DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. 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.
Current Status of 18/704,901
3. This Office Action is responsive to the amended claims of 25 April 2024.
4. Claims 1-23 have been examined on the merits.
Priority
5. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
6. The effective filing date is 26 October 2021.
Information Disclosure Statement
7. The information disclosure statements (IDS) submitted on 07/11/2024,
01/31/2025, 05/21/2025 and 12/12/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
8. In examples discussing making compounds of paragraphs [0096] – [0113], some uncommonly used terms, such as parts, p, a/a are used for measurement of substances instead of common weight and volume units. As a result of that, an artisan has difficulties in understanding a particular reaction, step, or outcomes. Applicant are strongly advised to use the commonly used terms to report the results.
Claim Objection
9. Claim 3 is objected to because of the following informalities:
Claim 3: line 1 “where in” should read “wherein”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
10. Claims 1-20 and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “under conditions sufficient” in claims 1 and 19 is a relative term which renders the claim indefinite. The term “under conditions sufficient” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The artisan would not know what condition is sufficient or not sufficient, thereby making the claim indefinite.
11. Claims 21 and 23 are also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for a different reason: As the independent claims, claims 21 and 23 do not define “compound (A)” and they are not dependent upon claim 1, thus making compound A undefined and thereby rendering the claims indefinite.
Claim Rejections - 35 USC § 103
12. 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.
13. Claim(s) 1-23 are rejected under 35 U.S.C. 103 as being unpatentable over:
NAKAMURA (WO2021/095835A1, pub. date: 5/20/2021. Referenced in IDS of 7/11/2024 and provided by Applicants), in view of
LI (Li et al “Optimization of Solvent Chasing in API Manufacturing Process: Constant Volume Distillation” Organic Process Research & Development 2009, 13, 73–77), further in view of
YAMASHITA (US10723742B2, pub. date: 6/17/2021), and
ZINELAABIDINE (Zinelaabidine et al “A Simple and Efficient Green Method for the Deprotection of N-Boc in Various Structurally Diverse Amines under Water mediated Catalyst-free Conditions” International Journal of Chemistry; Vol. 4, No. 3; 73-79, 2012), as evidenced by:
eRef1 (Nichols L. “ORGANIC CHEMISTRY LAB TECHNIQUES”, Organic Chemistry Lab Techniques. 2016). content page,
eRef2 (Division of Organic Chemistry, American Chemical Society “Common Solvents Used in Organic Chemistry” Common Solvents Used in Organic Chemistry: Table of Properties. Updated August 9, 2020),
eRef3 (Spectrum “Scientific Document, IS115 Isopropanol, USP, JP.” Ver 4.06. 15 December 2020),
eRef4 (Key J “Factors that Affect the Rate of Reactions” Factors that Affect the Rate of Reactions – Introductory Chemistry – 1st Canadian Edition. 2014), and
eRef5 (Jordan A et al. “Chlorinated Solvents: Their Advantages, Disadvantages, and Alternatives in Organic and Medicinal Chemistry” Chemical Reviews 2021,121 (3), 1582-1622. Published: December 22, 2020). Table 8, p 1589.
Determining the scope and contents of the prior art
NAKAMURA teaches benzoic acid salt of 4-[5-[(3S)-3-aminopyrrolidine-l-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile (Compound A), as a potent LSD 1 inhibitor and use of its composition as an anti-tumor agent to treat cancer (para [0002], p 1). The reaction of the Compound A with benzoic acid may be conducted in a single solvent, including hydrocarbons such as n-heptane and n-hexane; esters such as ethyl acetate, n-propyl acetate and butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone; alcohols such as methanol, ethanol, 1-propanol and 2-propanol; acetonitrile; tetrahydrofuran such as tetrahydrofuran and 2-methyltetrahydrofuran and, in mixed solvents of any of the above solvents and water (para [0036], p 7).
NAKAMURA teaches synthesis of a crystal of a benzoic acid salt of Compound A by mixing a solution of benzoic acid in methyl isobutyl ketone (not IPA in the instant application) to Compound A to obtained the titled crystal after being stirred for approximately 16.5 hours at room temperature (para [0127], p 20). The salt and/or crystalline form can be isolated and purified by well-known separation and purification techniques such as recrystallization, crystallization, distillation and column chromatography (para [0022], p 4).
LI teaches solvent exchange by distillation is a common unit operation in active pharmaceutical ingredient (API) manufacturing processes. For example, solvent exchanges are used in preparing a nonisolated intermediate for the next reaction step in preparation of solutions for crystallization (Introduction).
