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 .
DETAILED ACTION
1. This application is a 371 of PCT/GB2021/053346 12/17/2021; FOREIGN APPLICATIONS: UNITED KINGDOM 2020037.4 12/17/2020 UNITED KINGDOM 2108483.5 06/14/2021.
Claims 1-28, 30-31 are pending.
Response to Restriction Election
2. Applicant’s election of group I and the species compound 2,
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in the reply filed on December 18, 2025 is acknowledged. The election was made without traverse. According to applicants’ representative claims 1-5, 9, 11-13, 17, 19-20, 22, 24-28 read on the elected species. As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. The search and examination was continued until prior art was found that anticipated or rendered obvious a non-elected species that falls within the scope of the generic Markush claim reading on the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claims 6-8, 10, 14-16, 18, 21, 23, which do not read on the elected species are withdrawn.
Objections
3. Claim 1 is objected to for the following informality: The word “moeity” is a misspelling of moiety. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
4. Claims 22, 25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 22 states “wherein Ring A is selected from the group consisting of: a 6 membered aromatic and heteroaromatic ring, optionally wherein Ring A is phenyl”, while claim 25 states, “wherein Ring C is selected from the group consisting of: a 6 membered aromatic and a 6 membered heteroaromatic ring, optionally phenyl or pyridinyl.” Selecting from a group consisting of a member that is optionally present is a redundant definition since by definition selecting from the group consisting of provides for selection of the option. This calls into question whether the consisting of in the optional selection of the narrower scope, phenyl or pyridinyl, is merely exemplary of the broader terms, 6 membered aromatic and a 6 membered heteroaromatic ring, which may lead to confusion over the intended scope of the claim because the metes and bounds of the claim containing that language are unclear rendering the claim indefinite.
5. Claims 1-5, 9, 11-13, 17, 19-20, 22, 24-28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 has not a Markush group, but three separate Markush groups. The Markush group is selected from three subgroups each of which is composed of further Markush groups that are themselves composed of further Markush groups. The subgroups i) ii) and iii) are separated by and/or such that it is unclear what this means. In addition, the definition of ii)
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reference is made to R1 and R4 as an alkylenyl residue, however this is not an option for R1 and R4 in the aforementioned definitions, such that there a lack of antecedent basis. The reference to “a carbon atom in Ring A that is ortho to the carbon atom of ring A having the amide residue” is ambiguous when Ring A is other than a phenyl ring since ortho1 is terminology restricted to phenyl rings.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
6. Claim(s) 1, 11-12, 17, 20, 22, 24-28 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shimizu US 2011/0201815 A1. Shimizu teaches anticipatory compounds including but not limited to 5-(4-ethoxycarbonylpyridine-2-yl)-2,3-dihydro-indole-1-carboxylic acid benzyl ester on page 11 paragraph [0164]. This is a compound of claim 1 where Ring A is phenyl, Ring B is pyridine, L is the last selection and Ra and Rb are H, ring C is phenyl, n is 1, m is 0, p is 0, R1 is C1-alkylenyl residue, R2 is substituted alkyl or substituted alkoxy-alkyl, R4 is C1 alkylenyl, R3 is substituted alkyl, wherein the C1 alkylenyl R4 moiety is bonded to a carbon atom in Ring A that is ortho to the carbon atom of Ring A having the amide residue, and, together with the atoms to which they are bonded, the R1 and R4 moieties form a 5-membered ring.
7. Claim(s) 1-5, 9, 11-12, 20, 22, 24-27 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by STN Chemical Database entry for N[1,1'-Biphenyl]-3-carboxylic acid, 5-methoxy-4'-[[(phenylmethoxy)carbonyl]amino]-, RN 1261934-11-5, SR Chemical Catalog Supplier: Combi Blocks LLC ED Entered STN: 03 Feb 2011. This compound reads on claim 1 where Ring A is phenyl, Ring B is phenyl, L is the last selection, Ra and Rb are H, ring C is phenyl, R1 is H, n is 0, m is 1, p is 0, R3 is methoxy, R2 is substituted alkyl. This compound was entered in the database Chemcats, and is listed as being commercially available by the company CombiBlocks. The on sale bar is also met.
