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 .
Election/Restrictions
Applicants’ election without traverse of Group I in the reply filed on July 2nd, 206 is acknowledged.
Applicants’ election with traverse of the first compound of claim 14 in the reply filed on July 2nd, 2026 is acknowledged. The traversal is on the grounds that Group I share a targeting unit polymyxin B nonapeptide analogues derivation; a linker (divalent group X) with two terminal carboxylate groups; and an anti-inflammatory drug having a glucocorticoid structure; and the common property of releasing a glucocorticoid.
This is not found persuasive because the species of group I lack unity of invention because even though the inventions of these groups require the technical feature of a targeting unit polymyxin B nonapeptide and a glucocorticoid structure, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Gordeev et al. (US9771394B2; published 2017) in view of Moonen et al. (Moonen, L., Geryl, H., D’Haese, P.C. et al. Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury. BMC Nephrol 19, 343 (2018)) and Alas et al. (Mona Alas, Azam Saghaeidehkordi, Kamaljit Kaur; Peptide–Drug Conjugates with Different Linkers for Cancer Therapy. J. Med. Chem. 14 January 2021; 64 (1): 216–232), and further in view of (Dubashynskaya, N. V., Bokatyi, A. N., & Skorik, Y. A. (2021). Dexamethasone Conjugates: Synthetic Approaches and Medical Prospects. Biomedicines, 9(4), 341.). Please refer to claim 1 and 14’s prior art rejection.
The requirement is still deemed proper and is therefore made FINAL.
Claims 2-5, 7, 10-11, 32, and 34-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 2nd, 2026.
Priority
The instant application claims priority to 371 National Stage Application PCT/CN2022/106975, filed July 21st, 2022, under 35 U.S.C. 119(a)-(d), and claims benefit to provisional application 63224402, filed July 21st, 2021, under 35 U.S.C.119 (e). The priority date of July 21st, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) filed on August 7th, 2024, March 11th, 2025, and July 2nd, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claims Status
The claims listing filed on July 2nd, 2026 is pending. Claims 2-5, 7, 10-11, 32, and 34-35 are withdrawn from further consideration for the reasons set forth in the restriction requirement, 37 CFR 1.142(b). Claims 1, 6, 14, 19, 21-22, 24, 27-31, and 36 are being examined on the merits in this office action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6, 19, 21-22, 24, 27-31, and 36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for R1 attached to X by forming a bond with the C21 hydroxyl group, does not reasonably provide enablement for R1 attached to X formed by subtracting a single atom from any H-containing group within the structure. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The specification is directed to the development of targeted therapies for kidney-associated cancers that reduce the adverse effects of standard-of care drugs [00010-00012].
The breadth of claim 1 encompasses the limitations of Formula II-P-2:
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which comprises a cyclic peptide, with variables R11 and R12, coupled to two components: 1) R1 attached to X by any H-containing atom by removing an atom in any of the Markush group compounds and 2) the linker X. The nature of the invention is therapeutic; the invention is an active drug (payloads) connected to a kidney-affinity structure via a linker [0022]. The applicant uses dexamethasone as the active drug in its synthesis embodiments [1570]. The state of the prior art does not demonstrate reactions schemes using the precursor used by applicant, dexamethasone, that attack the H-containing atoms other than C21 hydroxyl to attach substituents.
(Dubashynskaya, N. V., Bokatyi, A. N., & Skorik, Y. A. (2021). Dexamethasone Conjugates: Synthetic Approaches and Medical Prospects. Biomedicines, 9(4), 341.)
For example, Dubashynskaya et al. state:
The 21-hydroxyl group of DEX is not associated with anti-inflammatory activity and is therefore the most suitable site for conjugation. In addition, the 21-hydroxyl is the most reactive due to its steric availability. Through this 21-hydroxyl, DEX can be covalently bound to COOH and NH2 groups of various vectors to form ester and amide bonds that are capable of chemical and enzymatic hydrolysis to release an active pharmaceutical substance. However, hydrolysis usually easier and faster with an ester than with an amide for release of the drug. [pg 4 pgh 3].
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Dubashynskaya et al. also teach conjugation via the C3 carboxylate using reversible addition fragmentation-chain transfer polymerization and Cu (II)-catalyzed azide-alkyne cycloaddition [pg 7-8]. However, the C3 carboxylate group is not a H-containing atom and therefore, outside the purview of the claim. The remaining examples that Dubashynskaya et al. teach all demonstrate coupling to the C21 hydroxyl group [pg 5-6 and 8-11].
While one of ordinary skill in the art may be able to using organic chemistry principles and literature to design reaction schemes using a glucocorticoid, like dexamethasone, to synthesize some compounds of Formula II-P-2 with X connected to R1 with a different H-containing atom, one of ordinary skill in the art also knows that this is dependent on many chemical principles such as, reactivity and electronegativity, steric hinderance, and energy differences. It is not predictable that every H-containing atom in R1 will be able to form a bond with every linker, especially because each R1 has 14-17 different H-containing groups, and there are 16 different R1s and 41 different X linkers.
The inventors provide direction by showing the synthesis procedures of example compounds 1-10 [00166-00209]. In all the examples, the dexamethasone ring is only connected via the formation of an ester bond using the hydroxyl group of C21. The inventors provide adequate support in the specification for compounds of Formula II-P-2, wherein R1 is attached to X via the C21 hydroxyl group. However, this does not extend the predictability that the reaction schemes reduced to practice by the applicant can be used to attach X to every H-containing atom of R1. Moreover, to practice the full scope of the claimed invention, the applicant would be burdened with discovering unique reactions to attach R1. This requirement to discover, test, and validate constitutes undue experimentation. Thus, while the applicant is enabled for R1 attached to X by forming a bond with the C21 hydroxyl group, the applicant is not enabled for the full scope of R1 attached to X formed by subtracting a single atom from any H-containing group within the structure.
Claims 6, 19, 21-22, 24, 27-31, and 36 do not further limit the genus of H-containing atoms of R1 to which the linker X forms a bond, and are therefore rejected for not being supported by the specification under the enablement requirement
Claims 19, 21-22, 24, 27-31, and 36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. While the applicant does have support for the compounds represented by the example 1 and 2 compounds reduced in practice to enhance delivery of anti-inflammatory and immunomodulating agent dexamethasone, they do not have support for the full genus of compounds of Formula II-P-2 to enhance delivery of anti-inflammatory and immunomodulating agents.
Claim 19 recites “possesses anti-inflammatory activity, or a therapeutic effect for a kidney disease, as determined by (i) alleviating or slowing kidney cytokines release; (ii) reducing one or more biomarker wherein the one or more biomarkers are selected from protein level(s), blood urea nitrogen, and serum creatinine; or, (iii) improving a condition of a patient in need of therapy, or of a mammal in animal tests, wherein the anti-inflammatory activity is a therapy for renal inflammation, inflammation diseases in kidney injury or dysfunction, or inflammation induced by a nephrotoxic substance, including a pharmaceutical nephrotoxic substance.” However, the specification does not support that the inventors possess the complete recited genus and that the complete genus is able to possess anti-inflammatory activity, or a therapeutic effect for a kidney disease.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus [MPEP 2163 ii)].
