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 is a 371 National Stage Entry of PCT/US2022/048745, filed on November 2, 2022, and claims benefit to domestic Provisional Application No. 63/275,378 filed on November 3, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 22, 2024 is acknowledged and has been considered.
Status of the Claims
Acknowledgement is made of the claims in the filed Application 18/705,175; Claims 1, 4, 5, 6, 7, 8, 9 10, 11, 14, 16 and 18 are amended; Claims 12 and 17 are original and claims 9, 20, 21, 22, 23, 24, 25, 26 and 27 are new. No new matter was introduced.
Thus, claims 1, 4-12, 14, and 16-27 represent all the claims currently under consideration.
Specification
The disclosure is objected to because of the following informalities:
The description of FiG.4A and FIG.4B are interchanged in the specification. It currently reads as, TNFα (FIG.4A), IFNγ (FIG.4B) ([0020]); However the figures it references to in the drawings, (page 7/8), display Fig.4A as IFNγ and FIG.4B as TNFα.
Appropriate correction is required.
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.
Claims 1, 5, 7, 8, 9, 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Ferguson D., 2017, (US 2017/0217960 A1, Published on August 3, 2017; cited in the IDS), hereon after, Ferguson.
Regarding claim 1, Ferguson 2017, teaches the genus, compounds of formula I, displayed in the table below, ([007-0033]) that encompasses the sub-genus in the instant claim 1, as discussed below.
Ferguson, 2017
Instant Application
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Ferguson’s reference displays a generic, NRaRb at the similar position where the instant claim has an amino group, NH2; Ferguson reveals that both Ra and Rb can be H, thus making NH2, as in the instant claim 1;
For substitution at R1 in the instant claim 1, Ferguson teaches substitution at the similar position (R2 in Ferguson’s reference) can be (C1-C6)alkyl wherein (C1-C6)alkyl is optionally substituted with (C3-C6)cycloalkyl and further provides this definition; specifically, (C1-C6)alkyl includes, methyl, isopropyl, butyl, iso-butyl, sec-butyl, and (C3-C6)cycloalkyl(C1-C6)alkyl includes cyclopropylmethyl, among others ([0107]).
For substitutions at R2 in the instant claim 1, Ferguson discloses functional groups at the similar position (R3 in Ferguson’s reference) that overlap with the instant application’s R2, as displayed in the table above. ([0010, 0044-0061]).
For substitutions at R4 in the instant claim 1, Ferguson’s teaches the genus compound where the substitution (R1 in Ferguson’s reference), can be at any of the four positions in the quinoline ring, 6, 7, 8 or 9. However, the reference discloses examples of compounds substituted at position 7 on the quinoline ring, which is the position labeled R4 in the instant application. (Examples 539 to 576, claims 19 and 21).
Regarding claim 5 which defines instant application’s R4 as -C(=O)(O-(C1-C4)alkyl; Ferguson shows examples in his reference that are substituted with an alkoxycarbonyl at C-7 of the quinoline ring as claimed in the instant application ([0151], Examples 549-576).
Concerning claims 7, 8, 9, 10 and 11; Ferguson informs artisans that Toll-Like receptors (TLR) sense infection by recognizing pathogen associated molecular patterns and triggering inflammation and therefore TLR ligands have been developed as vaccine adjuvants ([0003]). Ferguson further discloses the compounds in his reference are modifications of (i) imiquimod an FDA-approved immune response modifier ([0004]) that exerts its immunostimulatory effects through TLR expressed on plasmacytoid dendritic cells and B cells in humans and (ii) resiquimod, a potent dual TLR-7 and TLR-8 ligand ([0005]). He further informs artisans imiquimod (an exclusive TLR7) ligand and resiquimod (dual TLR 7/8) ligand prime limited immunity hence the compounds in the reference are targeted at triggering multiple receptors that shift the cytokine profile to a more desirable one ([0006]).
Regarding claims 7, Ferguson teaches on pharmaceutical compositions of a compound of formula I, and a pharmaceutically acceptable diluent or carrier ([0095], and claim 23).
Regarding claim 8, Ferguson teaches that some compounds in his disclosure are selective for TLR-7 over other toll-like receptors, such as, TLR-8 ([0102]), and that certain compounds may selectively activate TLR7 or TLR8 or alternate receptors (such as the inflammasome) in triggering the production of specific cytokines ([0103]).
Regarding claim 9, Ferguson teaches his invention provides a method for treating a pathological condition (e.g. a viral infection, a bacterial infection or cancer) by administering a compound of formula I or a pharmaceutically acceptable salt ([0096], [0098], [0100] and claim 24).
