PROCESS FOR THE PREPARATION OF 2,7-DIHYDROXY-9-FLUORENONE USEFUL FOR THE SYNTHESIS OF TILORONE AND ITS SALTS

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 . DETAILED ACTION Claims 11-26 of P. Jaisankar et al., US 18/702,639 (Nov. 5, 2021) are pending. Claims 11-19 are in condition for allowance. Claims 20-26 are rejected. 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 AIA 35 U.S.C. 103(a) are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. Claims 20-26 are under AIA 35 U.S.C. 103 as being unpatentable over I. Shemano et a., US 3,947,593 (1976) (“Shemano”) and/or Shemano in further view of I. Nikolaeva et al., Synthesis and antiviral activity of tilorone and its analogs, 22 Pharmaceutical Chemistry Journal, 641-644 (1988) (“Nikolaeva”); A. Patel et al., 75 Tetrahedron, 236-245 (2019) (“Patel”); N.G. Anderson, PRACTICAL PROCESS & RESEARCH DEVELOPMENT, 81-111 (2000) (“Anderson”) and/or I. McConvey et al., 16 Organic Process Research and Development, 612-624 (2011) (“McConvey”) as these secondary references are respectively cited below. Invention of Base Claim 20 Claim 20 recites as follows, where the product-by-process language is bolded: 20. A process for synthesizing tilorone and tilorone salts as an immunomodulator and a broad-spectrum antiviral agent, the process comprising: (i) dissolving 2,7-dihydroxy-9-fluorenone prepared according to the process of claim 1 in an organic solvent to obtain a solution; (ii) adding 2-bromo-N,N-diethylethylamine hydrobromide and a mineral alkali to the solution of (i) to obtain a mixture; (iii) refluxing the mixture of (ii) at a reflux temperature from 75 °C to 160 °C to obtain tilorone of formula (f): PNG media_image1.png 200 400 media_image1.png Greyscale (iv) acidifying the tilorone of (iii) with an acid to afford a tilorone salt. Claim Base claim 20 is schematically summarized by the Examiner below. PNG media_image2.png 200 400 media_image2.png Greyscale Per the above bolded language, the “2,7-dihydroxy-9-fluorenone” starting material of claim 20 and its dependents, which is “prepared according to the process of claim 1”, is a product by process recitation. 1 Although the cited product-by-process terms are nested within a method claim, this does not change the proper construction of the product-by-process limitation itself. MPEP § 2113(I); Biogen MA Inc. v. EMD Serono, Inc., 976 F.3d 1326, 1334 (Fed. Cir. 2020) (“[t]he nesting of the product-by-process limitation within a method . . . claim does not change the proper construction of the product-by-process limitation itself”); see also non-binding, non-precedential opinion in Ex parte Wohaibi, Appeal No. 2024-004112, 17/750,212 (PTAB 2025) discussing this Federal Circuit decision. In view of the foregoing, claim 20 and its dependents, with respect to comparison to the cited prior art below, do not require the method steps of claim 1 be performed because the “2,7-dihydroxy-9-fluorenone” produced by cited reference Shemano is not structurally different from that of claim 20.2 I. Shemano, US 3,947,593 (1976) (“Shemano”) Shemano teaches that compounds of the following general Formula I are useful in treating conditions of delayed hypersensitivity. Shemano at col. 1, lines 29-50. Shemano teaches that bis-amino ether derivatives of Formula I may be prepared by reacting one equivalent of a diol derivative of formula VIII: PNG media_image3.png 200 400 media_image3.png Greyscale , where W can be fluorene-9-one and R4 can be divalent oxygen, with two equivalents of Formula IX: PNG media_image4.png 200 400 media_image4.png Greyscale wherein Hal represents chlorine, bromine or iodine; A is a straight or branched alkylene chain of from 1 to 6 carbon atoms; and each of R and R is hydrogen, straight or branched lower alkyl of from 1 to 4 carbon atoms. Shemano at col. 5, lines 6-30. Shemano teaches that the reaction is conducted in the presence of a base. Shemano at col. 5, lines 30-31. With respect to the base and solvent, Shemano teaches Suitable bases for the above described reaction are sodium methoxide, sodium hydride, sodium amide, sodium hydroxide, and potassium hydroxide. Suitable solvents include aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated aromatics, such as, chlorobenzene; aprotic solvents, such as, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; alcohols, such as, ethanol or isopropyl alcohol; ketones, such as, acetone, ethers, such as, tetrahydrofuran