The inventors provide direction by demonstrating the synthesis procedures of example compounds 1-10 [00166-00209] and further show how example compounds 1 and 2 enhance dexamethasone levels in kidney compared to dexamethasone alone. However, this is the only experimentation described by the applicant. Examples 1 and 2 have similar structures to examples 1-10 in the specifications and the compounds of claim 14, but do not support that the entire genus of Formula II-P-2 has anti-inflammatory activity or a therapeutic effect for a kidney disease claimed. Nor, would one of ordinary skill in the art be able to attest to the complete genus’s ability to do so because the applicant does not disclose any other experiments using other species where X, is attached to another H-containing group of R1, or another glucocorticoid besides dexamethasone is used for R1, or R1 has a dioxolane group and other X linkers. These factors raise questions on the conjugate’s ability to possess anti-inflammatory activity or a therapeutic effect for a kidney disease because the conjugate’s functional properties are dependent on its structure. Thus, while the applicant has support for the conjugates represented by examples reduced to practice (e.g. examples 1-10; claim 14), they do not have support for the complete genus of variants to possess anti-inflammatory activity or therapeutic effect for kidney disease.
Claims 21-22, 24, 27-31, and 36 are rejected under the written description requirement for failing to limit the genus of Formula II-P-2 to compounds with support in the specification for the efficacies claimed.
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.
Claim 31 is 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 31 recites the limitation "the renal inflammation" in line 1. There is insufficient antecedent basis for this limitation in the claim.
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.
Claims 1, 6, 19, 21-22, 24, 27-31, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Gordeev et al. (US9771394B2; published 2017) in view of Moonen et al. (Moonen, L., Geryl, H., D’Haese, P.C. et al. Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury. BMC Nephrol 19, 343 (2018)) and Alas et al. (Mona Alas, Azam Saghaeidehkordi, Kamaljit Kaur; Peptide–Drug Conjugates with Different Linkers for Cancer Therapy. J. Med. Chem. 14 January 2021; 64 (1): 216–232).
Gordeev et al. state that the “adverse effects of polymyxins result from accumulation thereof in kidneys due to the binding of these molecules to kidney tubule cells (nephrons), followed by mammalian membranes disruption and subsequent nephrotoxicity” [Col 2 line 4]. The new polymyxins provided exhibit potent antibacterial activity in vitro and in vivo, while being markedly less toxic. The polymyxin compound claimed by Gordeev et al. reads on every variable of instant Formula II-P-2 except for instant R1 and X [claim 1].
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R1 corresponds to instant R11 and is CH2CH(CH3)2 or CH2Ph; and [a], [b], and [c] read on instant Formula II-P-2 when they are NH. R2 corresponds to instant R1 and X and R3 together correspond to instant X.
Gordeev et al. also specify that:
R2 may incorporate a different antimicrobial class structure acting at an additional biological target like “antibacterial agents or bioactive structural element” [Col 6 line 6]; and that the
“compounds provided herein hold potential for new safe treatment for a range of serious Gram-negative infections, presently exacerbated with high mortality rates and serious adverse effects, such as kidney injury” [Col 236 line 10].
While, Gordeev et al. does motivate of one of ordinary skill in the art to add a different structure geared towards an additional biological target in R2, Gordeev elucidates that it is antimicrobial in nature and does not specify that the structure is therapeutic towards kidney injury as their invention aims to be. Furthermore, Gordeev et al. do not teach X and R3 to result in a succinyl linker, reading on the instant elected species of X.
Moonen et al. state that acute kidney injury (AKI) is an important, risk factor in the development of chronic kidney disease (CKD) [pg 1 abstract background]. Persistence of inflammation after a renal ischemic injury has been observed and is thought to be an important mechanism underlying progression of acute-to-chronic renal injury. Moonen et al. found that treatment with dexamethasone attenuated development of fibrosis [pg 1 abstract results]. The effects of dexamethasone on renal fibrosis persisted during the 3 week follow up period, in contrast to vehicle-treatment, where progression of fibrosis was observed. However, expression levels of the pro-fibrotic genes re-approached those of vehicle-treated injured kidneys suggesting that the effects of dexamethasone on fibrosis beyond the treatment period are temporary.
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Figure 1:dexamethasone structure
Moonen et al. does not teach using a succinyl linker to attach the dexamethasone to.
Alas et al. highlight main linker chemistries utilized in the design of peptide-drug conjugates [Abstract]. Alas et al. state that enzyme cleavable ester or amide bonds have gained popularity as linkers because they can be designed for selective cleavage in the tumor microenvironment or in the lysosomes [pg 217 pgh 3 line 1]. Of the enzyme cleavable linkers reviewed, Alas et al. discusses a succinyl linker used to conjugate paclitaxel to a peptide [Fig 2 and pg 219 pgh 4 line 1]. The conjugate was designed so that the ester bond in the conjugate is cleaved by the esterases present in lysosomes releasing paclitaxel in the brain. The study showed that the total brain uptake of the conjugate was 4.5-fold higher compared to free paclitaxel,
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Thus, one of ordinary skill in the art would find the succinyl linker to be an obvious preference for attaching a drug like dexamethasone to, to allow dexamethasone to be released from Gordeev’s cyclic peptide in the kidney cells by cleavage from cell’s lysosomes.
The combination of Gordeev et al., Moonen et al, and Alas et al.’s disclosures would motivate one of ordinary skill in the art to use dexamethasone as the R2 structure and a succinyl group for Gordeev’s X and R3 portion to additionally target acute kidney injury because Gordeev et al. teach that their compound holds potential for safe treatment for Gram-negative infections exacerbated by adverse effects such as kidney injury, Moonen et al. teach that dexamethasone attenuates fibrosis caused by acute kidney injury and Alas et al teach that the succinyl group is cleaved by lysosomes in a cell. Therefore, prior to the effective filing date, it was obvious to combine the teachings and create a compound encompassed by the limitations Formula II-P-2 to design a compound to deliver dexamethasone to kidney cells and help kidney inflammation.
Regarding claim 6, Gordeev’s R1 corresponds to instant R11. Gordeev states that R11 is CH2Ph or CH2CH(CH3)2 [claim 1].
Regarding claim 19, Moonen et al. teach that short term anti-inflammatory therapy with dexamethasone only transiently attenuates ischemia induced fibrosis in acute kidney injury and prolonged anti-inflammatory treatment seems warranted to achieve long term benefit [pg 1 abstract conclusion]. Therefore, prior to the effective filing date, it is obvious that a compound comprising dexamethasone, like instant Formula II-P-2 would possess anti-inflammatory activity in a therapy for inflammation in kidney injury.
Regarding claims 21-22, 24, and 27, Gordeev et al. and Moonen et al. do not teach the results claimed for the compounds reading on Formula II-P-2. However, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestions of Gordeev and Moonen cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Regarding claim 28, Gordeev et al. claims a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier [claim 23].
