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
Claims 1-28 and 30 are pending in this application.
Claim Objections
Claims 9-11 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Examiner Notes
While claims 15 and 17 are free of the prior art, they stand rejected over a provisional non-statutory double patenting rejection.
Claim Rejections - 35 USC § 103
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.
Claims 1-8, 12-14, 16, 18-22, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Ali et al. (WO 2014/101120 A1 – previously cited) (“Ali”); in view of Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591 – previously cited) (“Meanwell”).
Regarding claims 1-8, 12-14, 16, 18-21, and 30, Ali discloses their compounds of Formula GII below as A2A inhibitors [0014] – which is the same intended use as the instant invention. Ali’s compounds render the instant claims obvious when: RGaa, Gba, Gca are H, C1-6 alkyl, alkoxy, F, Cl, etc.; GGf (corresponding to instant Y) can be -CH2-, ethyl, or -C(O)CH2; and RGe (corresponding to instant R5) can be polycyclic aryl/ heteroaryl.
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Ali specifically discloses the compounds below (pages 41-42 and 46), which read on the instant compounds in view of Meanwell when instant Y is alkyl, wherein a -CH2- has been replaced with
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and R5 is alkyl (ethyl, isopropyl, or cyclopropyl).
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(Ex. 13)
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(Ex. 8)
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(Ex. 40)
Ali also discloses the compound 9 below (page 38), which reads on the instant compounds, in view of Meanwell, when R5 is -SO2-alkyl.
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While Ali doesn’t specifically teach their compounds wherein the group corresponding to instant Y has a carbonyl next to the nitrogen bound to the alkyl chain in Ex. 8, 13, or 40; or an -NH- group in place of a -CH2- in the alkyl chain corresponding to Y in 9; the teachings of Meanwell are relied upon to leverage these differences.
Meanwell teaches that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates (abstract). Meanwell discloses introduction of a carbonyl next to the cyclic amine in compound 233 to make 235, results in a new H-bond acceptor, which significantly impacts the polarity and potentially potency of a compound (page 2554, col. 2, top half). Thus, Meanwell suggests that introduction of a carbonyl moiety in a cyclic amine is a known and common transformation in the context of bioisosteric modifications of drugs and lead compounds. Meanwell also teaches H and F are classical monovalent bioisosteres and that -CH2-, -O-, and -NH- are classical divalent bioisosteres (Table 1, page 2530, col. 1). Furthermore, Meanwell teaches that cyclopropyl has been examined as an isostere of alkyl groups based on their size similarity and improved metabolic stability (page 2539, col. 2, section 3.2.13).
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Therefore, regarding claims 1-8, 12-14, 16, 18-21, and 30, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by Ali’s disclosed formula GII and compounds 8-9 and 13 above, in view of Meanwell; In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). See MPEP 2144.08. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of A2A inhibitor compounds disclosed by Ali; in view of Meanwell’s teaching that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa – potentially playing key contributing roles in molecular recognition and mimicry and that introduction of a carbonyl to make a lactam from a cyclic amine, impacts the H-bond accepting properties and polarity of a compound, which may be beneficial in the context of lead and drug optimization; further because of Meanwell’s teaching that -CH2-, -O-, and -NH- are divalent bioisosteres. Accordingly, one having ordinary skill in the art would have been motivated to prepare any of the compounds embraced by the disclosed generic formula, by introducing a carbonyl by the cyclic amine moiety of Ali’s heterocycles 8 and 13; or swap a -O- for -NH- in 9 to arrive at the claimed invention.
Further regarding instant claim 21, the compound below, for example, is particularly obvious in light of the disclosures above:
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Regarding the F in the position corresponding to instant R1, Ali teaches their RGca group can be F, and Meanwell also teaches that H and F are bioisosteres. Therefore, the compound is obvious in view of Ali’s disclosure and in view of Ali’s preferred embodiment 8 in view of Meanwell’s teachings.