YAMASHITA teaches novel biphenyl compounds or salts thereof as LSD1 inhibitors, their pharmaceutical compositions as antitumor agents to treat cancer (Abstract). Preparation of Compound A is highlighted as Example 37 (step 3. Col 56) by de-protection of the Boc group on the intermediate (Compound B) to afford Compound A. YAMASHITA further teaches preparation of Compound A by the deprotection step to remove the Boc group performed in MeOH (1 mL) and a 12M HCl aqueous solution (1 mL) at room temperature, followed by stirring at room temperature for 30 minutes. The reaction solution was neutralized by the addition of water (1 mL) and a 2 M aqueous sodium hydroxide solution (6 mL). Chloroform was added thereto, the mixture was washed sequentially with water and saturated brine, and dried … (step 3, Col 56).
ZINELAABIDINE teaches reactions of De-Boc of Boc-amino acids in reflux water solvent without catalysts in 10 minutes.
Ascertaining the differences between the prior art and the claims at issue
The claims are generally drawn to making a specific benzoate salt form of an LSD1-inhibiting cancer drug intermediate of Compound (A) by focusing on a manufacturing route that avoids isolating the free-base compound as a dry solid before salt formation. Instead, the process keeps the material in solution through a solvent exchange from 2-methyl tetrahydrofuran to isopropyl alcohol. Benzoic acid is then added to form the benzoate salt. This approach reduces impurities and improves scale-up by careful controlling of solvent quality, including low-peroxide IPA and performing recrystallization.
NAKAMURA teaches making benzoic acid salt of Compound A from the free base of Compound A and benzoic acid without operation details of the process. NAKAMURA doesn’t teach the De-Boc of Compound B to make Compound A or a solvent exchange from 2-Me-THF to isopropyl alcohol in the instant claims.
LI teaches solvent exchange by distillation is a common unit operation in active pharmaceutical ingredient (API) manufacturing processes.
YAMASHITA teaches preparation of Compound A by the deprotection step to remove the Boc group from Compound B.
ZINELAABIDINE teaches De-Boc reactions of Boc-amino acids in reflux water solvent without catalysts in 10 minutes.
A combination of LI, YAMASHITA and ZINELAABIDINE’s teachings cures the defects of NAKAMURA.
Considering objective evidence present in the application indicating obviousness or nonobviousness
14. Regarding instant claims 1, 2 and 20, NAKAMURA teaches making benzoic acid salt of Compound A from free base of Compound A and benzoic acid, without operation details of the process. LI teaches solvent exchange by distillation is a common operation in API manufacturing processes. For example, solvent exchanges are used in preparing a nonisolated intermediate for the next reaction step in preparation of solutions for crystallization (Introduction). Assuming NAKAMURA’s process of making benzoate salt of Compound A is a non-solvent exchange process, the artisan would have expected to modify NAKAMURA’s process with LI’s teaching of solvent exchanges for crystallization to reach the instant claim 1. The artisan would have motivated to do such a modification to prevent solids precipitated/crystallized out and trapping solvent in the solids (see Introduction, LI). In addition, all the extraction steps in claim 1 and recrystallization step of claim 2 are daily routine operations for the artisan (Evidenced by eRef1), and the solvents involved in are all common ones used daily in laboratory (Evidenced eRef2). Therefore, claims 1, 2 and 20 are obvious over NAKAMURA in view of LI and evidenced by eRef1 and eRef2.
Regarding claim 3 cited IPA’s peroxide content < 10ppm, it’s an inherent property of the USP grade IPA used for the reaction (Evidenced by eRef3, the KI starch test stripes without color change indicating peroxide content <10 ppm).
Regarding claim 4 directed to de-Boc of Compound B to prepare Compound A in aqueous hydrochloric acid solution, YAMASHITA teaches the same reaction was performed in an aqueous hydrochloric acid solution (12 M) in MeOH (1:1 mL) in 30 minutes at room temperature. So, claim 4 is obvious over YAMASHITA and LI.
15. Regarding claims 5-17 drawn to optimization of reaction conditions of reaction temperature, time, pH value, extraction and crystallization, these are just reaction variables that would be adjusted by the synthetic chemist to affect the reaction rate/completion.
Patent law views optimization of reaction conditions (herein, changing solvent, varying temperature range, adjusting solution pH and separation of organics from aqueous layer) as not supporting 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA1969). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). See MPEP 2144.05(II)(A).