Regarding claims 29 and 30, Gordeev et al. does not specify using the composition in a method for treating inflammation. Moonen et al. administer 10mg/kg dexamethasone via intraperitoneal injection to mice [pg 2 pgh 5 line 8]. One of ordinary skill in the art knows that intraperitoneal injection is a type of parental administration as it bypasses the digestive tract by being delivered directly to the visceral peritoneum. Therefore, prior to the effective filing date one of ordinary skill in the art would find it obvious to administer a therapeutically effective amount of compound of Formula-II-P-2 transdermally, for the most reasonable expectation at being successful at treating inflammation.
Regarding claim 31, Moonen et al. evaluate the inflammatory suppression by dexamethasone on pathology progression and development of fibrosis in ischemia-reperfusion injured kidneys [pg 2 pgh 3 line 27]. Therefore, prior to the effective filing date, in combination of Gordeev et al. and Moonen et al’s teachings, one would find it obvious to use the method of transdermally administering a therapeutically effective amount of Formula II-P-2 comprising dexamethasone to treat acute kidney injury.
Regarding claim 36, Gordeev et al. claims a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier. Gordeev et al. does not specify using the composition in a method for treating inflammation. Moonen et al. evaluate the inflammatory suppression by dexamethasone on pathology progression and development of fibrosis in ischemia-reperfusion injured kidneys [pg 2 pgh 3 line 27]. Moonen et al. administer 10mg/kg dexamethasone via intraperitoneal injection to mice [pg 2 pgh 5 line 8]. Therefore, prior to the effective filing date one of ordinary skill in the art would find it obvious to administer a therapeutically effective amount of compound of Formula II-P-2 and a carrier to treat inflammation because Moonen et al. teach a method of treating inflammation using dexamethasone and instant Formula II-P-2 comprises of dexamethasone.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Claims 1, 6, 19, 21-22, 24, 27-31, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Gordeev et al. in view of Moonen et al. and Alas et al. as applied to claims 1, 6, 19, 21-22, 24, 27-31, and 36 above, and further in view of (Dubashynskaya, N. V., Bokatyi, A. N., & Skorik, Y. A. (2021). Dexamethasone Conjugates: Synthetic Approaches and Medical Prospects. Biomedicines, 9(4), 341.)
The combination of Gordeev, Moonen and Alas et al. teach a compound falling under the limitations of Formula II-P-2 to target kidney injury caused by Gram-negative infections and inflammation by delivering dexamethasone and a polymyxin derivative to kidney cells. Gordeev, Moonen and Alas et al. do not specifically motivate one of ordinary skill in the art to specifically create the elected species by attaching Alas’s succinyl linker to the 21-hydroxyl group of dexamethasone.
Dubashynskaya et al. teach:
The 21-hydroxyl group of DEX is not associated with anti-inflammatory activity and is therefore the most suitable site for conjugation. In addition, the 21-hydroxyl is the most reactive due to its steric availability. Through this 21-hydroxyl, DEX can be covalently bound to COOH and NH2 groups of various vectors to form ester and amide bonds that are capable of chemical and enzymatic hydrolysis to release an active pharmaceutical substance. [pg 4 pgh 3].
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Dubanshynskya combined with Gordeev, Moonen and Alas et al.’s compound direct one of ordinary skill in the art to the compound below because Dubashynskaya motivates one to form an ester or amide bond at the 21-hydroxyl group of dexamethasone because of its steric availability and bioavailability.
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Thus, it was obvious to make the elected compound prior to the effective filing date.
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, 6, 19, 21-22, 24, 27-31, and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-7, and 23 of U.S. Patent No. 9771394* in view of Moonen et al. (Moonen, L., Geryl, H., D’Haese, P.C. et al. Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury. BMC Nephrol 19, 343 (2018)) and Alas et al. (Mona Alas, Azam Saghaeidehkordi, Kamaljit Kaur; Peptide–Drug Conjugates with Different Linkers for Cancer Therapy. J. Med. Chem. 14 January 2021; 64 (1): 216–232)..
*US9771394B2 qualifies as prior art under 102 (a)(1). Therefore, its specification is also used to support the double patenting rejections.
Regarding claim 1, ‘394 claims a polymyxin compound that reads on every variable of instant Formula II-P-2 except for instant R1 and X[claim 1].
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R1 is CH2CH(CH3)2 or CH2Ph; and wherein
X is O, NH, N(C1-6alkyl), —NHC(═O)CH(CH2CH2NH2)O—, —OC(═O)CH(CH2CH2NH2)NH—, or —NHC(═O)CH(CH2CH2NH2)NH— connected to —C(═O)R2 at the latter NH group, and R3 is NH2, CH2NH2 or imidazolyl; or X is N and R3 is NH or N(C1-6alkyl) and R3 and X taken together comprise the group NHCH2CH2N or N(C1-6alkyl)CH2CH2N; and with the additional following provisions:
when X is O, —NHC(═O)CH(CH2CH2NH2)O—, or —OC(═O)CH(CH2CH2NH2)NH—, then R2 is C1-14alkyl, C3-12cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, arylheteroaryl, heteroarylaryl, dihydrofuran-2(3H)-one-3-yl, aryl-dihydrofuran-2(3H)-one-3-yl, C1-14alkyl-dihydrofuran-2(3H)-one-3-yl, tetrahydro-2H-pyran-2-one-3-yl, aryl-tetrahydro-2H-pyran-2-one-3-yl, C1-14alkyl-tetrahydro-2H-pyran-2-one-3-yl, NH(C1-14alkyl), NH(Ar), NH-(5 to 6-member heteroaromatic group containing at least one of N, S, and O atoms and the remaining atoms are carbon), OC1-14alkyl, OAr, NH(OC1-14alkyl), aryl[C(═O)OR4]r, biaryl[C(═O)OR4]r, aryl[OC(═O)R4]r, biaryl[OC(═O)R4]r, aryl-OC(═O)NR4R5, biaryl-OC(═O)NR4R5, or heteroarylalkyl; or R2 is (CR4R5)m(CR6R7)nC(═O)OR8, (CR4R5)m(CR6R7)nOC(═O)R8, (CR4R5)mN(C1-6alkyl)OC(═O)OR8, or L-P(═O)(OR11)(OR12);
when X is NH, N(C1-6alkyl), or NHC(═O)CH(CH2CH2NH2)NH— connected to C(═O)R2 at the latter NH, then R2 is aryl[C(═O)OR4]r, biaryl[C(═O)OR4]r, aryl[OC(═O)R4]r, biaryl[-OC(═O)OR4]r, aryl-OC(═O)NR4R5, biaryl-OC(═O)NR4R5, (CR4R5)m(CR6R7)nC(═O)OR8, (CR4R5)m(CR6R7)nOC(═O)R8, (CR4R5)mN(C1-6alkyl)OC(═O)OR8, dihydrofuran-2(3H)-one-3-yl, aryl-dihydrofuran-2(3H)-one-3-yl, C1-14alkyl-dihydrofuran-2(3H)-one-3-yl, tetrahydro-2H-pyran-2-one-3-yl, aryl-tetrahydro-2H-pyran-2-one-3-yl, C1-14alkyl-tetrahydro-2H-pyran-2-one-3-yl, or L-P(═O)(OR11)(OR12);
when R3 and X taken together comprise NHCH2CH2N or N(C1-6alkyl)CH2CH2N, then R2 is defined as above for when X is NH or —NHC(═O)CH(CH2CH2NH2)NH—;
wherein r is 1 or 2;
