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 6, 28, 30 are pending in the current application.
2. This application is a CON of 17/861,567 07/11/2022 ABN. 17/861,567 is a CON of 17/044,993 10/02/2020 ABN; 17/044,993 is a 371 of PCT/US2019/026075 04/05/2019
PCT/US2019/026075 has PRO 62/653,518 04/05/2018.
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.
3. Claims 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Alacio WO 2018064632 A1 (cited on the IDS) AND Tacke “Drug Design Based on the Carbon/Silicon Switch Strategy” Topics in Medicinal Chemistry (2016), 17, 29-59 (cited on the IDS) further in view of Munoz WO 2017177124 A1 (cited on the IDS). The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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.
Alacio teaches the non-silylated compounds of the claims as compound 1, at various places in the document including as the 1st compound on page 16, the product in Scheme 3 on page 56, Scheme 4 on page 58. Various experiments were performed with the compound 1 on page 269 and 285 showing that it aided in the function of mutant CFTR protein and as such could be used to treat cystic fibrosis.
Tacke discusses the use of silicon bioisosteres in drug design:
The carbon/silicon switch strategy, i.e., the strategic replacement of a carbon atom with a silicon atom (sila-substitution) within a well known drug, with the rest of the molecule being identical, is one of the methods that are currently used for the design and development of new silicon-based drugs. Some of the fundamental differences between carbon and silicon (e.g., differences in the covalent radii and electronegativities) can lead to marked alterations in the physicochemical and biological properties of the sila-drugs. In general, the silaanalogues share the same mode of action as the parent carbon compounds but may have altered biological properties. Incorporation of silicon into a drug can affect and, ideally, improve the pharmacological potency and selectivity, the pharmacodynamics, and the pharmacokinetics. [abstract page 29].... There are two different approaches that can be used for the design of silicon-based drugs: (1) synthesizing a silicon analogue of a known drug in which at least one carbon atom has been replaced by a silicon atom, with the rest of the molecule being identical (carbon/silicon exchange, carbon/silicon switch, sila-substitution) [page 30 ¶1]... many sila-drugs have been synthesized and pharmacologically characterized over the past five decades, and nowadays the carbon/silicon switch strategy is an established method in drug design, not only in academia but also in pharmaceutical industry [page 30 ¶2].....In the case of lipophilic organic substituents attached to a central carbon atom of a given drug, the corresponding sila-analogue is more lipophilic due to the different covalent radii of carbon and silicon. This change in lipophilicity can modify in many ways the in vivo properties of a drug.” [Page 31]....Following the first pioneering studies on biologically active organosilicon compounds five decades ago, silicon chemistry is nowadays accepted to be a novel source of chemical diversity in drug design. The carbon/silicon switch strategy, i.e., the strategic replacement of a carbon atom with a silicon atom (sila-substitution) within a well-known drug, with the rest of the molecule being identical, is one of the methods that are currently used for the design and development of new silicon-based drugs. As members of Group 14 of the periodic table, the elements carbon and silicon show many similarities in their chemical properties, but there are also some fundamental differences that can lead to striking differences in the physicochemical and biological properties of drugs and their corresponding sila-analogues. In general, the sila-analogues share the same mode of action as the parent carbon compounds (carbon/silicon bioisosterism) but may have altered biological properties. Generally, sila-substitution can affect and, ideally, improve the pharmacological potency and selectivity, the pharmacodynamics, and the pharmacokinetics. Thus, the strategic sila-substitution of existing drugs is a very promising approach for the search of new drug candidates that have beneficial properties. [Page 56-57]....In this context, it is important to note that up to now there are no indications for a silicon-specific toxicity associated with organosilicon compounds [Page 57].
In conclusion:
Generally, incorporation of silicon into a known drug can affect the pharmacological potency and selectivity, the pharmacodynamics, and the pharmacokinetics and therefore can lead to beneficial biological properties that can be used with a clear IP position. The carbon/silicon switch strategy allows to follow in the development footsteps of the already optimized parent carbon compound and thereby to speed up the development process of the sila-analogue. There is a very efficient chemical industry, with a special expertise in organosilicon chemistry, that can supply pharmaceutical industry with the silicon-based fine chemicals needed. Nowadays, the carbon/silicon switch strategy is already an established tool in drug design and development in pharmaceutical industry, and it is anticipated that this approach will play an increasingly important role in the future.[Page 57]
2. Ascertaining the differences between the prior art and the claims at issue.
The compounds of claim 6 and 28 are drawn to the carbon to silicon bioisosteres of the prior art compound 1, where a carbon atom has been replaced with a silicon atom.
