution of cyclocreatine phosphate as a Zwitterion complex in a first stage; (3) collecting the aqueous solution of cyclocreatine phosphate in a second flow cell; and (4) injecting a second aqueous solution of the base to the second flow cell in a second stage so as to control pH value and to generate an aqueous solution of cyclocreatine phosphate disodium dihydrate (CCrP-Na2).
Regarding points (1)-(3), Guidi teaches that flow chemistry is a widely explored technology whose intrinsic features both facilitate and provide reproducible access to a broad range of chemical processes that are otherwise inefficient or problematic; the foundational, distinguishing feature of the approach is a high degree of precision in the delivery of reagents/solutions and excellent control over the conditions to which the solutions are exposed; precise control results in excellent reproducibility and safety – making flow chemistry applicable not only to a range of disciplines, but also to researchers from university teaching labs to production-scale process chemists; flow chemistry has a number of inherent advantages compared to batch processes that increase reproducibility and safety, increase access to intermediates and conditions that are traditionally difficult to use, and allow for multistep processes to be performed more efficiently by linking multiple units (Guidi; Abstract; page 8910, Col. 1, paragraph 1 and Col. 2, paragraph 1; page 8930, Col. 1, Conclusion paragraph 1). Guidi further teaches that flow modules can be used in series, for example, two per-fluoro-alkoxy (PFA) reactors can be used for a chemical reaction (e.g., reduction) and subsequent quenching, and solutions of reagents are first passed through precooling loops to ensure controlled reactivity at sub-ambient temperatures and mixing is achieved using T-mixers (Guidi; page 8916, Col. 2, paragraph 3; page 8917, Fig. 7). One of ordinary skill in the art would recognize that the flow modules/reactors taught by Guidi correspond to flow cells, in a manner consistent with the instant claim. Furthermore, Guidi teaches that liquid/liquid workup modules can be included either for quenching/workup or for purification via basicification/acidification/back-extraction of carboxylic acids (Guidi; page 8926, Col. 1, paragraph 1 and Col. 2, paragraph 1). The prior art as taught by Ahmed and Guidi reside in the overlapping technical field of synthetic organic chemistry, such that one of ordinary skill in the art would be sufficiently motivated to incorporate the flow chemistry methods of Guidi into the batch chemistry method of Ahmed to realize its described advantages to arrive at an improved method for the synthesis of cyclocreatine phosphate. Furthermore, the skilled artisan would be sufficiently motivated to use at least two flow cells (one for the phosphorylation step and one for the workup/pH adjustment step) in a manner consistent with the teachings of Guidi and the instantly claimed invention, because it is predictable that the reaction yield and selectivity is expected to be improved because flow reactors control the reaction parameters much more strictly than batch reactions across all types of reactions.
Regarding point (4), Kaddurah-Daouk teaches creatine phosphate, creatine phosphate analogs, and uses therefor (Kaddurah-Daouk; Title). Of particular note, Kaddurah-Daouk teaches that in one embodiment, the phosphorylcyclocreatine is provided as the disodium salt trihydrate (Na2PCC•3H2O), which has improved solubility in comparison with the dilithium dihydrate of phosphorylcyclocreatine (Li2PCC•2H2O) or cyclocreatine itself (Kaddurah-Daouk; page 1, lines 16-20). The structure of Na2PCC•3H2O comprises disodium 1-carboxymethyl-2-imino-3-phosphonoimidazolidine, whose molecular structure reads directly on formula (IV) of the instant claim when R5 is Na and R6 is H (Kaddurah-Daouk; page 36, Example 4). Kaddurah-Daouk further teaches the preparation of Na2PCC•3H2O from Li2PCC•2H2O through the intermediate stage of the diammonium salt (NH4)2PCC:
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wherein the method comprises increasing the pH to between 7.2 and 7.6 by addition of 3M NaOH, filtering the solution to remove any particulate matter, and crystallizing the product from the filtrate (Kaddurah-Daouk; page 36, lines 14-18; Example 4; page 38, section (C), lines 15-19). One of ordinary skill in the art would recognize that the cyclocreatine phosphate described in step (2) of the Na2PCC•3H2O preparation method of Kaddurah-Daouk would exist as a Zwitterionic disodium ionic complex at pH 7.2 to 7.6, in a manner consistent with the instantly claimed invention (see Claim Interpretation for further details regarding the claimed ionizable functional groups). The prior art as taught by Ahmed and Kaddurah-Daouk reside in the closely overlapping technical field of the chemical synthesis of cyclocreatine phosphate, such that one of ordinary skill in the art would be sufficiently motivated to incorporate the teachings of Kaddurah-Daouk to the method of Ahmed to realize a cyclocreatine phosphate salt form with improved physicochemical properties. Furthermore, the skilled artisan would recognize that this improvement could be readily attained by substituting the LiOH base taught by Ahmed with NaOH as taught by Kaddurah-Daouk and implementing a final pH adjustment step through the addition of a second aqueous solution of NaOH to form an aqueous solution of cyclocreatine phosphate disodium, in a manner consistent with the instant claim.
