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 .
Claim Status
Claims 1-13 were filed on 10/19/2022. In a preliminary amendment, claims 1-13 were canceled and claims 14-33 were newly added. Claims 14-33 are currently pending.
Priority
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See filing receipt dated 3/3/2023. Receipt is acknowledged of certified copies of papers.
Claim Objections
Claim 14 is objected to because of the following informalities: in line 1 of claim 14, the limitation “N-N’-diacetyl-L-cystine” should be amended to recite: “N,N’-diacetyl-L-cystine”, wherein the first dash is replaced by a comma. Appropriate correction is required.
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.
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.
Claim(s) 14-29 and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Belov (“Syntheses of D-Labelled Oxidative Metabolites of Acrylamide and Acrylonitrile for the Quantification of Their Toxicities in Humans” Eur. J. Org. Chem. 2008, p. 4417-4425, of record in the IDS filed on 10/21/2022) in combination with Morgan (US 4827016, published on 5/2/1989) and further in view of Greene (“Greene’s Protective Groups in Organic Synthesis” fourth edition, 2007, excerpt including front matter; p. 775-779; and p. 582-588).
Applicant Claims
Applicant claims a process of making N,N-diacetyl-L-cystine (NDAC) comprising:
Forming a reaction mixture with a cystine derivative, wherein the cystine derivative is di-tert-butyl-L-cystine as a dihydrochloride form;
Adding acetic anhydride (Ac2O) as an acetylating agent to the reaction mixture and effecting acetylation to produce N,N’-diacetyl-di-tert-butyl-L-cystine;
Removing the tert-butyl groups to obtain NDAC; and
Isolating the N,N’-diacetyl-L-cystine from the reaction mixture.
NDAC is of the following structure according to p. 3 of the specification as filed:
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Determining the Scope and Content of the Prior Art (MPEP §2141.01)
Belov teaches the following Scheme on p. 4419:
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. Belov teaches that acetylating agent acetic anhydride (Ac2O) is added to a reaction mixture of di-tert-butyl-L-cystine dihydrochloride (6) and a base (pyridine) at 0°C to produce N,N-diacetyl-di-tert-butyl-L-cystine (7) in 85% yield. Compound (7) is then reduced with NaBH4 to produce N-acetyl-tert-butyl-L-cysteine (8) in 85% yield. Also see detailed experimental procedure for compound (7) on p. 4421.
Morgan teaches the treatment of dermal inflammations with topical application of compounds of the following structures:
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. See abstract. Morgan teaches that the active compounds include NDAC (referred to as N-DAC):
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. See example 1 in col. 7-8. Morgan further teaches the production of NDAC in col. 10, lines 34-61:
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. Thus, Morgan teaches adding acetylating agent acetic anhydride to a reaction mixture of L-cystine in the aqueous potassium hydroxide (a base) to produce NDAC in 22% yield and isolating the NDAC from the reaction mixture.
Greene is an encyclopedia of protecting groups in organic synthesis. On p. 775-776, Greene teaches that the -NHAc (acetamide) moiety is known to be introduced through reactions between an amine and acetic anhydride or acetyl chloride with or without base (“Formation” section). On p. 776-779, Greene further teaches that acetamides are quite difficult to hydrolyze and often require rather forcing conditions to achieve hydrolysis (“Cleavage” section).
On p. 582-584 Greene teaches that a tert-butyl ester protecting group is a relatively hindered ester, which makes it much less susceptible to nucleophilic additions than unhindered esters (“Formation” section). On p. 584-588 (“Cleavage” section), Greene further teaches that tert-butyl esters are stable to mild basic hydrolysis, to hydrazine and to ammonia and that the esters are cleaved by moderately acidic hydrolysis.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.02-03)
Belov does not teach or suggest the deprotection of compound (7) to produce and isolate N,N’-L-acetylcysteine (NDAC). Morgan does not teach or suggest the use of di-tert-butyl-L-cystine dihydrochloride as a starting material in the production of NDAC. Morgan instead teaches the use of the free acid to produce NDAC in 22% yield.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143)
It would have prima facie been obvious to one of ordinary skill in the art to combine the teachings of Belov, Morgan, and Greene to arrive at the instantly claimed process with a reasonable expectation of success before the effective filing date of the claimed invention. A person of ordinary skill would have been motivated to produce NDAC from intermediate (7):
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of Belov because Morgan teaches that NDAC, the free acid (-CO2H) analogue of compound (7) of Belov, is a compound with desirable bioactive produces. Further, Morgan teaches that the yield of the NDAC in the disclosed example is only 22%, indicating to the skilled artisan that there is room for improvement. Additionally, the skilled artisan would have a reasonable expectation of success of removing the tert-butyl ester group of compound (7) of Belov to arrive at NDAC based on the teachings of Greene. Greene teaches that the tert-butyl ester group can be cleaved under mild acidic hydrolysis, while the acetamide group is stable to hydrolysis. Therefore, if compound (7) of Belov was subjected to mildly acidic conditions, then the NDAC of Morgan would predictably be obtained. These arguments are further supported by steps (b) and (e) of Scheme 1 of Belov and step (d) of Scheme 2 of Belov on p. 4419. Step (b) of scheme 1 of Belov teaches that when compound (8), comprising both an acetamide (-NHAc) and a tert-butyl ester (-CO2tBu) moiety, is contacted with an aqueous base (basic hydrolysis conditions) that both protecting groups are retained to produce compounds (9R) and (10-R). Step (e) of Scheme 1 and step (d) of Scheme 2 of Belov then teach that contacting compounds comprising both an acetamide (-NHAc) and a tert-butyl ester (-CO2tBu) moiety (compounds 9/10/15) with aqueous acid (acidic hydrolysis conditions) removes the tert-butyl ester group, while the acetamide group remains intact to produce compounds 4/5/16 in said schemes. Therefore, the combination of Belov, Morgan, and Greene would predictably result in the instantly claimed process for producing NDAC by replacing one predictable N-acetylation process with another shown to have a superior yield. Also see MPEP 2143(B).
