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 .
Claims 1-12 are pending.
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.
Claims 1-12 are rejected under 35 U.S.C. 103 as being unpatentable over Kleiner, US5705670, Watanabe, Tetrahedron Letters 58 (2017) 3700–3703 and Watanabe JP 2012116776.
Kleiner at column 2, Example 1:
500 g (4.0 mol) of methanephosphonic acid dimethyl ester and 80 g of water are heated to 100.degree. C. and 320 g (4.0 mol) of 50% strength sodium hydroxide solution are added dropwise, while stirring vigorously. During this procedure, the temperature is increased slowly to 115.degree. C. The dropwise addition is carried out in total for 2 hours, 90% of the total amount being added in about 1 hour and the remaining amount likewise in one hour. The reaction mixture is subsequently stirred for 30 minutes. During the reaction, a total of 139 g of a methanol/water mixture distill off. The residue is evaporated in vacuo. After drying in a vacuum drying cabinet at 80.degree. C., 528 g of methanephosphonic acid monomethyl ester sodium salt are obtained with a purity of 98%, according to 31-P-NMR. The yield is 100% of theory.
The above highlighted part corresponds to hydrolysis of a phosphate diester to phosphate monoester wherein the phosphate is not a vinyl phosphate, rather alkylphosphate:
The difference thus is in the carbon radical attached to the P atom of the starting material and product. Other than this difference, the correlation
starting material (1) wherein R2=R1=2 carbon
product (2) wherein R1= 2 carbon
solvent = water
molar ratio = 1 (between 0.7 and 3.5)
is as per limitations of the base claim 1.
(more on this difference and salt of the acid difference later in this action)
Claim 2: 80% includes that of Kleiner
Claim 3: Sodium hydroxide of Kleiner is alkaline metal hydroxide
Claim 4: Solvent water is same as of Kleiner
Claim 5: 50% hydroxide is > the pH 11 to 14 (commonsense)
Claim 6: 100oC of Kleiner is close to instant 90oC (compare instant 40oC)
Claim 7: diethyl is same as Kleiner
Claim 8: Sodium hydroxide of Kleiner is alkaline metal hydroxide
Claim 9: Solvent water is same as of Kleiner
Claim 10: 50% hydroxide is > the pH 11 to 14 (commonsense)
Claim 11: 100oC of Kleiner is close to instant 90oC (compare instant 40oC)
Claim 12: diethyl is same as Kleiner
Difference: The above noted difference of the C radical attached to P, remains the same in the starting material and product (also see other examples of Kleiner with respect to this C radical), unperturbed, non-participant and plays spectator role in the chemistry of hydrolysis.
In addition, one of skill in the art would anticipate that, with two ester bonds in the starting material, with the use of one molar equivalent of hydroxide (base), only one of the ester bonds will be hydrolyzed, is plain matter of stoichiometry in chemical reactions wherein the reagent is not a catalytic.
Mechanistically, hydroxide attacks P of (1) to make a transition state which releasing the alkoxide (rupture of P-O alkoxide bond) generating the P-OH bond of (2), which gets deprotonated (salt formation with base) to make salt of the monoacid (sodium salt in Kleiner). The comparative data at page 11 Table 1 is consistent with this elementary mechanism of ester hydrolysis.
Motivation: As per Watanabe, the monoester is a synthetic intermediate for making commercial $
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trademark GGsTop. See ‘676 page on 1 and also Watanabe page 1 column A, and chemistry schemes throughout.
Arriving at alternate versions for making synthetic intermediates in the manufacture of previously known commercially important compounds (Watanabe), using known methods (Kleiner) is routine in the chemical process research.
Response to Remarks 06/12/2026:
Applicant argues that as instantly amended to read that the solvent contains water. Water is a solvent. Applicant is encouraged to point out ‘solvent’ other than ‘water’ in the working examples. Metal hydroxide needs to be in solution for the reaction and water is routinely used to dissolve metal hydroxides, even in phase transfer (PTC) conditions. This is one of commonsense. Further that nucleophilic attack on vinyl group of the vinyl phosphate can also occur is not persuasive. While the argument that conjugate addition on vinyl phosphate diester is known in the art, such reactions are expected to also depend on the nature of the nucleophile. For example, consider Applicant provided Feng Gao, Chem. Eur. J. 2009, 13 2-64-2070, 2009 (NPL 03/14/2024), reactions of vinyl phosphate with nucleophilic thiol and primary amine Schemes 3 and 4. While thiol adds to the double bond, tert.butyl amine demethylates by acting on the methoxy of the vinyl phosphate. This is consistent with Dorwald teachings (see below under section 112-1). No citation for hydroxide adding in conjugate fashion to any vinylphosphate is provided by the Applicant.
Note: By including water in claim
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, applicant differentiates the above Gao reference being a 102 prior art, because Gao teaches that tert.butyl amine as solvent and as a reactant, see Gao column B, page 2069, to make instant (2) with R1 = methyl, from instant (1) R1=R2=methyl.