Considering all of the points ascertained from the teachings of the prior art described above, it is reasonable to conclude that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Ahmed to incorporate the teachings of Guidi and Kaddurah-Daouk to implement (1) a continuous flow reactor (CFR) system including at least two flow cells; (2) a first flow cell to generate an aqueous solution of cyclocreatine phosphate as an ionic complex in a first stage; (3) collect the aqueous solution of cyclocreatine phosphate in a second flow cell; and (4) injecting a second aqueous solution of NaOH to the second flow cell in a second stage so as to control pH value and to generate an aqueous solution of cyclocreatine phosphate disodium dihydrate (CCrP-Na2). The motivation to do so would yield the predictable results of realizing a number of inherent advantages compared to batch processes that increase reproducibility and safety, increase access to intermediates and conditions that are traditionally difficult to use, and allow for multistep processes to be performed more efficiently by linking multiple units, as described above; furthermore, the motivation to combine Ahmed with Kaddurah-Daouk would yield the predictable results of realizing a form of cyclocreatine phosphate with improved solubility (i.e., substituting the Li salt of Ahmed with the Na salt of Kaddurah-Daouk), as described above, and this endeavor would result in the simple substitution of one known element for another to obtain predictable results. See MPEP § 2143(I)(B). Finally, the instant application (Example; Specification at pages 13-14) teaches that although the base is added stepwise, nothing is removed from the first reaction mixture at a pH of between 2.4 and 2.6 (i.e., the intermediate Zwitterion does not appear to be isolated or purified before it is fed to the second reaction zone). Therefore, this equates to modifying the order of addition to add the base stepwise rather than all at once, wherein Kaddurah-Daouk teaches the pH to obtain the desired cyclocreatine phosphate disodium final product (Kaddurah-Daouk; Example 4; page 38, section (C), lines 15-19). MPEP § 2144.04(IV) states that the “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.”
Regarding claim 2 depending from claim 1, Ahmed fails to explicitly teach the limitation further comprising mixing the aqueous solution of cyclocreatine intermediate of formula (III) and the first aqueous solution of the base to form a first feedstock, and mixing the first feedstock with the phosphoryl chloride in the first flow cell to generate the aqueous solution of cyclocreatine phosphate as a Zwitterion complex in the first stage, as recited in instant claim 1. Instead, Ahmed teaches an aqueous solution of 1-carboxymethyl-2-iminoimidazolidine (i.e., a compound of cyclocreatine intermediate of formula (III) of the instant claim) as a mixture in water and LiOH prior to the portionwise addition of an aqueous basic solution of phosphoryl chloride, as detailed above, wherein the initial mixture contains both aqueous solution of cyclocreatine intermediate of formula (III) and base (Ahmed; paragraph [0061]). One of ordinary skill in the art would recognize that the initial aqueous solution of 1-carboxymethyl-2-iminoimidazolidine (i.e., a compound of cyclocreatine intermediate of formula (III) of the instant claim) as a mixture in water and LiOH corresponds to the first feedstock described in the instant claim, the only difference being that the method of Ahmed forms this first feedstock as an initial starting solution, rather than obtaining it by mixing the aqueous solution of cyclocreatine intermediate of formula (III) and the first aqueous solution of the base as recited in instant claim 2. However, the differences between these method steps of Ahmed and instant claim 1 merely reflect a re-ordering of process steps, and is therefore non-inventive in nature. MPEP § 2144.04(IV) states that the “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.”
