Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Continued Examination under 37 CFR 1.114 after Final Rejection
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 15 September 2025 has been entered.
Status of Claims
Claims 1, 2, 4, 8, 10-12, 21, 23, 24, 27-29 and 53-55 are pending.
Claims 2, 4, 8, 10-12 and 28 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Groups II and III, and nonelected species. Election was made without traverse in the reply filed on 03 November 2023 to the Restriction/Election Office Action mailed 06 September 2023.
Claims 1, 21, 23, 24, 27, 29 and 53-55 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. §119(e) or under 35 U.S.C. §120, §121, or §365(c) is acknowledged. This application is a 371 of PCT/US2019/19426, filed 02/25/2019, which claims benefit of 62/740,088, 10/02/2018, and claims benefit of 62/635,325, 02/26/2018.
Applicant has complied with all of the conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §120 or §365(c).
Claims 1, 21, 23, 24, 27, 29 and 53-55 have the effective filing date of 26 February 2018.
Withdrawn Rejections/Objections
The objection to Claim 1, in the Final Office Action mailed 15 April 2025 is withdrawn in view of Applicants' amendment received 15 September 2025, in which the cited claim was amended.
The rejection of Claim 23 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inventor, or for pre-AIA the applicant regards as the invention, in the Final Office Action mailed 15 April 2025, is withdrawn in view of Applicants’ amendment received 15 September 2025, in which the cited claim was amended.
The rejection of Claims 1, 21, 23, 24, 27 and 29 under 35 U.S.C. §103 as being unpatentable over Alvarez et al. in view of Han et al. as evidenced by Qin et al. in view of Yoneyama-Hirozane et al., and Nguyen et al., in the Final Office Action mailed 15 April 2025, is withdrawn in view of Applicants' amendment received 15 September 2025.
Claim Rejections - 35 U.S.C. § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. §102 and §103 (or as subject to pre-AIA 35 U.S.C. §102 and §103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. §103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. §102(b)(2)(C) for any potential 35 U.S.C. §102(a)(2) prior art against the later invention.
Claims 1, 21, 27 and 53 are rejected under 35 U.S.C. §103 as being unpatentable over Alvarez et al. (International Patent Application Publication No. WO 2012/114204 A2) as evidenced by Qin et al. ((2019) Front. Pharmacol. 10(172): 1-12) in view of Han et al. ((2011) Mut. Res. 727: 86-103) as evidenced by and in view of Yoneyama-Hirozane et al. ((2017) Biochem. Biophys. Res. Comm. 486: 626-631), and Nguyen et al. ((2014) J. Mol. Model. 20(2216): 1-12).
[All references cited in the Final Office Action mailed 15 April 2025.]
Regarding claims 1 and 53, pertaining to a method for increasing the NAD+ serum levels in a subject with an aging-related disorder, comprising administering to the subject an effective amount of a macro domain 1 inhibitor,
Alvarez et al. shows methods of treating disorders associated with mitochondrial dysfunction by administering to a subject, suffering from or susceptible to a metabolic disorder, one or more compounds that increases nicotinamide adenine dinucleotide (NAD+) (pg. 2, para. [0007]). The compound is a PARP-1 inhibitor (pg. 2, para. [00012]). A PARP-1 inhibitor is a compound that decreases expression or activity of PARP-1. A decrease in PARP-1 expression or activity is defined by a reduction of a biological function of the PARP-1 protein (pg. 18, para. [00068]). Members of the PARPs family of protein include, minimally, PARP-14 (pg. 18, para. [00067]). Disorders associated with mitochondrial dysfunction include, minimally, an aging related disorder (pg. 2, para. [00011]).
Alvarez et al. does not explicitly show that PARP14 has a macro domain 1, with regard to claim1.
Qin et al. teaches that PARP14 has three macro domains, one of which is a macro 1 domain (pg. 1, Abstract).
That is, one embodiment of a PARP14 inhibitor, as shown by Alvarez et al., would be an inhibitor of the macro domain 1 of the PARP14 protein.
