DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-20 are pending.
Priority
Instant application 18/209,314, filed 06/13/2023 claims priority as follows:
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Information Disclosure Statement
All references from IDS(s) received 10/02/2024 have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-6 in the reply filed on 03/26/2026 is acknowledged.
Claims 7-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/26/2026.
Claim Objections
Claims 1 and 2 objected to because of the following informalities: claims 1 and 2 contain the grammatically incorrect phrase “should ensures”. Appropriate correction is required.
Claim 2 is objected to because of the following informalities: wherein R is ethyl (i.e., M is triethylamine). While the use of “i.e.” here appears to be a clarifying restatement and does not itself render the claim indefinite, applicant is advised to remove the parenthetical and simply state “wherein M is triethylamine”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-6 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.
Claims 1 and 2 recite the phrase “should ensures”. Claim 3 recites the phrase “should ensure”. The phrase “should ensures” is indefinite because the phrase contains a grammatical error; and the phrases “should ensures” and “should ensure” are indefinite because the word “should” in claim language creates uncertainty as to whether the following limitation (e.g. the temperature control of the system in claims 1-3) is a mandatory requirement of the claimed process, or merely a preferred or recommended condition. If the claim intends to require the stated temperature control, then “should” is inappropriate because it conveys a non-mandatory meaning. If it is merely advisory, then the metes and bounds of the claim are unclear because one cannot determine when a process falls outside the claims scope. See MPEP 2173.05(d).
In the interest of compact prosecution, the examiner suggests replacing the phrase “should ensures” or “should ensure” with mandatory language such as “the rate of dropwise addition is controlled such that the temperature change of the reaction system is within 10°C.”
Claim 1, step (2), substep ③ recites:
“for the nth dropwise addition, the aforementioned dropwise addition step is repeated, the temperature of the system is increased by 5° C to 15° C with each addition, and the molar equivalent of compound M is decreased with each addition since the second dropwise addition”
This language is indefinite for the following reasons:
The phrase “the aforementioned dropwise addition step” has an unclear antecedent. Substeps ① and ② each describe dropwise addition steps (the first at 1.8-2.2 molar equivalents, the second at 0.9-1.1 molar equivalents). The phrase “the aforementioned dropwise addition step” could refer to either substep ① or ②, or both collectively.
The phrase “the temperature of the system is increased by 5° C to 15° C with each addition” has ambiguous scope. It is unclear whether “each addition” refers to all additions starting from the first (including substeps ① and ②), or only to additions from the third onward (i.e. additions described by substep ③). This ambiguity is compounded by the statement that “the molar equivalent of compound M is decreased with each addition since the second dropwise addition”, which suggests (but does not make clear) that the temperature-increase language may also apply starting from the second addition.
The claim later states “n is an integer, and n ≥ 2”. If n = 2, then the “nth” (2nd) addition is already fully described in substep ②, creating a conflict. When n = 2, one cannot simultaneously comply with both substep ② and ③. Moreover, the claim fails to recite an upper limit for n. The specification only demonstrates n =3 (three additions of triethylamine, see Examples 1 and Experiments S1-S6 in Table 7). A person of ordinary skill in the art cannot ascertain the claim scope because there is no upper bound for this parameter.
Substep ③ requires that “the molar equivalent of compound M is decreased with each addition since the second dropwise addition” but provides no minimum molar equivalent. A person of ordinary skill in the art cannot ascertain the claim scope because there is no lower bound for this parameter.
Claim 3, in the Cl-IPM post-treatment process, recites “heating the reaction solution to 0° C to 5° C”. The corresponding passage for Cl-IPM post-treatment in the specification at page 7, lines 31-41, describes “cooling the reaction solution to 0° C to 5° C”. The inconsistency between the claim and specification creates a potential ambiguity about whether the actual process involves warming a cold solution upward or cooling a warmer solution downward to 0° C to 5° C.
The above-mentioned issues apply either to claims 1-6 directly or indirectly by virtue of the dependency of the claims. Accordingly, claims 1-6 are rejected.
Claim Rejections - 35 USC § 112(a)
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.
Claim 1 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Two issues are discussed below:
The specification, while being enabling for embodiments where M is R3N, does not reasonably provide enablement for the full scope of claim 1 as it encompasses M = pyridine.
The specification, while being enabling for embodiments where n = 3, does not reasonably provide enablement for the full scope of claim 1 as it encompasses an unbounded number of additions (n ≥ 2).
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), the following factors are considered to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims:
Claim 1 broadly encompasses pyridine as an alternative base. Pyridine (pKa ≈ 5.25 in water) is a fundamentally different type of base than triethylamine (pKa ≈ 10.75 in water). See the attached compilation of pKa values from D.A. Evans and D.H. Ripin. Pyridine is an aromatic amine with markedly lower basicity and different steric/electronic properties than a trialkylamine.
Claim 1 also broadly encompasses any number “n” of subsequent additions in substep 3. This is an arbitrarily large number of additions (e.g. n = 10, 20, 100, 1000).
