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
Three information disclosure statements (IDS), two duplicates submitted on 1 May, 2026, and one submitted on 28 July, 2026, are acknowledged and have been considered.
Status of the Application
Receipt is acknowledged of Applicant's claimed invention, filed 28 July, 2026, in the matter of Application N° 18/288,219. Said documents have been entered on the record.
Claims 1, 5, 29, 71, 130, 135 and 137 are amended. Claims 143-144 are new. No new matter was introduced.
Thus, Claims 1-2, 5, 22, 29, 51, 71, 130, 135, 137 and 143-144 represent all claims currently under consideration.
Response to Amendment/Arguments
Applicant’s amendment is sufficient to overcome the rejection of claims under 35 U.S.C. 112(a).
Regarding the rejection under 35 U.S.C. 103 over Augeri in view of Ritchie and MacDonald, Applicant's arguments filed 28 July, 2026 have been fully considered but are not persuasive.
Applicant argues that the relied-upon cyclopentanecarbonitrile compound of Augeri would not have been selected as a lead compound because Augeri discloses a broad genus and numerous individual compounds, and because the relied-upon compound was not among certain compounds selected for additional study. Applicant further characterizes the rejection as a series of selections from Augeri, including selection of the relied-upon compound, a particular subgenus, a heterocarbyl substituent, and ultimately tetrahydropyranyl, which applicant contends could only have been accomplished using the present disclosure as a roadmap. See Remarks, Pg 20-23.
These arguments are not persuasive. The rejection does not reconstruct a hypothetical starting compound through multiple selections from Augeri’s generic disclosure. Rather, Augeri expressly prepares and discloses the relied-upon cyclopentanecarbonitrile compound as an individual species having substantial structural similarity to the presently claimed compounds. The fact that Augeri discloses numerous additional compounds, or selected other compounds for additional study, does not negate the express disclosure of the relied-upon compound or establish that one of ordinary skill in the art would have disregarded it. Accordingly, Applicant’s reliance on the lead-compound analyses of Takeda and Otsuka does not establish that the expressly exemplified Augeri compound could not properly serve as a starting point for the obviousness analysis.
Applicant’s multiple-selection and hindsight arguments also do not address the rejection as actually made, which is based upon the combined teachings of Augeri and Ritchie and MacDonald, rather than Augeri alone. Augeri provides the closely related exemplified cyclopentane compound and expressly teaches tetrahydropyran as a contemplated structural alternative (Augeri, Pg. 17, Para 0153-0157.) Ritchie and MacDonald, in turn, provide comparative medicinal-chemistry information concerning the very ring systems relevant to the proposed modification. Notably, Ritchie and MacDonald include both cyclopentane and tetrahydropyran ring systems in their comparative analysis. The authors report that cyclopentane and other cycloalkyl rings exhibit ADME profiles very similar to monosubstituted benzene and do not appear to provide improvements in ADME profiles, whereas cyclic ethers such as 4-tetrahydropyran are identified as having attractive profiles, and 2-tetrahydropyran is specifically reported to reduce protein binding without decreasing permeability. Ritchie and MacDonald further explain that difference among ring systems and regioisomers can be used by medicinal chemists to make informed choices regarding which rings and regioisomers to employ based upon their expected effects on ADME-related parameters (Ritchie and MacDonald, Pg. 1066-1067 and Table 5.)
Although Ritchie and MacDonald evaluate these ring systems in the context of replacements for mono-substituted benzene, the reference is not relied upon as demonstrating that the identical benzene-replacement transformation is being performed in Augeri. Rather, Augeri itself supplies the tetrahydropyran structural alternative, while Ritchie and MacDonald provide independent comparative evidence concerning the medicinal-chemistry characteristics of cyclopentane and particular tetrahydropyran regioisomers. Thus, the proposed modification is not derived by selecting unrelated features from Augeri using Applicant’s disclosure as a roadmap. Instead, the cited references provide an articulated reason to investigate and select the tetrahydropyran alternatives already contemplated by Augeri in place of the cyclopentane ring of the relied-upon compound.