L is selected from O, NH, N(C1-6alkyl), C1-6alkylene, (CR4R5)m(CR6R7)n(CR9R10)o, CR4═CR6—(CR9R10)o, (CR4R5)m—CR6═CR10, O(CR4R5)m(CR6R7)n(CR9R10)o, NH(CR4R5)m(CR6R7)n(CR9R10)o, N(C1-6alkyl)(CR4R5)m(CR6R7)n(CR9R10)o, (CR4R5)m(CR6R7)n(CR9R10)oO, (CR4R5)m(CR6R7)n(CR9R10)oNH, and (CR4R5)m(CR6R7)n(CR9R10)oN(C1-6alkyl);
R4 through R7, R9, and R10 are independently H, NH2, halo, NH(C1-6alkyl), NH(OC1-6alkyl), C1-14alkyl, C3-6cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl; and
R8 is H, NH(C1-6alkyl), NH(OC1-6alkyl), C1-14alkyl, C3-6cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl; or
any two of R4 through R10, together with the atom(s) to which they are attached form a 4 to 7-member saturated or unsaturated heterocycle containing at least one O atom, or containing one O atom and an additional heteroatom independently selected from N and S and wherein the remaining atoms are carbon; or
any of i) R4 and R5, ii) R6 and R7, iii) R4 and R6, iv) R9 and R10, v) R6 and R10, and vi) R4 and R9, together with the atom to which they are attached form a C3-6cycloalkylene; or
any two of R4 through R10 together with the atom(s) to which they are attached form a 5 to 7-member saturated or unsaturated heterocycle wherein the ring optionally comprises an additional heteroatom selected from N, O, and S and wherein the remaining atoms are carbon; or
R6 and R8 together with the atom to which they are attached form a 4 to 6-member saturated heterocycle containing at least one O atom wherein the heterocycle optionally comprises an additional heteroatom selected from N, O, and S and wherein the remaining atoms are carbon; and
R11 and R12 are independently H, N(C1-6alkyl), C1-14alkyl, C3-6cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl; or
R11 and R12 together with the two oxygen atoms to which they are attached form a 5 to 7-member saturated heterocycle wherein the 2, 3, or 4 additional atoms are carbon; or
either or both of i) R4 and R11 and ii) R6 and R12 together with atoms to which they are attached form a 5 to 7-member saturated heterocycle containing one O atom and one P atom and where the remaining atoms are carbon;
wherein m, n, o, and p are independently selected from 0, 1, and 2, and wherein when L is (CR4R5)m(CR6R7)n(CR9R10)o, then m+n+o≧1; and
each of [a], [b], and [c] is independently selected from NH, N(C1-6alkyl) and O;
provided that when each of [a], [b], and [c] is NH, X is O, and R3 is CH2NH2, then R2 is not 5-methyl-heptyl. [claim 1]
R1 corresponds to instant R11 and is CH2CH(CH3)2 or CH2Ph; and [a], [b], and [c] read on instant Formula II-P-2 when they are NH. R2 corresponds to instant R1 and X and R3 together correspond to instant X.
‘394 does not claim using a glucocorticoid for its R2. ‘394 also specifies that:
“R2 may incorporate a different antimicrobial class structure acting at an additional biological target like “antibacterial agents or bioactive structural element” [Col 6 line 6]; and that the
“compounds provided herein hold potential for new safe treatment for a range of serious Gram-negative infections, presently exacerbated with high mortality rates and serious adverse effects, such as kidney injury” [Col 236 line 10].
While, ‘394 does motivate of one of ordinary skill in the art to add a different structure geared towards an additional biological target in R2, ‘394 elucidates that it is antimicrobial in nature and does not specify that the structure is therapeutic towards kidney injury as their invention aims to be. Furthermore, ‘394 does not teach X and R3 to result in a succinyl linker, reading on the instant elected species of X.
Moonen et al. state that acute kidney injury (AKI) is an important, risk factor in the development of chronic kidney disease (CKD) [pg 1 abstract background]. Persistence of inflammation after a renal ischemic injury has been observed and is thought to be an important mechanism underlying progression of acute-to-chronic renal injury. Moonen et al. found that treatment with dexamethasone attenuated development of fibrosis [pg 1 abstract results]. The effects of dexamethasone on renal fibrosis persisted during the 3 week follow up period, in contrast to vehicle-treatment, where progression of fibrosis was observed. However, expression levels of the pro-fibrotic genes re-approached those of vehicle-treated injured kidneys suggesting that the effects of dexamethasone on fibrosis beyond the treatment period are temporary.
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Figure 1:dexamethasone structure
Moonen et al. does not teach using a succinyl linker to attach the dexamethasone to.
Alas et al. state that enzyme cleavable ester or amide bonds have gained popularity as linkers because they can be designed for selective cleavage in the tumor microenvironment or in the lysosomes [pg 217 pgh 3 line 1]. Of the enzyme cleavable linkers reviewed, Alas et al. discusses a succinyl linker used to conjugate paclitaxel to a peptide [Fig 2 and pg 219 pgh 4 line 1]. The conjugate was designed so that the ester bond in the conjugate is cleaved by the esterases present in lysosomes releasing paclitaxel in the brain. The study showed that the total brain uptake of the conjugate was 4.5-fold higher compared to free paclitaxel,
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Thus, one of ordinary skill in the art would find the succinyl linker to be an obvious preference for attaching a drug like dexamethasone to, to allow dexamethasone to be released from ‘394’s cyclic peptide in the kidney cells by cleavage from cell’s lysosomes.
The combination of ‘394, Moonen et al, and Alas et al’s disclosures would motivate one of ordinary skill in the art to use dexamethasone as the R2 structure and a succinyl group for ‘394’s X and R3 portion to additionally target acute kidney injury because ‘394 teaches that their compound holds potential for safe treatment for Gram-negative infections exacerbated by adverse effects such as kidney injury, Moonen et al. teach that dexamethasone helps temporarily attenuate fibrosis caused by acute kidney injury, and Alas et al teach that the succinyl group is cleaved by lysosomes in a cell. Therefore, prior to the effective filing date, it was obvious to combine the teachings and create a compound encompassed by the limitations Formula II-P-2 to design a compound to deliver dexamethasone to kidney cells and help kidney inflammation.
Regarding claim 6, ‘394’s R1 corresponds to instant R11. ‘394 states that R11 is CH2Ph or CH2CH(CH3)2 [claim 1]. Therefore, prior to the effective filing date, it was obvious to claim a compound encompassed by the limitations Formula II-P-2, where instant R11 is CH2Ph.