Regarding claim 3 depending from claim 1, Kaddurah-Daouk teaches a preparation method for cyclocreatine phosphate disodium as detailed above, the method comprising adjusting the pH to between 7.2 and 7.6 by addition of 3M NaOH (Kaddurah-Daouk; page 38, section (C), lines 15-16). This pH range overlaps with the range recited in the instant claim. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Regarding claim 4 depending from claim 1, Kaddurah-Daouk teaches a preparation method for cyclocreatine phosphate disodium as detailed above, the method comprising the use of NaOH as the base (Kaddurah-Daouk; page 38, section (C)).
Regarding claim 5 depending from claim 1, Ahmed teaches that cyclocreatine phosphate can be administered as a pharmaceutically acceptable salt; a pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids; salts derived from inorganic bases include salts with one or more of the following cations: aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like; particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts (Ahmed; paragraph [0037]). Thus, based on the teachings of Ahmed alone, one of ordinary skill in the art could arrive at the process of claim 1, wherein each of R5 and R6 cations, independent of each other, is selected from a group including Na and K, as recited in the instant claim. Such an endeavor would be the result of choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, and would therefore be “obvious to try,” as described in MPEP § 2143(I)(E). Therefore, as with claim 1, it would have been prima facie obvious to combine Ahmed with Guidi and Kaddurah-Daouk to arrive at the claimed invention.
Claim 6 remains rejected under 35 U.S.C. 103 as being unpatentable over Ahmed et al. (US 2008/0242639 A1; PTO-892 of 10-02-2025; hereinafter “Ahmed”), in view of Guidi et al. (Chem. Soc. Rev. 2020, 49, 8910-8932; hereinafter “Guidi”) and Kaddurah-Daouk et al. (WO 94/16712; PTO-892 of 10-02-2025; hereinafter “Kaddurah-Daouk”) as applied to claims 1-5 above, and further in view of H. G. Brittain (Polymorphism in Pharmaceutical Solids, 1999, 95, page 203; PTO-892 of 10-02-2025; hereinafter “Brittain”) and N.G. Anderson (Practical Process Research & Development, 2000, page 237; PTO-892 of 10-02-2025; hereinafter “Anderson”).
Regarding claim 6 depending from claim 1, Kaddurah-Daouk teaches compositions including phosphorylcreatine and analogs of phosphorylcreatine and pharmaceutically acceptable salts (e.g., lithium, sodium) thereof; in one embodiment N-phosphoryl-cyclocreatine is provided as the disodium salt, trihydrate (Na2PCC•3H2O), which has improved solubility in comparison with cyclocreatine or the dilithium dihydrate of phosphorylcyclocreatine (Kaddurah-Daouk; page 4, lines 31-33 and page 5, lines 1-5).
Although Kaddurah-Daouk teaches wherein the pharmaceutical acceptable salt of the compound of formula (IV) is in a hydrated form including cyclocreatine phosphate disodium trihydrate, Kaddurah-Daouk fails to teach a hydrated form including cyclocreatine phosphate disodium dihydrate. However, since Ahmed teaches the preparation of cyclocreatine phosphate dilithium dihydrate (i.e., 1-carboxymethyl-3-phosphono-2-iminoimidazoline dilithium salt, dihydrate), one of ordinary skill in the art could reasonably expect to arrive at a hydrated form including cyclocreatine phosphate disodium dihydrate by incorporating the teachings of Kaddurah-Daouk (i.e., the use of NaOH base) in the method of Ahmed, as detailed in the claim 1 rejection above. Furthermore, Brittain teaches that hydrates can be prepared by recrystallization from water or from mixed solvents; they can also result, in some instances, from exposure of crystal solvates to an atmosphere containing water vapor, and well-defined multiple hydrate species can also form with organic molecules (Brittain; page 203, paragraphs 1-2). In addition, Anderson teaches that to control processing in the formation of hydrates it is often necessary to control the amount of water present during the crystallization (Anderson; page 237, paragraph 2). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at a pharmaceutical acceptable salt of the compound of formula (IV) in a hydrated form including cyclocreatine phosphate disodium dihydrate based on the combined teachings of Ahmed, Guidi, and Kaddurah-Daouk and through optimization within prior art conditions or through routine experimentation, as evidenced by Brittain and Anderson. See MPEP § 2144.05(II)(A).
