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 1, 4, 8-10, 15-16 of R. J. Sharpe, US 17/755,474 (04/29/2022) are pending, under examination on the merits and are rejected.
Withdrawal of Office Action Finality
A request for continued examination of US 17/755,474 under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/14/2025 has been entered.
Withdrawal Claims Rejection- Statutory Double Patenting
Provisionally rejection of claims 5-6 under 35 U.S.C. 101 as claiming the same invention as that of claims 3-4 of co-pending Application No. 18/980,032, claim set filed on 12/13/2024, is withdrawn in view of claims 5-6 have been canceled by Applicant in the reply filed on 07/14/2025.
Maintained 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 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.
The rejection of claims 1, 4, 8-10 and 16 under 35 U.S.C. 103 over the combination of J. C. Kauer, et al, 30 The Journal of Organic Chemistry 1431-1436 (1965) (“Kauer”) with G. A. Olah, et al. 44 J. Org. Chem. 4272–4275 (1979) (“Olah”) in view of H. Zhang et al, EP3483158 A1 (2019) (“Zhang”); G.L. Larson, "Silicon-Based Blocking Agents." Silicon Compounds: Silanes and Silicones 71-99 (2013) (“Larson”); L. Domingo et al., 7 Org. Biomol. Chem., 3576-3583 (2009) (“Domingo”) and B. Nand, et al, 19 Current organic chemistry 790-812 (2015)(“Nand”) is maintained.
The rejection of claim 15 as applied above for the rejection of claim 1 in further view of M. Honzumi, et al, 43 Tetrahedron letters, 1047-1049 (2002) (“Honzumi”) is maintained.
The Claims
The claims are directed to a process for preparing a compound of Formula (II), where per claims 8 and 9, Formula (II) is a starting material for Formula (I). Examiner schematically summarizes claim 9 as follows:
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Wherein:
the non-nucleophilic base is chosen from 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine; 1,5,7-triazabicyclo[4.4.0]dec-5-ene; alkali metal salts of tertiary alkoxides;
the hydrogenation catalyst is chosen from palladium on carbon (Pd/C);platinum on carbon (Pt/C); Raney nickel; Pd(OH)2 on carbon; Pd on barium sulfate; and Pd on calcium carbonate, poisoned with lead or sulfur; and
the (R2)3Si-X is chosen from trimethylsilyl chloride, trimethylsilyl bromide, triethylsilyl chloride, and triethysilyl.
A. Olah, et al. 44 J. Org. Chem. 4272–4275 (1979) (“Olah”)
Olah teaches a method for preparation of 1,4-bis((trimethylsilyl)oxy)cyclohexa-1,3-diene through silylation of 1,4-cyclohexanedione with chlorotrimethylsilane in the presence of triethyl amine at room temperature with high yield as follows:
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Olah at page 4274, Table III, Entry h; Id. at page 4273, Scheme 1; Id. at page 4274, col. 2 (General Procedure for the Preparation of Enol Silyl Ethers from Carbonyl Compounds (“[t]he products were further purified by distillation”)).
Olah meets each and every limitation of first claim 1, step (a), except Olah’s base triethylamine does not meet the instantly claimed base limitation as indicated by strikeout text below:
claim 1 . . . (a) contacting cyclohexane-1,4-dione with a non-nucleophilic base
(i) a compound of the formula (R2)3Si-X, wherein X is chosen from chloro, bromo, or iodo, and R2 is a C1-C5 alkyl group, or
(ii) trimethylsilyl trifluormethanesulfonate . . .
J. C. Kauer, et al, 30 The Journal of Organic Chemistry 1431-1436 (1965) (“Kauer”)
Kauer teaches that introduction of a two-carbon bridge via the Diels-Alder reaction of a 1,4-disubstituted 1,3-cyclohexadiene is a convenient route to 1,4-disubstituted bicyclo [2.2.2] octanes. Kauer at page 1432, col. 1, line 1-3 (see Kauer Scheme I).
With ethylene and cyclohexa-1,3-diene-1,4-dicarboxylic acid as an example, Kauer teaches the following Diels-Alder reaction.
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Kauer at page 1432, left col, Scheme I; page 1434, left col. Dimethylbicyclo[2.2.2]oct-2-ene-1,4-dicarboxylate (8) and page 1435 , left col. Dimethylbicyclo[2.2.2]octane-1,4-dicarboxylate (10).
Kauer teaches a Diels-Alder reaction similar to the limitation of claim 1, step (b):
(b) reaction with ethylene at a temperature of about 200 °C to about 300 °C and a pressure of about 3000 to 5000psi.
except that Kauer performs the reaction on a different reactant at temperature of 165 ˚C and at 1000 atmospheres (14,696 psi) of ethylene, whereas claim 1 requires reaction with ethylene at a temperature of about 200 °C to about 300 °C and an ethylene pressure in the range of 3000 – 5000 psi.
