DETAILED ACTION
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 the Claims
Claims 1-21 are pending.
Status of Priority
The present application is a continuation of a 35 U.S.C. § 371 national stage patent application of International patent application PCT/EP2021/082395, filed on November 22, 2021. This application also claims the benefits of foreign priority to EP20209174.0, filed on November 23, 2020.
Specification - Abstract
The abstract of the disclosure is objected to because it can be more informative and descriptive. For example, the abstract can be amended as follows:
The present invention relates to a process for preparing a compound of formula (I),
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comprising reacting a compound of formula (II),
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with trimethylsilyl azide (TMSN3) and a chlorinating agent in acetonitrile, wherein the process is performed under continuous-flow conditions and wherein R1 and R2 of formulas (I) and (II) are as defined in the description.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
On pg. 2, last two lines should read, “POCl3 was found to be the best chlorinating agent in terms of kinetics, solubility and general reaction performance .
On pg. 10, line 10, also include the expanded form of “IT” to clarify the meaning of “IT.”
Appropriate correction is required.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 1 is objected to because of the following informalities:
For clarity, claim 1 should read,
“comprising reacting a compound of formula II… with trimethylsilyl azide (TMSN3) and a chlorinating agent in acetonitrile under continuous-flow conditions”
instead of
“comprising the flow chemistry, three components reaction of a compound of formula (II)…with trimethylsilyl azide (TMSN3) and a chlorinating agent in acetonitrile.”
Appropriate correction is required.
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 1-21 are 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 claims contain 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 use the invention.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims a continuous-flow process for preparing a compound of formula (I),
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comprising reacting a compound of formula (II),
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with trimethylsilyl azide (TMSN3) and a chlorinating agent in acetonitrile, wherein R1 and R2 of formulas (I) and (II) are as defined in the description.
State of the prior art, the predictability or lack thereof in the art
Prior art referred to:
Chandgude et al. (Chandgude) (Chandgude, A. L. et al. Convergent Three-Component Tetrazole Synthesis. Eur. J. Org. Chem. 2016, 2383-2387.)
Roberto (Roberto, M. F. Translation of a Chemical Reaction from Batch to Continuous Flow via Process Analytical Technology and Chemometrics. Ph.D. Dissertation, University of Washington, 2014.)
Glasnov et al. (Glasnov) (Glasnov, T. N. et al. The Microwave-to-Flow Paradigm: Translating High-Temperature Batch Microwave Chemistry to Scalable Continuous-Flow Processes. Chem. Eur. J. 2011, 17, 11956-11968.)
Adam et al. (Adam) (US20130116236A1; published May 9, 2013).
The synthesis of a 1,5-disubstituted tetrazole of the present invention has been previously taught by Chandgude in a one-pot batch process (pg. 2383, Introduction section, right col., last paragraph and pg. 2384, right col., Table 1) rather than under continuous-flow conditions as disclosed in the present invention. While directly translating a batch production scheme to a continuous flow production scheme can still yield product, a continuous flow reactor can run more efficiently when the production scheme is designed specifically for continuous flow conditions (Roberto, pg. 12, last paragraph, 2nd and 3rd sentences). Continuous flow conditions are not predictable, but rather, can be designed through the understanding of intermediate formation rates, production pathways, target chemical formation mechanisms, and understanding of batch design limitations (Roberto, pg. 12, last paragraph, last three sentences). For a reaction under continuous flow conditions, typically a reaction temperature, pressure, residence time, and flow rate are reported (Glasnov, pg. 11961, left col., scheme 2b).
Additionally, the invention as claimed in instant claims 19-21 has previously been disclosed by Adam (pg. 58, para. 0762-0763) under batch reaction conditions, not continuous flow conditions. See the “Claim Rejections - 35 USC § 102” section below for details.
The amount of direction or guidance present and quantity of experimentation necessary
According to the prior art, a continuous-flow reactor is most effective when employed efficiently. Thus, the conditions used in a batch reactor may not be the same in a continuous-flow reactor. This is reflected in the present invention. According to Chandgude, the synthesis of a 1,5-disubstituted tetrazole occurs at a temperature of 180oC (pg. 2384, right col., Table 1). Under the flow conditions presented in the instant invention, the internal temperature is around 112.5oC (instant specification, pg. 10, line 10), yet, in instant claim 7, a temperature range is given. Examiner understands that to obtain the different products presented on pg. 11 and 12 of the instant specification, different reaction temperatures and pressures and residence times may be used. However, absent further guidance, a POSITA would require undue experimentation to determine the optimal reaction temperature, pressure, and residence time needed to obtain each of the tetrazole compounds of instant formula I at the reported yields.