Regarding claim 10, Ferguson reveals his invention provides a method for stimulating an immune response, comprising of administering a compound of formula I, or a pharmaceutically acceptable salt ([0097] and claim 25).
Regarding claim 11, Ferguson teaches a method of treating a cancer and further reveals the imquidazolequinoline-based compounds in his disclosure trigger more desirable ratio of pro- to anti-inflammatory cytokines ([0007], 0096-0100] and claim 26).
While Ferguson’s teaches the genus of the compound of formula I, that encompasses the sub-genus in the instant application, examples in his reference only have the n-butyl group
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, substituted at the position labeled R1 in the instant application (R2 in Ferguson’s reference). Ferguson does not exemplify any compounds that are substituted at the R1 position as claimed in the instant application wherein
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.
However, Ferguson expressly teaches in his reference that it is possible to substitute the instant R1 position, (R2 in Ferguson’s reference), with isobutyl or cyclopropylmethyl ([0107]). In addition, Ferguson discloses examples of compounds with an n-butyl group, as shown in compound 558, among others.
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Per the MPEP § 2144.08 (c), in establishing prima facie case of obviousness, the closer the physical and /or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in prior art, the greater the expectation the claimed subject matter will function in an equivalent manner to the genus. Ferguson exemplifies compounds with overlapping substituents at instant R2 and R4 positions as with the instant application. In addition, his reference exemplifies compounds with a straight chain four-carbon substituent (n-butyl) at the instant R1 position. The instant application claims substituents with 4 carbons at the same position, one branched (isobutyl) and the other with a cyclic substituent (cyclopropylmethyl).
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to take teachings of Ferguson and modify the substituent at the instant R1, to arrive at the instant application with a compound of formula I, where the instant R1 is substituted with 4-membered carbon branched or with a cyclic substituent; wherein R1 is
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; with R2 and R4 substituted with overlapping chemical species, as taught by Ferguson (instant claim 1), and wherein R4 is an alkoxycarbonyl at C-7 of the quinoline ring as exemplified in Fergusons reference (instant claim 5); a pharmaceutical composition of the compound, and a pharmaceutically acceptable diluent or carrier (instant claim 7), and a method of modulating a TLR-7 or TLR-8 receptor with the compound, a method of treating a pathological condition, stimulating an immune response in a subject by administering to the subject the compound and a method of treating a disease or a condition selected from cancer, autoimmune and inflammatory disease or condition (instant claims 8, 9, 10 and 11), with reasonable expectation of success.
One of ordinary skill in the art would be motivated because as disclosed by Ferguson, imquidazolequinoline-based compounds like those in his disclosure trigger more desirable ratio of pro- to anti-inflammatory cytokines; secondly, Ferguson has taught compounds substituted with n-butyl - a straight chain four membered carbon group - at the instant R1 position, thus one would be motivated make other substituents bearing four carbons. Additionally, prior art teaches structurally similar molecules that target TLR7 and TL8 and used as treatment of cancer, autoimmune and inflammatory diseases or conditions.
Claims 1, 4, 5, 6, 7, 8, 9, 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Ferguson D., 2017, (US 2017/0217960 A1, Published on August 3, 2017; cited in the IDS), hereon after, Ferguson, in view Larson et al., 2017, (Larson et al., Design and Synthesis of N1-Modified Imidazoquinoline Agonist for Selective Activation of Toll-Like Receptors 7 and 8. ACS Med. Chem. Lett., 2017, 8, 1148-1152, Published October 16, 2017), hereon after Larson.
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Regarding claims 1, 5, 7, 8, 9, 10 and 11, the teachings of Ferguson as set forth above are incorporated herein.
Regarding claim 4 in the instant application, that limits the substitution at Applicant’s instant R2 to -CH2-(OH)Me or CH2(p-Phe)-CH2NH2; Ferguson teaches instant R2 (R3 in the reference) can be (C1-C6)alkyl that is substituted with an aryl, further substituted with (C1-C6)alkyl which is substituted with NRuRv where each Ru and Rv is independently H ([0010], [0015], [0037]. Additionally, Fergusons discloses compound 558, with CH2(p-Phe)-CH2NH2 as an example (Example 558).
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Regarding claim 6, Ferguson exemplifies compound 558 above which differs from the instant claim 6 – compounds 3 and 4, only at the n-butyl substituent, with the instant claim substituted with isobutyl (claim 6, compound 3) and cyclopropylmethyl (claim 6, compound 4).