Furthermore, on claims 5-7 directed to reaction temperatures and times of the de-BOC reaction, ZINELAABIDINE teaches preparation of amino acids from De-Boc of Boc-amino acids in reflux water solvent in 10 minutes without any catalysts. YAMASHITA teaches the same reaction was performed in an aqueous hydrochloric acid solution (12 M) in MeOH (1:1 mL) in 30 minutes at room temperature. So, claims 5-7 are obvious by combination of ZINELAABIDINE and YAMASHITA . It is worth noting prolong reaction time, increasing acid concentration and heating the reaction to certain temperatures are pushing the reaction to completion under these conditions, and beneficial to the reaction. That is common and well known to the artisan (Evidenced by eRef4).
16. Regarding claims 8-11 directed to general extraction operation after completion of a reaction, the artisan would be expected to cool down the temperature (see General Procedure, p 78, ZINELAABIDINE) of the reaction mixture before adding water to quench the reaction to minimizes side reactions and forming impurities and decrease the solubility of the product in the aqueous layer before extraction with MTBE, adjust pH of the solution to release the free base product into the organic layer and separate it as clean as possible from the aqueous NaOH layer to remove impurities to get purer product (Ln 1-13, Step 3, Col 46, YAMASHITA). Specially, for the workup steps (i-a to i-g) of claim 8 after de-Boc reaction, these are routine steps/operations for the reaction in all laboratory settings. YAMASHITA teaches similar operations after the de-Bon reaction with neutralization by the addition of water (1 mL) and a 2 M aqueous sodium hydroxide solution (6 mL). Chloroform (instead MTBE or 2-Me THF) was used to extract the product, the mixture was washed sequentially with water and saturated brine, and dried … (step 3, Col 56). The difference between YAMASHITA’s teaching and the instant application is the solvent used. Both MTBE and 2-Me THF are commonly used solvents substituting chloroform, DCM, diethyl ether and THF, etc. due to health and environmental concerns in pharmaceutical industry (Evidenced by eRef5).
The artisan would be motivated to do these operations that are routinely used in lab settings to optimize the operations to get purer products. This is especially true since neither the claims nor the Specification indicate how the routine operations of the temperature, pH and separation of organics from aqueous layer within dependent (emphasis) claims 9-13 are critical.
Regarding claims 12-17 directed to another routine operation of crystallization to purify solid compounds, changing temperature, seeding crystal and changing/mixing solvents are essential steps for crystallization. In addition, NAKAMURA teaches preparation of a crystal of a benzoic acid salt of Compound A by mixing a solution of benzoic acid in methyl isobutyl ketone (not IPA in the instant application) to Compound A to obtained the titled crystal after being stirred for approximately 16.5 hours at room temperature (para [0127], p 20); NAKAMURA teaches the reaction of the Compound A with benzoic acid may be conducted in a single solvent, including hydrocarbons such as n-heptane and n-hexane; esters such as ethyl acetate, n-propyl acetate and butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone; alcohols such as methanol, ethanol, 1-propanol and 2-propanol; acetonitrile; tetrahydrofuran such as tetrahydrofuran and 2-methyltetrahydrofuran and, in mixed solvents of any of the above solvents and water (para [0036], p 7).
Therefore, claims 5-17 are prima facie obvious over combination of NAKAMURA LI, YAMASHITA and ZINELAABIDINE evidenced by eRef1, eRef52, eRef3, eRef4, and eRef5.
17. Regarding claim 19, steps (i)-(iv) are obvious over combination of NAKAMURA LI and YAMASHITA for claims 4 and 14. Furthermore, NAKAMURA teaches the salt and/or crystalline form of compound A can be isolated and purified by well-known separation and purification techniques such as recrystallization, crystallization, distillation and column chromatography (para [0022], p 4). Thus, claim 19 is obvious NAKAMURA in view of LI and YAMASHITA.
Regarding claim 22 directed to a pharmaceutical composition comprising benzoate salt of Compound A from claim 1, NAKAMURA teaches benzoic acid salt of (Compound A) as a potent LSD 1 inhibitor and use of its composition as an anti-tumor agent to treat cancer (para [0002], p 1). Claim 22 is obvious over NAKAMURA in view of LI.
Regarding claims 18, 21 and 23, they’re just the product/process result of purification. Since the process is obvious (see above), claims 18, 21 and 23 (the results of the process) are obvious.
Conclusion
18. No claims are presently allowable as written.
19. Examiner Note:
The definition of a/a is provided near the end of Specification: a/a refers to the peak area by HPLC (para [0110], p 35).
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/B.T./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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