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, 10, 11, 14, 16, 19, 25, 27, 29, 52, 53, 56, 58, 59, 63-65, 69, 75, 77-81, 88, and 101-104 are pending. Claims 2-9, 12, 13, 15, 17, 18, 20-24, 26, 28, 30-51, 54, 55, 57, 60-62, 66-68, 70-74, 76, 82-87, and 89-100 are cancelled. Examiner previously required a restriction (dated October 27, 2025). In response, Applicant elected, without traverse, Group I which encompasses claims 1, 10, 11, 14, 16, 19, 25, 27, 29, 52, 53, 56, 58, 59, 63, 64, 77, and 88, as well as new claims 101-104. Accordingly, claims 65, 69, 75, and 78-81 are withdrawn.
Status of Priority
The present application claims priority to U.S. Provisional Application no. 63/415,590, filed on October 12, 2022; 63/456,403, filed on March 31, 2023; and 63/532,327, filed on August 11, 2023.
Election/Restrictions
As a reminder, Applicant elected, without traverse, Group I which corresponds to claims 1, 10, 11, 14, 16, 19, 25, 27, 29, 52, 53, 56, 58, 59, 63, 64, 77, and 88, as well as new claims 101-104. Applicant also elected the following species, without traverse:
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and indicated that claims 1, 10, 27, 52, 64, 77, 88, and 101-104 read on the elected species. The elected species was not found in the prior art and, thus, the search was expanded.
Specification - Disclosure
The disclosure is objected to because of the following informalities:
On pg. 144, para. 0245, the instant specification states:
“In one aspect, provided herein is a compound of formula (I-H)… wherein [the variables] are as defined for a compound of formula (I)…” which should read instead:“In one aspect, provided herein is a compound of formula (I-H)… wherein [the variables] are as defined for a compound of formula (II)…”
Reasoning: Abstract of the disclosure refers to formula (II), not formula (I). Additionally, formula (II) includes all the limitations listed in instant claim 1 whereas formula (I) does not.
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 19 is objected to because of the following informalities:
Claim 19 recites:
“The compound of claim 1… wherein R3 is selected from the group consisting of …
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…”
One of the cyclobutyls listed can be removed to avoid repetition.
Appropriate correction is required.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Sprott et al. (Sprott) (WO2015/154039A2; published October 8, 2015).
Sprott teaches inhibitors of cyclin-dependent kinase 7 (CDK7) (see abstract). One of the compounds disclosed by Sprott with a structure that is closest to the instant compounds is the following:
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(see pg. 103, Example 28. Synthesis of compound 1029). Compound 1029 corresponds to a compound of instant claim 1 wherein:
m = 2
n = 0
X = -NH-
R3 = C3 alkyl substituted with one Ra
wherein Ra = -N(C1 alkyl)2
R5 = R7 = H
R6 = R9 = H
t = 2
Y5 = Y3 = C; Y2 = CH; Y1 = Y4 = N
Ra = Cl and heteroaryl (i.e., indole)
s = 2
However, it is noted here that Ra = heteroaryl is NOT encompassed by instant claim 1. Hence, the compounds disclosed in Sprott do not overlap with the claim scope of instant claim 1. As such, the instant invention is considered novel.
Moreover, Sprott does not suggest modifying the heteroaryl substituent to a 4-10 membered heterocyclyl group (i.e., an R3 group that is encompassed in instant claim 1) for the purpose of improving inhibition of SLC6A19. As stated above, the compounds disclosed in Sprott are described as CDK7 inhibitors, and the reference contains no teaching, suggestion, or motivation to alter the framework of the CDK7 inhibitors disclosed in Sprott to target SLC6A19 activity. Thus, the instant invention is considered nonobvious.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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, 10, 11, 14, 16, 19, 25, 27, 29, 52, 53, 56, 58, 59, 63, 77, 88, and 101-104 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A compound of formula (I-H):
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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
m, n, X, R6, R9, R11a, R11b, R12a, R12b, Ra, Rb, Y1, Y2, Y3, Y4, Y5, s, and t are as recited in instant claim 1
R3 is as recited in instant claim 1 and EXCLUDING 6-20 membered heteroaryl, -C1-6alkyl(6-20 membered heteroaryl) and wherein when R3 is 6-10 membered heteroaryl, the 6-10 membered heteroaryl is unsubstituted
R4 is as recited in instant claim 1 EXCLUDING -C1-6alkyl(5-20 membered heteroaryl)
R5 is H, halo, or C1-6alkyl
wherein the C1-6alkyl is optionally substituted with one or more halo
R7 is as recited in instant claim 1 EXCLUDING 6-20 membered heteroaryl
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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.