How Prior art differs from the instant claims; While Ferguson teaches the genus where the instant R2 position can be (C1-C6)alkyl that is substituted with an OH group [[0010], [0012] and [0040]); He fails to distinctly teach an examples with the 2-hydroxypropyl substituent as in the instant application, where R2 is -CH2-(OH)Me (instant claim 4) and compounds 1 and 2 (instant claim 6).
Larson et al. teaches compound 12b, shown below, substituted with 2-hydroxyl propyl, at the instant R2 position as in the instant claim 4, wherein R2 is optionally -CH2-CH(OH)Me and as in the instant claim 6 compounds 1 and 2. Larson also reveals compounds with a 2-hydroxyl propyl substituent have selectivity for both TLR7 and TLR8 (Abstract). Larson discusses findings on structural activity relationships (SAR) that inform artisans that the presence of an alkyl hydroxy group at N1 position (instant R2 position) enhanced TLR8 activation; and that a terminal amino group of a N1-p-aminomethylbenzyl substituted imidazoquinoline, similar to substituent in instant claim 6 compounds 3 and 4, extends to into a pocket within the TLR8 ectodomain and formed favorable hydrogen bonding interactions with carbonyl group of glycine 351. (page 1150).
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Larsons teaches that SAR studies of the imidazoquinolines found activation of both TLR7 and TLR8 increases with alkyl chain length at the instant R1 position, and peaks with a butyl at TLR7 and a pentyl at TLR8 (page 1149).
Thus, it would have been obvious to one of ordinary skill in the art to modify and combine the teachings of Ferguson and Larson before the effective filing date of the claimed invention to arrive at the instantly claimed invention with reasonable expectation of success. Ferguson teaches compound 558 as shown above and Larson teaches compound 12b; Similarly, the instant invention claims, a compound wherein the instant R2 is optionally substituted with -CH2-(OH)Me (i.e., 2-hydroxyl propyl) or CH2(p-Phe)-CH2NH2 (i.e., N1-p-aminomethylbenzyl substituted imidazoquinoline), (instant claim 4); and where the compound of formula I is selected from the group consisting of compounds 1-4 as recited in the instant claim 6; where the instant R1 is iso-butyl group (compounds 1 and 3) or a cyclopropylmethyl group (compounds 3 and 4). The instant invention is modified at instant R1 position, whereas both Ferguson and Larson have n-butyl group, the instant application has isobutyl or cyclopropylmethyl group. As discussed in the rejection above, n-butyl has four carbons and similarly, both the isobutyl and cyclopropylmethyl groups have four carbons each which makes them isomers.
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. In re Norris, 179 F.2d. 970, 84 USPQ 458 (CCPA 1970). 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. In re Finely, 81 USPQ 383 (CCPA 1949); 84 USPQ 458 (CCPA 1950), see MPEP § 2144.09.
Claims 1, 7, 8, 9, 10, 11, 12, 14, 16-27 are rejected under 35 U.S.C. 103 as being unpatentable over Glick et al. 2019, (Glick et al., US 2019/0127368 A1, “NLRP3 Modulators”, Published on May 2, 2019) hereon after, Glick.
Glick teaches a broad genus of compounds of formula I, shown below, and discloses several examples including compound 101 ([0019] and Table 1);
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Regarding claim 1; Glick recites a compound with the structure of formula I that overlaps with the subgenus in the instant application at the instant application R2 and R4 positions (i.e., R1 and R3 respectively, in Glick’s reference). For substitution at the instant R1 position (R2 in Glick’s reference), Glick teaches can be unsubstituted, unbranched C1-6 alkyl; Glick further discloses example compound 101, among others with n-butyl substituted at the instant R1 position.
Glick does not teach or exemplify a compound substituted at the instant R1 position with isobutyl or cyclopropylmethyl group as in the instant claims.
However,
Glick teaches that the genus of compounds of formula I in his disclosure or their pharmaceutically acceptable salts and/or drug combination of the compounds modulate, agonize or partially agonize, NLRP3 (nucleotide-binding oligomerization protein 3), and TLR7 and / or TLR 8 ([0007]).
Regarding claim 7, Glick defines pharmaceutical composition to refer to mixture of a compound with other excipients such as carriers, diluents, stabilizers, among others ([0047]).
Regarding claim 8, Glick teaches methods of modulating e.g., agonizing, partially agonizing, antagonizing, NLRP3 and TLR7 and /or TLR8 activities that include contacting NLRP3 and TLR7 and /or TLR8 with a compound or pharmaceutically acceptable salt or compositions of compounds of formula I ([0021]).