It is noted that Kaur also teaches the following reduction of compound 8 to compound 10.
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Kauer at page 1435, col. 1 (“Dimethyl Bicyclo[2.2.2]octane-1,4-dicarboxylate (10)”).
Differences between the Combination of Kauer and Olah from the Claims
One of ordinary skilled artisan combining Olah and Kauer, by subjecting the Olah product 5h to a Diels-Alder type reaction with ethylene, arrives at the following process.
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Combining Olah and Kauer in the above fashion teaches each and every limitation of claim 1 except:
(i). the Olah base Et3N is not a base chosen from 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine; 1,5,7-triazabicyclo[4.4.0]dec-5-ene; alkali metal salts of tertiary alkoxides;
(ii) the structure of Kauer compounds 8 and 10 (comprising -C(O)CH3) differs from the presumed claim 1 silicon intermediate; and
(iii). the claimed reaction temperature and ethylene pressure ranges, however, upon optimizing the Diels-Alder temperature and ethylene pressure to within the claim 1 ranges of about 200 °C to about 300 °C and about 3000 to about 5000 psi, one of ordinary skill arrives at the claimed reaction temperature and ethylene pressure ranges.
H. Zhang et al, EP3483158 A1 (published on 05/15/2019) (“Zhang”)
Zhang is cited here to provide a motivation to combine Olah with Kauer in the manner proposed. MPEP § 2143. Zhang teaches that:
Liver cancer is one of the most malignant tumors with the highest morbidity and mortality. There are 466,000 new cases of liver cancer and 422,000 cases of liver cancer deaths in China every year. Studies have shown that the FGFR4-FGF19 signaling pathway is closely related to hepatocellular carcinoma (HCCs), while FGFR4 is the subtype highly expressed in human hepatocytes, with a variety of FGFR4 variants found in liver cancer patients. Selective inhibition of FGFR4 without inhibiting other subtypes FGFR1, FGFR2, and FGFR3 may avoid certain toxicity and may be an important therapeutic target for the treatment of liver cancer.
Zhang at page 2, [0003], emphasis added.
Zhang teaches that compound 14 is an exemplary FGFR4 inhibitor of his formula (I).
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Zhang at page 34 (Example 14).
Zhang further teaches that bicyclo[2.2.2]octane-1,4-diol (14a) is a starting material for synthesis of FGFR4 inhibitor compound 14.
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Zhang at page 34, line 1-15 and page 2, [0004]-[0005].
Therefore, one ordinary skilled artisan seeking to use compound 14 which is a FGFR4 inhibitor for liver cancer treatment is motivated to synthesize its known prior art intermediate bicyclo[2.2.2]octane-1,4-diol (14a).
L. Domingo et al., 7 Org. Biomol. Chem., 3576-3583 (2009) (“Domingo”)
Domingo is cited here for providing a reasonable expectation of success to one of ordinary skill upon combining Olah and Kauer as proposed. MPEP § 2143.02. As intimated above and as discussed in more detail below in the analysis section, the Examiner proposes combining Olah with Kauer to arrive at the following process.
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Domingo teaches that the Diels–Alder (DA) reaction is arguably one of the most powerful reactions in the arsenal of the synthetic organic chemist. Domingo at page 3576, col. 1. Domingo further teaches that by varying the nature of the diene and dienophile, many different types of carbocyclic structures can be built up. However, not all possibilities occur easily. For instance, the Diels–Alder reaction between butadiene (1) and ethylene (2) must be forced to take place: after 17 hours at 165 °C and 900 atmospheres, it gives a 78% yield. Domingo at page 3576, col. 1. However, Domingo teaches that the presence of electron-withdrawing groups in the dienophile and electron-releasing groups in the diene or vice versa can drastically accelerate the process. Domingo at page 3576, col. 1.
Because Domingo teaches that electron withdrawing groups in the diene can accelerate the Diels-Alder reaction, and that Diels-Alder reaction is a powerful general-purpose rection, one of ordinary skill would have a reasonable expectation of success that the above-proposed Diels-Alder reaction (where the diene is substituted with electron releasing oxygen groups) would readily proceed and would require temperature and ethylene pressure optimization.
G.L. Larson, "Silicon-Based Blocking Agents." Silicon Compounds: Silanes and Silicones 71-99 (2013) (“Larson”)
Larson reviews on silicon-based blocking agents and teaches that the reaction of trimethylchlorosilane with an alcohol liberates HCl, which must be trapped. This is normally achieved with the presence of a tertiary amine. The deprotection of the trimethylsilyl group is usually accomplished by mild hydrolysis in aqueous or alcohol medium. Larson at page 73, left col. The Trimethylsilyl, TMS, Group, paragraph 3, line 1-2(emphasis added).
