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 the Claims
The listing of claims filed 07 January 2025 has been reviewed.
Claims 1-5, 10, 21, 23, 25, 30, 39, 41, 43, 73, 89, 91-92, 110, 123, and 132 are pending.
Claims 3-5, 10, 21, 23, 25, 30, 39, 41, 43, 73, 89, 91-92, 110, 123, and 132 are amended.
Claims 6-9, 11-20, 22, 24, 26-29, 31-38, 40, 42, 44-72, 74-88, 90, 93-109, 111-122, 124-131, and 133-135 are cancelled.
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed on 07 January 2025 is acknowledged and has been considered.
Benefit of Earlier Filing Date
The instant application was filed 13 June 2024; it is a national stage application of PCT/US2022/052690, filed 13 December 2022, and claims the benefit of U.S. Provisional Patent Application No. 63/289,736, filed 15 December 2021. Applicant’s claim is acknowledged.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it uses a phrase which can be implied, specifically the phrase, “The present disclosure provides…” A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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.
Claims 1, 2-5, 10, 21, 23, 25, 30, 39, 41, 43, 73, 89, 91-92, 110, 123, and 132 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 written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites, “A method of preparing a compound of formula (I), comprising reacting a compound of formula (II) with a weak base in a water-miscible organic solvent…” The phrase “weak base” is a broad genus and, according to its broadest reasonable interpretation, includes any weak base. For example, weak bases includes both organic bases (e.g., pyridine) and inorganic bases (e.g., K2CO3). The instant Specification states, “The term “weak base,” as used herein, refers to an organic or inorganic base of which the conjugate acid has a pKa of about 7 to about 12 in aqueous solution. Exemplary inorganic weak bases include, but are not limited to, alkali metal carbonates (e.g., Na2CO3, K2CO3, Cs2CO3), alkali metal bicarbonates (e.g., NaHCO3, KHCO3), and alkali metal phosphates (e.g., Na3PO4, Na2HPO4, NaH2PO4, K3PO4, K2HPO4, KH2PO4). Exemplary organic weak bases include, but are not limited to, alkylamines (e.g., triethylamine, diethylamine, t-butylamine, n-butylamine, di-isopropylethylamine, and dimethylamine), pyridine, piperidine, morpholine, and DABCO.” (p. 26, Lines 32-38). The only weak base disclosed in an exemplary reaction is K2CO3. Thus, the instant application lacks sufficient variety in the disclosed weak bases to reflect the variance within the genus which is encompassed by the phrase “weak base.” Furthermore, based on the limited number of examples provided for the claimed genus, “weak base,” a representative number of examples to support the claimed genus is lacking and a person having ordinary skill in the art (PHOSITA) would conclude that Applicant is not in possession of the claims, as currently recited.
Based on the prior art, which primarily suggests an acid is needed for removing a t-butyl group, the successful removal of a t-butyl group using a weak base would have been unexpected to a person having ordinary skill in the art (PHOSITA). For example, Wuts (Wuts & Greene, Greene’s Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006, Chapter 5, p. 533-646) states, “t-Butyl esters are stable to mild basic hydrolysis, to hydrazine and to ammonia. They are cleaved by moderately acidic hydrolysis…” (p. 584). Additionally, Wuts indicates TFA, a strong acid, is often the reagent used in removing t-butyl groups (p. 585, 9.). Thus, the prior art teaches t-butyl groups are stable under basic conditions and suggests said groups should be removed under acidic conditions. Since Wuts discloses some weak bases (i.e., hydrazine and ammonia) fail to remove t-butyl groups and makes no mention of any weak bases which would be expected to remove t-butyl groups, Wuts’ teachings fail to suggest or draw a clear line as to which “weak bases” would or would not be capable of removing t-butyl groups. Accordingly, a PHOSITA is not in possession of the knowledge of which weak bases would or would not lead to the removal of the t-butyl group.
Examiner recommends amending claim 1 to recite only the weak bases which are supported by the disclosure.
Claims 2-5, 10, 21, 23, 25, 30, 39, 41, 43, 73, 89, 91-92, 110, 123, and 132 are objected to as being dependent on a rejected claim, either directly or indirectly, without resolving the issue.
Claims 1, 2-5, 10, 21, 23, 25, 30, 39, 41, 43, 73, 89, 91-92, 110, 123, and 132 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
While the Specification, in view of the prior art, reasonably provides enablement for a method of preparing a compound of formula (I) by reacting a compound of formula (II) with K2CO3, it does not reasonably provide enablement for a method of preparing a compound of formula (I) by reacting a compound of formula (II) with any weak base.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Wands factors are analyzed with respect to the claimed elements in turn below.