Regarding claim 9, Glick informs artisans the compound of formula I are useful for treating a condition, disease or disorder in which a decrease in NLRP3 and TLR7 and /or TLR8 activities (e.g. a condition, disease or disorder associated with repressed or impaired NLRP3 and TLR7 and /or TLR8 signaling) contributes to the pathology, symptoms or progression of the condition, disease or disorder (e.g. cancer), in a subject (e.g. a human) (Abstract).
Regarding claim10, Glick teaches methods of inducing an immune response e.g. an innate immune response in a subject in need thereof after administering an effective amount of compound of formula I or a pharmaceutically acceptable salt thereof or compositions containing the same ([0023]).
Regarding claims 11, Glick teaches methods of treating cancer that include administering to a subject in need thereof compound of formula I or pharmaceutically acceptable salt or compositions thereof ([0022]). Glick discloses in some cases the condition or disease is an autoimmune disease. ([0368]) and further teaches that Toll-Like receptors (TLR) play a key role in in the inflammatory and innate immune response and compound of formula I are used in methods that increase production of inflammatory cytokines in a subject ([0352]).
Regarding claim 12, Glick teaches treatment of various cancers in a subject including lung, pancreatic, myeloid leukemia, chronic lymphocytic leukemia, chronic myeloproliferative neoplasm, chronic myelogenous leukemia, melanoma, among others ([0030]).
Regarding claim 14, Glick discloses condition, disease or disorder treated with these compounds or pharmaceutically acceptable salt include autoimmune diseases which include, rheumatoid arthritis, systemic lupus erythematosus (SLP), inflammatory bowel diseases, among others ([0368]).
Regarding claims 16, 19, 22, and 25; Glick teaches methods of activating an immune response which include administering immunological agent to a subject along with the compounds described in the reference ([0359]). In addition, Glick discloses the methods of administering one or more additional therapies e.g. one of more additional therapeutic agents or regiment including immunotherapy, or an additional immunomodulatory moiety (Combination Therapy – [0371] – [0395]).
Regarding claims 17, 20, 23 and 26, Glick teaches the compounds in the reference can be administered with one, two, three, four, five, six or more additional therapeutic agents. The reference reveals “non-limiting” examples of additional chemotherapeutic agents selected from an alkylating agent (- cytostatic agent - examples shown in the reference), an anti-metabolite, a cytokine, an immune checkpoint inhibitor, other immunomodulatory agents such as interleukin-2 (IL-2), IL-10, transforming growth factor-β (TGFβ), among others, an antibody (with examples shown in the reference), cytotoxic antibiotic, one or more antifungal agents or one or more antibiotics ([0028], [0375-0389]).
Glick further teaches the methods for treatment with the disclosed compounds, can further include administering one or more anti-viral agents selected from a group consisting of interferon, a nucleotide analogue, a polymerase inhibitor, calcineurin modulator including cyclosporine immune inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a nonnucleoside polymerase inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, and combinations thereof ([0390]).
Regarding claims 18, 21, 24 and 27; Glick teaches the additional therapy or regimen can be administered to the subject at different times prior, during or after administration or contacting of compounds of formula I; in some cases the additional therapy or regimen is administered prior to administering the compounds or pharmaceutically acceptable salts thereof compounds of formula I, about an hour, 6 hours, 12 hours, 48 hours, or 1 week prior or about 1 month prior to contacting with or administering the compounds or pharmaceutically acceptable salts thereof compounds of formula I ([0391]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the instantly claimed invention with reasonable expectation of success in view Glick’s teachings. Additionally, per MPEP § 2144.09 (I), a prima facie case of obviousness maybe made when chemical compounds have very close structural similarities and similar utilities.
Accordingly, it would have been obvious to apply the prior art disclosed by Glick to claim a compound of formula (I) as in the instant application (instant claim 1) and a pharmaceutical composition of the compound and a pharmaceutically acceptable diluent or carrier (instant claim 7); and a method comprising of contacting the TLR-7 or TLR-8 receptor with the compound (instant claim 8) and administering to a subject a compound of the claimed invention or a pharmaceutically acceptable salt for treatment of a disease or a condition consisting of cancer, an autoimmune and an inflammatory disease (instant claims 10 and 11) and further limitations as recited in instant claims 12 and 14; a method that further comprises of administering to the subject an immune modulatory therapy (instant claims 16, 19, 22 and 25), comprising of additional immune modulating therapies or agents or combinations thereof, (instant claims 17, 20, 23 and 26) and wherein the compound is administered after immune modulatory therapy (instant claims 18, 21, 24 and 27).