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.
8. Claim(s) 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over S TN Chemical Database entry for N[1,1'-Biphenyl]-3-carboxylic acid, 5-methoxy-4'-[[(phenylmethoxy)carbonyl]amino]-, RN 1261934-11-5, SR Chemical Catalog Supplier: Combi Blocks LLC ED Entered STN: 03 Feb 2011 as applied to claim 1-5, 9, 11-12, 20, 22, 24-27 above, and further in view of Bartlett “Exploiting Chemical Diversity for Drug Discovery”, 2006, pages 113-118. The compound was entered in the database Chemcats, and is listed as being commercially available by the company Combi Blocks which sells compounds for high-throughput screening. Bartlett discusses compounds with this utility and explains that they are “are capable of providing 70,000-450,000+ compounds each from stock, generally as dry powder/dry film or as solutions in DMSO (from cherry-picked selections or pre-plated sets).” However no evidence of a solution offered for sale has been obtained. Since this compound was sold for high throughput screening purposes and such compounds typically cannot be used without placing them in solutions for cell screening purposes, it would be obvious to place the compound in DMSO to facilitate such screening. Ex parte Douros et al. (POBA 1968) 163 USPQ 667; “It is clearly obvious to add a carrier or solvent to an unpatentable compound. This combination does not become new and patentable because of the presence of the solvent or carrier, Ex parte Billman, 71 USPQ 253 ; In re Riden et al., 50 CCPA 1411, 318 F.2d 760, 1963 C.D. 794, 796 O.G. 863, 138 USPQ 112 ; In re Pieroh et al., 50 CCPA 1471, 319 F.2d 248, 797 O.G. 6, 138 USPQ 238 ; In re Rosicky, 47 CCPA 859, 276 F.2d 656, 755 O.G. 929, 125 USPQ 341, 1960 C.D. 197.”
9. Claims 1-5, 9, 11-13, 17, 19-20, 22, 24-28 are rejected under pre-AIA 35 U.S.C. 103 as being unpatentable over Bi “The discovery of potent agonists for GPR88, an orphan GPCR, for the potential treatment of CNS disorders” Bioorg. Med. Chem. Lett. 2015, 25, 1443− 1447 (cited on the IDS) in view of Silverman, R.B. The Organic Chemistry of Drug Design and Drug Action 1992, Academic: New York, pg 19. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art
Bi teaches compounds of the same general core formula (I) of claim 1 where A is phenyl, B is phenyl, L is a cyclopropane, C is various aromatic and heteroaromatic rings, R1 is a substituted alkyl substituted with amino. Table 1 on page 1445 show compounds with various Ar:
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Bi conducted an extensive SAR on the compounds which correspond to all of the claimed embodiments with respect to B-R2, C-R5. In Table 1 the Ar corresponding to instant C was found to work well as a pyridyl (55) and pyrimidyl (58) as well as a phenyl substituted with fluorine (43-45) accounting for the R5 substitution in the elected species and that of claim 20. In Table 2 on page 1446 the C ring was substituted variously including with a number of groups including those in claim 13 such as methoxy (87, 88) “fine tuning of the para-substitution on the distal phenyl ring.” “Improvement of the activity was observed with smaller alkyl or alkoxyl substitutions (99, 100, 103, 104 and 108) with 4-ethyl 99 and 4-methoxymethyl 108 showing the best potency.” The 4-methoxymethyl is the R2 group of the elected species in claim 13. The R ring in Table 2 is also shown as a pyridine corresponding to B in claim 24.
Silverman teaches that “Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties.” He goes on to state “Erlenmeyer’s 1948 definition of “classical isosteres” as “atoms, ions, or molecules in which the peripheral layers of electrons can be considered to be identical”. Table 2.2 lists several of these classical isosteres under heading 1a, establishing that –OH and –NH2 are classical bioisosteres.
Ascertaining the differences between the prior art and the claims at issue.