or dioxane; water; or mixtures of these solvents. Shemano at col. 5, lines 53-63. In working Example 5, Shemano teaches the following synthesis of 2,7-Bis(2-diethylaminoethoxy)fluoren-9-one dihydrochloride (i.e., Tilorone dihydrochloride). EXAMPLE 5 2,7-Bis(2-diethylaminoethoxy)fluoren-9-one dihydrochloride A solution of 2-diethylaminoethyl chloride obtained from 15.5 g (0.09 mole) of 2-diethylaminoethyl chloride hydrochloride in 100 ml of toluene (dried over molecular sieves) is added to a mixture of 6.4 g (0.03 mole) of 2,7-dihydroxyfluoren-9-one and 3.3 g (0.06 mole) of sodium methoxide in 200 ml of toluene (dried over molecular sieves). This mixture is heated to reflux with stirring for three hours. Upon cooling, the mixture is filtered to remove the precipitated sodium chloride. The toluene solution is washed three times with water, then once with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. This mixture is filtered, and the filtrate acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, recrystallized from butanone with enough methanol added to effect solution, and the product dried at 100°C for 24 hours under vacuum to give 2,7-bis(2-diethylaminoethoxy) fluoren-9-one di hydrochloride. M.P. 235-237°C. Shemano at col. 10, line 62 to col. 11, line 17. Shemano Example 5 is summarized by the Examiner as follows: PNG media_image5.png 200 400 media_image5.png Greyscale Shemano at col. 10, line 62 to col. 11, line 17. Differences between Shemano and Claim 20 Shemano teaches every element of claim 20; but Shemano differs to the extent that it does not combine the teachings into a single embodiment or working example. Shemano working Example 5 differs from claim 20 in that claim 20 requires 2-bromo-N,N-diethylethylamine hydrobromide whereas Shemano employs the neutral chloro analog obtained from the hydrochloride salt. PNG media_image6.png 200 400 media_image6.png Greyscale Shemano working Example 5 further differs from claim 20 in that sodium methoxide is employed as the base, whereas claim 20 requires “a mineral alkali”. 3 It is noted that Shemano Example 5 meets the claim 20 reagent addition recitations of: Claim 20 . . . (i) dissolving 2,7-dihydroxy-9-fluorenone prepared according to the process of claim 1 in an organic solvent to obtain a solution; (ii) adding 2-bromo-N,N-diethylethylamine hydrobromide and a mineral alkali to the solution of (i) to obtain a mixture . . . because in Shemano Example 5, a solution of 2-diethylaminoethyl chloride in toluene is added to a mixture of 2,7-dihydroxyfluoren-9-one and sodium methoxide in toluene. Obviousness Rationale Claim 20 is obvious because one of ordinary is motivated by Shemano to modify Shemano Example 5 by: (1) replacing Shemano’s sodium methoxide with the claimed sodium or potassium hydroxide (NaOH or KOH) as the base because Shemano teaches that these are suitable alternative and equivalents of sodium methoxide. Shemano at col. 5, lines 53-55; and (2) replacing Shemano’s neutral 2-chloro-N,N-diethylethylamine (obtained from the HCl salt) with 2-bromo-N,N-diethylethylamine hydrobromide because Shemano teaches that Br is a suitable equivalent of Cl in the amines of formula IX. Shemano at col. 5, line 24. thereby meeting every limitation of claim 20. Note that as discussed in detail above, claim 20 and its dependents do not require that the method steps of claim 1 be performed because the claim 20 recitation of “2,7-dihydroxy-9-fluorenone prepared according to the process of claim 1” is product-by-process language, and Shemano’s 2,7-dihydroxy-9-fluorenone is not structurally different from that prepared by the method of instant claim 1 See above footnotes 1 and 2. One of ordinary skill has a reasonable expectation that either of sodium or potassium hydroxide as the base in combination with 2-bromo-N,N-diethylethylamine hydrobromide (an amine salt, rather than the neutral amine), as proposed above, will appropriately react in Example 5, in view of Shemano and/or I. Nikolaeva et al., Synthesis and antiviral activity of tilorone and its analogs, 22 Pharmaceutical Chemistry Journal, 641-644 (1988) (“Nikolaeva”). In this regard, Shemano Example 2 teaches sodium hydroxide as the base, in the reaction of 2-(diethylamino)ethyl chloride hydrochloride (an amine salt) with the 3,9-dihydroxyfluoranthene, to give and analogous product. Shemano at col. 10, lines 22-30 (Example 2). Shemano Example 2 is summarized by the Examiner