One of ordinary skill in the art would have been motivated to do so because of any of the following reasons (i) as has been taught in prior art imquidazolequinoline-based compounds have been shown to trigger a more desirable ratio of pro- to anti-inflammatory cytokines (ii) activation of TLR7 increases with alkyl chain length and peaks with a butyl group (at R1 in instant claim 1) , so one would be motivated to make butyl isomers, branched or with a cyclopropylmethyl as in the instant invention (iii) prior art teaches an alkyl hydroxyl group at instant R1 position (N1 in Larson) enhances TLR8 activations, while the N1-p-aminomethylbenzyl extends into the pocket within TLR8 forming favorable hydrogen bonds interactions and (iv) other structurally similar molecules that target TLR7 and TL8 have been reported / shown in prior art, used in methods for treatment of cancer, autoimmune, inflammatory diseases and as stimulants for use in immunotherapies, administered along with other additional immunomodulatory agents prior to administration or contact with the compounds of the claimed invention as taught by Glick.
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, 4-12, 14, 16-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 18, 21, 22, 23, and 24 of U.S. Patent No. 9034336 B2, (hereon after ‘336), alone or in view Larson et al., 2017, (Larson et al., Design and Synthesis of N1-Modified Imidazoquinoline Agonist for Selective Activation of Toll-Like Receptors 7 and 8. ACS Med. Chem. Lett., 2017, 8, 1148-1152, Published October 16, 2017), (hereon after Larson), or further in view of Glick et al. 2019, (Glick et al., US 2019/0127368 A1, “NLRP3 Modulators”, Published on May 2, 2019) hereon after ‘368. Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1; Claims 1-12, 18, and 21 in ‘336 disclose a genus of formula I, that overlaps with the instantly claimed species, where all limitations recited in instant R2 and R4 positions overlap with the genus in ‘336;
Regarding instant R1, wherein
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, claim 1 in ‘336 discloses description of the substitution at that position as to include (C1-C6)alkyl, optionally substituted with (C3-C6)cycloalkyl; and further provides this definition; specifically (C1-C6)alkyl includes butyl, iso-butyl and (C3-C6)cycloalkyl(C1-C6)alkyl includes cyclopropylmethyl. Notably, isobutyl or cyclopropylmethyl in the instant claim 1 are isomers of butyl shown in compounds exemplified in ‘336.
Additionally, ‘336 exemplifies compounds with an amino group, NH2, as in the instant claim 1. Furthermore, Larson, teaches activation of TLR7 increases with alkyl chain length at instant R1 position and peaks with the butyl. Thus, although the instant claim 1 and ‘336’s claims 1-12, 18, and 21 are not exactly identical, they are not patentably distinct as they disclose identical species that read on to the instantly claimed subgenus. Accordingly, claims 1-12, 18, and 21 in ‘336 alone or further in view of Larson render the instant claim 1 obvious.
Regarding instant claim 4; Claims 1, 2, 10, 11 and 21 in ‘336 describe substitution at the instant R2 position, which is limited to 2-hydroxypropyl in claim 11 in ‘336 and further displays examples of compounds substituted with the 2-hydroxypropyl in claim 21, for example compound 522. Furthermore regarding substitution at the instant R2 position, Larson reveals that the N1-alkylhydroxyl group favors TLR8 activation and potency. Although the instant claim 4 and 336’s claims 1, 2, 10, 11 and 21 are not exactly identical, they disclose identical chemical species wherein the R2 is optionally substituted -CH2-CH(OH)Me. Accordingly, claims 1, 2, 10, 11 and 21 in ‘336 alone, or further in view of Larson render the instant claim 4 obvious.
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Regarding instant claim 5; Claims 1, 2, 4 and 21 in ‘336 recite limitations that describe the instant R4 position as RK-O-C(=O)- where Rk is (C1-C6)alkyl as in claims 1 and 2 in ‘336 which is further limited as a methoxy carbonyl - claim 4 in ‘336. In addition, ‘336 shows examples such as compound 522 above with methoxy carbonyl among others. Additionally, ‘336 discloses that the presence of the ester group at the instant R4, unexpectedly provided compounds that activate inflammatory cytokine response even in the absence of TLR7 or TLR8 agonist activity. Thus, although the instant claim 5 and claims 1, 2, 4 and 21 in ‘336 are not exactly identical, they disclose identical chemical species wherein the R4 is -C(=O)O-(C1-C4)alkyl group for the same purpose. Accordingly, claims 1, 2, 4 and 21 in ‘336 render the instant claim 5 obvious.
