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 .
Priority
This application, filed 25 October, 2023, is a national stage application of PCT/CA2022/050676, filed 2 May, 2022, which claims benefit of the prior filed application PRO 63/182,185, filed 30 April, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 15 May, 2024 is acknowledged and has been considered.
Election/Restrictions
Applicant’s election without traverse of Group I (Claims directed to Compounds and Compositions of Formula I and their Methods of Use) in the reply filed on 9 April, 2026 is acknowledged.
Applicant's election with traverse of Species A (Fused 6,6 bicyclic Q/Q' as exemplified) in the reply filed on 9 April, 2026 is acknowledged.
Applicant's argument that all embodiments of Q/Q' form a fused bicyclic ring system is also acknowledged. However, the definitions of Q/Q' encompass multiple alternative structural embodiments, including alkylene, hetero-atom-interrupted linkers, and imine/N-C linkages, which result in structurally distinct bicyclic systems differing in ring composition, heteroatom content, and bonding structure. These alternatives would require separate searches and examinations. Accordingly, the requirement for election of species is proper and maintained.
The requirement is still deemed proper and is therefore made FINAL.
Status of the Application
Receipt is acknowledged of Applicant's claimed invention, filed 9 April, 2026, in the matter of Application N° 18/288,219. Said documents have been entered on the record.
Claim 1 has been amended. Claims 72-73, 81, 86, 109, 121, 129, and 140-142 are canceled. No new matter was introduced.
Thus, Claims 1-2, 5, 22, 29, 51, 71, 130, 135, and 137 represent all claims currently under consideration.
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 1-2, 5, 22, 29, 51, 71, 130, 135, and 137 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 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.
The claims encompass compounds of Formula I…“and/or prodrugs thereof,” thereby including all compounds that are converted into active drug after administration. While the specification defines a prodrug in functional terms (instant Specification, Pg. 11, Para 0037) and provides general examples of conventional promoieties (e.g., phenyl esters, aliphatic esters, acyloxymethyl esters, carbamates and amino acid esters – instant Specification, Pg. 78, Para 00282) and routine methods for their preparation (e.g., acylation of hydroxy or amino groups – instant Specification, Pg. 95, Para 00335), such disclosure is insufficient to enable the full scope of the claimed prodrugs without undue experimentation because the specification does not identify which modification of the claimed compounds will result in prodrugs that are capable of conversion to the active drug, nor does it provide guidance correlating structure with successful activation, stability, or bioavailability. Given the breadth of the claims and the unpredictability associated with prodrug design and in vivo conversion, one of ordinary skill in the art would not be able to make and use the full scope of the claimed “prodrugs thereof” without undue experimentation.
Claims 1-2, 5, 22, 29, 51, 71, 130, 135, and 137 are 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 certain embodiments within the scope of the claims, does not reasonably provide enablement for the full scope of Q embodiments. 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 election of species made for purposes of examination does not limit the scope of the claims, which continue to encompass the full breadth of the defined linker Q.
The instant claims are directed to compounds comprising a linker Q defined broadly as C1-4 alkylene, alkenylene, or C=N or N=C, optionally substituted and optionally interrupted by one or more heteromoieties. However, the specification predominantly exemplifies compounds having a fused 6,6 bicyclic ring system corresponding to a narrow subset of Q. In particular, 53 of the 57 exemplified species in Table 1 share the same isoquinolin-type bicyclic core, with only four examples representing alternative linker lengths or bonding types (e.g., C1 or C3 alkylene linkers or imine variants – instant Specification, Pg. 41-50, Table 1, as in instant Claim 71). The specification does not provide sufficient guidance to enable one of ordinary skill in the art to make and use compounds across the full scope of the claimed Q variations, particularly with respect to how changes in linker length, saturation, or heteroatom incorporation affect ring formation, stability, and functionality.
According, the specification does not enable the full scope of the claimed invention without undue experimentation.
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 71 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.
The claim is incomplete in itself because it incorporates subject matter from the specification (“…the compounds listed in Table 1”). Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). See MPEP §2173.05(s).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5, 22, 29, 51, and 130 are rejected under 35 U.S.C. 103 as being unpatentable over Augeri et al. (US 2012/0225857 A1, cited in IDS), hereinafter Augeri, in view of Ritchie and MacDonald (European Journal of Medicinal Chemistry 124 (2016) 1057-1068.)
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Augeri teaches l-(4-(5-amino-6-(l-oxo-l,2,3,4 tetrahydroisoquinolin-6-yl)pyrazin-2-yl)phenyl)cyclopentanecarbonitrile (‘857, Pg. 14, Para 0136) shown top right, which significantly overlaps the instantly claimed Formula I, (as in instant Claim 1) shown middle right, wherein X1 is CR1 and R1 is H, X2 and X3 are each independently CR2 and R2 is H, X4 is N, X5 is CH (as in instant Claim 22), Q is a C2 alkylene linker (as in instant Claim 5), Cy1 is phenyl (as in instant Claim 29), and Cy2 is a cyclopentane substituted with R12 which is CN.