below. PNG media_image7.png 200 400 media_image7.png Greyscale Shemano at col. 10, lines 22-30 (Example 2). Similarly, at page 642, I. Nikolaeva et al., Synthesis and antiviral activity of tilorone and its analogs, 22 Pharmaceutical Chemistry Journal, 641-644 (1988) (“Nikolaeva”) teaches the following example with KOH as the base. PNG media_image8.png 200 400 media_image8.png Greyscale Nikolaeva at page 642 (“2-[Symbol font/0x62]-(Diethylamino)ethoxy-7-methylfluoren-9-one, Hydrochloride”). Similarly, A. Patel et al., 75 Tetrahedron, 236-245 (2019) (“Patel”) teaches treatment of 2,7-dihydroxy-9-fluorenone with 2-chloro-N,N-diethylethylamine hydrochloride in presence of KOH in toluene/H2O at refluxing temperature for 8.0 hours offered Tilorone in 85% yield. See Patel at page 242, col. 1, referencing Scheme 3). Every limitation of claim 20 is met by the proposed modification of Shemano and claim 20 is obvious. The limitations of claim 21 are clearly met because Shemano Example 5 is conducted at toluene reflux (about 110 °C). The limitations of claim 22 are met because Shemano Example 5 employs toluene. Claim 23 is obvious in further view of N.G. Anderson, PRACTICAL PROCESS & RESEARCH DEVELOPMENT, 81-111 (2000) (“Anderson”) and/or I. McConvey et al., 16 Organic Process Research and Development, 612-624 (2011) (“McConvey”). Claim 23 is obvious because one of ordinary skill is motivated by Shemano in further view of either of Anderson or McConvey to replace the toluene of Shemano Example 5 with acetonitrile as the solvent for the following reasons. Anderson teaches that solvents are selected to increase reaction rates, to increase the reproducibility and ease of running reactions, and to ensure that the desired quality and yield of product is reached and that other important considerations are to decrease waste and allow for efficient solvent recovery and reuse. Anderson at page 81. Anderson teaches routine methods of solvent selection in organic synthesis. E.g., see Anderson at page 83 et seq. Anderson clearly teaches that solvent selection is a result-effective variable. MPEP § 2144.05(II)(B). Respecting claims 19, Anderson teaches that acetonitrile is a suitable reaction solvent for scale-up. Anderson at page 86 (Table 4.3. Solvents Useful for Scale-up). McConvey teaches that acetonitrile (MeCN) is a core solvent in the chemical industries, particularly the pharmaceutical industry. McConvey at page 612, col. 1. McConvey teaches that MeCN is regarded as a good solvent because of its ability to dissolve a wide variety of fine chemical and pharmaceutical ingredients, with an acceptable environmental profile. McConvey at page 613, col. 1. McConvey teaches that MeCN is also relatively inert, due to the strong C−C bond which can only be hydrolysed under extreme conditions, making it an excellent reaction solvent. McConvey at page 613, col. 1. Claim 23 is obvious because one of ordinary skill is motivated by either of Anderson or McConvey to replace the toluene of Shemano Example 5 with acetonitrile as the solvent. One of ordinary skill has a reasonable expectation of success, because Shemano teaches a listing that includes solvents within wide-ranging classes and that suitable solvents include aprotic solvents, such as, N,N-dimethylformamide, N,N dimethylacetamide. Shemano at col. 5, lines 53-63. Anderson clearly teaches that solvent selection is a result effective variable suitable for optimization. One of ordinary skill in the art is motivated to develop workable or optimum ranges for result-effective parameters, where Applicant can rebut a prima facie case of obviousness by showing the criticality (unexpected result) of the range. MPEP § 2144.05; see also, In re Boesch, 617 F.2d 272,276 (CCPA 1980); In re Aller, 220 F.2d 454, 456 (CCPA 1955). The limitations of claim 24 are met by the above proposed use of KOH as the base. Shemano teaches that KOH is a suitable base for this reaction. Shemano at col. 5, lines 53-63. The limitations of claim 25 are met because the product of Shemano Example 5 is tilorone chloride. The limitations of claim 26 are met because the product of Shemano Example 5 is tilorone dihydrochloride and the claim 26 language “is an orally active interferon inducing agent” is not interpreted as claim limitation because it does not change the structure of claim 26. Claim scope is not limited by claim language that does not limit a claim to a particular structure. MPEP § 2111.04(I). In any case, Zhou teaches that tilorone is an interferon inducer with anticancer activity. D. Zhou et al., 64 European Journal of Medicinal Chemistry, 432-441 (2013) (see Abstract). Subject Matter Free of the Art of Record Claims 11-19 are free of the art of record. The closest art of record it the combination of G. Niznik et al., US 3,875,237 (1975) (“Niznik”); X. Peng et al., CN 103819347 A (2014) (“Peng”); K. Enomoto, JPS6397667A (1988); and T. Bruice et al., 81 Journal of the American Chemical Society, 3416-34 (1959) (“Bruice”). The Process of Claim 11 The process steps of claim 11 are more easily understood with reference to the specification working examples which are schematically summarized below by the Examiner. Specification Example 2 teaches the following oxidation, per claim 1 step (i): PNG media_image9.png 200 400 media_image9.png Greyscale Specification at pages 7-8. Specification Example 3 teaches the following nitration, per claim 1, step (ii). PNG media_image10.png 200 400 media_image10.png Greyscale Specification at page 8. Specification Example 4 teaches the following reduction, with iron powder, following by acid mediated conversion of the intermediate diamine to dihydroxy compound, per claim 1, step (iii). PNG media_image11.png 200 400 media_image11.png Greyscale PNG media_image12.png 200 400 media_image12.png Greyscale Specification at pages 8-9. J. Zhang et al., 20 Molecules, 21458–21463 (2015) (“Zhang”) Zhang teaches that Tilorone dihydrochloride (1) has great potential for inducing interferon against pathogenic infection. PNG media_image13.png 200 400 media_image13.png Greyscale Zhang teaches that 2,7-dihydroxy-9-fluorenone (the final product of claim 11, i.e., compound (e)) is an intermediate in the synthesis of Tilorone dihydrochloride (1). Zhang at page 21460 (Scheme 2). Zhang synthetic method is much different that that of claim 11. Zhang is only cited here as providing motivation to one of ordinary skill to prepare 2,7-dihydroxy-9-fluorenone. G. Niznik et al., US 3,875,237 (1975) (“Niznik”) Respecting the first step of claim 11, in Example 1, Niznik teaches synthesis of 2,7-dihydroxy-9-fluorenone (claim 1 formula (b)) according to the following procedure: EXAMPLE 1 Into a solution of 50 grams (0.301 mol) fluorene in 200 ml (220 grams) dimethyl sulfoxide, was bubbled oxygen introduced through a fritted tube at the rate of about 150 ml/min. Thereafter, 0.1 ml (0.0019 mol) of 50% aqueous sodium hydroxide was added to the stir ring mixture. External cooling was required in order to maintain the temperature at between 25-30°C. After stirring the mixture for an hour, analysis showed that 28% conversion of the fluorene to fluorenone had occurred; thereafter another 0.1 ml of the above mentioned aqueous base was added with stirring while at the same time passing oxygen continuously through the solution. After 4 hours, and after a total of four 0.1 ml additions of the aqueous sodium hydroxide had been incorporated, it was found that the reaction had gone to approximately 97% conversion to fluorenone. A final 0.1 ml addition of the alkali-metal hydroxide solution brought the reaction to 99.8% conversion after a total of five hours stirring. The mixture was precipitated into 3 liters of water and the formed slurry was stirred at 60°C. for 4 hours, cooled, filtered, and dried to yield 53.13 grams (0.295 mol) fluorenone having a melting point of 74-78.5°C. Niznik at col. 3, lines 4-27 (Example 1). Niznik is summarized by the Examiner as follows: PNG media_image14.png 200 400 media_image14.png Greyscale . X. Peng et al., CN 103819347 A (2014) (“Peng”) Peng teaches a method for synthesizing 2,7-dinitrofluorenone by reacting fluorenone with a mixture of concentrated sulfuric acid and concentrated nitric acid under reflux, where after the reaction was complete, water was added and the mixture was filtered to obtain 2,7-dinitrofuorenone. Peng at page 3, [0001]. Respecting the first step of claim 11, in Example 1, step (1), Peng teaches air oxidation of fluorene to fluorenone. Example 1 step (1): (1) 33.2 g (0.2 mol) of fluorene, 240 ml of tetrahydrofuran, and 16.8 g of sodium hydroxide were added to a 1000 ml three-necked flask equipped with a reflux condenser, an air purging tube, and a mechanical stirrer. The mixture was stirred, air was introduced, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was filtered and concentrated. The solid obtained