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 .
Priority
The instant application is a 371 National Stage Entry of PCT/PCT/IB2023/054078 filed on April 21, 2023 which claims priority to foreign application No. IT102022000008048 filed on April 22, 2022.
No English Translation
The Examiner notes that no certified translation of the Foreign Application IT102022000008048 filed on April 22, 2022 has been placed on record. If applicant wants the application to be accorded benefit of the non-English language application, a certified translation is required (see 35 U.S.C. 119(b)(3), 37 CFR 1.55(g)(1)-(4)). Applicant is advised that any showing of priority that relies on a non-English language application is prima facie insufficient if no certified translation of the application is on file.
Claim Objections
Claims 1-5 are objected to because of the following informalities:
The claims are currently written in a plural format which creates grammar issues, in addition to unnecessary language that complicates the claim. See also the 35 USC 112 rejections below regarding ambiguity issues.
Claim 1 recites “KCC2 inhibitors” but should read “A KCC2 inhibitor” (A KCC2 inhibitor
Claim 2 recites “The KCC2 inhibitors according to claim 1, characterized in that said selected KCC2 inhibitors have formula (I) or its pharmaceutically acceptable salts, solvates, and tautomers wherein” but should read “The KCC2 inhibitor according to claim 1, wherein the KCC2 inhibitor is of formula (I) or a pharmaceutically acceptable salt, solvate, or tautomer thereof wherein…” (The KCC2 inhibitor wherein the is of formula (I) or a pharmaceutically acceptable saltor tautomerthereof wherein..).
Claim 2 is also missing a final conjunction, “halogen; R3 and R4 are each independently… and should read “halogen; and R3 and R4 are each independently…” (halogen; and R3 and R4 are each independently…).
Claim 3 recites “The KCC2 inhibitors according to claim 2” but should read “The KCC2 inhibitor according to claim 2” (The KCC2 inhibitor
Claim 3 is also missing a final conjunction, “iodine; R3 and R4 are each independently…” and should read “iodine; and R3 and R4 are each independently…” (iodine; and R3 and R4 are each independently…).
Claim 4 recites “The KCC2 inhibitors according to claim 1, characterized in that they are selected from the group consisting of furosemide and azosemide.” but should read “The KCC2 inhibitor according to claim 1, selected from the group consisting of furosemide and azosemide.” (The KCC2 inhibitor
Claim 5 recites “The KCC2 inhibitors according to claim 1, characterized in that they are:” which should read “The KCC2 inhibitor according to claim 1, wherein the KCC2 inhibitor has the structure:” (The KCC2 inhibitor wherein the KCC2 inhibitor has the structure .
Appropriate correction is required.
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.
Claims 1-2 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 recites “KCC2 inhibitors for the use in the treatment of age-related cognitive decline unrelated to a neurodegenerative disease.” which is ambiguous, describing a compound (A KCC2 inhibitor) or composition (multiple KCC2 inhibitors together) with an intended use or functional limitation. For the purposes of applying art, claim 1 is interpreted as a compound product with intended use:
A KCC2 inhibitor for the treatment of age-related cognitive decline unrelated to a neurodegenerative disease.
Claim 2 recites the limitation "said selected KCC2 inhibitors". There is insufficient antecedent basis for this limitation in the claim since no previous “selected KCC2 inhibitors” has been recited, only “KCC2 inhibitors”.
Claim 2 recites “have formula (I) or its pharmaceutical acceptable salts, solvate, and tautomers” which could read one of two ways:
1a. A KCC2 inhibitor of Formula I or 1b. pharmaceutical acceptable salts, solvate, and tautomers of Formula I (1b would appear to be a composition mixture).
2a. A KCC2 inhibitor of Formula I or a pharmaceutical acceptable salt, solvate, or tautomer thereof.
For the purposes of applying art, claim 2 is interpreted as listing in the alternative:
A KCC2 inhibitor of Formula I or a pharmaceutical acceptable salt, solvate, or tautomer thereof.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 1-4 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 the treatment of age-related cognitive decline unrelated to a neurodegenerative disease with furosemide, does not reasonably provide enablement for the treatment of age-related cognitive decline unrelated to a neurodegenerative disease with any KCC2 inhibitor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the nature of the invention,
2- the breadth of the claims,
3- the state of the prior art,
4- the predictability of the art,
5- the amount of direction or guidance provided
6- the presence or absence of working examples,
7- the quantity of experimentation necessary, and
8- the relative skill of those in the art.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Undue experimentation is required by one skilled in the art to determine enablement of the instant disclosure as claimed due to the following:
The nature of the invention (1) and the breadth of the claims (2)
The nature of the invention and breadth of claims is the intended use of treatment of age-related cognitive decline unrelated to a neurodegenerative disease with a KCC2 inhibitor broadly (claim 1) or a KCC2 inhibitor of Formula 1 (claims 2-3) or furesomide or azosemide (claim 4).
