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. Claims 1, 6, 11-12, 14-16, 20-21, 23-24, 34, 55-57, 59 are pending in the current application.
2. This application is a CON of 16/761,354 05/04/2020 ABN; 16/761,354 is a 371 of PCT/US2018/058969 11/02/2018; PCT/US2018/058969 has PRO 62/643,074 03/14/2018; PCT/US2018/058969 has PRO 62/580,740 11/02/2017.
Request for Continued Examination
3. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 7, 2026 has been entered.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on July 7, 2026 was filed after the mailing date of the Notice of Allowance April 7, 2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 of this title, 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.
5. Claims 1, 6, 11-12, 14-16, 20-21, 23-24, 34, 56-57, are rejected under 35 U.S.C. 103 as being unpatentable over Curtin US 20120122842 A1 in view of Stepan “Application of the Bicyclo[1.1.1]pentane Motif as a Nonclassical Phenyl Ring Bioisostere in the Design of a Potent and Orally Active γ-Secretase Inhibitor.” J. Med. Chem. 2012, 55, 3414−3424. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Curtin discloses compounds of Formula IVb on page 91.
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These compounds have the claimed structure W as the 12th embodiment in claim 1, isoindoline, where L2 is a bond, R1 and R2 are H, and R5 being equivalent to the A-L1 construct where R5 is defined at [2263] as aryl, heterocyclyl, or alkyl substituted by R9,OR9, R9, NHR9, where R9 is aryl or heterocyclyl, which can itself be substituted by additional aryl or heterocyclyl as per paragraph [2265].
Examples include those on page 108 ff:
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The Curtin compounds were evaluated for their NAMPT and ROCK inhibitory activity as shown on page 245 ff. From the assay the first compound shown above, Example 1, exhibited IC50 value of 0.0125 μM towards NAMPT, making it a clear lead compound. The additional compounds also displayed high potency, see Table 1.
Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties. Stepan details the replacement of phenyl rings in pharmaceuticals with bicyclo[1.1.1]pentane. According to Stepan “An additional finding resulting from this work is the significant changes in physicochemical attributes upon introduction of the bicyclo[1.1.1]pentane unit, most notably manifested by significant improvements in passive permeability and aqueous solubility relative to 1. As such, our work provides a compelling case for applications of this bicyclo[1.1.1]pentane system in drug discovery as a strategy to “escape the flatland” imposed by aryl systems10 and alter the overall physicochemical characteristics during lead optimization.” Page 3415. Leading to the conclusion “Although limited in scope, our SAR studies into alternative replacements of the fluorophenyl group in 1 indicate the superiority of the bicyclo[1.1.1]- pentane functionality over conventional phenyl ring replacements (e.g., alkyl/cycloalkyl spacers) with respect to achieving the desired balance between γ-secretase inhibition, aqueous solubility/permeability, and in vitro metabolic liability. This work therefore highlights the physicochemical changes induced by this unusual phenyl bioisostere and showcases its potential use as a tactic to “escape the flatland” of multiple aryl systems in drug discovery.”
Ascertaining the differences between the prior art and the claims at issue.
The only difference between the compounds of the instant claim 1-6 and those of Yeung is the bioisosteric replacement of a phenyl ring with a bicyclo[1.1.1]pentane.
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Versus
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Resolving the level of ordinary skill in the pertinent art AND Considering objective evidence present in the application indicating obviousness or nonobviousness.
The level of ordinary skill in the art is high, and would be a medicinal chemist. The experienced medicinal chemist, who would make these compounds, would be motivated to prepare these bicyclo[1.1.1]pentane bioisosteres based on the expectation that such bioisosteres would have similar properties to the prior art phenyl compounds and upon the routine nature of such experimentation in the art of medicinal chemistry. Based upon Stepan, there is a reasonable expectation of success in making these bicyclo[1.1.1]pentane variants and them having the property of ROCK/NAMPT inhibition. One would be motivated to do so to “‘escape the flatland’ imposed by aryl systems and alter the overall physicochemical characteristics during lead optimization.” There is evidence of the possibility of improved potency and drugability. The well-established use of a bicyclo[1.1.1]pentane moiety as a phenyl replacement has been reviewed and is part of the medicinal chemist toolkit.1 Thus a finding of obviousness is appropriate in this case.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
6. Claims 1, 6, 11-12, 14-16, 20-21, 23-24, 34, 55-57, 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 13, 17-18, 20-22, 25, 45, 48, 50, 62, 64-67, of copending Application No 18/462,918. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘918 application while slightly narrower, being drawn to only the compounds of the instant claims where D is a limited group of bicycles they are the compounds of the instant claims. The D groups in the ‘737 are those of instant claim 6 and 11. The D group in the first embodiment in claim 1 is bicyclo[1.1.1]pentane of instant claim 11 and includes the elected species. W is equivalent to instant W and A is equivalent to instant A. Specific instant W embodiments of claim 41 are those of the claim 57. The AIII group in claim 72 includes the phenyl ring of the instantly elected species. Claim 18 and 65 in the first embodiment is drawn to the elected species W. Claims 64-65 are nearly identical to claim 57. The species in claim 66 are identical or nearly so. The elected species is the first compound of page 54/66 of claim 66. The second compound on page 29/66 of claim 66 differs only by the position of the chlorine atom on the pyran from the elected species. The last two compounds in the second column of page 32/66 of claim 65 are the monofluorinated analogs of the elected species. The second compound in the second column on page 42/66 is the F to Cl isolog of the elected species. The last compound on the 1st column of page 53/66 is the enantiomer of the elected species.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
7. 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 Stockdale “Pharmaceuticals that contain polycyclic hydrocarbon scaffolds” Chem. Soc. Rev., 2015, 44, 7737—7763. “A team at Pfizer lead by Stepan347 recently demonstrated that bicyclo[1.1.1]pentane could act as a benzene function replacement for the g-secretase inhibitor of BMS-708,163 (129) with the synthesis and biological evaluation of 130, which demonstrated greater activity and drugability (Fig. 13). This, however, was not the first example of benzene ring replacement using the bicyclo[1.1.1]pentane system. In 1996 Pellicciari reported348 that (S)-(+)-2-(30 carboxybicyclo[1.1.1]pentyl)glycine (131) was a structurally novel, potent and selective, mGluR1 antagonist modeled off (+)-methyl(4-carboxyphenyl)glycine (132), which was known to exhibit mGluR1 antagonist properties (Fig. 13). Lastly on this front, both these pieces of work inspired Adsool et al.349 to prepare a benzene isostere of 4-phenylaniline (133) using the bicyclo[1.1.1]pentane scaffold (i.e. 134) for an in-house drug discovery program.” [Page 7755 col. 1]
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