3. Resolving the level of ordinary skill in the pertinent art.
One of ordinary skill in the art would make sila-analogs of the prior art compound 1 since they would “share the same mode of action as the parent carbon compounds (carbon/silicon bioisosterism) but may have altered biological properties.” “Generally, sila-substitution can affect and, ideally, improve the pharmacological potency and selectivity, the pharmacodynamics, and the pharmacokinetics.” There are no silicon specific side effects. Finally this strategy has already been applied to related CFRR modulators as disclosed by Munoz. Munoz took ivacaftor and made various sila bioisosteres on page 7ff. As discussed on page 5, “[0005] A potential strategy for improving e.g., a drug's metabolic properties, efficacy, and/or safety profile is silicon modification. At the same time, because the general properties are similar to those of carbon, replacement of carbon by silicon would not be expected to affect e.g., the biochemical potency and/or selectivity of the drug as compared to the original chemical entity that contains only carbon.” The compounds had better activity than lumactofor as shown in Table 2 on page 66ff. Since this strategy had been successfully applied even within this narrow field of CFTR modulators, it would be even more obvious to apply it to additional CFTR modulators.
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.
4. Claims 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10,570,115 in view of Tacke “Drug Design Based on the Carbon/Silicon Switch Strategy” Topics in Medicinal Chemistry (2016), 17, 29-59 AND Munoz WO 2017177124 A1. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘115 patent are drawn to compound 1, which is the non-silylated analog of the claimed compounds. The compounds of the instant claims are obviousness type double patenting for the same reasoning/rationale as set forth in the 103 rejection over Alacio above.
Allowable Subject Matter
5. The following is a statement of reasons for the indication of allowable subject matter: Claim 28 and 30 are allowed. Claim 28 is drawn to the analogs of the Alacio compounds that require more than simple carbon to silicon bioisosteric substitution. All of the Alacio compounds have a terminal cycloalkyl while most the compounds in claim 28 do not. There is no teaching or suggestion to remove this feature from the species of Alacio. These compounds also require silicon atoms in various places. The other more closely related compounds such as compound 2-10, 2 – 13, 2 – 1 and 2 – 17 which do have the terminal cyclopropane have replaced a hydrogen with the TMS group which is not taught in the prior art. Functionally TMS is like a t-butyl group, however no such compounds are found in Alacio, with the t-butyl group on the phenyl ring or at other positions. For these reasons the compounds of claim 28 are allowable over the prior art.
Claim 30 is drawn to the germanium analogues of the Alacio compounds where the carbon has been replaced with a germanium atom. While germanium bioisosteres are known, their use has been much more limited as compared to silicon. A post filing review discusses the state-of-the-art, Xu “Recently developed organogermanium(IV) compounds as drug candidates and synthetic tools in drug discovery” Org. Biomol. Chem., 2025, 23, 7852.
Germanium carries a very high risk of both neurotoxicity and nephrotoxicity that will most likely limit its use, see Xu page 7853. Xu on page 7854 discusses the silicon bioisosteric strategy specifically referencing the Tacke paper that explains that the germanium strategy is not that well explored “Although less explored, the “germanium switch” is often investigated alongside the “silicon switch” to enable comparative analysis and provide comprehensive insights. Until now, only several research reports on the “germanium switch” in drug discovery could be collected, and the pharmacological characterization of germanium analogues should be discussed on a case-by-case basis.” Xu discusses several examples of this strategy, however almost all of these articles are post filing and none appear to have resulted in a drug candidate. Of course the authors of the review are working in this area of organogermanium synthesis and tend to have a forward-looking view of the technology. The author submitted the conclusion, “(3) Expanded studies on the in vitro and in vivo behaviour of organogermanium derivatives—including their mechanisms of action and toxicity—are essential.” Despite germanium sitting below silicon in the periodic table it is a very large atom compared to carbon with about 6 times of molecular weight and an atomic radius around double. Generally molecular weight is reduced in drug design for number of reasons and making Ge incorporation unlikely to improve properties in most drugs. Given the aforementioned toxicity issues a clear motivation is lacking to make a germanium analog.
Conclusion
6. 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.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
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