The instant specification defines age-related cognitive decline unrelated to a neurodegenerative disease means,
“all disorders that can occur with aging of the central nervous system unrelated to a diagnosis of neurodegenerative disease (e.g. Alzheimer’s, Parkinson’s, Huntington’s). This condition is characterized by problems of memory, language, thoughts and judgements with various degrees of severity.” (see instant spec. at p. 9).
The broadest reasonable interpretation includes any KCC2 inhibitor, capable of the intended result of treating age-related cognitive decline unrelated to a neurodegenerative disease.
The state (3) and predictability (4) of the art
MPEP § 2164.05(a) states if a publication demonstrates that those of ordinary skill in the art would not find that a particular invention was not enabled years after the filing date, the publication would be evidence that the claimed invention was not possible at the time of filing.
Regarding known inhibitors of KCC2, Delpire et. al.1 discloses that bumetanide and furosemide inhibits NKCC1, NKCC2 and KCC2 - although at much higher concentrations (see Delpire at p. 5383 left col. last paragraph - right col. ¶1; p. 5386, left col. ¶2-3). Delpire thus teaches furosemide is mainly an NKCC inhibitor.
Regarding inhibiting KCC2 to treat cognitive decline, Simonnet et. al.2 teaches silencing KCC2 compromises spatial and contextual memory (see Simonnet at Abstract). Simonnet goes on to say “our results establish a causal relationship between KCC2 expression and cognitive performance and suggest that impaired rhythmopathies and neuronal hyperexcitability are central to the deficits caused by KCC2 silencing in the adult mouse brain” (see id). Simonnet thus teaches inhibiting KCC2 negatively impacts cognition.
Virtanen et. al.3 states:
“It has been recently observed that changes in the cellular mechanisms supporting learning and memory in the aging brain involve reorganization of excitatory signaling, whereby high synapse specificity is replaced by multi-input synapses. A key factor here might be functional downregulation of KCC2, and this would fit with the general principle that the dynamic ranges of physiological capacities (see earlier) tend to become narrower during aging and senescence. Age-dependent KCC2 downregulation may also explain the improvement of cognition that is achieved by reducing neuronal hyperexcitability with anticonvulsant agents in elderly patients with mild cognitive impairment (MCI). Whether KCC2 down regulation is involved in the age-dependent loss of dendritic spines in cortical neurons is not known. Nevertheless, KCC2 may well turn out to be an important factor in the chain of events which leads from MCI to major neurodegenerative diseases, including Alzheimer's.” (emphasis added, see Virtanen at p. 388 ¶3).
Virtanen thus teaches the downregulation of KCC2 that occurs with aging likely leads to mild cognitive impairment.
Moore et. al.4 states,
“KCC2 deficits have been detected in several neurodegenerative disorders and reducing intracellular CI⁻ levels can rescue memory deficits in a mouse model of Huntington's disease, suggesting that increasing KCC2 function may be therapeutically beneficial for disorders associated with memory deficits. In support of this, it was shown that mice performed better in the spatial memory tasks compared to their WT litter mates, suggesting that increasing KCC2 function may improve memory retention.” (emphasis added, see Moore at p. 8 right col. ¶3).
Moore thus teaches increasing KCC2 function is expected to improve cognitive function, not decreasing.
The prior art casts doubt that, and expressly teaches away from, using any KCC2 inhibitor to improve cognitive function in a subject. The prior art suggests that furosemide can inhibit KCC2, but is largely considered an NKCC inhibitor.
The amount of direction or guidance provided (5) and the presence or absence of working examples (6)
The specification provides the following embodiments:
Example 1 tested KCC2 levels in humans 75-80 years and 20-25 years, finding KCC2 was upregulated in the 75-80 year old population compared to the 20-25 year old population (see instant spec. at Figure 1a and p. 12).
Example 2 tested administering a sedative to and elderly and young mice populations, finding the elderly mice exhibited an over-sedation reaction, likely due to hyper-inhibitory GABAergic transmission, in accordance with KCC2 upregulation (see instant spec. at Figures 1b and 2, and p. 13).