Regarding instant claim 6; Claim 21 in ‘336 discloses compound 522.
US Patent 9034336 B2
Instant Application
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Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons; The instant claim 6, compounds 1 and 2 and 336’s example 522 have identical substituents in two of three substituted positions.
Compounds 1 and 2 differ from 336’s exemplified compound as follows; while example 522 has a butyl substituent, compounds 1 and 2 are substituted with isomers of butyl, namely an isobutyl group in compound 1 and a cyclopropylmethyl group in compound 2. Additionally, claims 1, and claims 6-8 in ‘336 disclose, substitution at that position can include (C1-C6)alkyl, optionally substituted with (C3-C6)cycloalkyl; Further the reference provides a definition; specifically (C1-C6)alkyl includes butyl, iso-butyl and (C3-C6)cycloalkyl(C1-C6)alkyl includes cyclopropylmethyl (col 5, line 18-22). Although the instant claim 6 and claim 21 in ‘336 are not exactly identical, they disclose identical chemical species wherein the substitutions in all three compounds are isomers of butyl. Thus, claim 21 in ‘366 renders instant claim 6, compounds 1 and 2 in the instant application obvious.
Regarding instant claims 7, 8, 9, 10 and 11; Claims 22, 23 and 24 in ‘336 recite a pharmaceutical composition of the recited compounds, or a pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier (as in instant claim 7); ‘336 further reveals pharmaceutical composition of the recited compounds are used in methods for treating pathological conditions comprising administering a compound or pharmaceutically acceptable salt to a subject as in instant claim 9; claim 23 in ‘336 discloses a method for stimulating an immune response in an animal comprising administering the recited compound (as in instant claim 10); claim 24 recites a method of treating cancer in an animal comprising administering a compound or its pharmaceutically acceptable salt; further the reference reveals the recited compounds target the TLR7/8 receptors and activate inflammatory cytokine (as in instant claim 11). Notably, ‘336 reveals the recited compounds modulate TLR7 and TLR8 and the reference shows examples of assays that screen for binding ability in vitro;
Additionally, Glick’s reference, ‘368, which discloses similar genus of compounds - that overlap with instant claim 1, teaches that the recited compounds modulate TLR7 and /or TLR8 activities, when TLR7 and /or TLR8 are contacted with the compounds or their pharmaceutically acceptable salt – as instant claim 8;
Reference ‘368 teaches the recited compounds modulate, agonize or partially agonize Toll-Like receptors 7/8, thus, they are useful for treating conditions or diseases associated with repressed or impaired TL7 and/ or TLR8 signaling. The conditions or diseases include an autoimmune disease.
Therefore, while the instant claims 7, 8, 9, 10 and 11 and claims 22, 23 and 24 in ‘336 are not exactly identical, they are drawn towards a pharmaceutical composition of the recited compounds or pharmaceutically acceptable salt, and a pharmaceutically acceptable diluent or carrier (instant claim 7) and methods of use that target the TLR7 and TL8 receptors and conditions or diseases impacted by these receptors namely, modulating TLR-7 or TLR-8 receptor (instant claim 8), treating a pathological condition (instant claim 9), stimulating an immune response in a subject (instant claim 10) and method of treating a disease or condition selected from cancer, autoimmune and inflammatory disease (instant claim 11). It can be assumed that administering the same compounds, or pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier, that target the same receptors in a subject will produce the same result because the claimed compounds modulating the same receptors in a subject. Accordingly, claims 22, 23 and 24 in ‘336 alone or in view of ‘368, render claims 7, 8, 9, 10 and 11 obvious.
Regarding instant claims 12; claims 24 in ‘336 is drawn towards a method of treating cancer in an animal comprising of administering the recited compound or pharmaceutically acceptable salt. While the claim in ‘336 is drawn towards the genus cancer, the instant claim 12 is drawn towards species of cancer, wherein the cancer is multiple myeloma, pancreatic cancer or lung cancer.
Reference ‘368 teaches that therapeutic amounts of the recited compounds are administered to a subject in need thereof, to treat the various species of cancer that include lung, pancreatic and various forms of blood cancers as in instant claim 12.
