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 1-12 are pending in the current application.
2. This application is a DIV of 17/276,837 03/17/2021 ABN; 17/276,837 is a 371 of PCT/EP2019/074986 09/18/2019. FOREIGN APPLICATIONS: EP 18195316.7 09/18/2018
EP 19164195.0 03/20/2019.
Response to Restriction Election
3. Applicant’s election of the species, compound IIc, in the reply filed on April 5, 2026 is acknowledged. The election was made without traverse. According to applicants’ representative claims 1-8 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is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claims 9-12, which do not read on the elected species is withdrawn.
Claim Rejections - 35 USC § 112 (b)
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 1-8 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. Regarding claim 1, the phrases "particularly n," “particularly wherein n is”, “particularly <700 g/mol, “more particularly <500 g/mol, or even <400 g/mol” make the claim indefinite. Claim 5 refers to “particularly, subcutaneous administration”. It is improper to speak of preferred embodiments within a claim since this is the purpose of a dependent claim. This renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding the parenthetical group "(fluorine)" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation n is 2 to 10, and the claim also recites n is 2, 3, 4, 6 and 8 as well as 2, 3, and 4, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
5. Claims 1-8 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 states “a compound comprising two or more cyclohexanolpentakisester moieties described by a general formula (I)”. The claim also uses both “”comprising or consisting of” to describe L. MPEP § 2173.05(h), states “A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group ‘comprising’ or ‘consisting essentially of’ the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim.”
Claim Rejections - 35 USC § 112 (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
6. Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 7 is drawn to the X definition CO2- which is not part of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 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.
7. Claims 1-4, 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Konieczny “Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors.” Organic & Biomolecular Chemistry, 2016 14(8), 2504-2514 AND Berridge “THE INOSITOL TRISPHOSPHATE/CALCIUM SIGNALING PATHWAY IN HEALTH AND DISEASE Physiol Rev 96: 1261–1296, 2016, Published August 10, 2016 (Both cited on the IDS). 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:
Determination of the scope and content of the prior art (MPEP 2141.01)
Konieczny teaches inositol phosphates which are the Formula I of claim 1 where n is 2, i.e. inositol with 5 phosphates (X is OPO32-) linked by linkers. The compounds in Figure 1 of structure 6, 8, 10, 12 are the claimed compounds.
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The compounds 5, 6, 7 and 8 have an either a C3 alkyl (5 and 6) or a C4 alkyl (7 and 8), substituted with oxygen, i.e. two oxygen substitutions on each end of the linker. The compounds 9, 10, are C4 alkyl substituted with one oxygen at each terminus. The specification on page 4 at lines 21-34 states that substitution covers not only substitutions in the traditional sense where a hydrogen atom is replaced by some group in an alkyl chain like a “carbonyl O”, which is referred to as the “narrower sense” and describes the oxo in linkers above in 5-8, but also substitutions where the connection of atoms to the more general structure is not necessarily through a carbon atom. At least for the divalent atoms the linkage described by substitution includes ethers where the atom is O.
The Konieczny compounds were “antagonists of IP3R1 with reasonable affinity”:
The activities of (1,2,3,4,6)IP5 (4) and the dimer 6 are directly compared in Fig. 3. Neither 4 nor 6 (100 µM) evoked Ca2+ release, but they reduced the sensitivity of the Ca2+ release evoked by (1,4,5)IP3 by 2.4 ± 0.2 and 20.9 ± 0.7-fold, respectively, without affecting the maximal response or Hill coefficient. Hence the dimer 6, like the monomer 4, is a competitive antagonist, but 6 has an apparent affinity that is 8.8 ± 1.0-fold greater than 4 (Table S3 in ESI†). The results with 6, suggesting that a dimer of (1,3,4,5,6)IP5 retained the lack of efficacy of (1,3,4,5,6)IP5 while displaying improved affinity, prompted analysis of seven additional dimeric analogs of 2-O-butyryl-(1,3,4,6)IP4 and (1,2,3,4,6)IP5 (Fig. 1C). None of the dimers (5–12, 100 µM) evoked Ca2+ release, and they all significantly decreased the sensitivity to (1,4,5)IP3 without affecting the maximal Ca2+ release or Hill coefficient (Fig. 4 and Table 1). All of the dimers (5–12) are therefore competitive antagonists. (Page 2510 column 1)
Konieczny explains in the first line of the abstract “Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that are widely expressed in animal cells, where they mediate the release of Ca2+ from intracellular stores evoked by extracellular stimuli.”