Example 3 tested elderly mice before and after furosemide administration, which appeared to improved spatial memory (see instant spec. at Figurs 3a and 3b and pp. 13-14).
Example 4 tested furesomide’s ability to inhibit KCC2 in vitro, and determined furesomide to be an inhibitor of KCC2 at high concentrations (see instant spec. at pp. 14-15 Tables 1-2).
Instant example 4’s results are supported by the prior art’s finding that furesomide is a weaker KCC2 inhibitor compared to its NKCC inhibiting properties (as taught by Delpire).
Instant examples 1-2 are contradicted by the prior art’s findings that natural aging is associated with down-regulation of KCC2 (as taught by Simonnet, Virtanen, Moore).
The instant specification fails to identify the causal link between the alleged KCC2 inhibition and the effect shown in instant example 3, the effect shown for furosemide cannot be plausibly generalized to KCC2 inhibitors based on the prior art, nor can it be plausibly generalized to compounds of formula (I) according to claims 2-4, since there is no indication that the structural modifications involved would still allow to retain the effects shown for furosemide.
The specification provides enablement for the treatment of age-related cognitive decline with furesomide.
Therefore, the full scope of the intended use of treatment in claims 1-4 are not enabled.
The quantity of experimentation necessary (7) and the relative skill of those in the art (8)
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. Because of the unknown predictability in the art (as discussed above) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that KCC2 inhibitors could be used as treatments for age-related cognitive decline unrelated to a neurodegenerative disease.
Brenner v. Manson states "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (Brenner v. Manson 383 U.S. 519, 536, 148 USPQ 689, 696 (1966), cited in Genentech Inc. vs. Nova Nordisk 42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, little experimentation provided is drawn to the nexus between inhibiting KCC2 and the treatment of cognitive decline. A review of the prior art fails to reveal that KCC2 inhibitors are useful as cognitive decline treatments, and actively teaches away from such a use of KCC2 inhibitors. Determining if a KCC2 inhibitor would be therapeutic for cognitive decline would require careful analysis and replicability of a composition comprising a compound of Formula I or screening of existing compounds for KCC2 inhibition, formulation into a suitable dosage form, assay testing to correlate clinical efficacy, identifying off-targets, subjecting to animal trials, and subjecting to clinical trials.
All this is undue experimentation given the limited guidance and direction provided by Applicants.
Conclusion
Accordingly, the inventions of claims 1-4 do not comply with the enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Suggested Amendment
Examiner suggests amending to limit the KCC2 inhibitor to furosemide as in claim 5 and cancelling the other claims to overcome the instant rejection.
Claim Rejections - 35 USC § 112(a) – Written Description
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.
Claim 1 is 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.
Claim 1 appears to have an intended use or a functional limitation, “treatment of age-related cognitive decline unrelated to a neurodegenerative disease” attached to another function “KCC2 inhibitor” with no structure. Applicant has not provided enough evidence to support what structure of “KCC2 inhibitor” exhibits the claimed function. Applicant has only examined one species, furosemide, for KCC2 inhibitory activity (see instant spec. at pp. 14-15 Tables 1-2 and Example 4) and ability to improve cognitive function (see instant spec. at Figures 3a and 3b and pp. 13-14 Example 3). How would an artisan know what to make in order to achieve a compound of claim 1?
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.
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.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/191471 A1 to Ben-Ari et. al.5 in view of Bie et. al.6 and Delpire.
Regarding claims 1-5 and a KCC2 inhibitor for treating age-related cognitive decline unrelated to a neurodegenerative disease, Ben-Ari teaches compositions for treating neurodegenerative disease with Parkinsonian syndromes in a subject comprising an effective modulator of a chloride transporter that is an inhibitor of a transporter involved in the importation of chloride into neurons (see Ben-Ari at claim 1) wherein the inhibitor may be an NKCC inhibitor (see Ben-Ari at claim 4) such as furosemide, azosemide, or bumetanide (see Ben-Ari at claim 6). Ben-Ari teaches an embodiment where the composition is used in a method for treating behavioral and/or cognitive symptoms of a neurodegenerative disease with parkinsonian syndromes (see Ben-Ari at p. 36 ¶6).
The prior art differs from the instant claims as follows: While Ben-Ari teaches furosemide or azosemide as NKCC inhibitors for treating neurodegenerative disease or cognitive symptoms of a neurodegenerative disease, Ben-Ari does not specify the instantly claimed intended use of treating age-related cognitive decline unrelated to a neurodegenerative disease.