Alvarez et al. does not show: 1) (a) a macro domain 1 inhibitor selected from NCI-61610 (C34H24N6O2), NCI-25457 (C24H16N2O), NCI-345647_a (C30H26O10), NCI-670283 (C25H24O2), or NCI-127133 (C21H18N2O4), or combinations thereof [Claims 1 and 53].
Han et al., Yoneyama-Hirozane et al., and Nguyen et al. provide information from which one of ordinary skill in the art of increasing NAD+ serum levels in a subject with an aging-related disorder, as shown by Alvarez et al., would have administered an effective amount of the macro domain 1 inhibitor NCI-61610, NCI-25457, NCI-345647_a, NCI-670283 or NCI-127133, by way of addressing the limitations of claims 1 and 53.
Regarding claims 1 and 53, Han et al. teaches that Macro domains are ancient, highly evolutionarily conserved domains that are widely distributed throughout all kingdoms of life. The ‘macro fold’ is roughly 25 kDa in size and is composed of a mixed α–β fold. They function as binding modules for metabolites of NAD+, including poly(ADP-ribose) (PAR), which is synthesized by PAR polymerases (PARPs) (pg. 86, Abstract [nexus to Alvarez et al.- PARPs modulate NAD+]). Humans contain at least 10 genes that encode 11 members of the macro domain family, which includes macroH2A (and its various isoforms including macroH2A1/macroH2A2), MACROD1 (LRP16), MACROD2 (C20orf133), C6orf130, MACROD3 (GDAP2), ALC1 (CHD1L, CHDL), and macroPARPs (PARP-9; PARP-14; PARP-15; Table 1) (pg. 87, column 2, para. 1 thru pg. 88, column 1, lines 1-4 and Table 1) ([MACROD1 = Macro Domain 1] [nexus to Alvarez et al.- PARP14]).
On the basis of what the described study shows, it is apparent that macro domains are unique evolutionarily conserved domains that regulate diverse functions (pg. 99, column 2, para. 2). The macro domain family is conserved almost universally across all three domains of life: bacteria, archaea, and eukaryotes, and, therefore, the macro domain is seen as a new potential therapeutic target (pg. 99, column 1, para. 1). Macro domains show an association with the sirtuin family of enzymes because of their ability to bind the ADPR-related derivatives that are produced by sirtuins. Recently, it was shown that sirtuins play important roles in the aging process (pg. 99, column 2, lines 16-20 [nexus to Alvarez et al.- treat aging related disorders]).
That is, Han et al. teaches that the term ‘macro domain’ encompasses a broad family of macro domain derivatives (including Macro Domain 1) and that macro domains, which are found in PARPs, are highly conserved functionally, genetically and structurally, and are binding sites for nicotinamide adenine dinucleotide (NAD). In addition, macro domains are related to the aging process via their association with sirtuins.
Regarding claims 1 and 53, Yoneyama-Hirozane et al. shows a study in which the macrodomain-containing PARP14 enzyme was purified. Co-crystal structures of PARP14 with certain hit compounds revealed that the inhibitor compounds bind to the NAD+-binding site (pg. 626, Abstract [nexus to Alvarez et al.- PARP inhibitors modulate NAD] [nexus to Han et al.- PARP macro domains bind NAD]). A large subset of the PARP family catalyzes mono-ADP-ribosylation. Most of these combine an ADP-ribosyltransferase domain with ADP-ribose-binding macrodomains (pg. 626, column 1, para. 1 thru column 2, lines 1-6). Macrodomain-containing purified PARP14 was used because it possesses the conserved ADP-ribose binding motif (pg. 630, column 1, para. 2). The described study provides an ideal platform for the discovery of PARP14 inhibitors (pg. 630, column 2, para. 2).
That is, Yoneyama-Hirozane et al. teaches that PARP14 specifically contains a macro domain which represents a highly conserved ADP-ribose binding motif, and shows that inhibitors of PARP14 bind to the NAD+ binding site which suggests that they would have beneficial therapeutic effects.