The compounds of Bi above have an amino group (-NH2) b to the amide nitrogen, while the instant claims are drawn to -OH isosteres of the prior art compound. At least where the R1 substituent is alkyl substituted by -ORc where Rc is H The instant claims are drawn to the hydroxy isosteres of the Bi amino compounds in the narrowest embodiments of claim 5 as circled below:
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The circled groups correspond to the -OH isosteres of the Bi compounds of Figure 2, compounds 19 and 21 shown below.
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Resolving the level of ordinary skill in the pertinent art
One of ordinary skill would be motivated to make the compounds of the invention because he or she would expect the compounds to have similar properties. Bi completely removed the amino group, “As shown in Figure 2, we modified the amino alkyl side chain, to determine the effect on potency. The SAR in this region indicated that there was little tolerance for modification. The data clearly showed that the primary amino group was important for potency, as without it, compounds were completely inactive (e.g., compare analogs 1 and 10).” [Page 1444, Figure 2].
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Making a conservative substitution like an amino to -OH isostere, rather than complete removal of the polar character by replacing amino with H, would be expected to maintain activity. Silverman teaches that “Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties.” He goes on to state “Erlenmeyer’s 1948 definition of “classical isosteres” as “atoms, ions, or molecules in which the peripheral layers of electrons can be considered to be identical”. Table 2.2 lists several of these classical isosteres under heading 1a, establishing that –OH and –NH2 are classical bioisosteres. The experienced medicinal chemist would be motivated to prepare these bioisosteres based on the expectation that such bioisosteres would have similar properties and upon the routine nature of such experimentation in the art of medicinal chemistry. Based upon the teachings of Silverman making the bioisosteric -OH variant of the amino compounds of Bi would be expected to give compounds with similar GPR88 activity, which is what has been shown.
Rejections Under the Judicially Created Doctrine of Improper Markush Grouping
10. Claims 1-5, 9, 11-13, 17, 19-20, 22, 24-28 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The only non-variable atoms in Formula I is an amide. This structure is insubstantial to the disclosure of the compounds in the specification. According to the specification the compounds are inhibitors of GPR88. The specification discloses only around 10 compounds of the instant claims. These compounds are homogenous. The compounds all have a B ring as phenyl, C ring as pyridine or phenyl and A as only phenyl or the known phenyl isostere bicyclo[1.1.1]pentane. The claims are drawn to nearly any ring for A, B and C as well as various additional rings on pages 6-7 outside of A and B as defined on the first page. Assuming some of these could be prepared there is no expectation that such diverse compounds would have the same or similar properties. It is well known that molecular structure is correlated with physical properties and in particular in heterocyclic chemistry the change from one ring to another often results in dramatic changes in properties. Pozharskii et. al. Heterocycles in Life and Society Wiley, 1997, pgs. 1-6: "It is rumored that the Russian scientist Beketov once compared heterocyclic molecules to jewelry rings studded with precious stones. Several carbon atoms thus make up the setting of the molecular ring, while the role of the jewel is played by an atom of another element, a heteroatom. In general, it is the heteroatom which imparts to a heterocycle its distinctive and sometimes striking properties..."
The SAR for these compounds is already known. The compounds shar the same basic core as the Research Triangle Institute compounds, Jin “Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake” J. Med. Chem. 2018, 61, 6748−6758 (cited on the IDS). “For example, the aromatic ring on site A is essential for activity but has limited substitution tolerance, suggesting the binding space around this region is constrained.” [Page 6749 col. 1].
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“On site B, the 4′- position of the biphenyl ring is well tolerated with small- to large-sized alkyl or alkoxy groups, which likely exits through a hydrophobic binding pocket to the extracellular loop consistent with a binding position in the GPR88 homology model.” Basically the active core is a biphenyl amide with a terminal phenyl or pyridine. All of the compounds, have a very specific structure absent from the instant claims. In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
Conclusion
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/ Primary Examiner, Art Unit 1621
1 “Ortho” 1. Prefix indicating that a benzene compound has two substituted groups in the 1,2 positions (i.e. on adjacent carbon atoms). The abbreviation o- is used; for example o-dichlorobenzene is 1,2-dichlorobenzene. Compare meta-; para-. A Dictionary of Chemistry (6 ed.) Edited by: John Daintith, Oxford University 2008.