Further regarding claims 8 and 13-14, Ali discloses compound 9, which reads on the instant compounds when R5 is -SO2-alkyl and Y is alkyl, wherein a -CH2- is replaced with -NR8-, wherein R8 is H (such as
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or
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). Therefore, it would have been obvious to one of ordinary skill to replace a -O- in 9 with -NH- to arrive at the instant claims in view of Meanwell’s teachings. Applicant is advised that compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Further regarding claim 13, wherein Y is a branched alkyl group, Applicant is advised that H vs. Me is considered an obvious modification in the absence of superior, unexpected results. See MPEP 2144.09. Thus, Ali’s compounds, wherein the group corresponding to instant Y is a straight ethylene chain, read on the instant compounds when one of the H is replaced by a Me to produce a branched alkyl chain.
Further regarding claim 16, Ali discloses the compound 40 above, wherein their group corresponding to instant R5 is a cyclopropyl.
Further regarding claim 19, Ali discloses compound 13 above, wherein their group corresponding to instant R5 is an ethyl.
Further regarding claim 20, Ali discloses their compound 9 above, and Meanwell further teaches that cyclopropyl has been examined as an isostere of alkyl groups based on their size similarity and improved metabolic stability (page 2539, col. 2, section 3.2.13); furthermore, Ali’s compound 40 shows a cyclopropyl in the position corresponding to instant R5.
Therefore, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by Ali’s disclosed compounds in view of Meanwell. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of compounds disclosed by Ali in view of Meanwell. Accordingly, one having ordinary skill in the art would have been motivated to substitute the methyl in the -SO2-Me of compound 9 for a cyclopropyl to arrive at the instant claims.
Regarding claim 22, Ali discloses pharmaceutical compositions comprising their compounds and acceptable excipients (reading on carrier) ([0085] and [0102]).
Claims 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over Ali et al. (WO 2014/101120 A1) (“Ali”); in view of Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591) (“Meanwell”); as applied to claims 1-8, 12-14, 16, 18-22, and 30; further in view of Sek et al. (Int. J. Mol. Sci. 2018, 19, 3837, 23 pages) (“Sek”).
The teachings of Ali and Meanwell are disclosed above and incorporated herein.
Ali teaches their compounds are A2A- receptor agonists (abstract).
While Ali in view of Meanwell does not teach: (i) treatment of cancers, like head and neck squamous cell carcinoma (HNSCC), breast cancer, and melanoma (claims 23-24); (ii) or administration with another agent, like a PD-1 antagonist, such as pembrolizumab (claims 25-28); the teachings of Sek are relied upon for these disclosures.
Sek teaches that therapeutic agents have been developed to target downstream adenosine receptors (A1R, A2AR, A2BR, A3R) to enhance anti-tumor immune responses (abstract) and that the A2AR is overexpressed in some cancers, such as head and neck squamous cell carcinoma (HNSCC), and in several breast and melanoma cell lines (page 5, last para.). Sek specifically teaches that inhibition of A2AR in combination with anti-PD-1, has been shown to elicit enhanced anti-tumor T cell responses (page 9, para. 1, 13-20). Sek also teaches pembrolizumab as a PD-1 inhibitor being administered in combination with an A2A inhibitor for treating solid cancers (table 1, page 10, 3rd from last row).
Therefore, regarding claims 23-28, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Ali’s A2A receptor inhibitors alone or in combination with a known PD-1 inhibitor, such as pembrolizumab, in view of Sek. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Ali in view of Meanwell’s disclose their compounds and pharmaceutical compositions thereof as A2AR inhibitors. Further because Sek teaches A2AR is overexpressed in some cancers, such as head and neck squamous cell carcinoma (HNSCC), breast cancer, and melanoma; that targeting adenosine receptors enhances anti-tumor immune responses; and that inhibition of A2AR in combination with anti-PD-1, such as pembrolizumab, has been shown to elicit enhanced anti-tumor T cell responses.
Applicant is advised that similar properties may normally be presumed when compounds are very close in structure. Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985) (“When chemical compounds have very close structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious. Dillon, 919 F.2d at 697-98, 16 USPQ2d at 1905; In re Wilder, 563 F.2d 457, 461, 195 USPQ 426, 430 (CCPA 1977); In re Linter, 458 F.2d 1013, 1016, 173 USPQ 560, 562 (CCPA 1972) (see MPEP 2144.08(d)).
Furthermore, with respect to a mixture of the two claimed reagents, the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” See MPEP2144.06. It is therefore obvious to provide a mixture of the two agents.