A person of ordinary skill would have been further motivated to isolate the NDAC from the combined process of Belov, Morgan, and Greene in order to use the NDAC as a topical treatment for dermal inflammations, as taught by Morgan.
Regarding claims 15-21, Belov teaches that the acetylation step is carried in the presence of a base (pyridine) with stirring at a temperature of between 0-4°C for 2 days (48 hours). Morgan teaches that the acetylation step is carried out in the presence of a base (potassium hydroxide) with stirring from 0°C to room temperature (rt, about 20-25°C) for 1 hour. As Belov teaches that the reaction is carried out at 0-4°C for 48 hours, the skilled artisan would be motivated to increase the temperature of the reaction in order to reduce the time of reaction. Further, Morgan teaches that the analogous acetylation reaction can be carried out within the claimed temperature range (rt) and reaction time (1 hour) and Greene teaches that the tert-butyl ester group is stable to hydrolysis under basic conditions. Therefore, there is a reasonable expectation of success that the acetylation reaction can be carried out at temperatures above 0°C. Further regarding claim 21, it would be prima facie obvious to stop the reaction when complete and the degree of precipitation of the product would depend on the reaction solvent and temperature. Also see MPEP 2144.05 regarding the obviousness of ranges and reaction optimization.
Regarding claims 22, 23, 28, and 29, On p. 584-588 (“Cleavage” section), Greene teaches that tert-butyl esters are stable to mild basic hydrolysis, to hydrazine and to ammonia and that the esters are cleaved by moderately acidic hydrolysis. Greene specifically teaches that the acids that can be used to cleave the tert-butyl ester group include formic acid (HCO2H-see example 1 on p. 584 in the “Cleavage” section). Greene also teaches that the acidic hydrolysis can be carried out under a variety of conditions, including those which are carried out at a temperature in the claimed range and within the claimed reaction time. Further, Greene teaches that the acetamide group is stable under acidic hydrolysis conditions and the formation of a suspension would depend upon the specific reaction conditions used. Therefore, there is a reasonable expectation of success of the skilled artisan optimizing the reaction temperature and duration to arrive at the instantly claimed process. Also see MPEP 2144.05 regarding the obviousness of ranges and reaction optimization.
Regarding claims 24-27, Belov teaches the use of pyridine, an organic base. Morgan teaches the use of aqueous potassium (alkali metal) hydroxide, an inorganic base. The skilled artisan would be motivated to replace the pyridine of Belov with the conditions of Morgan because replacing one set of predictable acetylation conditions with another is prima facie obvious. Further, there is a reasonable expectation of success because Greene teaches that the tert-butyl ester group is very stable to hydrolysis. Further, Belov teaches that the tert-butyl ester group and the acetamide group of compound (8) of Scheme 1 remain intact after contact with aqueous Na2CO3 (another aqueous inorganic base) and that compound (7) can be contacted with aqueous NaHCO3 (sodium bicarbonate) during the work-up to isolate said compound. Also see MPEP 2143(B) and MPEP 2144.07.
Regarding claim 33, it would have been prima facie obvious to telescope the combined process of Belov, Morgan, and Greene through optimization in order produce a more efficient process.
Claim(s) 30-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Belov (“Syntheses of D-Labelled Oxidative Metabolites of Acrylamide and Acrylonitrile for the Quantification of Their Toxicities in Humans” Eur. J. Org. Chem. 2008, p. 4417-4425, of record in the IDS filed on 10/21/2022) in view of Morgan (US 4827016, published on 5/2/1989) and Greene (“Greene’s Protective Groups in Organic Synthesis” fourth edition, 2007, excerpt including front matter; p. 775-779; and p. 582-588), as applied to claims 14-29 and 33 above, and further in view of Hollander (“The resolution of inactive cystine and isolation of pure dextrorotary cystine” J. Biological Chemistry, 1931, p. 243, of record in the IDS filed on 10/21/2022).
Applicant Claims
Applicant claims the method of claim 14, wherein step (d) comprising adding a water-immiscible organic solvent, preferably ethyl acetate, to the N,N’-diacetyl-L-cystine and stirring vigorously to effect precipitation and/or solidification and isolating the solid with centrifugation or filtration.
Determining the Scope and Content of the Prior Art (MPEP §2141.01)
Morgan teaches that the NDAC is a solid. See col. 10, lines 34-61.
Hollander teaches that NDAC is a water soluble solid and that it is insoluble in acetone, chloroform, ether, and ethyl acetate (claim 31). See p. 245.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.02-03)
The combination of Belov, Morgan, and Greene does not teach the instantly claimed isolation step.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Belov, Morgan, Greene, and Hollander to arrive at the instantly claimed process with a reasonable expectation of success before the effective filing date of the claimed invention. A person of ordinary skill would have been motivated to isolate the NDAC by precipitation because Hollander teaches that this is a known method in the art to isolate NDAC. The NDAC would predictably precipitate from the reaction mixture of the combined process of Belov, Morgan, and Greene if one of the solvents, including ethyl acetate, that NDAC is insoluble in as taught by Hollander is added to said mixture. It would have been further prima facie obvious to isolate the precipitated solid using a well-known solid/liquid separation method, including filtration or centrifugation. Morgan uses both techniques to isolate and purify NDAC in the example in col. 10. Also see MPEP 2143(A).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY C BONAPARTE whose telephone number is (571)272-7307. The examiner can normally be reached 11-7.
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/AMY C BONAPARTE/Primary Examiner, Art Unit 1692