The breadth of the claims – Claim 1 recites, “A method of preparing a compound of formula (I), comprising reacting a compound of formula (II) with a weak base in a water miscible organic solvent…” Accordingly, the claim is broad in scope as it encompasses any weak base. Furthermore, the instant Specification states, “The term “weak base,” as used herein, refers to an organic or inorganic base of which the conjugate acid has a pKa of about 7 to about 12 in aqueous solution. Exemplary inorganic weak bases include, but are not limited to, alkali metal carbonates (e.g., Na2CO3, K2CO3, Cs2CO3), alkali metal bicarbonates (e.g., NaHCO3, KHCO3), and alkali metal phosphates (e.g., Na3PO4, Na2HPO4, NaH2PO4, K3PO4, K2HPO4, KH2PO4). Exemplary organic weak bases include, but are not limited to, alkylamines (e.g., triethylamine, diethylamine, t-butylamine, n-butylamine, di-isopropylethylamine, and dimethylamine), pyridine, piperidine, morpholine, and DABCO.” (p. 26, Lines 32-38). Thus, the instant Specification provides a broad, open-ended list of exemplary weak bases.
The nature of the invention – The invention relates synthetic chemistry and, more specifically, to a method by which a compound of formula (I) can be synthesized by reacting a compound of formula (II) with a weak base in a water-miscible organic solvent.
The state of the prior art – This can be ascertained by reviewing the Background of the Specification and relevant literature. The Specification states, “The successful removal of the t-butyl group of the compounds of formula (I) is unexpected as it is well-known in the art that t-butyl esters are stable to mild basic hydrolysis and typically cleaved by moderately acidic hydrolysis... or the use of a strong base such as KOH… Indeed, prior to the present disclosure, deprotection of the compound of formula (II) was typically achieved by treating it with an acid, e.g., trifluoroacetic acid in dichloromethane or methanesulfonic acid or sulfuric acid in a mixture of water and acetonitrile, and, in certain cases, strong bases such as NaOH in a mixture of tetrahydrofuran and water or LiOH in a mixture of methanol and water were used.” (p. 27, Lines 16-24). The prior art supports Applicant’s assertion, as Wiles (WO 2017/035409 A1; IDS dated 07 January 2025, Cite No. AQ) reports a similar reaction (p. 187, ¶ [0647]. Scheme 6-6) with TFA in DCM. Additionally, Kazzouli (Kazzouli et al., “A mild and selective method for the N-Boc deprotection by sodium carbonate”, Tetrahedron Letters, Vol. 47, Issue 48, 27 November 2006, p. 8575-8577), which studies N-Boc deprotection, indicates said deprotection has been achieved under strong acidic conditions using CF3COOH, H2SO4, TsOH, MsOH, and Lewis acids as well as under thermal conditions around 150°C (p. 8575, Col. 1, Introduction). Furthermore, Kazzouli states, “…very few methods for basic deprotection have been described.” and discloses a method by which Boc-protected amines can be deprotected using Na2CO3 in DME (p. 8575, Col. 1, Results and discussion). Notably, Na2CO3 did not result in deprotection for all substrates (p. 8576, Table 1).
The level of one of ordinary skill – The level of skill in the art is high and it may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the chemical arts and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
The level of predictability in the art – The chemical arts are generally unpredictable. The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. MPEP § 2164.02(II) explains that a correlation between the claimed invention and the evidence provided in an application, along with a correlation between the evidence and the models recognized in the art, are required:
“Correlation” as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications).
Further, reacting one compound of formula (II) with a specific weak base does not necessarily mean reacting said compound of formula (II) with a different, structurally dissimilar weak base will also result in a compound of formula (I) being synthesized. Additionally, a wide range of compounds are encompassed by the formula (I) and formula (II) structures. Accordingly, reacting one compound of formula (II) with a specific weak base may be successful and reacting a different compound of formula (II) with the same weak base may be unsuccessful in preparing a compound of formula (I).