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 1-8, 12-28, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-9 and 16-22 of copending Application No. 18/015,364 (Copending ‘364); in view of Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591) (“Meanwell”)
Regarding instant claims 1-8, 12-21, and 30, Copending ‘364 claims the compounds of Formula I below and pharmaceutical compositions thereof, which read on the instant compounds when Y C1-5 alkyl, wherein a -CH2- is substituted for -O-, -S-, or -SO2- and R5 is halogen, aryl, alkyl, etc.(reading on instant Y being straight or branched alkyl wherein a -CH2 – group has been replaced by -NH-).
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Regarding instant claims 22-28, Copending ‘364 claims a method of treating cancer (Copending ‘364 claims 17-19) comprising administration of their compounds of Formula I. Copending ‘364 also speaks to coadministration of an additional therapeutic agent that is a PD-1 antagonist, such as pembrolizumab (Copending ‘364 claims 20-22).
Applicant is reminded, similar properties may normally be presumed when compounds are very close in structure. (“When chemical compounds have very close’ structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious.
While Copending ‘364 doesn’t specifically teach their compounds wherein Z (corresponding to instant Y-R5 wherein Y is alkyl with a -CH2- replaced by -NH-; the teachings of Meanwell are relied upon to leverage these differences.
Meanwell teaches that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates (abstract). Meanwell also teaches H and F are classical monovalent bioisosteres and that -CH2-, -O-, -S-, and -NH- are classical divalent bioisosteres (Table 1, page 2530, col. 1).
Therefore, regarding claims 1-8, 12-19, 21, and 30, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by Copending ‘364’s disclosed compounds of Formula I above, in view of Meanwell. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of A2A inhibitor compounds disclosed by Copending ‘364, in view of Meanwell’s teaching that -CH2-, -O-, -S-, and -NH2- are bioisosteres. Accordingly, one having ordinary skill in the art would have been motivated to prepare any of the compounds embraced by the disclosed generic formula, by replacing a -O-, -S-, or -CH2- in the group corresponding to instant Y in Copending ‘364’s compounds with a -NH- to arrive at the claimed invention.
Applicant is reminded that compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.
Furthermore, Applicant is reminded that a novel useful compound that is isomeric with the prior art compound is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compound. Therefore, it would have been obvious to one of ordinary skill to expect similar properties of structurally similar compounds since they are suggestive of one another. It has been held that a compound, which is structurally isomeric with a compound of the prior art, is prima facie obvious absent unexpected results.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Claims
Claim amendments are acknowledged and have been entered. No new matter has been introduced.
Claim Rejections - 35 USC § 112(b)
Applicant’s arguments, see pages 29, filed 05/20/2026, with respect to 35 USC § 112(b) rejections have been fully considered and are persuasive. The 35 USC § 112(b) rejections of the claims has been withdrawn.
Claim Rejections - 35 USC § 112(d)
Applicant’s arguments, see pages 29-30, filed 05/20/2026, with respect to 35 USC § 112(d) rejections have been fully considered and are persuasive. The 35 USC § 112(d) rejections of the claims has been withdrawn.
Claim Rejections - 35 USC § 102
In view of claim amendments, 35 USC § 102 rejections over Ali have been withdrawn. Applicant’s arguments regarding 35 USC § 102 rejections over Zheng have been considered and are persuasive. The 35 USC § 102 rejections over Zheng have been withdrawn.
Claim Rejections - 35 USC § 103
Applicant’s arguments regarding 35 USC § 103 rejections over Zheng have been considered and are persuasive. The 35 USC § 103 rejections over Zheng have been withdrawn.
Applicant’s arguments regarding the 35 USC § 103 rejections over Ali in view of Meanwell, however, are not persuasive. These rejections are maintained in this final rejection.
As an initial note, Applicant is advised that MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)).
Applicant asserts that Examiner’s statements regarding the instant compounds being embraced by Ali’s disclosure is incorrect. This is not persuasive – the statement of rejection was clearly made over Ali in view of Meanwell. The instant compounds, as stated in this final rejection, are embraced by Ali in view of Meanwell.