after concentration was mixed with 400 ml of 60% alkaline water and stirred for 2 h. The mixture was then filtered, washed three times with water, and dried to obtain 35 g of crude fluorene ketone, with a yield of 97.2%. Peng at page 3, [0010]. Peng Example1, step (1) is summarized by the Examiner as follows: PNG media_image15.png 200 400 media_image15.png Greyscale Respecting the second step of claim 11, in Example 1, step (2), Peng teaches nitration of the above-produced fluorenone to produce 2,7-dinitrofluorenone according to the following procedure: Example 1 step (2): (2) 18 g of fluorenone and 18.8 ml of water were added to a 250 ml four-necked round-bottom flask equipped with a mechanical stirrer, reflux condenser, thermometer, and constant-pressure dropping funnel. The mixture was stirred and heated to 80 °C in an oil bath. 27.3 ml of a mixed acid of concentrated nitric acid and concentrated sulfuric acid (containing 11.25 ml of concentrated nitric acid) was added. After reflux for 1h, the remaining mixed acid was added dropwise and refluxed for 6 h. After the reaction was completed, water was added to quench the reaction. The mixture was tillered to obtain 25.7 g of 2,7-dinitrofluorenone, with a yield of 95.2%. Peng at page 4, lines 1-4. Peng Example1, step (2) is summarized by the Examiner as follows: PNG media_image16.png 200 400 media_image16.png Greyscale K. Enomoto, JPS6397667A (1988) Respecting the third step of claim 11, Enomoto teaches that: 2,7-dinitro-9-fluorenone is first subjected to aeration using hydrochloric acid and iron powder to obtain 2,7-diamino-9-7fluorenone Enomoto at page 3, col. 2, lines 1-3. CAS indexes this reaction as follows: PNG media_image17.png 200 400 media_image17.png Greyscale See, CAS – CASREACT Indexing of K. Enomoto, JPS6397667A (1988). T. Bruice et al., 81 Journal of the American Chemical Society, 3416-34 (1959) (“Bruice”) Respecting the fourth step of claim 11, Bruice teaches synthesis of 1-hydroxyanthraquinone, according to the following scheme: PNG media_image18.png 200 400 media_image18.png Greyscale . The experimental procedure is reproduced below. 1-Hydroxyanthraquinone.—Several attempts to prepare this substance by literature procedures proved unsatisfactory. The following method was employed. 1-Aminoanthraquinone (10 g., 0.045 mole) was dissolved in 100 ml. of concentrated sulfuric acid at 70°. After cooling, 750 g. of cracked ice was added followed over a 30-min. period (0-3°) by a solution of 4.0 g. of sodium nitrite (0.047 mole) in 25 ml. of water. After stirring at 0-3° for 20 min. the solution of the diazotized amine was poured slowly into 500 ml. of boiling 10% aqueous sulfuric acid. Boiling was continued for 30 min. followed by chilling and collection of the solid product. Extraction of the latter four times with 750-ml. aliquots of 2% potassium hydroxide solution followed by acidification of the extract yielded the 1-hydroxyanthraquinone which after collection, washing with water and recrystallization from benzene with re-heptane (charcoaling) amounted to 7.15 g. (71.5%) DIFFERENCES BETWEEN THE CITED ART AND CLAIM 11 Difference between Claim 11, step (i) and Niznik and Peng Niznik and Peng teach every limitation of claim 11, step (i), except neither of these references teach the claim 11 step bolded below: 11 . . .(i) reacting fluorene of formula (a): PNG media_image19.png 200 400 media_image19.png Greyscale with an organic solvent and a mineral alkali at a temperature from 20 °C to 30 °C, followed by filtering, mixing with ice, blending, and again filtering, to obtain fluorenone of formula (b): PNG media_image20.png 200 400 media_image20.png Greyscale . . . Difference between Claim 11, step (ii) and Peng Peng teaches every limitation of claim 11, step (ii), except Peng does not teach the claim 11 ratio of nitric to sulfuric acid as bolded below: Claim 11 . . . (ii) refluxing the fluorenone obtained in (i) with water and a mixed acid comprising concentrated sulfuric acid and concentrated nitric acid in a 1 : 1 ratio, followed by filtering, to obtain 2,7-dinitro-9-fluorenone of formula (c): PNG media_image21.png 200 400 media_image21.png Greyscale . . . Difference between Claim 11, step (iii) and Enomoto As discussed above, Enomoto provides the following short statement regarding preparation of 2,7-diamino-9-fluorenone: 2,7-dinitro-9-fluorenone is first subjected to aeration using hydrochloric acid and iron powder