Regarding claims 1 and 53, Nguyen et al. shows a study which reports on the discovery of potential inhibitors for the nsP3 macro domain of CHIKV (chikungunya virus) (pg. 1, column 1 Abstract [nexus to Han et al. and Yoneyama-Hirozane et al.- macro domains bind inhibitors]). The nsP3 macro domain is considered to complex with ADP-ribose derivatives and RNA. It is also believed to control the metabolism of ADP-ribose 1-phosphate and/or other ADP-ribose derivatives with regulatory functions in the cell (pg. 2, column 1, para. 1 [nexus to Alvarez et al.- PARPs complex with ADP-ribose as poly(ADP-ribose) polymerases]). The ligand ADP-ribose, and the active site of the nsP3 macro domain is considered the binding site for this ADP-ribose ligand (pg. 2, column 1, last para. thru column 2, line 1 [nexus to Yoneyama-Hirozane et al.- macro domains represent an ADP-ribose binding motif]). The top five hit inhibitor compounds are NCI-61610, NCI-25457, NCI-345647_a, NCI-670283, and NCI-127133 (pg. 7, column 2, para. 2; and pg. 6, Table 2).
That is, Nguyen et al. shows that the potential inhibitors of the nsP3 macro domain of chikungunya virus bind to a site in said macro domain which complexes with ADP-ribose derivatives, which is a characteristic of macro domain 1 of the PARP proteins. This same macro domain site also binds NAD.
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for increasing the NAD+ serum levels in a subject with an aging-related disorder comprising administering to the subject an effective amount of an agent that inhibits a poly(ADP-ribose) polymerase (PARP), as shown by Alvarez et al. as evidenced by Qin et al., by administering (a) a Macro Domain 1 inhibitor as a PARP14 inhibitor, such as one of NCI-61610, NCI-25457, NCI-345647_a, NCI-670283 or NCI-127133 [Claims 1 and 53], as shown by Nguyen et al., with a reasonable expectation of success.
Han et al. teaches that the macro domains are unique evolutionarily conserved domains, and that said macro domains show an association with the sirtuin family of enzymes which have been shown to play important roles in the aging process. Yoneyama-Hirozane et al. teaches that the macro domain of PARP14 represents a highly conserved ADP-ribose binding motif which binds inhibitors that then compete with the natural binding of NAD+ metabolites, and Nguyen et al. shows examples of such types of inhibitors (i.e., “NCI”- named inhibitors, as cited in instant claim 1) which bind to a domain pocket in a(n) nsP3 alphavirus protein which performs the function of other macro domains in the family (i.e., it complexes with ADP-ribose derivatives), and which has the same three-dimensional structure (i.e., a mixed α-β fold; pg. 2, column 1, para. 2) shown by PARP macro domain binding pockets (per Han et al.).
Therefore, it would have been obvious to one of ordinary skill in the art of administering PARP14 inhibitors for increasing levels of NAD+ to have understood from the teachings of Han et al., Yoneyama-Hirozane et al., and Nguyen et al. that any inhibitor (including a Macro Domain 1 inhibitor) that interacts with a macro domain (e.g., Macro Domain 1) in a PARP (including PARP14) could be administered with the reasonably predictable expectation that the inhibitor binding the macro domain would result in successfully increasing the levels of NAD+ (MPEP 2143 (I)(G)).
One of ordinary skill in the art would have been motivated to have made that modification, because Han et al. shows that of all of the proteins that contain macro domains, PARP-14 is the only protein which contains three so-called Macro Domains (as opposed to one or two such domains in other proteins) (Han et al., pg. 87, Fig. 1, red blocks). Therefore, the chances for therapeutic success would be increased when using a Macro Domain 1 inhibitor compound to specifically target PARP14 with the intention of increasing levels of NAD+.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Alvarez et al. further addresses the limitations of claims 21 and 27.
Regarding claim 21, exemplary PARP-1 inhibitors are known to inhibit NAD+ consumption, and include, minimally, PJ34. Other PARP-1 inhibitors are known in the art (pg. 19, para. [00072]).