Applicant needs to point out where Kleiner teaches away from the instant base claim limitations. The process parameters of Kleiner fall under the scope of the base claim and are also found in the working examples. That one of skill in the art would expect Kleiner process would work, is supported by the post provisional filing date teaching of Pham, Journal of Medicinal Chemistry (2022), 65(14), 10045-10078:
Pham teaches at top of page 10048 Scheme 1
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Pham supplementary material:
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Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art.
Accordingly, the claims do not recite an unobvious distinction over the prior art. Further, a reference is relevant not only for what it expressly teaches, but also for what it would have conveyed to one of ordinary skill in the art. See In re Opprecht, 12 USPQ2d 1235, 1236 (Fed. Cir. 1989); In re Bode, 193 USPQ 12 (CCPA 1976). In light of the foregoing discussion, the Examiner finds that the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art at the time the invention was made, in view of the cited references and the knowledge generally available in the art. Accordingly, the claims are rejected under 35 U.S.C. § 103.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-8, 10-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pham, Journal of Medicinal Chemistry (2022), 65(14), 10045-10078.
Pham teaches at top of page 10048 Scheme 1
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Pham supplementary material:
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corresponds to claims 1-5, 8, 10, 12, wherein the solvent is water.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-12 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for narrow range of process parameters such as solvents, base, temperature, pH molar ratio, does not reasonably enable for any and all process parameters. For example, it is not seen wherein the specification enabling disclosure is found for any and all solvents or any and all (amount of) base.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The determination that "undue experimentation" would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the relevant factual considerations.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). These include: (1) breadth of the claims; (2) nature of the invention; (3) state of the prior art; (4) amount of direction provided by the inventor; (5) the level of predictability in the art; (6) the existence of working examples; (7) quantity of experimentation needed to make or use the invention based on the content of the disclosure; and (8) relative skill in the art.
All of the factors have been considered with regard to the claims, with the most relevant factors discussed below.
The invention is drawn to hydrolysis of a vinyl phosphate diester (1) to make vinyl phosphate monoester phosphoric acid (2).
Ester hydrolysis of phosphate diester to monoester phosphoric acid is known in the art by using sodium hydroxide or potassium hydroxide in water, as in Kleiner, US5705670 Example 1. Further Kleiner chemistry is limited to the said hydroxides. Such a hydrolysis reaction is unreported with respect to the instant vinyl diester, prior to the instant provisional application.
The scope of the claimed process is wide with respect to the R1 and R2 group. For example, the alkyl groups could be primary, secondary or tertiary thus rendering the size and shape of the group around in the P of phosphate group (more on this later).
The term ‘solvent’ is an umbrella term that includes hydroxylic solvent such as water (as in Kleiner), alcohols, or aprotic solvents such as DMSO, DMF or hydrocarbon solvents such as hexane and toluene. This in turn also raises issues with respect to the scope of the ‘base’. One of skill in the art would at once understand that carbonates such as sodium carbonate would not dissolve in hydrocarbon solvents to participate in the reaction. If PTC conditions are implied, the specification is silent with respect to how much of ‘water’ needs to be present (see claim language
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). Similarly, there is no guidance of how much of the base is needed to selectively hydrolyze only one of the two ester groups. The term ‘basic substance’ is not limited to inorganic bases as in claim 3, because term, with broadest interpretation, encompasses organic amine bases such as pyridine or pyrrolidine. This is of relevance because, not only this term raises breadth issue but also reactivity of the base other than for the intended hydrolysis. For example (as argued by the Applicant, see Remarks page 7 of 9 penultimate sentence in first full paragraph), the terminal vinyl carbon is susceptible to reaction with nucleophiles such as amines.
Bulky R1 and R2 groups, for example tert. butyl groups, may cause shielding around P atom such that Michael addition, as alluded to by the Applicant, could predominate.
Further how to choose R1 and R2 in starting material (1), to make R1 in product (2) is not taught in the specification. The unpredictability in the art is taught by Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface pg. 1-15. According to Dorwald :… the outcome of organic reactions is highly dependent on all structural features of a given starting material, and unexpected products may readily be formed...”
Disclosure in the specification is also consistent with the unpredictability in the art. For example, the working examples are limited with respect to ‘solvent containing water’ and base. The only solvent disclosed is water and the only base disclosed is sodium hydroxide. Similarly, the Examples are limited with respect to temperature and pH. Further within this narrow limitations, as seen in the Table 1, a range of ‘reaction selectivity’ is noted. For example, change in the molar ratio changes the selectivity to PO.5M ester formed.
There is a substantial gap between what is taught in the specification and what is being claimed. For these reasons, one skilled in the art would be faced with undue amount of research. The specification lacks disclosure sufficient to make and use the invention, in predictable manner, commensurate with the scope of the claims.
MPEP 2164.01(a) states, “A conclusion of Iack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. ln re Wright, 999 F.2d 1557,1562, 27 USPQ 2d 1510, 1513 (Fed. Cir. 1993).'' That conclusion is clearly justified here. Thus, undue experimentation would be required to make and use Applicants' invention.
Applicant's amendment necessitated the new 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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