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While the species above differs from instant Formula I as the Cy2 selection is a cycloalkyl, rather than the instant heterocylcoalkyl, Augeri further teaches the genus shown bottom right (‘857, Pg. 4, Para 0047), which broadly suggests R1 (the equivalent of instant Cy2) can be a 2-12 membered heterocarbyl, and exemplifies 4-tetrahydropyran (as in instant Claim 51) in the Cy2 position (‘857, Pg. 17, Para 0153).
Ritchie and MacDonald identify cyclopentane and tetrahydropyran rings, including both 2- and 4-tetrahydropyran, as alternative ring systems and teaches that cyclic ethers such as tetrahydropyran improve physicochemical and pharmacokinetic properties, with 2- tetrahydropyran in particular reducing protein binding without decreasing permeability (2016, Pg. 1066, Para 1 and Pg. 1067, Table 5).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to replace the cyclopentane or 4-tetrahydropyran substituent as taught by Augeri with a 2-tetrahydropan as a known alternative ring system to achieve the recognized benefits described in Ritchie and MacDonald.
Regarding Claim 130, Augeri teaches a formulation comprising a compound of claim 1 and a pharmaceutically acceptable excipients or diluent. (‘857, Pg. 37, Claim 22).
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 1-2, 5, 22, 29, 51, 71, 130, 135, and 137 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-2, 5, 19, 25, 27, 35, 41, 69, 71, 98, 106-107, 126, 132, 136, 138, and 141 of copending Application No. 18/288,222 in view of Patani and LaVoie (“Bioisosterism: A Rational Approach in Drug Design”, Chem. Rev. 1996, 96, 3147-3176).
The ’222 claims recite compounds having the same core scaffold as the instant claims, but require a halogen at position X4 or X5, whereas the instant claims encompass the corresponding unsubstituted position. Although the reference claims and the instant claims employ some differences in structural nomenclature, such differences do not result in a meaningful distinction in scope. For example, the reference formula does not explicitly recite Cy2 as a separate variable, but instead defines it as a substituent of Cy1, which nevertheless encompasses the same structural embodiments as the instant claims. This can be found in the Species list (Table 1 in both disclosures), where for example, the ’222 Compound I-1 differs from the instant Compound I-3 only wherein X5 is CF versus CH (see Examiner’s Comparison Table below).
It would have been prima facie obvious to one of ordinary skill in the art to replace the hydrogen with a fluorine because Patani and LaVoie teach that fluorine to hydrogen replacement represents routine, well-known bioisosteric variations. More specifically, the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained (Patani and LaVoie, Pg. 3149-3150, §II.A.1. and Fig. 1-3). Accordingly, the claimed compounds are not patentably distinct from the reference claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5, 22, 29, 51, 71, 130, 135, and 137 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-2, 5, 19, 26-27, 35, 98, 106, 121, 130, 132, 136, 138, and 141 of copending Application No. 18/288,213 in view of Patani and LaVoie (“Bioisosterism: A Rational Approach in Drug Design”, Chem. Rev. 1996, 96, 3147-3176) and St. Jean and Fotsch (“Mitigating Heterocycle Metabolism in Drug Discovery”, J. Med. Chem. 2012, 55, 6002−6020).
Although the reference claims and the instant claims employ different structural nomenclature, such differences do not result in a meaningful distinction in scope. The reference claims recite compounds having the same core scaffold as the instant claims but differ in that the instant positions X4 and X5 are defined as carbon atoms, substituted with hydrogen or halogen, as long as one of them is halogen, whereas the instant claims encompass embodiments in which one of these positions is nitrogen and the other is unsubstituted (CH). Accordingly, the difference between the claims are limited to (i) carbon-to-nitrogen substitution at one ring position and (ii) the presence or absence of a halogen substituent at the other position (see Examiner’s Comparison Table below).
These differences are considered to be obvious variations because such modifications represent routine and well-known strategies in medicinal chemistry. In particular, carbon-to-nitrogen substitution within ring systems is a common heteroatom modification used to modulate electronic properties, polarity, and binding interactions (St. Jean and Fotsch, Pg. 6011, Table 3), while halogen-to-hydrogen substitution (and vice versa) constitutes a well-established bioisosteric replacement used to explore target affinity while maintaining steric and lipophilic characteristics (Patani and LaVoie, Pg. 3149-3150, §II.A.1. and Fig. 1-3). Accordingly, it would have been obvious to modify the reference compounds to arrive at the instant compounds by such routine substitutions.
This is a provisional nonstatutory double patenting rejection.
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Instant Compound I-3
‘213 Compound I-42
‘222 Compound I-1
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Donna M. Nestor whose telephone number is (703)756-5316. The examiner can normally be reached generally (w/flex): 5:30a-5p EST M-Th.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney Klinkel can be reached at 571-270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.M.N./ Examiner, Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627
Prosecution Insights