Regarding claim 27, pertaining to Alzheimer’s disease [species election],
Alvarez et al. teaches that aging related disorders include diseases such as, minimally, Alzheimer's disease (pg. 21, para. [00081]).
Claims 23, 24, 29, 54 and 55 are rejected under 35 U.S.C. §103 as being unpatentable over Alvarez et al. as evidenced by Qin et al. in view of Han et al. as evidenced by and in view of Yoneyama-Hirozane et al., and Nguyen et al., as applied to claims 1, 21, 27 and 53 above, and further in view of Sinclair et al. (International Patent Application Publication No. WO 2016/176437 A1).
[Sinclair et al. cited in the Final Office Action mailed 14 April 2025.]
Regarding claim 29, Alvarez et al. further shows that the specification for the dosage unit forms of the described invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved (pg. 25, para. [00095]).
Regarding claim 55, Alvarez et al. as evidenced by Qin et al. in view of Han et al. as evidenced by in view of Yoneyama-Hirozane et al., and Nguyen et al. address the limitations of claim 1 (a).
Alvarez et al. as evidenced by Qin et al. in view of Han et al. as evidenced by and in view of Yoneyama-Hirozane et al., and Nguyen et al., as applied to claims 1, 21, 27 and 53 above, do not show: 1) the enzyme is selected from mononucleotide adenylyl transferase1 (NMNAT1), NMNAT2, NMNAT3, or nicotinamide phosphoribosyl transferase (NAMPT or NAMPRT) [Claim 23]; 2) inflammasome activation is suppressed, wherein inflammation is decreased, or an inflammatory response is depressed or suppressed [Claim 24]; 3) the PARP14 mutant is administered to the subject at a dose of between 0.5-5 grams per day [Claim 29]; 4) the method comprises administering to the subject an effective amount of (b) a PARP14 mutant, or fragment thereof, or a nucleic acid encoding same, wherein the PARP14 mutant comprises at least one substitution, mutation, insertion, deletion, or combination thereof, in macro domain 1, wherein the PARP14 mutant increases the level or activity of an enzyme involved in NAD+ biosynthesis, an enzymatically active fragment of such an enzyme, a nucleic acid encoding an enzyme involved in NAD+ biosynthesis, or an enzymatically active fragment of such a nucleic acid [Claim 54]; and 5) the method comprises administering to the subject an effective amount of (b) [Claim 55].
Regarding claim 54, and claim 55 (b), pertaining to administering (b) a PARP14 mutant, or fragment thereof, or a nucleic acid encoding same, wherein the PARP14 mutant comprises at least one substitution, mutation, insertion, deletion, or combination thereof, in macro domain 1, wherein the PARP14 mutant increases the level or activity of an enzyme involved in NAD+ biosynthesis, an enzymatically active fragment of such an enzyme, a nucleic acid encoding an enzyme involved in NAD+ biosynthesis, or an enzymatically active fragment of such a nucleic acid,
Sinclair et al. shows a method for preventing, treating or providing increased resistance to neuropathy and/or pain and associated disorders thereof. The method comprises administering to the subject an effective amount of an agent that increases the level of NAD+ in the subject (pg. 3, para. [0016] [nexus to Alvarez et al.- administer an agent which increases the level of NAD+]). The agent is used to treat neurological disorders that result in memory loss or impaired cognitive functions, such as Alzheimer's disease (pg. 14, para. [00116] [nexus to Alvarez et al.- treat Alzheimer’s disease]). The agent that increases the level of NAD+ is an inhibitor of an NAD+ consuming enzyme such as PARP (pg. 7, para. [0046] [nexus to Alvarez et al.- PARP inhibitors]).
Further regarding claims 54 and 55, Sinclair et al. shows that, in some embodiments, the agent is selected from the group consisting of an enzyme involved in NAD+ biosynthesis, an enzymatically active fragment of such an enzyme, a nucleic acid encoding for an enzyme involved in NAD+ biosynthesis, and an enzymatically active fragment of such a nucleic acid (pg. 8, para. [0063]).
Sinclair et al. further addresses the limitations of claims 23, 24 and 29.