Applicant argues the Examiner failed to provide a reason to select any of Examples 8, 13, 40, and 120, or intermediate 9 from Ali as lead compounds or starting points among the “237 disclosed compounds”, stating that the election of a lead must be supported by data and clear motivation, without using hindsight reasoning. Applicant asserts the Examiner has not provided any evidence that a POSA would have reasonably expected the proposed changes to impact the activity of the A2a and A2b inhibitors, and that neither Ali nor Meanwell provides this motivation. Applicant states that Meanwell doesn’t teach replacing -CH2- with -NH- would maintain activity of compound, and as such impermissible hindsight was used to make this determination. Applicant asserts the Examiner failed to provide any rationale as to why the teachings of Meanwell would augment, rather than diminish the activity of Ali’s compounds.
Regarding claim 21, Applicant argues Examiner failed to provide a reason to elect examples 8 and 13 as lead compounds, and further states that insufficient motivation is provided for a H for F replacement or for addition of the carbonyl moiety.
Regarding claims 8 and 13-14, Applicant argues no motivation was provided for electing compound 120 as a lead compound. Applicant argues that swapping C and N from a chain to a ring does not constitute positional isomers because it allegedly changes the carbon skeleton.
Regarding claim 16, Applicant argues no motivation was provided for electing compound 40 and that no prima facie case of obviousness was made, since addition of a carbonyl makes the compounds not-isomeric.
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).
In response to applicant's arguments against the references individually, 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 arguments that Examiner failed to provide motivation for electing Examples 8, 13, 40, and 120, or intermediate 9 from Ali; it is clearly stated on the record that Examples 8, 13, 40, and 120 are disclosed by Ali as A2A inhibitors, therefore, one of ordinary skill would have been motivated to elect any of the compounds in Ali’s disclosure, including Examples 8, 13, 40, and 120. Regarding intermediate 9, Ali discloses this compound as an intermediate toward the synthesis of their A2A inhibitors, therefore, one of ordinary skill would have been motivated to elect this compound to use toward the synthesis of Ali’s A2A inhibitors, and Ali’s A2A inhibitors in view of Meanwell. Thus, Applicant’s arguments are not persuasive and fail to overcome the obviousness rejection of record.
In response to Applicant’s arguments that the proposed changes to Ali’s compounds in view of Meanwell may diminish the activity of Ali’s compounds, and that therefore Examiner failed to provide motivation and a reasonable expectation of success, Applicant is advised that MPEP 2143.02(I) makes clear that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). Thus, Ali discloses their compounds as A2A inhibitors, Meanwell teaches bioisosteric modifications are routine in the field of medicinal chemistry and provides guidance on common modifications, some of which are outlined herein. Therefore, one of ordinary skill would have been motivated to modify Ali’s compounds, in view of Meanwell, with a reasonable expectation of success in achieving improved results.
Regarding claim 21, clear motivation was provided on the record that would lead one of ordinary skill to modify Ali’s compound by replacing H for F and introducing a carbonyl; namely: (i) “Meanwell teaches that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry”; (ii) “H and F are classical monovalent bioisosteres and that -CH2- and -NH- are classical divalent bioisosteres (Table 1, page 2530, col. 1)”; and (iii) “Meanwell discloses introduction of a carbonyl next to the cyclic amine in compound 233 to make 235, results in a new H-bond acceptor, which significantly impacts the polarity and potentially potency of a compound (page 2554, col. 2, top half). Thus, Meanwell suggests that introduction of a carbonyl moiety in a cyclic amine is a known and common transformation in the context of bioisosteric modifications of drugs and lead compounds.” Since Ali discloses their compounds as A2A inhibitors, one of ordinary skill would have been motivated to perform any of the bioisosteric modifications outlined by Meanwell with a reasonable expectation of success.
Regarding claims 8 and 13-14, Applicant is advised that Examiner never explicitly said specified that swapping the N for C would result in “position isomers” as purported by Applicant. The Examiner advised applicant of the following: “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).” In the present case, Examiner intended that the compounds in question are homologs, resulting from the successive addition of a -CH2- group and swapping the N of the ring for C, to arrive at the instant compounds in view of Meanwell. Nevertheless, Examiner has streamlined arguments of the rejection for clarity of the record. Applicant is advised that “[A] prior art reference must be considered in its entirety, i.e., as a whole” W.L. Gore& Associates, Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983) (see MPEP 2141.02 VI). Thus, while the rejections listed above present a modified interpretation of the teachings of the previously cited prior solely for the purpose of clarity, the claims remain rejected over the prior art of record.