Claims 7 and 9-10 remain rejected under 35 U.S.C. 103 as being unpatentable over Ahmed et al. (US 2008/0242639 A1; PTO-892 of 10-02-2025; hereinafter “Ahmed”), in view of Ayres et al. (Org. Lett. 2016, 18, 5528-5531; PTO-892 of 10-02-2025; hereinafter “Ayres”).
Regarding claims 7 and 10, Ahmed teaches that cyclocreatine phosphate can be prepared in large quantities from inexpensive starting materials to afford a stable product (Ahmed; Abstract). Ahmed further teaches that cyclocreatine phosphate can be prepared by reacting cyclocreatine with phosphorous oxychloride under basic conditions (Ahmed; paragraph [0042]; Scheme 2):
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The cyclocreatine structure (Ahmed; Scheme 2, left) taught by Ahmed reads directly on formula (III) of instant claims 7 and 10 when R1 is H and R2 is CH2CO2H, the cyclocreatine phosphate structure (Ahmed; Scheme 2, right) taught by Ahmed reads directly on formula (IV) of instant claim 7 when R5 is a mono-valent cation (i.e., R5 is Li+) and R6 is H, and the formation of cyclocreatine phosphate (i.e., the compound of formula (IV)) results from reacting cyclocreatine (i.e., the compound of formula (III)) with phosphoryl chloride by N-phosphorylation (Ahmed; Scheme 2 and paragraphs [0042] and [0061]), in a manner consistent with instant claim 7. Furthermore, Ahmed teaches a method for the synthesis of cyclocreatine:
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wherein ethylenediamine is allowed to react with sodium chloroacetate, and the product is treated with NaOH and cyanogen bromide to afford cyclocreatine (Ahmed; paragraph [0041], Scheme 1). Of particular note, the product of the first reaction step of Scheme 1 detailed above reads directly on formula (I) of instant claims 7 and 10 when R3 is CH2CO2Y, wherein Y is Na, and cyanogen bromide is structurally similar to formula (II) of instant claims 7 and 10.
Thus, Ahmed teaches every limitation of instant claims 7 and 10, with the exception of the compound of formula (II), wherein Ahmed teaches the use of cyanogen bromide for the preparation of cyclocreatine (i.e., R4 is Br) instead of trichloroacetonitrile (i.e., R4 is CCl3), as recited in the instant claims. However, Aryes teaches the N-cyanation of secondary amines using trichloroacetonitrile as an inexpensive cyano source, an approach that is operationally simple with an improved safety profile and distinct selectivity that favors comparably to the highly toxic cyanogen bromide reagent (Aryes; Title; Abstract; page 5528, Scheme 1). The prior art as taught by both Ahmed and Aryes resides in the closely overlapping technical field of synthetic organic chemistry and chemical reagents that serve as competent cyano sources (i.e., cyanogen bromide as taught by Ahmed and trichloroacetonitrile as taught by Aryes), such that the skilled artisan would be sufficiently motivated to substitute the cyano reagent of Aryes into the method of Ahmed with a reasonable expectation of success. Such an endeavor would involve the simple substitution of one known prior art element for another to obtain predictable results, as described in MPEP § 2143(I)(B). Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have modified Ahmed to incorporate the teachings of Aryes to replace the cyanogen bromide reagent of Ahmed with trichloroacetonitrile (i.e., the compound of formula (II) of instant claims 7 and 10) to arrive at the claimed invention. The motivation to do so would achieve the predictable results of utilizing an inexpensive cyano source with an improved safety profile and distinct selectivity while avoiding the use of highly toxic cyanogen bromide, as described above.
Regarding claim 9 depending from claim 7, Ahmed teaches that cyclocreatine phosphate can be administered as a pharmaceutically acceptable salt; a pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids; salts derived from inorganic bases include salts with one or more of the following cations: aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like; particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts (Ahmed; paragraph [0037]). Thus, based on the teachings of Ahmed alone, one of ordinary skill in the art could arrive at the process of claim 1, wherein each of R5 and R6 cations, independent of each other, is selected from a group including Na and K, as recited in the instant claim. Such an endeavor would be the result of choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, and would therefore be “obvious to try,” as described in MPEP § 2143(I)(E). Therefore, as with claim 7, it would have been prima facie obvious to combine Ahmed with Aryes to arrive at the claimed invention.