Regarding claim 23, Sinclair et al. shows that in some embodiments, the enzyme is NMNAT-1, NMNAT2, NMNAT3 or NAMPT (pg. 8, para. [0063]).
Regarding claim 24, the described invention is a method for preventing or treating neurotoxic damage in a subject. The method comprises administering to a subject who has undergone, minimally, inflammation or auto-inflammation (pg. 4, para. [0024]). NMNAT1 or NMNAT3 over-expression will demonstrate protection against inflammation (pg. 46, para. [00289]). The described invention is an agent that increases NAD+ delivered in place of anti-inflammatory therapies (pg. 14, para. [00120]).
Regarding claim 29, in some embodiments, the agent that increases the level of NAD+ is administered at a dose of between 0.5-5 grams per day (pg. 11, para. [0087]).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the method for increasing the NAD+ serum levels in a subject with an aging-related disorder, comprising administering to the subject an effective amount of (a) at least one specific macro domain 1 inhibitor, as shown by Alvarez et al. as evidenced by Qin et al. in view of Han et al. as evidenced by and in view of Yoneyama-Hirozane et al., and Nguyen et al., as applied to claims 1, 21, 27 and 53 above, by also administering a PARP14 mutant, or fragment thereof, or a nucleic acid encoding same, wherein the PARP14 mutant increases the level or activity of an enzyme involved in NAD+ biosynthesis, an enzymatically active fragment of such an enzyme, a nucleic acid encoding an enzyme involved in NAD+ biosynthesis, or an enzymatically active fragment of such a nucleic acid [Claim 54 and 55 (b)], with a reasonable expectation of success, because Sinclair et al. shows a method comprising administering to the subject an effective amount of an agent that increases the level of NAD+ in the subject, which is the function of the macro domain 1 inhibitor compound shown by Alvarez et al. as evidenced by Qin et al. in view of Han et al. as evidenced by and in view of Yoneyama-Hirozane et al., and Nguyen et al., as applied to claims 1, 21, 27 and 53 above (MPEP 2143 (I)(G)).
In addition, Sinclair et al. shows that PARP inhibitors can be formulated as administered agents which are enzymes involved in NAD+ biosynthesis. More specifically, the agent that increases the level of NAD+ is an inhibitor of an NAD+ consuming enzyme such as CD38 or PARP (pg. 7, para. [0046]) (MPEP 2143 (I)(G)).
That is, Sinclair et al. recognizes that a pathway to increasing NAD+ levels is not only a direct one by increasing enzymes that boost NAD+ synthesis, but also “indirectly” by decreasing or inhibiting levels of a(n) NAD+ consuming enzyme such as PARP. That is, Sinclair et al. (in view of the abovecited prior art) provides motivation for producing PARP mutants or recombinant proteins that would decrease the levels and/or activity of PARP including PARP14 (thereby increasing levels of NAD+).
In addition, it is noted that administering either (a) a macro domain 1 inhibitor (of PARP14) or (b) a PARP14 mutant would result in the same (or duplicative) biophysiological result(s)- i.e., the increase in NAD levels in the serum of a subject. It is noted that continuous, repetitive or duplicative parts or steps are claim language scenarios that demonstrate a prima facie case of obviousness (MPEP 2144.04 (V)(E) and (VI)(B)).
One of ordinary skill in the art would have been motivated to have made that modification, because the administration of a composition comprising both a macro domain 1 inhibitor and a PARP14 mutant which increases the level or activity of an enzyme involved in NAD+ biosynthesis, would optimize the therapeutic quality of said composition by synergistically increasing the NAD+ serum levels of a patient in need via two different biophysical modes of action. Such a composition would, in turn, increase the therapeutic value of its administration to treat disorders or diseases related to decreased NAD+ serum levels, such as an age-related disorder, as shown by Alvarez et al., and neuropathy and/or pain and associated disorders thereof, as shown by Sinclair et al.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Arguments
Applicant’s arguments, pp. 7-11, filed 15 September 2025, with respect to the prior art references cited in the 35 U.S.C. §103 rejection, have been fully considered but they are either not persuasive or are moot because the arguments do not apply to the references as they are applied in the context of the current rejection, or as new grounds necessitated by Applicant’s amendment, in which new claims 53-55 were added.