With regards to claim 16, as outlined herein, Ali discloses the compound 40 above, corresponding to instant R5 being cyclopropyl. Ali also discloses compound 8, with an isopropyl in the position corresponding to instant R5. Therefore, it would have been obvious to swap the isopropyl of 8 with cyclopropyl to arrive at the instant compounds, in view of Meanwell, as outlined above. Applicant is advised the courts have stated that “[A] prior art reference must be considered in its entirety, i.e., as a whole” W.L. Gore& Associates, Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983) (see MPEP 2141.02 VI). Thus, while the rejections listed above present a modified interpretation of the teachings of the previously cited prior art solely for the purpose of clarity, the claims remain rejected over the prior art of record.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Ali discloses their compounds of Formula GII below as A2A inhibitors [0014] – which is the same intended use as the instant invention. Ali’s compounds render the instant claims obvious when: RGaa, Gba, Gca are H, C1-6 alkyl, alkoxy, F, Cl, etc.; GGf (corresponding to instant Y) can be -CH2-, ethyl, or -C(O)CH2; and RGe (corresponding to instant R5) can be polycyclic aryl/ heteroaryl.
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Ali specifically discloses the compounds below (pages 41-42 and 46), which read on the instant compounds in view of Meanwell when instant Y is alkyl, wherein a -CH2- has been replaced with
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and R5 is alkyl (ethyl, isopropyl, or cyclopropyl).
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(Ex. 13)
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(Ex. 8)
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(Ex. 40)
Ali also discloses the compound 9 below (page 38), which reads on the instant compounds, in view of Meanwell, when R5 is -SO2-alkyl.
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Meanwell teaches that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates (abstract). Meanwell discloses introduction of a carbonyl next to the cyclic amine in compound 233 to make 235, results in a new H-bond acceptor, which significantly impacts the polarity and potentially potency of a compound (page 2554, col. 2, top half). Thus, Meanwell suggests that introduction of a carbonyl moiety in a cyclic amine is a known and common transformation in the context of bioisosteric modifications of drugs and lead compounds. Meanwell also teaches H and F are classical monovalent bioisosteres and that -CH2-, -O- and -NH- are classical divalent bioisosteres (Table 1, page 2530, col. 1). Furthermore, Meanwell teaches that cyclopropyl has been examined as an isostere of alkyl groups based on their size similarity and improved metabolic stability (page 2539, col. 2, section 3.2.13).
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Therefore, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by Ali’s disclosed formula GII and compounds 8-9 and 13 above, in view of Meanwell. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of A2A inhibitor compounds disclosed by Ali, in view of Meanwell’s teaching that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry and that introduction of a carbonyl to make a lactam from a cyclic amine, impacts the H-bond accepting properties and polarity of a compound, which may be beneficial in the context of lead and drug optimization; further because of Meanwell’s teaching that -CH2- and -NH- are divalent bioisosteres. Accordingly, one having ordinary skill in the art would have been motivated to prepare any of the compounds embraced by the disclosed generic formula, by introducing a carbonyl by the cyclic amine moiety of Ali’s heterocycles 8 and 13; or swap a -O- for -NH- in 9 to arrive at the claimed invention.
Double Patenting
Applicant’s arguments, see pages 38-40, filed 05/20/2026, with respect to obviousness type double patenting rejections over U.S. Patent No. 10,011,615 B2 (US ‘615); 10,688,082 B2 (US ‘082); 11,498,923 B2 (US ‘923) have been fully considered and are persuasive. The obviousness type double patenting rejections over U.S. Patent No. 10,011,615 B2 (US ‘615); 10,688,082 B2 (US ‘082); 11,498,923 B2 (US ‘923) have been withdrawn.
However, as it pertains to copending Application No. 18/015,364 (Copending ‘364); Applicant traverses the rejection but fails to specifically point out the deficiencies of the rejection. As such, the provisional non-statutory double patenting rejection over Copending ‘364 is maintained for the reasons outlined in this office action.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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