Thus, while claim 24 in ‘336 and instant claim 12 are not exactly identical they are not patentably distinct from each other because, they are directed towards treatment of the genus of cancer in ‘336 and species of cancer in the instant claim in a subject; furthermore the recited compounds are known from ‘368 to treat the species claimed in the instant application. It is therefore understood that administering recited compounds to a subject with cancer and to a subject wherein the cancer is myeloma, pancreatic cancer or lung cancer would produce the same result. Accordingly, claim 24 in ‘336 alone or further in view of ‘368 renders claim 12 obvious.
Regarding instant claims 14; Claim 22 in ‘336 recites a pharmaceutical composition of the recited compounds, claim 23 recites a method of stimulating an immune response and claim 24 recites a method for treating cancer; In addition, ‘336 discloses the recited compounds activate inflammatory cytokine response and the type of cytokine (IL-1β) triggered by the compounds of the invention demonstrate that they activate the inflammasome unlike other known TLR7/8 agonists.
Reference ‘368 discloses the recited compounds or their pharmaceutically acceptable salts modulate TLR7 and /or TLR8 receptors and are useful for methods of treating conditions or disease that include cancer and autoimmune disease, and including systemic lupus erythematosus and rheumatoid arthritis.
Thus, while claims 22 - 24 in ‘336 and instant claim 14 are not exactly identical they are not patentably distinct from each other because, (i) they are directed towards treating conditions or diseases that are known to be associated with impaired, repressed or signaling of TLR7/8 and modulation of TLR7/8 receptors in a subject (ii) the compounds administered are targeting the same receptors and functioning in the same way regardless of the condition or disease. Administering compounds that target the same receptors and conditions or a diseases, that are impacted by the same receptors , such as cancer or autoimmune, would be expected to have same results in a subject. Furthermore, ‘368 teaches methods for treating species autoimmune disease as claimed in an instant application wherein the autoimmune disease is systemic lupus erythematosus or rheumatoid arthritis (instant claim 14). Accordingly, claims 22-24 in ‘336 alone or further in view of ‘368 render claim 14 obvious.
Regarding instant claims 16 – 27; Claim 23 in the ‘336 recites a method of stimulating an immune system comprising or administering an effective amount of the recited compound of a pharmaceutically acceptable salt. Claim 24 in ‘336 recites a method of treating cancer, claims 13 and 26 in ‘336 recite the use of an antigen associated with a bacteria or virus or with tumor cell or tumor cell lysate used in along with the recited compounds.
Reference ‘368 teaches the recited compounds or their pharmaceutically acceptable salts are used with additional therapies such as immune modulating therapies (as in instant claims 16, 19, 22 and 25). ‘368 discloses some of the methods of inducing the immune response include administering to a subject an effective amount of the recited compounds or their pharmaceutically acceptable salts, administered in combination with one, two, three, four, five, six or more additional therapeutic agents; that include interleukin-2 (IL-2), cytostatic agent, an antibody, a cytokine, cyclophilin, one or more anti-viral agents selected from a group consisting of interferon (as in instant claims 17, 20, 23 and 26). Further, ‘368 teaches the administration of the recited compound after the immune modulatory therapy (as in instant claims 18, 21, 24 and 27).
Thus, although claims 13, 22, 23, 24 and 26 in ‘336 and the instant claims, 16 – 27 are not identical, - the patented claims in ‘336 read onto the instant claims in view of reference ‘368 as follows; they disclose administering an effective amount of the recited compound or pharmaceutically acceptable salt, to a subject to treat a condition related or impacted to TLR7/8 receptors – cancer, autoimmune and inflammatory condition, further comprising of stimulating the immune system by administering an immune modulatory therapy as in instant claims16, 19, 22 and 25, and the immune modulatory therapy is administered in combination with other recited additional agents as in instant claims 17, 20, 23 and 26 and the administration of the compounds is done after the immune modulatory therapy. Accordingly, claims 13, 22, 23, 24 and 26 in ‘336 and further in view of ‘368, render claims 16-27 obvious.
Claims 1, 4, 5, and 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7, 9, 11 and 12 of U.S. Patent No. 10730871 B2, hereon after ‘871, alone or in view Larson et al., 2017, (Larson et al., Design and Synthesis of N1-Modified Imidazoquinoline Agonist for Selective Activation of Toll-Like Receptors 7 and 8. ACS Med. Chem. Lett., 2017, 8, 1148-1152, Published October 16, 2017), (hereon after Larson).