Larson also teaches one procedure of acid-catalyzed cleavage of trimethylsilyl ether as follows:
Acid-Catalyzed cleavage of trimethylsilyl ethers.
The silylated alcohol (0.4 mmol) in dichloromethane (4 mL) is treated with a drop of 1N HCl and the reaction mixture is stirred for 30 min.
In a transeterification approach a 0.5 M solution of the trimethylsilylated alcohol in methanol is treated with pyridinium p-toluenesulfonate (PPTS) at room temperature for 30 min. The lower boiling trimethyl- methoxysilane is removed by distillation.
Larson at page 90, right col. Deprotection Of Silyl Ethers, paragraph 1-2 (emphasis added). Thus, Larson fairly teaches one ordinary skill that trimethylsilyl can be cleaved by HCl with methanol as the solvent.
B. Nand, et al, 19 Current organic chemistry 790-812 (2015)(“Nand”)
Nand teaches that DBU (preferred IUPAC name as 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine, is a sterically hindered amidine base. It is a non-nucleophilic base. It is advantageous to use DBU in organic reactions as it is cheap, commercially available, homogenous and most importantly recoverable. Nand at page 790, paragraph 1, line 1-2, line 10-12.
M. Honzumi, et al, 43 Tetrahedron letters, 1047-1049 (2002) (“Honzumi”)
Honzumi teaches a method of hydrogenation of alkene in the presence of silyl ether group with 10% Pd/C as the catalyst resulting the reduction product with an excellent yield as follows:
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Honzumi at page 1049, Scheme 2.
Obviousness Rational
In sum, each of the instantly claimed steps is taught separately in the art. One of ordinary skill seeking to prepare Zhang’s compound 14 taught as an FGFR4 inhibitor can readily envision combining each of the art known claim 1 steps so as to arrive at this compound.
One ordinary skill in the art seeking to utilize bicyclo[2.2.2]octane-1,4-diol 14a (claimed Formula (I)) as an intermediate for Zhang’s FGFR4 inhibitor compound 14 is motivated to prepare 14a by first preparing compound 5h from 4h as taught by Olah (but replacing Olah’s triethylamine with DBU) and thereafter react Olah compound 5h with ethylene by way of the Diels-Alder process taught by Kauer, so as to prepare the claimed compound of formula (II) and thereafter employ a Pt or Pd type hydrogenation (as taught by Kauer and/or Honzumi) and finally deprotect using methanol/hydrochloric acid as taught by Larsen so as to arrive at desired compound 14a. This proposed modification of the prior art can be summarized as follows:
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One ordinary skill is motivated to modify Olah as proposed above by replacing the triethyl amine with DBU because Larson teaches that the reaction of trimethylchlorosilane with an alcohol liberates HCl, which must be trapped and can be achieved with the presence of a tertiary amine; Nand teaches that DBU is a sterically hindered non-nucleophilic base amidine base (tertiary amine), it is cheap, commercially available, homogenous and recoverable. Accordingly practice of the cited reference combination as proposed above arrives a process meeting each and every limitation of claims 1-2, 5, therefore, claims 1-2, 5 are obvious.
One of ordinary skill has a reasonable expectation that the above proposed Diels-Alder ethylene process of Kauer can be successfully applied to Olah diene 5h in view of the teachings of Domingo for the reasons discussed in detail above.
One of ordinary skilled artisan is motivated to optimize the ethylene concentration (pressure) and temperature of the above proposed process to within the claimed temperature and pressure ranges in view of Domingo’s teaching that the electron withdrawing/releasing groups will have an impact on the reaction’s rate/facility. Such temperature and concentration optimization are of routine nature. MPEP § 2144.05(II).1 Note that there is no evidence that claimed pressure and temperature ranges are critical; rather the specification recites the claimed ranges without further explanation. Specification at pages 2-4, [0005] and [0008]. Domingo clearly teaches that Diels-Alder reactions require different ethylene pressures/concentrations and temperatures depending upon the diene that reacts with ethylene.
The rational supporting the above proposed method is combining prior art elements according to known methods to yield predictable results. MEPE 2143.I.(A). The above proposed obviousness rational meets each and every limitation of independent claims 1 8 and 16, therefore, claims 1, 8 and 16 are obvious.
The limitations of claim 4 are met because the above § 103 rational employs trimethylsilyl chloride as taught by Olah.
Claims 9-10 are obvious because the above proposed method comprises a step of deprotection in the presence of HCl and methanol.
Claims 15 is obvious because one ordinary skill is motivated to modify the above proposed method by replacing the hydrogenation catalyst palatium oxide with 10% Pd/C as Honzumi teaches that hydrogenation of alkene in the presence of silyl ether group with 10% Pd/C as the catalyst can get the reduction product with an excellent yield.