Prior-art references must be considered for their combined teachings, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant further argues that Ritchie and MacDonald is a general matched molecular pair analysis that does not provide target-specific medicinal-chemistry guidance or evaluate biological activity and that Augeri concerns MST1 inhibitors whereas the presently claimed compounds inhibit HPK1. Applicant therefore contends that the cited art would not have provided a reasonable expectation that the proposed modification would retain biological activity or produce an HPK1 inhibitor. See Remarks Pg 24-26.
These arguments likewise do not overcome the rejection. Ritchie and MacDonald is not relied upon as teaching MST-1 or HPK1 inhibition, nor as demonstrating the biological activity of the presently claimed compounds. Rather, it is relied upon for its comparative teachings concerning the recognized ADME characteristics of the relevant ring systems. Indeed, the reference expressly acknowledges that the effect of ring replacement may vary with ring identity and regiochemistry and uses the observed differences to provide medicinal chemists with guidance in selecting among ring systems and regioisomers. Thus, the variability identified in Ritchie and MacDonald does not teach away from consideration of tetrahydropyran; rather, the reference specifically identifies characteristics favoring its embodiments over cyclopentane for particular ADME-related considerations.
Further, the reason for modifying a prior-art compound need not be the same reason or advantage contemplated by Applicant. See MPEP §2144. Augeri itself identifies desirable pharmacokinetic properties as relevant considerations for its compounds. Accordingly, the absence of target-specific MST1 or HPK1 biological data in Ritchie and MacDonald does not negate the teaching for which that reference is relied upon. Taken together, Augeri’s express teaching of cyclopentane and tetrahydropyran as structural alternatives and Ritchie and MacDonald’s comparative teachings regarding cyclopentane and tetrahydropyran provide an articulated, prior-art based reason for making the proposed structural modification. The fact that the prior art did not additionally predict the particular HPK1 activity or HPK1/Lck selectivity subsequently asserted by Applicant does not, by itself, negate that motivation. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant additionally asserts that the presently claimed compounds exhibit advantageous selectivity for HPK1 over Lck, relying upon the results reported in Tables 3 and 4. See Remarks, Pg. 24. These results have been considered but are insufficient on the present record to outweigh the evidence supporting obviousness. To establish unexpected results, Applicant bears the burden of establishing that the asserted results are in fact unexpected and significant. See MPEP §716.02(b). Further, evidence of unexpected results should provide an appropriate comparison with the closest prior art, and objective evidence relied upon to establish nonobviousness must be reasonably commensurate in scope with the claims. See MPEP §§ 716.02(d) and 716.02(e).
Here, Applicant identifies HPK1 activity and reduced Lck activity for particular compounds but has not provided comparative evidence establishing that the asserted HPK1/Lck selectivity is unexpected relative to the closest prior-art compound or otherwise demonstrated that the asserted selectivity results unexpectedly from the structural modification relied upon for patentability. Nor has Applicant established that the results reported for the particular tested compounds are reasonably commensurate with the scope of the claimed genus. Accordingly, while the asserted advantageous properties have been considered, Applicant has not established unexpected results sufficient to outweigh the evidence supporting the prima facie case of obviousness. See MPEP §716.02(c).
Applicant’s arguments and evidence do not overcome the prima facie case of obviousness, and the rejection under 35 U.S.C. 103 is maintained and updated based on amendment.
Regarding the nonstatutory double patenting rejection, Applicant requests that consideration of the rejection be held in abeyance until the scope of the allowable subject matter is determined. See Remarks, Pg 27. Applicant’s request is acknowledged. However, as the presently rejected claims remain pending and no allowable subject matter has yet been identified, the nonstatutory double patenting rejection is maintained and updated based on amendment.
Claim Rejections - 35 USC § 103 (MAINTAINED)
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.
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Claims 1, 5, 22, 29, 51, 130 and 144 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). Additionally, Z can be N or CR1, which allows for the instantly equivalent CY1 to be aryl or heteroaryl (as in instant Claims 1, 29 and 144).
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 (MAINTAINED)
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, 137 and 143-144 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, 137 and 143-144 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 is 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
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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