Claims 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Ahmed et al. (US 2008/0242639 A1; IDS reference; hereinafter “Ahmed”), in view of Ayres et al. (Org. Lett. 2016, 18, 5528-5531; hereinafter “Ayres”) as applied to claims 7 and 9-10 above, and further in view of Wuts et al. (Greene’s Protective Groups in Organic Synthesis, 4th Ed., 2007, pages 537 and 598-599; hereinafter “Wuts”).
Regarding claims 8 and 11, claims 7 and 10 are rendered obvious over Ahmed in view of Ayres, as detailed above.
Although Ahmed teaches that it can be desirable to protect a functional group during preparation of CCr (i.e., cyclocreatine, a compound of claimed formula (III)) or CCrP (i.e., cyclocreatine phosphate, a compound of claimed formula (IV)), and that variations of the methods above can be made, for example, other reagents, conditions, and protecting groups can be used to form the same compounds (Ahmed; paragraphs [0040] and [0060]), Ahmed and Aryes fail to explicitly teach wherein each of R2 and R3, independent of each other, is CH2CO2CH2C6H5, as recited in instant claims 8 and 11. However, Wuts teaches that carboxylic acids are protected for a number of reasons: (1) to mask the acidic proton so that it does not interfere with base-catalyzed reactions; (2) to mask the carbonyl group to prevent nucleophilic addition reactions; and (3) to improve the handling of the molecule in question (e.g., to make the compound less water soluble, to improve its NMR characteristics, or to make it more volatile so that it can be analyzed by gas chromatography) (Wuts; page 537, paragraph 1). Of particular note, Wuts teaches that benzyl esters (RCO2CH2C6H5) are commonly utilized and readily prepared, and the most useful property is that they are readily cleaved by hydrogenolysis (Wuts; page 598, ‘Formation’ paragraph and examples; page 599, ‘Cleavage’ paragraph and examples).
The prior art as taught by Ahmed and Wuts reside in the closely overlapping technical field of synthetic organic chemistry, such that the skilled artisan would be sufficiently motivated to incorporate the teachings of Wuts into the method of Ahmed. Furthermore, since Ahmed teaches that protecting groups may be employed in the reaction methods, and Scheme 1 of Ahmed shows a reaction embodiment wherein R2 is CH2CO2H and wherein R3 is CH2CO2Y, wherein Y is Na, the skilled artisan would be further motivated to incorporate the teachings of Wuts as it pertains to carboxyl group protection with a reasonable expectation of success. Such an endeavor would involve the simple substitution of one known prior element for another to obtain predictable results, as described in MPEP § 2143(I)(B). Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have modified Ahmed to incorporate the teachings of Wuts to implement a method wherein each of R2 and R3, independent of each other, is CH2CO2CH2C6H5, as recited in instant claims 8 and 11. The motivation to do so would achieve the predictable results of (1) masking the acidic proton so that it does not interfere with base-catalyzed reactions; (2) masking the carbonyl group to prevent nucleophilic addition reactions; and (3) improving the handling of the molecule in question (e.g., to make the compound less water soluble, to improve its NMR characteristics, or to make it more volatile so that it can be analyzed by gas chromatography), as described above.
Based on the combined teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success of arriving at the instantly claimed method. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 3 December 2025, asserting that the teachings of the cited prior art, alone or in combination, do not disclose or make obvious Applicant’s claimed process and methods have been fully considered but they are not persuasive.
Applicant recites the overall features of the presently claimed invention, asserts that none of the prior art teaches or suggests the specific architecture and sequence of operations that yield the benefits described in the claimed invention, and argues the following:
“(1) Claimed two-stage Continuous Flow Reactor (CFR) arrangement with staged base injection and Zwitterion control is not taught or suggested in the cited art in the claimed manner. (i) Novel staged flow architecture: Ahmed teaches batch phosphorylation; Guidi teaches flow chemistry advantages in general and some flow modules for other reactions, but Guidi does not teach the specific two-cell CFR architecture claimed herein in which, (a) a first flow cell produces a Zwitterion cyclocreatine phosphate intermediate under carefully controlled feed stoichiometry and mixing, and (b) a second flow cell receives that intermediate and performs a separate, controlled pH adjustment via injection of a second base stream to effect selective conversion to a stable, pharmaceutically useful sodium salt (disodium) with controlled hydration characteristics. The claimed arrangement couples the in-situ formation of a Zwitterion in one stage with post-formation pH tuning in a second stage, with the two stages linked in continuous flow and no isolation of the intermediate. This is conceptually and functionally different from the batch procedures in Ahmed, which involve portion-wise additions and offline crystallization. (ii) Predictability vs. technical details: The Examiner's combination presumes that the skilled artisan would be motivated to insert Guidi’s flow apparatus into Ahmed's process. But the mere availability of flow modules in Guidi does not teach or suggest the exact order, where nothing is removed between stages, the manner of mixing feedstock/base in the first stage prior to POCl3 addition, the degree of pH control used in the second stage, nor the resulting reduction of bis-N-phosphoramidate impurity. The claimed method provides a specific process sequence and operational parameters that yield improved product quality and process robustness, not taught by the cited references….