Berridge on page 1268 Table I has an entry for Nephrolithiasis which links increased INsP3/Ca2+ signaling to kidney stones.
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Berridge in Section XII. NEPHROLITHIASIS on page 1285 explains these effects further:
Nephrolithiasis arises due to an increase in kidney calcification that results in the formation of kidney stones (17). These stones, which consist mainly of calcium phosphate and calcium oxalate, can develop both in the lumen of the kidney tubules and in the surrounding tissue. In addition to obstructing the tubule lumen, these Ca2+ crystals may also damage the kidney through inflammatory reactions driven by cytokines such as TNF-a (184). There are multiple causes of nephrolithiasis, which is a complex disease. Stone formation has been linked to mutations of a number of genes that function in Ca2+ signaling. A number of these genes such as CaSR (77, 339), ITPKC (177), and Orai1 (78) function in the InsP 3 / Ca2+ signaling pathway. The Ca2+-sensing receptor (CaSR) is strongly expressed on the baso-lateral membrane of the thick ascending loop of Henle (TALH) cells where it reacts to increases in extracellular Ca2+ by initiating the formation of InsP3 that then releases Ca2+ from the ER to activate Ca2+ entry through the Orai1 channel. The ITPKC gene encodes the InsP3-kinase that phosphorylates and inactivates the Ca2+ -mobilizing activity of InsP 3 (FIGURE 2). Mutations in the ITPKC gene will result in an increase in the InsP 3/ Ca2+ signaling pathway that will enhance the transepithelial flux of Ca2+ that contributes to the formation of kidney stones.
Antagonizing the function of InsP3 via its receptor, IP3R, would be expected to reduce intracellular calcium as shown by the cartoon on page 1265 (Figure 4) and treat or reduce the occurrence of kidney stones.
Ascertainment of the difference between the prior art and the claims
Konieczny studied the structure–activity relationships of his IP3R antagonists but does not discuss their therapeutic use.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness.
It would have been obvious at the time the invention was made to administer the known compounds of Konieczny to patients suffering from various crystallization disorders such as nephrolithiasis. By antagonizing the IP3R receptors this will result in a decrease in the InsP3/ Ca2+ signaling pathway that will decrease the transepithelial flux of Ca2+ that contributes to the formation of kidney stones. The invention represents nothing more than the obvious application of the known compounds to patients suffering from disorders known to be associated with the pharmacology disclosed by Konieczny.
8. Claims 7-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Konieczny as applied to claims 1-4, 6 above and further in view of Agnelli “Dimeric Aminoglycosides as Antibiotics” Angew. Chem. Int. Ed. 2004, 43, 1562 –1566 and Rossi “Synthetic partial agonists reveal key steps in IP3 receptor activation.” NATURE CHEMICAL BIOLOGY VOLUME 5 NUM BER 9 SEPTEMBER 2009 page 631-639 (Both cited on the IDS).. 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:
Determination of the scope and content of the prior art (MPEP 2141.01)
Konieczny teaches inositol phosphates which are the Formula I of claim 1 where n is 2, i.e. inositol with 5 phosphates (X is OPO32-) linked by various linkers which are those of claim 1 as discussed above. The compounds in Figure 1 of structure 6, 8, 10, 12 are the closest to the claimed compounds. Konieczny developed a straightforward synthesis shown in Scheme 3 and 4 (Page 2507):
Synthesis of dimeric analogs of IP4 and IP5. For the synthesis of dimers 5–12, we envisioned the retrosynthetic analysis depicted in Scheme 2. Dimers 5–12 could be reached from the corresponding polyols 18 applying sequentially perphosphorylation and global deprotection protocols. The key to obtain all these compounds, differentially substituted on C-2, from a common intermediate (19) was to introduce orthogonal protective groups (PG and PG′) at an early stage of the synthesis. In this way, 19 could serve as the sole precursor for both series (2-O-butyrylated and 2-O-phosphorylated derivatives) by selective removal of PG. Esters and ethers 19 could, in turn, be prepared by dimerization of the corresponding monomers 20 using the appropriate linkers. Since this process involved the relatively hindered secondary alcohols 20, we were keen to explore the feasibility of this approach. Finally, starting from myo-inositol (13) selective introduction of the required protective groups was expected to lead to monomers 20. (Page 2506 column 1)..... Replacing halo-electrophiles with the more reactive ditosylates 2635 and 2736 and applying a protocol37 which involved KOH as base and a more polar solvent (DMSO) furnished the desired dimers (25a,b) in a clean way and in good yields.3
With the key intermediate dimers in our hands, we proceeded to the next steps, which involved installation of the butyryl and phosphate groups. Pd-catalyzed hydrogenolysis of 23a,b and 25a,b led to the corresponding diols 28, which were esterified upon exposure to butyric anhydride to give 29 in very good yields (Scheme 4).