The amount of direction provided by the inventor and g) the existence of working examples – The instant Specification discloses exemplary synthesis processes using a singular weak base, namely K2CO3 (p. 32, Example 2; p. 33, Example 3). There are no working examples provided in the instant Specification which utilize other weak bases.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure – The amount of experimentation is extensive, as it includes screening any/all weak bases other than K2CO3. Since a process using K2CO3 is the only working example provided in the instant Specification, a skilled artisan would need to conduct experiments to determine which other alkali metal carbonates as well as which alkali metal bicarbonates, alkali metal phosphates, and/or organic weak bases can be used in preparing a compound of formula (I) by the instantly claimed method.
Scope of Enablement Conclusion – In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a PHOSITA to use the full scope of the claimed invention since it would be unclear to a PHOSITA which weak bases could be using in practicing the claimed method, as all weak bases would not be reasonably expected to be useful for this carrying out this reaction involving all compounds of formula (I) and formula (II). Furthermore, as discussed above, the prior art teaches away from using weak bases for the removal of t-butyl groups. The Specification provides only three example reactions involving compounds of formulas (I) and (II) and all three reactions use the same weak base (i.e., K2CO3). Since using a weak base is taught away from in the prior art, a PHOSITA could not extrapolate the use of a single weak base in only a few reactions of compounds of formula (II) and (I) to the use any weak base given that the prior art predominantly indicates strong acids (i.e., TFA or HCl) are used in such reactions.
Claims 2-5, 10, 21, 23, 25, 30, 39, 41, 43, 73, 89, 91-92, 110, 123, and 132 are objected to as being dependent on a rejected claim, either directly or indirectly, without resolving the issue.
Allowable Subject Matter
Claims 1-5, 10, 21, 23, 25, 30, 39, 41, 43, 73, 89, 91-92, 110, 123, and 132 contain allowable subject matter. None of the prior art of record nor a search in the pertinent art area teaches a method of preparing a compound of formula (I) comprising reacting a compound of formula (II) with a weak base in a water-miscible organic solvent.
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The following is a statement of reasons for the indication of allowable subject matter:
A method of preparing a compound of formula (I) comprising reacting a compound of formula (II) with a weak base in a water-miscible organic solvent is claimed.
The closest prior art is Wiles (WO 2017/035409 A1; IDS dated 07 January 2025, Cite No. AQ). Shown below is a scheme disclosed by Wiles (p. 187, ¶ [0647]. Scheme 6-6):
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Wiles discloses Compound S5, which is a compound of formula (II), wherein R1 is -C(O)Rb, Rb is C1 alkyl, R2 is H, R3 is H, X1 is N, X2 is CRd wherein Rd is H, X5 is CRd wherein Rd is H, X3 is CRe wherein Re is H, and X4 is CRf wherein Rf is 6-membered heteroaryl containing 2 N heteroatoms having a methyl substitution. Additionally, Wiles discloses Compound S6, which is a compound of formula (I), wherein R1 is -C(O)Rb, Rb is C1 alkyl, R2 is H, R3 is H, X1 is N, X2 is CRd wherein Rd is H, X5 is CRd wherein Rd is H, X3 is CRe wherein Re is H, and X4 is CRf wherein Rf is 6-membered heteroaryl containing 2 N heteroatoms having a methyl substitution. In step 5 disclosed by Wiles, Compound S5 is reacted with TFA (trifluoroacetic acid), a strong acid, in DCM (methylene chloride), an organic solvent. The instantly claimed method differs from Wiles’ method because, in the instantly claimed method, the compound of formula (II) is reacted with a weak base. Wiles provides no suggestion or motivation to replace TFA with a weak base. Furthermore, Wuts (Wuts & Greene, Greene’s Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006, Chapter 5, p. 533-646) states, “t-Butyl esters are stable to mild basic hydrolysis, to hydrazine and to ammonia. They are cleaved by moderately acidic hydrolysis…” (p. 584). Thus, the prior art teaches t-butyl groups are stable under basic conditions and suggests said groups should be removed under acidic conditions. Accordingly, the successful removal of a t-butyl group using a weak base would have been unexpected to a PHOSITA.
Thus, while Wiles’ method shares some similarities with the instantly claimed method, specifically regarding the structures of formula (I) and formula (II), a skilled artisan would not have been motivated to replace a strong acid with a weak base in the reaction.
Conclusion
Claims 1-5, 10, 21, 23, 25, 30, 39, 41, 43, 73, 89, 91-92, 110, 123, and 132 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANNA L BAUER whose telephone number is (571)272-5752. The examiner can normally be reached 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, ADAM C MILLIGAN can be reached at (571)270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/B.L.B./Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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