Regarding claim 19, ‘394 does not teach that Formula II-P-2 possess anti-inflammatory activity or a therapeutic effect for a kidney disease. Moonen et al. teach that short term anti-inflammatory therapy with dexamethasone only transiently attenuates ischemia induced fibrosis in acute kidney injury and prolonged anti-inflammatory treatment seems warranted to achieve long term benefit [pg 1 abstract conclusion]. Therefore, prior to the effective filing date, it was obvious to claim that Formula II-P-2 possesses anti-inflammatory activity determined by improving the condition of a patient in need of therapy, or of a mammal in animal tests wherein the anti-inflammatory activity is a therapy for inflammation in kidney injury.
Regarding claims 21-22, 24, and 27, ‘394 and Moonen et al. do not teach the results claimed for the compounds reading on Formula II-P-2. However, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestions of ‘394 and Moonen cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Regarding claim 28, ‘394 claims a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier [claim 23]. Therefore, prior to the effective filing date, it was obvious to claim a pharmaceutical composition comprising a therapeutically effective amount of Formula II-P-2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier.
Regarding claims 29 and 30, ‘394 does not claim using the composition in a method for treating inflammation. Moonen et al. administer 10mg/kg dexamethasone via intraperitoneal injection to mice [pg 2 pgh 5 line 8]. One of ordinary skill in the art knows that intraperitoneal injections are a type of parental administration as they bypass the digestive tract by being delivered directly to the visceral peritoneum. Therefore, prior to the effective filing date one of ordinary skill in the art would find it obvious to claim a method of treating inflammation by administering a therapeutically effective amount of compound of Formula-II-P-2 transdermally, for the most reasonable expectation at being successful at treating inflammation.
Regarding claim 31, ‘394 does not claim a method for treating inflammation, wherein the renal inflammation is acute kidney injury. Moonen et al. evaluate the inflammatory suppression by dexamethasone on pathology progression and development of fibrosis in ischemia-reperfusion injured kidneys [pg 2 pgh 3 line 27]. Therefore, prior to the effective filing date, in combination of ‘394 and Moonen et al’s teachings, one would find it obvious to claim the method of transdermally administering a therapeutically effective amount of Formula II-P-2 comprising dexamethasone to treat acute kidney injury.
Regarding claim 36, ‘394 claims a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier. ‘394 does not claim using the composition in a method for treating inflammation. Moonen et al. evaluate the inflammatory suppression by dexamethasone on pathology progression and development of fibrosis in ischemia-reperfusion injured kidneys [pg 2 pgh 3 line 27]. Moonen et al. administer 10mg/kg dexamethasone via intraperitoneal injection to mice [pg 2 pgh 5 line 8]. Therefore, prior to the effective filing date one of ordinary skill in the art would find it obvious to claim a method of treating inflammation by administering a therapeutically effective amount of compound of Formula II-P-2 and a carrier to treat inflammation because Moonen et al. teach a method of treating inflammation using dexamethasone and instant Formula II-P-2 comprises of dexamethasone.
Claim 14 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-7, and 23 of U.S. Patent No. 9771394 in view of Moonen et al. and Alas et al. as applied to claims 1, 6, 19, 21-22, 24, 27-31, and 36 above, and further in view of (Dubashynskaya, N. V., Bokatyi, A. N., & Skorik, Y. A. (2021). Dexamethasone Conjugates: Synthetic Approaches and Medical Prospects. Biomedicines, 9(4), 341.).
The combination of ‘394, Moonen and Alas et al. teach a compound falling under the limitations of Formula II-P-2 to target kidney injury caused by Gram-negative infections and inflammation by delivering dexamethasone and a polymyxin derivative to kidney cells.’394, Moonen and Alas et al. do not specifically motivate one of ordinary skill in the art to specifically claim the elected species by attaching Alas’s succinyl linker to the 21-hydroxyl group of dexamethasone.
Dubashynskaya et al. teach:
The 21-hydroxyl group of DEX is not associated with anti-inflammatory activity and is therefore the most suitable site for conjugation. In addition, the 21-hydroxyl is the most reactive due to its steric availability. Through this 21-hydroxyl, DEX can be covalently bound to COOH and NH2 groups of various vectors to form ester and amide bonds that are capable of chemical and enzymatic hydrolysis to release an active pharmaceutical substance. [pg 4 pgh 3].
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Dubanshynskaya’s teachings combined with Gordeev, Moonen and Alas et al.’s compound direct one of ordinary skill in the art to the compound below because Dubashynskaya motivates one to form an ester or amide bond at the 21-hydroxyl group of dexamethasone because of its steric availability and bioavailability.
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Thus, it was obvious to claim the elected species prior to the effective filing date.
Claims 1, 6, 19, 21-22, 24, 27-31, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 9-11, 18, 23-26 of copending Application No. 17794141 in view of Moonen et al.
Regarding claim 1, ‘141 claims a compound that reads on every variable of instant Formula II-P-2 except for instant R1 [claims 1 and 5].
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wherein R1 and R2 is independently attached to X, by subtracting a single H atom from (H)nR1 and (H)oR2 at any one of the following H-containing group(s) independently selected from NH, OH, and CONH; and wherein (H)nR1 is independently selected from axitinib, brivanib, sunitinib, pazopanib, and semaxanib; or (b)
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and when an optional group R1 is absent, then the fragment R1X is replaced with R11,
wherein R11a is H;
when an optional group R2 is absent, then the fragment R2Z is replaced with R12a, wherein R12a is H;
optional A10 is Dab or Glu;
each optional divalent group X is independently selected from
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and either the left side or the right side of group X is connected to R1;
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; wherein the left side of X is connected to R1; and
C(=0), (C1-12alkylene)OC(=0), C(=O)(CRR6),(CR7R8)r(CR9R10)sC(=0), C(=O)O(CRR6)(CR7R8)r(CR9R10)C(=0), C(=0)N(Ra)(CRR6)p(CR7R8)r(CR9R10)sC(=0),
C(=O)O(CRR6)pS-S(CR7R8)r(CR9R10)sC(=0),
C(=O)(CRR6)pS-S(CR7RB)r(CR9R10)sOC(=0),
C(=0)N[(CRR6)p(CR7R8)rNHC(=0)A14](CR9R10)sC(=0), C(=0)N[(CRR6)(CR7R8)rN(C1-6alkyl)C(=0)A14](CR9R1)
C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR5R6)p(CR7R8)rOC(=0) (CR9R10)sC(=0), C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR5R6)pC(=O)O(CR7R8)r (CR9R10)sC(=0), C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] (CR5R6)pOC(=O)(CR7R8)r (CR9R10)sC(=0), C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] CH2CH2C(=O)OCH2CH2C(=0), C(=O)N[CH2CH2NHC(=O)CH2CH2CH(NH2)COOH] CH2CMe2C(=O)OCH2CH2C(=0), (S)-C(=0)N[CH2CH2NHC(=0)CH2CH2CH(NH2)COOH]CH2CH2C(=0), (R)-C(=0)N[CH2CH2NHC(=0)CH2CH2CH(NH2)COOH]CH2CH2C(=0), (S)-C(=0)N[CH2CH2NHC(=0)CH2CH2CH(NH(C=0)R7)COOH]CH2CH2C(=0), and (R)-C(=O)N[CH2CH2NHC(=0)CH2CH2CH(NH(C=O)R7)COOH]CH2CH2C(=0);R6, R7, R8, R9, and R10 are independently H or C1-14alkyl;RS is H or C1-14alkyl;Rsa is H; or wherein any two of R5, R6, R7, R8, R9, and R10, together with the carbon atom(s) to which they are attached form an unsaturated C3-6cycloalkylene;
integers p, r, and s are independently selected from 0, 1, and 2;
when fragments (CR5R6)p(CR7R8)r(CR9R10)s or (OCR5R6)p(CR7R8)r(CR9R10)s are present, then [p + r + s] >1; and wherein when fragments (CR5R6)p(CR7RB)r or (OCR5R6)p(CR7RB)r are present, then [p + r]≥1 [claims 1 and 5].