The subject matter of instant claims 19-21 has previously been disclosed by Adam under batch conditions, not continuous flow conditions. Since claims can only be directed towards novel inventions, Examiner assumes that Applicant is claiming a process of preparing (S)-1-(5-tert-Butyl-3-(1-methyl-1H-tetrazol-5-ylmethyl)-3H-[1,2,3] triazolo [4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol,
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, under continuous flow conditions since the nature of the invention is related to flow chemistry. However, the specification provides no guidance on essential flow parameters (e.g., temperature, pressure, residence time, reagents) for this process. Accordingly, undue experimentation would be required for a POSITA to devise a continuous-flow process for the invention claimed in instant claims 19-21.
The presence or absence of working examples
In the instant case, the specification only provides working examples of tetrazole compounds wherein:
R1 is an unsubstituted alkyl, cycloalkyl, aryl, or arylalkyl;
R2 is
-CH2-X, wherein X is a halogen, aryloxy, alkyoxycarbonyl, or haloalkyl or
an aryl optionally substituted with one substituent independently selected from halogen and alkoxy or
R1 and R2 together form alkylene
Additionally, the specification only provides working examples of the following (see pg. 10 of instant specification for details):
The compound of formula (II) is injected in the flow chemistry reactor at a concentration of 6.0 M in acetonitrile;
The chlorinating agent is POCl3 and is injected neat into the flow chemistry reactor;
TMSN3 is injected neat into the flow chemistry reactor;
Present at the start of the three-component reaction is 1.5 equivalents of TMSN3;
The internal temperature of the reactor content is around 112.5oC;
The residence time is about 12.5 min;
The reaction flow is cooled to room temperature;
The reaction is quenched with aqueous solution of sodium hydroxide.
The breadth of the claims
The claims are broad insofar as the instant claims recite a process of making a 1,5-disubstituted tetrazole compound of formula (I) under continuous flow conditions wherein the tetrazole compound can possess a structurally diverse range of chemical groups.
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 2-5, 7-11, 13, 16, 17, 20, and 21 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.
Regarding claims 2-5, 7-10, 13, 16, 17, and 20, the phrases "in particular" or “more particularly” render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The term “around” in claims 2-5 and 7-9 is a relative term which renders the claim indefinite. The term “around” 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 ambiguity is compounded by applying the same qualitative term to parameters of different units (i.e., concentration, temperature, and reagent equivalencies) and magnitudes, where each numeric value can imply different numerical variances (e.g., a one-unit change in oC does not impact reaction outcome as much as a one-unit change in reagent equivalency and, therefore, each value corresponding to different units should have different numerical variances). Accordingly, the metes and bounds of the claims are uncertain and the claims are rendered indefinite.
Regarding claim 11, the phrases “reaction completion” and “continuously” render the claim indefinite as these terms are not defined by the instant specification. In particular, the term “continuously” could imply various reaction monitoring frequencies. Further, the term “reaction completion” is subjective to the POSITA conducting the experiment. For example, “reaction completion” may be defined as the point in a reaction when the starting material peak from a GC or LC-MS spectra reaches a certain threshold. Depending on what threshold used, it may also impact reaction times. Thus, the metes and bounds of the claim cannot be ascertained and the claim is rendered indefinite.
Claim 21 recites “The process according to claim 1 wherein R3 is hydroxyl". There is insufficient antecedent basis for this limitation in the claim. Claim 21 depends on claim 1 which does not mention the variable, R3.
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.
Claims 19-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Adam et al. (Adam) (US20130116236A1; published May 9, 2013).
Adam discloses the preparation of (S)-1-(5-tert-Butyl-3-(1-methyl-1H-tetrazol-5-ylmethyl)-3H-[1,2,3] triazolo [4,5-d]pyrimidin-7-yl-pyrrolidin-3-ol,
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from trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester,
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and 5-(chloromethyl)-1-methyl-1H-tetrazole (pg. 58, Example 151, para. 0762) (reads on instant claim 19).
Alternatively, (S)-1-(5-tert-Butyl-3-(1-methyl-1H-tetrazol-5-ylmethyl)-3H-[1,2,3] triazolo [4,5-d]pyrimidin-7-yl-pyrrolidin-3-ol,
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, can also be synthesized by reacting (S)-1-(5-tert-butyl-3H-[1,2,3] triazolo [4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol,
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, with 5-(chloromethyl)-1-methyl-1H-tetrazole (pg. 58, Example 151, para. 0763) (reads on instant claims 20 and 21).
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).
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.
Claims 20 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1, 3, and 22 of U.S. Patent Application No. 18/644,781.
Although the claims at issue are not identical, they are not patentably distinct from each other because there is overlap between the instant claims and the claim set from the co-pending application.
For example, U.S. Patent Application No. 18/644,781 claims a process for the preparation of a compound of formula (I), such as the following compound:
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(wherein R1 = OH),
which comprises reacting a compound of formula (II), such as the following compound:
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(wherein R1 = OH),
with a compound of formula (III):
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, wherein X is a halogen,
in the presence of an organic acid.
This process is encompassed by claims 1, 3, and 22 of U.S. Patent Application No. 18/644,781. This process is also encompassed by instant claims 20 and 21.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY H. MURRAY can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624