Nature of the invention:
The invention relates to chemical synthesis involving precise temperature-controlled, stepwise addition of a base to scavenge acid (HBr/HCl) generated during the reaction of phosphorus oxyhalide with 2-haloethylamine. In this context, the choice of base is not a trivial substitution: the base must effectively sequester hydrogen halide at cryogenic temperatures (-70° C to -40° C) in dichloromethane, and the resulting amine hydrohalide salt must not interfere with the reaction or subsequent post-treatment steps.
State of the prior art and predictability in the art:
The prior art includes various methods for the synthesis of Br-IPM or Cl-IPM, such as those in MATTEUCCI (WO 2007002931 A2; cited in IDS) or DUAN (US 20170210769 A1; cited in IDS). Neither reference discloses the use of pyridine as a base. Both use triethylamine exclusively.
The applicant’s own specification demonstrates unpredictability. Comparative examples 3 and 4 show that the seemingly minor change from batchwise to single addition of the same base (triethylamine) at the same stoichiometry reduces the yield from 45-65% to 32-35%. The application characterizes this as an unexpected result and underscores the sensitivity of the claimed reaction system to process variables. If even the manner of addition of the same base dramatically impacts yield, a person of ordinary skill in the art could not predict with any reasonable confidence that substituting pyridine, having markedly different basicity, nucleophilicity, steric profile, for triethylamine would produce X-IPM in meaningful amounts.
Similarly, the specification provides no basis to predict how the process would perform at values of n substantially different from 3. At high values of n (e.g. 10 or higher), later additions would necessarily involve vanishingly small quantities of base. Meanwhile, the cumulative temperature increase (5° C to 15° C per addition) could push the temperature of the reaction above the -40° C upper boundary recited in step (2) well before the final nth addition is reached. The specification provides no teaching regarding how to manage these competing constraints at values of n other than 3.
Level of ordinary skill in the art:
The person of ordinary skill would be an organic chemist with an advanced degree (e.g. Ph.D.) and possess several years of professional experience, with some familiarity for process chemistry.
The amount of direction provided:
The specification provides detailed direction for only one specific base embodiment: M = triethylamine, n =3. The specification offers no prophetic examples, reaction conditions, expected yields, or post-treatment procedures for pyridine as compound M. The specification (page 6, lines 9-12) acknowledges that special handling is needed when M is a gas (trimethylamine), but is silent on the unique challenges posed by pyridine.
Existence of working examples:
All seven working examples (Example 1 for Cl-IPM and Table 7, S1-S6) in the specification use triethylamine as compound M and n=3 additions. No working examples are provided where M is pyridine or where n is not 3. The specification provides no guidance on how to select the molar equivalent for a fourth, fifth, or subsequent addition, how to manage the cumulative temperature increase, or what yields or purities to expect.
See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. The person of ordinary skill seeking to practice the full scope of claim 1 would need to conduct extensive experimentation to determine whether pyridine can serve as compound M while achieving a meaningful yield of X-IPM, and if so, what temperature ranges, stoichiometries, and addition rates are required. Further, they would need what post-treatment procedures would be necessary given that the byproduct of pyridine (pyridinium halide) has different solubility and physical properties than triethylamine hydrohalide. Moreover, for values of n substantially greater than 3, they would need to determine what molar equivalents should be used for each successive addition and how to manage the cumulative temperature increase. This is not routine optimization of known parameters but rather requires the practitioner to solve questions of operability that the specification leaves entirely unanswered.
Claims 2-6 are not rejected because claim 2 (which claims 3-6 depend from) narrows compound M to triethylamine and requires that n = 3, thereby resolving the issues identified above.
Close prior art cited but not applied
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
For claims 1-6, the closest prior art is DUAN (US 20170210769 A1; cited in IDS). DUAN discloses a process for producing Br-IPM by dissolving 2-bromoethylamine hydrobromide and POBr3 in DCM under nitrogen, cooling to -70°C, adding the full amount of triethylamine in DCM in a single addition at -70°C, warming to 0°C, quenching with water, and filtering (see Example 1, Step 3, para. [0106]). The claimed process differs from Duan’s process in at least the following ways: (i) the solution of compound M in DCM is added dropwise in n ≥ 2 discrete batches rather than in a single addition; (ii) each batch is added at a progressively higher temperature window (the system temperature increasing by 5-15°C with each successive addition); and (iii) the molar equivalents of compound M are progressed (the first batch comprises 1.8-2.2 equivalents of M relative to POX3, the second batch comprises 0.9-1.1 equivalents, etc.).
While portion wise addition of reagents is a generally known laboratory technique for moderating exothermic reactions, the prior art does not teach or suggest the specific combination of staged temperature windows with decreasing molar equivalents of base across multiple additions in the context of X-IPM synthesis, nor does the prior art provide any motivation to depart from the established single-addition protocol at a fixed temperature.
Moreover, the applicant’s specification provides direct comparative evidence (comparative Examples 3 and 4) demonstrating that, under otherwise identical conditions (same reagents, total equivalent, post-treatment), the batchwise addition achieves yields of 45-65% with HPLC purities of 93-97%, whereas the single addition yields only 32-35%. This constitutes evidence of an unexpected result that would not have been predictable from the teachings of Duan, which provide no indication that the single-addition approach is suboptimal or that yield improvements of this magnitude could be achieved by subdividing the base addition into temperature-staged portions with decreasing stoichiometry.
Conclusion
Claims 1-6 are rejected. Claims 7-20 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621