…Here, the specification of the instant Application identifies specific problems (toxic reagents, impurity formation, low yields, scale-up hazards., reduction in chemical waste) and provides a stepwise process that addresses these problems in a way not taught or suggested by the primary references. (ii) The claimed process requires (and the specification provides) a specific feed arrangement (first feedstock composition, proportions of base in the first and second feed, timing and order of POC13 addition, and pH set points) that together produce the improved outcomes; these process specifics are non-trivial and are not mere predictable optimization….
…(5) Secondary considerations (objective indicia), as disclosed in the specification of the instant Application. (i) The specification documents practical benefits and improvements (reduced use of toxic reagents, improved safety, enhanced reproducibility and scalability, and reduced impurity and chemical waste, see Summary, Detailed Description and Examples of the instant Application). These provide objective evidence of non-obviousness and serve to counter the Examiner's prima facie case because they (a) address known problems in the art and (b) show that the claimed approach produces valuable technical results that are not shown or suggested by the prior art combination.
Additionally, the Applicant submits that for the specific combination of Ahmed and Guidi, the Applicant submits that while Guidi discusses flow reactor advantages, Ahmed's batch procedure and Guidi's general flow module teachings do not render the claimed specific two-cell staged pH protocol obvious, particularly in light of the beneficial reduction of undesired bis-N-phosphoramidate impurity as taught by the Specification. The specific staged- order, stoichiometry, and in-line pH modulation are not suggested by the cited combination, and prediction of impurity suppression and reproducible scale up is not a trivial or routine expectation. For a specific combination of Ahmed and Kaddurah-Daouk, the Applicant submits that substituting LiOH with NaOH for a more soluble disodium salt is a known option as described by Ahmed; however, the claimed invention requires particular processing to produce the disodium species in a CFR with controlled pH in the second stage. The Examiner's reliance on simple substitution does not recognize the specific process-dependent results in the Specification.”
These arguments have been fully considered, but are not found to be persuasive. As detailed in the maintained 103 rejections above, the method of Ahmed teaches a two-step process involving the generation of the Zwitterion cyclocreatine phosphate intermediate that mixes the feedstock/base in the first stage prior to POCl3 addition, followed by a controlled pH adjustment step by a second addition of base wherein no isolation of the intermediate is performed, in a manner consistent with process of amended claim 1 (Ahmed; paragraphs [0056] and [0061]; Scheme 4, step G). Since Ahmed specifically teaches that the base is very cautiously added portionwise (e.g., 16-20 portions) over a period of 2 hours, with mechanical stirring and cooling (Ahmed; paragraph [0061]), the skilled artisan would realize that this exothermic reaction could be more predictably controlled through the utilization of a continuous flow reactor, and as such would look to the teachings of Guidi to improve upon the batch method. Thus, incorporating flow chemistry modules as an alternative reaction platform is rendered obvious in view of the teachings of Guidi, who teaches that flow chemistry has a number of inherent advantages compared to batch processes that increase reproducibility and safety, increase access to intermediates and conditions that are traditionally difficult to use, and allow for multistep processes to be performed more efficiently by linking multiple units (Guidi; Abstract; page 8910, Col. 1, paragraph 1 and Col. 2, paragraph 1; page 8930, Col. 1, Conclusion paragraph 1). Thus, the skilled artisan would be sufficiently motivated to implement a continuous flow reactor method based on the teachings of Ahmed in view of Guidi to realize these improvements over traditional batch methods with a reasonable expectation of success. See MPEP § 2143(I)(A). Furthermore, the motivation to combine Ahmed with Kaddurah-Daouk would permit the skilled artisan to pursue a form of cyclocreatine phosphate with improved solubility (i.e., substituting the Li salt of Ahmed with the Na salt of Kaddurah-Daouk) by using NaOH as the base instead of LiOH to adjust the pH to between 7.2 and 7.6 in a manner consistent with the instant claims (Kaddurah-Daouk; page 1, lines 16-20; page 38, section (C), lines 15-16), as described, and this endeavor would result in the simple substitution of one known element for another to obtain predictable results. See MPEP § 2143(I)(B). Finally, the instant application (Example; Specification at pages 13-14) teaches that although the base is added stepwise, nothing is removed from the first reaction mixture at a pH of between 2.4 and 2.6 (i.e., the intermediate Zwitterion does not appear to be isolated or purified before it is fed to the second reaction zone). Therefore, this equates to modifying the order of addition to add the base stepwise rather than all at once, wherein Kaddurah-Daouk teaches the pH to obtain the desired cyclocreatine phosphate disodium final product (Kaddurah-Daouk; Example 4; page 38, section (C), lines 15-19). See MPEP § 2144.04(IV).