However,
Regarding inhibiting KCC2, Delpire discloses that bumetanide and furosemide inhibits NKCC1, NKCC2 and KCC2 - although at much higher concentrations (see Delpire at p. 5383 left col. last paragraph - right col. ¶1; p. 5386, left col. ¶2-3). Delpire thus teaches furosemide is mainly an NKCC inhibitor.
Regarding for treatment of cognitive decline, Bie teaches hippocampal GABAergic transmission is involved in memory acquisition and consolidation (see Bie at Abstract). Bie states “hippocampal GABAergic interneurons regulate the excitation of pyramidal cells and synchronize the activity of neural networks in the cortex and the hippocampus, thereby modulating memory network dynamics” (see Bie at p. 1 left col ¶1). Bie teaches the conductance of GABAA receptor is critically modulated by membrane anion-chloride cotransporters KCC2 and NKCC1 (see Bie at p. 1 right col. ¶2). Bie goes on to teach that reductions of BDNF, a regulator of the GABAergic system, and/or increase of proBDNF, the stored version of BDNF, in various brain regions (e.g., hippocampus and cortex) were associated with the impaired cognition in Alzheimer’s disease (AD) and aged populations (see Bie at p. 2 left col. ¶1). Bie teaches administration of bumetanide, an NKCC1 inhibitor, in an AD rat model mitigated impaired performance in a cognitive recall test (see Bie at p. 2 right col. section 2.4 and p. 6 left col. ¶2 - right col. ¶1).
While Bie studies the effect of NKCC inhibitor bumetanide in an Alzheimer’s disease model, Bie’s teachings in regards to the role of NKCC and GABAergic transmission are still relevant to cognitive decline, including in aged populations.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2144.07, a prima facie case of obviousness exists for the selection of a known material based on its suitability for its intended use. Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). It would have been obvious to an artisan to expect a known NKCC inhibitor such as furosemide or azosemide or bumetanide, also known to exhibit KCC2 inhibition, (as taught by Ben-Ari and Delpire) to be capable of treating age-related cognitive decline unrelated to a neurodegenerative disease with a reasonable expectation of success because the prior art teaches NKCC is important for the GABAergic system which influences cognitive function, and that the functionally similar NKCC inhibitor bumetanide showed improvement in cognitive function in vivo (as taught by Bie). Even though the prior art examines the effect of NKCC inhibitor bumetanide in an Alzheimer’s disease model (as taught by Bie), an artisan would still have a motivation to pursue testing in an age-related cognitive decline not associated with a neurodegenerative disease because of the role NKCC plays in cognitive decline in aged populations (as suggested by Bie).
Furthermore, it is well-within the ordinary skill in art to:
identify relevant pathologies between diseases in order to identify suitable treatment options,
identify known species of a functional genus with members known to treat a condition.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
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.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of copending Application No. 18/858,0157.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding instant claim 1 and a KCC2 inhibitor for use in the treatment of age-related cognitive decline unrelated to a neurodegenerative disease, App’015 claims a KCC2 inhibitor for the use in the treatment of cognitive decline of Formula III (App’015 claim 1), further structurally narrowed (App’015 claims 2-4). App’015 further claims wherein the cognitive decline is age-related cognitive decline (App’015 claims 5-6).
The copending claims differ as follows: while App’015 claims KCC2 inhibitors for use in the treatment of cognitive decline or agre-related cognitive decline, App’015 does not specify wherein the age-related cognitive decline is unrelated to a neurodegenerative disease.
However, it would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed invention with a reasonable expectation of success in view of the copending claims for at least the following reason(s):
Regarding the difference in intended use, this is not a patentably distinct difference. The claims are still drawn to KCC2 inhibitors, with an intended use of treating cognitive decline. An artisan would readily appreciate that the structural limitations of App’015 are encompassed by the functional limitation of instant claim 1 (a KCC2 inhibitor), with a significantly overlapping intended use (treating cognitive decline or an age-related cognitive decline), and thus would be capable of performing the instantly claimed intended use.
This is a provisional nonstatutory double patenting rejection.
Claims 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 9,822,368 B28 in view of Hithersay et. al.9 and Delpire.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding instant claim 1 and a KCC2 inhibitor for use in the treatment of age-related cognitive decline unrelated to a neurodegenerative disease, US’368 claims a method for reducing one or more symptoms associated with Down syndrome in a subject comprising administering an effective amount of a modulator of a chloride transporter, wherein said modulator comprises bumetanide (US’368 claim 1), further limited by dose (US’368 claim 2) and administration route (US’368 claim 3), and wherein the subject is diagnosed with or affected by Down syndrome (US’368 claims 4-5).