to obtain 2,7-diamino-9-7fluorenone Enomoto at page 3, col. 2, lines 1-3. Thus, Enomoto teaches the claim 11 concept of an iron/HCl rejection, but does not teach the claim 11 requirement that the HCl be concentrated, that alcohol be included, as well as the other process limitations as bolded below: Claim 11 . . . (iii) dissolving the 2,7-dinitrobenzene-9-fluorenone obtained in (ii) in a water/alcohol solution, followed by adding iron powder and concentrated hydrochloric acid under reflux condition, followed by suction filtration, to obtain 2,7-diamino-9-fluorenone of formula (d): PNG media_image22.png 200 400 media_image22.png Greyscale Difference between Claim 11, step (iv) and Bruice Bruice differs from claim 11, step (iv), only in that that amine [Symbol font/0xAE] alcohol conversion mediated by sodium nitrite occurs in a different, but structurally related compound. Thus, Bruice does not meet the claim 11, step (iv) chemical formula requirements as bolded below and the product limitation that compound (e) be produced: (iv) dissolving the 2,7 diamino-9-fluorenone obtained in (iii) in water and a first mineral acid having ratio 1: 1.33 with addition of sodium nitrite, cooling at a temperature from -10 °C to 0 °C, followed by refluxing with a second mineral acid and water, and filtering, to obtain 2,7-dihydroxy-9-fluorenone of formula (e): PNG media_image23.png 200 400 media_image23.png Greyscale . Claims 11-19 Art Not Obvious over the Cited Art It first noted that there is strong motivation to develop synthetic strategies to prepare 2,7-dihydroxy-9-fluorenone (the product of claim 11) in view of Zhang’s teaching that it is an intermediate for the synthesis of Tilorone dihydrochloride (1)). Claims 11-19 are not found obvious over the cited art because, absent a hindsight analysis based on the teachings of the instant specification, one of ordinary skill is not motivated to piece together the individual teachings of each cited reference to arrive at the invention of claim 11. Even upon combining each separate synthetic strategy of each cited reference, still every claim 11 limitation is not met. For example, it is noted the cited art does not provide motivation to perform the claim 11, step bolded below: 11 . . .(i) reacting fluorene of formula (a): PNG media_image19.png 200 400 media_image19.png Greyscale with an organic solvent and a mineral alkali at a temperature from 20 °C to 30 °C, followed by filtering, mixing with ice, blending, and again filtering, to obtain fluorenone of formula (b): PNG media_image20.png 200 400 media_image20.png Greyscale . . . Further, Enomoto provides scant details regarding the iron reduction procedure and does not suggest Applicant’s claim 11 requirement of alcohol as a solvent. Still further, Bruice differs from claim 11, step (iv), in that that amine [Symbol font/0xAE] alcohol conversion mediated by sodium nitrite occurs in a different compound. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER R PAGANO whose telephone number is (571)270-3764. The examiner can normally be reached 8:00 AM through 5:00 PM. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. ALEXANDER R. PAGANO Examiner Art Unit 1692 /ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692 1 Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. MPEP § 2113(I). The patentability of a product does not depend on its method of production. MPEP § 2113(I). If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. MPEP § 2113(I) (citing In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)). However, the structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art. MPEP § 2113(I). 2 The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art. MPEP § 2113(I) (citing In re Gamero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979) (“[t]he structure should be considered when assessing the patentability of product-by-process claims over the prior art, especially . . . where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product)); see also, Greenliant Systems, Inc. v. Xicor LLC, 692 F.3d 1261, 1268 (Fed. Cir. 2012); Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1370 (Fed. Cir. 2009). 3 Mineral alkali is interpreted as an inorganic compound (i.e., no carbon) comprising an alkali metal, for example potassium or sodium hydroxide. See e.g., Hawley's Condensed Chemical Dictionary, page 1201 (16th ed., 2016, R.J. Larrañaga ed.); specification at page 4, lines 22-23.