‘141’s R1 and X correspond to instant R1 and X, respectively. For example, the first three X groups of (a) and C(=O)(CRR6),(CR7R8)r(CR9R10)sC(=0), C(=0)O(CRR6)(CR7R8)r(CR9R10)C(=0), and C(=O)(CRR6)pS-S(CR7RB)r(CR9R10)sOC(=O) of (c) when R5-R10 are H and p, r, or s are 0-2 read on the instant X linkers, when A10 and A11 are not present (optional). ‘141 does not claim R1 to be glucocorticoid drug, instead of the drugs axitinib, brivanib, sunitinib, pazopanib, and semaxanib.
Moonen et al. state that acute kidney injury (AKI) is an important, risk factor in the development of chronic kidney disease (CKD) [pg 1 abstract background]. Persistence of inflammation after a renal ischemic injury has been observed and is thought to be an important mechanism underlying progression of acute-to-chronic renal injury. Moonen et al. found that treatment with dexamethasone attenuated development of fibrosis [pg 1 abstract results]. The effects of dexamethasone on renal fibrosis persisted during the 3 week follow up period, in contrast to vehicle-treatment, where progression of fibrosis was observed. However, expression levels of the pro-fibrotic genes re-approached those of vehicle-treated injured kidneys suggesting that the effects of dexamethasone on fibrosis beyond the treatment period are temporary.
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Figure 1:dexamethasone structure
The combination of ‘141 and Moonen et al.’s disclosures would motivate one of ordinary skill in the art to use dexamethasone in place of the R1 drugs to target acute kidney injury because Moonen et al. teach that dexamethasone helps temporarily attenuate fibrosis caused by acute kidney injury. Therefore, prior to the effective filing date, it was obvious to claim a compound encompassed by the limitations Formula II-P-2 by attaching dexamethasone in place of ‘141’s R1.
Regarding claim 6, ‘141’s R11 corresponds to instant R11. ‘141 states that R11 is CH2Ph [claim 5]. Therefore, prior to the effective filing date, it was obvious to claim a compound encompassed by the limitations Formula II-P-2, where instant R11 is CH2Ph.
Regarding claim 14, every component except for R1 of ‘141’s formula II read on species below when X is C(=O)(CRR6)p(CR7R8)r(CR9R10)sC(=0) where two of p, r, and s are 1 and one is 0 and A10 and A11 are not present (optional).
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Therefore, prior to the effective filing date, it was obvious to claim the above species because ‘141 claims every structural limitation except replacing R1 with dexamethasone in place of the cytotoxic and immunomodulation compound and Moonen et al. teach dexamethasone’s efficacy in treating kidney injury.
Regarding claim 19, ‘141 does not claim that Formula II-P-2 possess anti-inflammatory activity or a therapeutic effect for a kidney disease. Moonen et al. teach that short term anti-inflammatory therapy with dexamethasone only transiently attenuates ischemia induced fibrosis in acute kidney injury and prolonged anti-inflammatory treatment seems warranted to achieve long term benefit [pg 1 abstract conclusion]. Therefore, prior to the effective filing date, it was obvious to claim that Formula II-P-2 possesses anti-inflammatory activity as determined by improving a condition of a patient in need of therapy, or of a mammal in animal tests wherein the anti-inflammatory activity is a therapy for inflammation in kidney injury.
Regarding claims 21, ‘141 and Moonen et al. do not teach the results claimed for the compounds reading on Formula II-P-2. However, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestions of ‘141 and Moonen cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Regarding claim 22, ‘141 claims the compound of claim 1 wherein when administered to a mammal, said compound exhibits preferential accumulation in kidneys, with a ratio for its molar concentration in kidneys compared to that in blood between about 10 and 500. [claim 21]. Therefore, prior to the effective filing date it was obvious to claim the compound of Formula II-P-2, wherein when administered to a mammal, said compound exhibits preferential accumulation in kidneys, with a ratio for its molar concentration in kidneys compared to that in blood of between about 5 and 500 because the instant range encompasses ‘141’s range [MPEP 2144.05].
Regarding claim 24, ‘141 claims the compound of claim 1 wherein when administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (in molar amount) of an agent (H)nR1, said compound exhibits about 1.5- to 15-fold higher loading (tissue concentration) of agent (H)nR1 in kidneys, as compared to the standard therapeutic dosing of (H)nR1 [claim 25]. Therefore, prior to the effective filing date it was obvious to claim the compound of Formula II-P-2, wherein when administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (in molar amount) of an agent (H)nRl, said compound exhibits about 1.5- to 15-fold higher loading (tissue concentration) and/or drug exposure (area-under-the-curve, AUC) of agent (H)nRl in kidneys, as compared to the standard therapeutic dosing of free drugs (H)nRl, because the instant compound would behave similarly to ‘141’s compound.
Regarding claim 27, ‘141 claims the compound of claim 1, wherein when administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (in molar amount) of an agent(s) (H)nR1 and/or (H)oR2, said compound exhibits at least 2-fold higher loading (tissue concentration) of agent(s) (H)nR1 and/or (H)oR2 in kidneys, as compared to the standard therapeutic dosing of (H)nR1 [claim 26]. Therefore, prior to the effective filing date it was obvious to claim the compound of Formula II-P-2, wherein when administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (in molar amount) of an agent (H)nRl, exhibits at least 2-fold reduced rate of adverse effects and/or off-target toxicity manifestation, as compared to the standard therapeutic dosing of (H)nRl because it would behave similarly to ‘141’s compound.
Regarding claim 28, ‘141 claims a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier [claim 30]. Therefore, prior to the effective filing date, it was obvious to claim a pharmaceutical composition comprising a therapeutically effective amount of Formula II-P-2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier.