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 to make and use the invention based on the content of the disclosure, 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 compounds of formula (II):
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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, R2, R3, R5, R6, R7, R8, R9, R10, R11a, R11b, and X are as defined elsewhere in the instant specification and instant claim 1. The instant invention also provides methods of preparing compounds of formula (II), methods of inhibiting SLC6A19 and methods of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof
State of the prior art
See “Examiner’s note on novelty and nonobviousness.”
Other prior art referenced:
Cheng et al. (Cheng) (Cheng, Q. et al. British Journal of Pharmacology 2017, 174, 468-482).
Cheng identifies novel inhibitors of SLC6A19 (see Table 1 on pg. 475). The list of compounds disclosed by Cheng are SLC6A19 inhibitors with structures that are distinctly different from the instant compounds. For example, benztropine was identified as a competitive inhibitor of SLC6A19 (see “Key results” section of Abstract, pg. 468). Benztropine has the following structure:
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. More specifically, none of the listed compounds have the core structure of the instant compounds.
The predictability or lack thereof in the art
As stated above, the prior art does not disclose compounds having the same core structure as the presently claimed compounds in regards to SLC6A19 inhibition. Thus, there is limited predictability as to which substituent combinations or positional modifications would yield compounds exhibiting SLC6A19 inhibition.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
Even though the instant specification provides data on the SLC6A19 inhibition activity of compounds of diverse structures (see Examples B-1 and B-2 of instant specification), it does not include data on the SLC6A19 inhibition activity of any compounds of Formula (I-H) comprising structural elements that are outside the scope of the enabling elements listed above. For example, there are no working examples of a compound of Formula (I-H) wherein:
R3 is 6-20 membered heteroaryl or - C1-6alkyl(6-20 membered heteroaryl) and wherein when R3 is 6-10 membered heteroaryl, the 6-10 membered heteroaryl is unsubstituted
R4 is -C1-6alkyl(5-20 membered heteroaryl)
R7 is 6-20 membered heteroaryl
Thus, the specification is not adequately reflecting the structural diversity of the claimed genus.
The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure
As stated previously, the instant specification does not provide any working examples of a compound of Formula (I-H) comprising structural elements that are outside the scope of the enabling elements listed above.
Moreover, as previously noted, there is a lack of predictability in the prior art with respect to SLC6A19 inhibition of compounds wherein these compounds comprise of the core structure of the instant compounds. The specification does not provide guidance regarding which substituents, beyond those exemplified, would be suitable for incorporation into the claimed core structure. For example, although R3 can be broadly defined as a 5-20 membered heteroaryl, the working examples are limited to 5-membered heteroaryl substituents. The disclosure does not identify which specific 6-20 membered heteroaryl groups (with what number of heteroatoms and at what positions within the heteroaryl ring these heteroatoms are located) would result in a compound exhibiting SLC6A19 inhibitory activity, nor does it provide direction as to appropriate combinations with other variable groups in the compound.
In the absence of clear guidance, a person of ordinary skill in the art would require undue experimentation to:
make all compounds comprising structural elements that are outside the scope of the enabling elements listed above and
determine which of those compounds (within the full scope of instant claim 1) are exhibit SLC6A19 inhibitory activity.
The breadth of the claims
The claims are broad insofar as the instant claims recite a compound of formula (I-H) wherein the compound can possess a structurally diverse range of chemical groups.
Claims 10, 11, 14, 16, 19, 25, 27, 29, 52, 53, 56, 58, 59, 63, 77, 88, and 101-104, which are dependent on claim 1, are also rejected for further requiring and/or reciting the non-enabling elements listed above.
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.
Claim 63 is 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.
Claim 63 recites the limitation:
“
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.” Claim 63 is dependent on claim 1 which does not define the variables “r” and “q.” Thus, there is insufficient antecedent basis for this limitation in the claim.
Allowable Subject Matter
Claim 64 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form.
Conclusion
Claims 1, 10, 11, 14, 16, 19, 25, 27, 29, 52, 53, 56, 58, 59, 63, 77, 88, and 101-104 are rejected. Claim 64 is objected to. 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