Therefore, the claim rejections are maintained for the reasons of record and the reasons set forth above.
Applicant argues the following:
“(2) Unexpected advantages in impurity profile and process safety/scaleability demonstrated (as disclosed in the specification). (i) The specification specifically addresses the problem of the undesirable bis-N-phosphoramidate impurity resulting from conventional batch phosphorylation (see the specification discussion and Scheme 4 of the instant Application). The specification discloses that the claimed CFR approach, with staged feed and pH control, reduces the formation of this impurity and improves yield and purity (see FIG. 1 and Example discussion of the instant Application). While Ahmed discloses batch phosphorylation and Kaddurah-Daouk discusses salt forms, none of those references disclose (or would have led to) the particular approach of staging the reaction in flow to reduce the formation of this impurity. That improvement is not merely a recitation of an expected advantage; rather, it is a process-dependent result that flows from the claimed sequence and control over reaction streams. (ii) Further, the specification discloses that replacing cyanogen bromide with trichloroacetonitrile in the de novo synthesis reduces toxicity and supply chain risk while yielding higher overall process yield…”
These arguments have been fully considered, but are not found to be persuasive. Although the instant specification mentions the undesirable bis-N-phosphoramidate impurity resulting from previous work, the working example is silent regarding this impurity and due to the lack of a comparative batch example it is unclear to what extent this impurity is removed. Nevertheless, the teachings of Guidi espouse several advantages to flow chemistry reactors compared with traditional batch system, including excellent control over reaction conditions leading to high reproducibility and safety (Guidi; Abstract; page 8910, Col. 1, paragraph 1 and Col. 2, paragraph 1; page 8930, Col. 1, Conclusion paragraph 1), such that the skilled artisan would be sufficiently motivated to incorporate these teachings into the method of Ahmed with a reasonable expectation of success, as detailed above. MPEP § 2144(IV) states that “It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.”
Regarding point (ii), The Examiner notes that independent claims 7 and 10 that recite the use of trichloroacetonitrile do not depend from amended claim 1, and therefore do not rely on the recited continuous flow reactor (CFR) features as argued by Applicant. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Therefore, the claim rejections are maintained for the reasons of record and the reasons set forth above.
Applicant argues the following:
“(4) No single cited prior art discloses the claimed entire combination or the process advantages achieved when the elements are combined as claimed. (i) Ahmed: discloses phosphorylation chemistry but in batch and with LiOH; does not disclose staged flow cells with staged base injection for Zwitterion stabilization and pH-driven salt formation in the continuous manner claimed. (ii) Guidi: teaches general advantages of flow chemistry and modular flow devices, but does not teach the specific feed/pH/staging details or the use of those modules to avoid bis-N-phosphoramidate formation in cyclocreatine phosphorylation. (iii) Kaddurah-Daouk: discloses disodium salts and some hydration forms in the context of different examples, but does not teach the two-cell continuous process as claimed. (iv) Wuts/Brittain/Anderson: teach general hydrate formation, protecting group choice, and crystallization control; none of these references teach the inventive combination of de novo trichloroacetonitrile cyanation, first-stage Zwitterion formation in flow, and second-stage pH control to obtain a pharmaceutically acceptable sodium salt with improved impurity profile.”