Regarding claims 29 and 30, ‘141 does not claim using the composition in a method for treating inflammation. Moonen et al. administer 10mg/kg dexamethasone via intraperitoneal injection to mice [pg 2 pgh 5 line 8]. One of ordinary skill in the art knows that intraperitoneal injections are a type of parental administration as they bypass the digestive tract by being delivered directly to the visceral peritoneum. Therefore, prior to the effective filing date one of ordinary skill in the art would find it obvious to claim a method of treating inflammation by administering a therapeutically effective amount of compound of Formula-II-P-2 transdermally, for the most reasonable expectation at being successful at treating inflammation.
Regarding claim 31, ‘141 does not claim a method for treating inflammation, wherein the renal inflammation is acute kidney injury. Moonen et al. evaluate the inflammatory suppression by dexamethasone on pathology progression and development of fibrosis in ischemia-reperfusion injured kidneys [pg 2 pgh 3 line 27]. Therefore, prior to the effective filing date, in combination of ‘141 and Moonen et al’s teachings, one would find it obvious to claim the method of transdermally administering a therapeutically effective amount of Formula II-P-2 comprising dexamethasone to treat acute kidney injury.
Regarding claim 36, ‘141 claims a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier [claim 30]. ‘141 does not claim using the composition in a method for treating inflammation. Moonen et al. evaluate the inflammatory suppression by dexamethasone on pathology progression and development of fibrosis in ischemia-reperfusion injured kidneys [pg 2 pgh 3 line 27]. Moonen et al. administer 10mg/kg dexamethasone via intraperitoneal injection to mice [pg 2 pgh 5 line 8]. Therefore, prior to the effective filing date one of ordinary skill in the art would find it obvious to claim a method of treating inflammation by administering a therapeutically effective amount of compound of Formula II-P-2 and a carrier to treat inflammation because Moonen et al. teach a method of treating inflammation using dexamethasone and instant Formula II-P-2 comprises of dexamethasone.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6, 19, 21-22, 24, 27-31, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 12, and 27 of copending Application No. 18580921 in view of Moonen et al.
Regarding claim 1, ‘921 claim a compound of Formula V-p or Formula V that read on every variable of instant Formula II-P-2 except for instant R1 [claim 1].
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wherein R1 is a residue formed by subtracting a single H atom from a precursor structure (H)nR at any one of the following H-containing groups independently selected from NH, OH, SH, C(=0)OH, CONH, SO2NH, and S(=0)NH when present in (H)nR1; and wherein each (H)nR is independently selected from:
a) a cytotoxic compound and an immunomodulating compound that possesses activity or is capable of inducing activity against one or more cancer cells;
b) afatinib, ARS-1630, axitinib, BGB-324, BLU-554, brivanib, (R)-1-((4-((4- fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f] [1,2,4]triazin-6-yl)oxy)propan-2-ol, cabozantinib, cediranib, ceritinib, ciforadenant, derazantinib, dovitinib, emtansine, englerin, monomethyl auristatin E, irinotecan, maytansinoid, neratinib, nilotinib, nintedanib, ozogamicin, paclitaxel, pazopanib, regorafenib, sacituzumab, selpercatinib, semaxanib, sorafenib, sunitinib, SN-38, temsirolimus, tivantinib, tivozanib, vatalanib, veliparib, and vinblastine; or variants thereof; and
c) a nitrogen-containing heterocyclic structure comprised in the (H)nR1 provided in (a) and (b) connected at a heterocyclic nitrogen atom present within (H)nR1; wherein the nitrogen atom becomes a nitrogen atom with a single positive charge, selected from imidazolium, pyrazolium, pyridinium, or indazolium group;
R6, R7, R8, R9 and R10 are independently selected from H, NH2, halo, NH(Ci-6alkyl), NH(OC1-6alkyl), C1-14alkyl, C3-6cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, and heteroarylalkyl;
R5 is H, NH2, NH(Ci-6alkyl), NH(OC1-6alkyl), C1-14alkyl, C3-6cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl;
or wherein any two of R5 through R10, together with the atom(s) to which they are attached form a 4 to 7-member saturated or unsaturated heterocycle containing at least one O atom, or containing one O atom and an additional heteroatom independently selected from N and S and wherein the remaining atoms are carbon; or wherein
any two of R5 through R10, together with the carbon atom(s) to which they are attached form a 4 to 7-member saturated or unsaturated C3-6cycloalkylene; or any of i) R5 and R6, ii) R6 and R7, and iii) R9 and R10, together with the atom to which they are attached form a saturated or unsaturated C3-6cycloalkylene; or wherein
any two of R5 through R10 together with the atom(s) to which they are attached form a 5 to 7-member saturated or unsaturated heterocycle wherein the ring optionally comprises an additional heteroatom selected from N, O, and S, and wherein the remaining atoms are carbon; or the resulting ring comprises 1,3-dioxol-2-one heterocycle; or wherein
R6 and R8 together with the atom to which they are attached form a 4 to 6-member saturated heterocycle containing at least one O atom wherein the heterocycle optionally comprises an additional heteroatom selected from N, O, and S, and wherein the remaining atoms are carbon; or the resulting ring comprises 1,3-dioxol-2-one heterocycle; and
R18 is H or C12alkyl;
R19 is H, C1p2alkyl, C(=O)H, C(=O)Cpi12alkyl, C(=O)OCpi12alkyl, C(=O)OCi12- alkyl, C(=O)NHC12alkyl, SO2C1p2alkyl, SO2aryl, C(=O)C3-7cycloalkyl, C(=O)OC3-7cycloalkyl, C(=O)NHC3-7cycloalkyl, C(=O)NHC12alkyl, SO2C3-7cycloalkyl, or Al;
each optional group L is selected from alkyl, CR20R210C(=O)CR22R23 and CR20R21C(=O)OCR22R23;R20 through R23 are independently selected from H, C1p2alkyl, or C3-7cycloalkyl; or any of the two adjacent groups R20 and R21 or R22 and R23 independently taken together form a C3-7cycloalkyl group;
A8 is optional and when present is selected from amino acid residue independently selected from unsubstituted or substituted at any N atom and where each of the amino acid residues, when present, is selected from alpha-, beta-, or gamma-amino acids, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine, Thr, Trp, Tyr, Val, D-Ala, D-Arg, D-Asn, D-Asp, D-Cys, D-Glu, D-Gln, D-His, D-Ile, D-Leu, D-Lys, D-Met, D-Phe, D-Pro, D-Ser, D-homoserine, D-Thr, D-Trp, D-Tyr, D-Val, 3-aminoproline, 4- aminoproline, biphenylalanine (Bip), D-Bip, 2,3-diaminopropionic acid (Dap), 2,4- diaminobutyric acid (Dab), 2,5-diaminopentanoic acid, azetidine-2-carboxylic acid, azetidine-3- carboxylic acid, piperidine-2-carboxylic acid, 6-aminopiperidine-2-carboxylic acid, 5- aminopiperidine-2-carboxylic acid, 4-aminopiperidine-2-carboxylic acid, 3-aminopiperidine-2- carboxylic acid, piperidine-3-carboxylic acid, 6-aminopiperidine-3-carboxylic acid, 5- aminopiperidine-3-carboxylic acid, 4-aminopiperidine-3-carboxylic acid, piperazine-2- carboxylic acid, 6-aminopiperazine-2-carboxylic acid, 8-azabicyclo[3.2.1]octane-2-carboxylic acid, 4-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3 -amino-8-azabicyclo [3.2.1] octane- 2-carboxylic acid, 6-azabicyclo[3.1.1]heptane-2-carboxylic acid, 3-amino-6- azabicyclo[3.1.1]heptane-2-carboxylic acid, and 4-amino-6-azabicyclo[3.1.1]heptane-2- carboxylic acid, 4-amino-3 -arylbutanoic acid, 4-amino-3-(3-chlorophenyl)butanoic acid; and 5- amino-4-arylpentanoic acid;
integer h is 0, 1, or 2;
integer t is 0, 1, or 2; and
integers u and w are independently 0 or 1. [claim 1]
The region of the carbonyl after A8 through R18 correspond to instant X. The region reads on the instant X linker Markush groups when L not present (optional), R5-R10 are H, R18 is H, and R19 is H, C(=O)H, or C(=O)NHCalkyl. ‘921’s R1 corresponds to instant R1. ‘921 does not claim R1 to be glucocorticoid drug, instead of a cytotoxic compound and an immunomodulating compound that possesses activity or is capable of inducing activity against one or more cancer cells.