Regarding instant claims 4-5 and a compound of Formula I, US’368 claims wherein said modulator is administered with at least one inhibitor of a transporter involved in the importation of chloride into neurons, wherein said inhibitor may be furosemide or azosemide (US’360 claim 6).
The patented claims differ from the instant claims as follows: US’368 claims methods of using bumetanide, furosemide, or azosemide, which instant application claims as KCC2 inhibitors with an intended use. US’368 does not specify the instant intended use of treating an age-related cognitive decline unrelated to a neurodegenerative disease.
However,
Hithersay non-Alzheimer’s cognitive decline in Down syndrome subjects is difficult to identify because of intellectual disability (see Hithersay at Purpose of review). Hithersay teaches older subjects with Down syndrome often present with cognitive decline (see Hithersay at Recent findings).
Delpire discloses that bumetanide and furosemide inhibits NKCC1, NKCC2 and KCC2 - although at much higher concentrations (see Delpire at p. 5383 left col. last paragraph - right col. ¶1; p. 5386, left col. ¶2-3).
Therefore, it would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed invention with a reasonable expectation of success in view of the copending claims for at least the following reason(s):
US’368 claims a method of administering a modulator of a chloride transporter bumetanide and an inhibitor of a transporter involved in the importation of chloride into neurons such as the instantly claimed furosemide or azosemide. While US’368 does not specify their ability to inhibit KCC2, US’368 still claims a method that encompasses the instantly claimed intended use; by administering furosemide or azosemide to treat a subject with Down syndrome, US’368 is fulfilling the intended use of treating an age-related cognitive decline unrelated to a neurodegenerative disease because the prior art teaches Down syndrome subjects are pre-disposed to age-related cognitive decline, unrelated to a neurodegenerative disease such as Alzheimer’s, in addition to being pre-disposed to Alzheimer’s (as taught by Hithersay). Moreover the prior art teaches bumetanide and furosemide are known to inhibit KCC2 (as taught by Delpire).
Accordingly the claims are not patentably distinct.
Conclusion
Claims 1-5 are objected to.
Claims 1-5 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SOPHIA J REILLY whose telephone number is (703)756-5669. The examiner can normally be reached 9:00 am - 5:00 pm EST M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, KORTNEY KLINKEL can be reached at 571-270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SOPHIA REILLY/Examiner, Art Unit 1627
1 Cite No. 3 in the IDS filed October 18, 2024. Delpire et. al. "Small-molecule screen identifies inhibitors of the neuronal K-CI cotransporter KCC2" Proceedings of the National Academy of Sciences, 2009, 106, 13, 5383-5388, DOI: 10.1073/pnas.0812756106. Hereinafter Delpire.
2 Cite No. 7 in the IDS filed 10/18/24. Simonnet et. al. "Silencing KCC2 in mouse dorsal hippocampus compromises spatial and contextual memory", bioRxiv, 2022, 1-29. DOI: 10.1101/2022.02.18.481031. Published online February 18, 2022. Hereinafter Simonnet.
3 Cite No. 5 in the IDS filed October 18, 2024. Virtanen et. al. "The Multifaceted Roles of KCC2 in Cortical Development", Trends in Neurosciences, 2021, 44, 5, 378-392. DOI: 10.1016/J.TINS.2021.01.004 Published online February 24, 2021. Hereinafter Virtanen.
4 Cite No. 6 in the IDS filed October 18, 2024. Moore et. al. "Developmental Regulation of KCC2 Phosphorylation Has Long-Term Impacts on Cognitive Function" Front. Mol. Neurosci. 2019, 12, 173, DOI: 10.3389/fnmol.2019.00173. Hereinafter Moore.
5 Published December 4, 2014. Hereinafter Ben-Ari.
6 Cite No. 2 in the IDS filed 10/18/24. Bie et. al. "Suppression of hippocampal GABAergic transmission impairs memory in rodent models of Alzheimer’s disease" European Journal of Pharmacology 2022, 917, 174771, 1-8. DOI: 10.1016/j.ejphar.2022.174771. Hereinafter Bie.
7 371 of PCT/IB2023/054081 filed April 21, 2023. Hereinafter App’015.
8 Patented November 21, 2017. Hereinafter US’368.
9 Hithersay et. al. "Cognitive decline and dementia in Down syndrome" Current Opinion in Psychiatry 2017, 30, 2, 102-107. DOI: 10.1097/YCO.0000000000000307. Abstract Only. Hereinafter Hithersay.
Prosecution Insights