These arguments have been fully considered, but are not found to be persuasive. As detailed in the maintained 103 rejections above, it would have been prima facie obvious for the skilled artisan to perform the two-step batch method of Ahmed in a two-stage continuous flow reactor system as taught by Guidi to pursue the inherent advantages of this reaction platform compared with traditional batch methods, including increased reproducibility and safety, increased access to intermediates and conditions that are traditionally difficult to use, and to allow for multistep processes to be performed more efficiently by linking multiple units, with a reasonable expectation of success (Guidi; Abstract; page 8910, Col. 1, paragraph 1 and Col. 2, paragraph 1; page 8930, Col. 1, Conclusion paragraph 1). Further incorporating the method of Kaddurah-Daouk with the teachings of Ahmed and Guidi would permit the skilled artisan to pursue a disodium salt with an improved solubility as compared to the dilithium salt of Ahmed, as described above (Kaddurah-Daouk; page 1, lines 16-20), and the pH adjustment method steps of Kaddurah-Daouk in combination with Ahmed equates to modifying the order of addition to add the base stepwise rather than all at once. The instant Specification does not show through comparative examples that stepwise addition of base in another compartment would be different than or superior to adding the base stepwise in the same container and/or continuously. MPEP § 2144.04(IV) states that the “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.”
Regarding point (iv), The Examiner notes that independent claims 7 and 10 that recite the use of trichloroacetonitrile do not depend from amended claim 1, and therefore do not rely on the recited continuous flow reactor (CFR) features as argued by Applicant. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Therefore, the claim rejections are maintained for the reasons of record and the reasons set forth above.
Applicant argues the following:
“Ayres/Aryes disclose trichloroacetonitrile usage for N-cyanation in certain contexts, but do not disclose the integration of that de novo reagent into a multistage continuous flow process specifically tailored for cyclocreatine production and downstream N-phosphorylation. The decision to use trichloroacetonitrile here is accompanied by procedural modifications (protecting group choices, aqueous feed conditions, staged pH control) that together provide an unexpected improvement in yield, impurity profile, manufacturability and reducing chemical waste.
…(3) The Examiner's “obvious to try” rationale does not account for the non-trivial process optimization and unexpected results produced by the claimed method. (i) The Examiner relies on the idea that the substitution of Li+ with Na+, or adopting flow reactors, is a predictable interchange…
…Ayres/Aryes: teach trichloroacetonitrile for N-cyanation; again, none teach combining that reagent with the claimed CFR structure and staged pH control tailored for cyclocreatine/CcRP synthesis…
…For the specific combination of Ahmed and Ayres, and Ahmed, Ayres, and Wuts, the Applicant submits that Ayres's teaching that trichloroacetonitrile can serve as an alternative cyano source does not by itself teach or suggest incorporation into an overall CFR process for cyclocreatine where downstream staged phosphorylation and pH control are used. Likewise, Wuts teaches generic protecting group choices; the Examiner's combination relies on routine optimization but fails to account for the non-predictable advantages resulting from the totality of the claimed process.”
These arguments have been fully considered, but are not found to be persuasive.
In response to Applicant’s argument that the references fail to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., a multistage continuous flow process) are not recited in the rejected claim(s). The Examiner notes that independent claims 7 and 10 that recite the use of trichloroacetonitrile do not depend from amended claim 1, and therefore do not rely on the recited continuous flow reactor (CFR) features as argued by Applicant. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Furthermore, as indicated in the maintained 103 rejections above, Aryes teaches the N-cyanation of secondary amines using trichloroacetonitrile as an inexpensive cyano source, an approach that is operationally simple with an improved safety profile and distinct selectivity that favors comparably to the highly toxic cyanogen bromide reagent (Aryes; Title; Abstract; page 5528, Scheme 1). As such, and in a manner consistent with the written description (Specification; page 7, paragraph [0026]), the skilled artisan would be sufficiently motivated to substitute the highly toxic cyanogen bromide reagent employed in the method of Ahmed with the safer trichloroacetonitrile reagent of Aryes with a reasonable expectation of success. MPEP § 2143(I)(B).
Therefore, the claim rejections are maintained for the reasons of record and the reasons set forth above.
Conclusion
No Claims are allowed.
Applicant’s amendment under 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p) on 3 December 2025 necessitated and prompted the maintained ground(s) of rejection presented in this Office Action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/D.R./Examiner, Art Unit 1692
/AMY C BONAPARTE/Primary Examiner, Art Unit 1692