Moonen et al. state that acute kidney injury (AKI) is an important, risk factor in the development of chronic kidney disease (CKD) [pg 1 abstract background]. Persistence of inflammation after a renal ischemic injury has been observed and is thought to be an important mechanism underlying progression of acute-to-chronic renal injury. Moonen et al. found that treatment with dexamethasone attenuated development of fibrosis [pg 1 abstract results]. The effects of dexamethasone on renal fibrosis persisted during the 3 week follow up period, in contrast to vehicle-treatment, where progression of fibrosis was observed. However, expression levels of the pro-fibrotic genes re-approached those of vehicle-treated injured kidneys suggesting that the effects of dexamethasone on fibrosis beyond the treatment period are temporary.
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Figure 2:dexamethasone structure
The combination of ‘921 and Moonen et al.’s disclosures would motivate one of ordinary skill in the art to use dexamethasone in place of the R1 drugs to target acute kidney injury because Moonen et al. teach that dexamethasone helps temporarily attenuate fibrosis caused by acute kidney injury. Therefore, prior to the effective filing date, it was obvious to claim a compound encompassed by the limitations Formula II-P-2 by attaching dexamethasone in place of ‘921’s R1.
Regarding claim 6, ‘921’s R11 corresponds to CH2Ph [claim 1]. Therefore, prior to the effective filing date, it was obvious to claim a compound encompassed by the limitations Formula II-P-2, where instant R11 is CH2Ph.
Regarding claim 14, the region of the carbonyl after A8 through R18 corresponds to instant X. ‘921’s Formula V and V-P region reads on the X linker of the species below when L not present (optional), R5-R10 are H, R18 is H, and R19 is H.
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Therefore, prior to the effective filing date, it was obvious to claim the above species because ‘921 claims every structural limitation except replacing R2 with dexamethasone in place of the active component and Moonen et al. teach dexamethasone’s efficacy in treating kidney injury.
Regarding claim 19, ‘921 does not claim that Formula II-P-2 possess anti-inflammatory activity or a therapeutic effect for a kidney disease. Moonen et al. teach that short term anti-inflammatory therapy with dexamethasone only transiently attenuates ischemia induced fibrosis in acute kidney injury and prolonged anti-inflammatory treatment seems warranted to achieve long term benefit [pg 1 abstract conclusion]. Therefore, prior to the effective filing date, it was obvious to claim that Formula II-P-2 possesses anti-inflammatory activity as determined by improving a condition of a patient in need of therapy, or of a mammal in animal tests wherein the anti-inflammatory activity is a therapy for inflammation in kidney injury.
Regarding claims 21-22, 24 and 27, ‘921 and Moonen et al. do not teach the results claimed for the compounds reading on Formula II-P-2. However, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestions of ‘921 and Moonen cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Regarding claim 28, ‘921 claims a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier [claim 27]. Therefore, prior to the effective filing date, it was obvious to claim a pharmaceutical composition comprising a therapeutically effective amount of Formula II-P-2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier.
Regarding claims 29 and 30, ‘921 does not claim using the composition in a method for treating inflammation. Moonen et al. administer 10 mg/kg dexamethasone via intraperitoneal injection to mice [pg 2 pgh 5 line 8]. One of ordinary skill in the art knows that intraperitoneal injections are a type of parental administration as they bypass the digestive tract by being delivered directly to the visceral peritoneum. Therefore, prior to the effective filing date one of ordinary skill in the art would find it obvious to claim a method of treating inflammation by administering a therapeutically effective amount of compound of Formula-II-P-2 transdermally, for the most reasonable expectation at being successful at treating inflammation.
Regarding claim 31, ‘921 does not claim a method for treating inflammation, wherein the renal inflammation is acute kidney injury. Moonen et al. evaluate the inflammatory suppression by dexamethasone on pathology progression and development of fibrosis in ischemia-reperfusion injured kidneys [pg 2 pgh 3 line 27]. Therefore, prior to the effective filing date, in combination of ‘921 and Moonen et al’s teachings, one would find it obvious to claim the method of transdermally administering a therapeutically effective amount of Formula II-P-2 comprising dexamethasone to treat acute kidney injury.
Regarding claim 36, ‘921 claims a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier [claim 27]. ‘921 does not claim using the composition in a method for treating inflammation. Moonen et al. evaluate the inflammatory suppression by dexamethasone on pathology progression and development of fibrosis in ischemia-reperfusion injured kidneys [pg 2 pgh 3 line 27]. Moonen et al. administer 10mg/kg dexamethasone via intraperitoneal injection to mice [pg 2 pgh 5 line 8]. Therefore, prior to the effective filing date one of ordinary skill in the art would find it obvious to claim a method of treating inflammation by administering a therapeutically effective amount of compound of Formula II-P-2 and a carrier to treat inflammation because Moonen et al. teach a method of treating inflammation using dexamethasone and instant Formula II-P-2 comprises of dexamethasone.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1, 6, 14, 19, 21-22, 24, 27-31, and 36 are rejected on the grounds of nonstatutory double patenting. Claims 1, 6, 14, 19, 21-22, 24, 27-31, and 36 are provisionally rejected on the ground of nonstatutory double patenting. Claims 1, 6, 19, 21-22, 24, 27-31, and 36 are rejected under 35 U.S.C. 112(a). Claim 31 is rejected under 35 U.S.C. 112(b). Claims 1, 6, 14, 19, 21-22, 24, 27-31, and 36 are rejected under 35 U.S.C. 103.
Correspondence
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/SACHI JAUHARI/ Examiner, Art Unit 1654
/CHRISTINA M MARCHETTI BRADLEY/ Primary Examiner, Art Unit 1654
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