Applicant’s Argument
Applicant argues on the ground that:
To establish a prima facie case of obviousness, all claim limitations must first be taught or suggested by the prior art. Olah fails to disclose or suggest all of the features of the presently claimed invention. In the current invention, the dione reacts with DBU and TMSCI in CH2Cl2 at 40 °C for 2 hours to produce the intermediate diene with a yield of 74%, see, for example, the data in example 1. However, for Olah, the dione reacts with Et3N TMSCI and Li2S in CH3CN, at 25 °C for 16 hours to produce the intermediate diene, the reaction time is 16 hours, see Olah's data in table III. In Olah at page 4272, right col. In Olah, the TMSCI needs to work together with Li2S to make the silylation reaction happen. There is no such requirement for the presently claimed invention. Furthermore, in the amended claim 1, the non-nucleophilic base is chosen from 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine; 1,5,7- triazabicyclo[4.4.0]dec-5-ene; alkali metal salts of tertiary alkoxides, Et3N is not included in the claim.
Page 5, the last paragraph to page 1, the first paragraph in the Remarks submitted on 05//15/2025.
These arguments have been fully considered but not persuasive. It is noted that Applicant is not arguing on unexpected result. While Olah does not teach all the claim limitations, however, as mentioned in the 103 rejection above that the combination of Olah, Kauer, Zhang, Larson L. Domingo and Nand teaches each a method meeting each and every limitation of claims 1 and 8, therefore, claims 1 and 8 are obvious. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. MPEP 2145.IV.
With regards Applicant’s arguments that Li2S is not required by the claimed invention, both the instant claim 1 and claim 8 all using the transitional term "comprises", which is an inclusive or open-ended and does not exclude additional, unrecited elements or method steps. MPEP 2111.03(I).
Applicant argues that one ordinary skill has no motivation to conduct the Diels-Alder reaction at a temperature of about 200°C to about 300°C and a pressure of about 3000 to 5000 psi. Page 6 in the Remarks submitted on 05//15/2025.
This argument is not persuasive. As mentioned in the PTOL-303 Advisory Action, Kauer fairly teaches one ordinary skill that the reaction condition including reaction temperature and pressure needs to be optimized. Regarding the claimed ranges of the temperature and pressure, generally, such differences will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such range is critical. "[W] here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP § 2144.05(II) (citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Herein, no evidence of record provides evidence the claimed temperature/pressure are critical, therefore, the prima facie case that the claimed method is obvious over the prior art is not rebutted. MPEP 716.02(d) (citing In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960)).
Maintained Non-statutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
Provisionally rejection of claims 1, 4, 8-10, 15-16 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-8 and 11-12 of co-pending Application No. 18/980,032, claim set filed on 05/14/2025 (published as US 20250109152A1).
Regarding claims 1, the conflicting claim 1 claims a process for preparing compounds of the Formula (II):
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(II),
wherein R1 is a group of the formula of the formula --Si(C1-C6 alkyl)3, which comprises:
(a) contacting cyclohexane-1,4-dione with a non-nucleophilic base, in the presence of a compound of the formula (R2)3Si-X, wherein X is chosen from chloro, bromo, or iodo, and R2 is a C1-C6 alkyl group followed by;
(b) reaction with ethylene at a temperature of about 200° to about 300°C and a pressure of about 3000 to 5000psi,
Wherein the non-nucleophilic base is 2,3,4,6,7,8,9,10-octahydropyrimido[1m2-a]azepine.
The conflicting claim 1 meets each and every limitations of the instant claim 1, therefore, claims 1-3 are obvious.
Conflicting claim 2 further claims that the process of claim 1, wherein the compound of the formula (R2)3Si-X is chosen from trimethylsilyl chloride, trimethylsilyl bromide, triethylsilyl chloride, and triethysilyl bromide; which meets each and every limitations of the instant claim 4, therefore, claim 4 is obvious.
Regarding claims 8-10 and 15-16 which are anticipated by the conflicting claims 6-8 and 11-12 respectively.
Terminal Disclaimer
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Applicant’s response the double patenting rejection
Applicant replied the nonstatutory double patenting rejection as follows:
Applicant respectfully submits that once the remaining rejections are overcome and the Examiner has indicated allowable subject matter, Applicant will determine whether the filing of a terminal disclaimer is appropriate.
Remarks at page 7 of the Remarks submitted on 05/15/2025.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANK S. HOU whose telephone number is (571)272-1802. The examiner can normally be reached 6:30 am-2:30 pm Eastern on Monday to Friday. 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 on (571)2705241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/FRANK S. HOU/Examiner, Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 MPEP § 2144.05(II) citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation (claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%).