Both 28 and 29 were then used to reach the final targets. Thus, careful treatment of these dimers (especially in the case of 29) with aqueous TFA furnished octaols and decaols 30, in nearly quantitative yields (Scheme 4). Perphosphorylation of these crude polyols was accomplished as described for 17b (Scheme 1) to obtain the protected polyphosphates 31. The latter were debenzylated upon hydrogenolysis in the presence of sodium bicarbonate to yield the octakis and decakis phosphate salts 5–12.39 (Page 2508, column 1)
Agnelli working on related glycoside dimers, also tethered two units of biologically active aminoglycosides with various linkers. By tethering neamine and nebramine through the -OH moiety of the cyclohexane group the dimers were formed (See Figure 3 on page 1564). Compound 19-C has the linker of the elected species in claim 8.
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“At the same time the relative distance between the two neamine cores was systematically probed by using “unobtrusive” polyglycol tethers between 9 and 14 atoms in length, with the expectation that the activity would reach a maximum at the optimal distance between the two sites.” (Page 1563). A straightforward synthesis is given in Scheme 2 where the tosylates (17a-17h) were the preferred linking intermediates. According to Agnelli, “The influence of the length and hydrophilicity of the linker was assessed by preparing two series of compounds: one with C2-symmetric hydrophilic polyglycol tethers and theother with hydrophobic polymethylene tethers, as shown in Figure 3. (Page 1563)....When tested against AS-wt RNA, they displayed Kd values and activities analogous to those of their polyether-linked counterparts. (Page 1564 column 1).” That is the both the alkyl groups 19g and 19h gave similar results to the polyglycol groups.
Rossi who was working on compounds related to the phosphoinositol dimers of Konieczny used polyol linkers to join the two inositol groups. Compounds 3 and 4 in Figure 1 (c) used this type of linker:
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“[H]omodimers of IP3 with longer linkers (3 and 4) also bind to IP3R with greater affinity than IP3....” (Page 633). The physical difference between the two moieties where n is 6 or n is 180 is 1.5nm versus 8nm according to Table, yet the biological activity is nearly the same.
Ascertainment of the difference between the prior art and the claims
The compounds of the prior art differ from the compounds claimed by the type of linker, which was an ester type linkage in compounds 6 and 8 and an ether linkage in compounds 10 and 12, but is a polyglycol in the claimed compounds. This could also be described as a bioisosteric replacement of a methylene group with an oxygen at least for the compound 12, where if one of the carbons in the alkyl linker were replaced with an oxygen the compound IIa in claim 8 would be produced.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness.
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to change the ester or polyalkyl linker to a polyol to produce the instant invention. Konieczny already used two types of linkers and the change would not fundamentally alter the core structure required for biological activity, the bis-phosphoinositol. Agnelli shows the routine nature of this experimentation in the glycoside dimer field and suggests that the preparation would be straightforward with a reasonable expectation of success. There would have been a reasonable expectation of success of making the compounds since Agnelli’s tosylate intermediates would dovetail nicely into the synthesis of Konieczny which also used tosylate linkers. Rossi is further evidence showing the routine use of these linkers in the same area as Konieczny and also shows that the length of the polyglycol chain is not critical. By antagonizing the IP3R receptors with these ligands it is expected to decrease in the InsP3/Ca2+ signaling pathway that will decrease the transepithelial flux of Ca2+ that contributes to the formation of kidney stones.
9. Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Konieczny AND Berridge as applied to claims 1-4, 6 above, and further in view of GRASES ES 2486441 A1 [English equivalent is US 11,207,365 B2]. Konieczny AND Berridge do not discuss routes of administration. GRASES on column 3 lines 5 to 65 describe similar inositol polyphosphates for treating renal lithiasis, urolithiasis or nephrolithiasis in a similar manner to the instant claims. This treatment method is described column 4 lines 9 to 11 involve the method of administration of claim 5 “oral, parenteral, enteral or intravenous administration”. It would have been obvious at the time the invention was made to use known administration routes that have been used for very similar inositol polyphosphates to treat the same conditions of nephrolithiasis and other crystallization type diseases.
Conclusion
10. 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
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