Regarding instant claims 1; Claims 1, 4 and 12 in ‘871 disclose a genus compounds of formula I, that overlap with the claimed species; NRaRb, is defined such that Ra = H and Rb = H, making NH2 as in the instant claim, all the limitations of instant R2 and R4 overlap with limitations recited for the similar positions in ‘871; whereas for instant R1 wherein
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, claim 1 in ‘871 discloses description of the substitution at that position as to include (C1-C6)alkyl, optionally substituted with (C3-C6)cycloalkyl; and further provides this definition; specifically (C1-C6)alkyl includes butyl, iso-butyl and (C3-C6)cycloalkyl(C1-C6)alkyl includes cyclopropylmethyl. Importantly, ‘871 exemplifies compounds with an amino group, NH2, as in the instant claim 1 and examples in the reference show a butyl group at instant R1 position. Both isobutyl or cyclopropylmethyl in the instant claim 1 R1 position, are isomers of butyl and as discussed above Larson, teaches activation of TLR7 increases with alkyl chain length at instant R1 position and peaks with the butyl group.
Thus, although claims 1, 4 and 12 in ‘871 and instant claim 1 are not exactly identical, they are not patentably distinct as they disclose identical species that overlap or read on to the instantly claimed subgenus. Accordingly, claims 1, 4 and 12 in ‘871 alone or further in view of Larson render the instant claim 1 obvious.
Regarding instant claim 4; Claims 1, 4, 9, and 11 in ‘871 describe substitution at the instant R2 position, which is limited to (C1-C6)alkyl that is substituted with aryl that is substituted with (C1-C6) further substituted with NH2 as described in claims 1 and 11 in ‘871. Additionally, the reference exemplifies of compounds substituted with the -CH2-(p-Phe-)CH2NH2 as shown in claims 4 and 9, for example compound 558. Furthermore regarding substitution at the instant R2 position, Larson reveals that the N1-alkylhydroxyl group favors TLR8 activation and potency.
Thus, although the instant claim 4 and ‘871’s claims 1, 4, 9 and 11 are not exactly identical, they disclose identical chemical species wherein the R2 is optionally substituted with -CH2-(p-Phe-)CH2NH2. Accordingly, claims 1, 4, 9 and 11 in ‘8717, alone, or further in view of Larson render the instant claim 4 obvious.
Regarding instant claim 5; Claims 1, 2, 4, 7, and 9 in ‘871 recite limitations that describe the instant R4 position as RK-O-C(=O)- where Rk is (C1-C6)alkyl – claims 1 and 2 in ‘871, that is further limited to Rk is (C1)alkyl - claim 7 in ‘871. In addition, ‘871 shows examples in claim 4 and in 9, compound 558, and that are substituted with alkoxy carbonyl at the instant R4 position. Thus, although the instant claim 5 and claims 1, 2, 4, 7 and 9 in ‘871 are not exactly identical, they disclose identical chemical species wherein the R4 is -C(=O)O-(C1-C4)alkyl for compounds intended for the same purpose. Accordingly, claims 1, 2, 4 and 21 in ‘336 render the instant claim 5 obvious.
Regarding instant claim 6; Claim 9 in ‘871 discloses the compound below, also known as example 558 in the reference.
US Patent 10730871 B2
Instant Application
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Although the instant claim 6, compounds 3 and 4, and ‘871’s compound 558, are not exactly identical, they are not patentably distinct from each other because of the following reasons; the instant application’s compounds and 558 have identical substituents in two of three substituted positions.
Instantly claimed compound 3 and 4 only differ from exemplified compound as follows; while compound 558 has n-butyl substituent, compounds 3 and 4 are each substituted with a butyl isomer namely, an isobutyl group in compound 3 and a cyclopropylmethyl group in compound 4. Additionally, ‘871 teaches substitution at that position can be (C1-C6)alkyl, optionally substituted with (C3-C6)cycloalkyl as recited in claim 1 of the reference which further provides this definition; specifically (C1-C6)alkyl includes butyl, iso-butyl and (C3-C6)cycloalkyl(C1-C6)alkyl includes cyclopropylmethyl. (col 8 lines 30-35). Thus, claim 9 in ‘871 renders claim 6, compounds 3 and 4 in the instant application obvious.
Conclusion
No claims are found allowable.
Claims 1, 4-12, 14, 16-27 are rejected.
Other relevant, prior art, not used in this office action, published before the effective filing date of the instant application are;
Hideo et al. 1999, JPH1180156A (Published on 26 March 1999)
Chou et al. 2021, WO 2021/086689 A1 (Published on 06 May 2021 - Priority date 29/10/2019)
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/P.O./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
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