1. Applicant remarks (pg. 7, para. 4 thru pg. 8) that Applicant has shown that PARP14 is a previously unrecognized regulator of NAD+ levels. Additionally, Applicant has shown that targeting and inhibiting macro domain 1 of PARP14 will increase NAD+ levels. The cited references lack any guidance to target PARP14, let alone the macro domain 1 of PARP14, to treat an aging-related disorder, as required by claim 1.
In addition, Alvarez discloses treating disorders associated with mitochondrial dysfunction (such as aging) by administering a PARP1 inhibitor. Alvarez does not teach any PARP14 inhibitors or PARP14 mutants, nor does Alvarez teach or suggest that PARP14 can modulate NAD+ levels or act as a therapeutic target for aging related disorders. As the Examiner pointed out, the only mention of PARP14 in Alvarez is to state that PARP14 is a "PARP family member". Moreover, as discussed in more detail below, Alvarez does not teach or suggest targeting a macro domain, let alone macro domain 1, because PARP1 lacks micro domains.
However, in response to Applicant, it is evident from the cited prior art that poly(ADP-ribose) polymerase (PARP) proteins are grouped into one family of proteins because they all share at least the one function of transferring negatively-charged ADP-ribose groups from donor NAD+ molecules onto their target proteins. (See the secondary reference of Yoneyama-Hirozane et al. (pg. 626, Abstract); and also Schweiker et al. ((2018) Mini-Rev. Med. Chem. 18(19): 1659-1669 (shown here as pp. 1-12) (provided here); pg. 1, column 1, para. 1).) That is, all members of the PARP family of proteins encode intracellular ADP-ribose transferase enzymes (ARTDs) (Yoneyama-Hirozane et al., pg. 626, column 2, lines 2-6); Schweiker et al. pg. 1, column 1, para. 1). Therefore, even though the primary reference of Alvarez et al. does not exemplify PARP14, it is evident from the teachings of Alvarez et al. that PARP inhibitors can be generated (regardless of what the biological mechanism is for this inhibition). The teachings also show that such a PARP inhibitor would increase NAD levels, which is the intended use of the instant claim 1 method. Therefore, it would have been obvious to one of ordinary skill in the art to have tried to have generated a PARP inhibitor for any of the proteins in the PARP family, including PARP14.
Further in response to Applicant, although PARP1 may lack canonical macro domains, the protein functions like its family member proteins. Qin et al. teaches that apart from the self-evident importance of the catalytic domain, the unique macro domains can engage in biological metabolism through binding mono (ADP-ribose). PARP14 can modify mono-ADP-ribosylation on target proteins (pg. 2, column 1, para. 1)- but so can the other PARP proteins. Qin et al. further teaches that PARPs perform posttranslational mono-/poly-ADP-ribosylation modification on target proteins, which include PARPs themselves. The negatively charged linear or branched chains of poly (ADP-ribose) on target proteins change the biochemical properties of these macromolecules, leading to the alteration of their structures and functions. Activated PARP breaks down NAD+ into nicotinamide and ADP-ribose, and connects 50–200 ADP-ribose units to the target proteins via covalent bonds (Qin et al., pg. 2, column 2, para. 2).
That is, because all members of the PARP family share (minimally) the same function of performing mono-/poly-ADP-ribosylation on target proteins, it would have been obvious to have selected any of one of the members of the PARP family (including PARP14), shown by Alvarez et al., for the purpose of generating a PARP inhibitor (including one which inhibits the macro domain of those PARP proteins which contain such a domain). In spite of the fact that PARP1 may not comprise a canonical macro domain, it would not dissuade one of ordinary skill in the art to try to generate a PARP inhibitor, as shown by Alvarez et al., by selecting one of the PARP proteins taught by Alvarez et al. (i.e., PARP-1, PARP-2, PARP-3, PARP-4, PARP-5a, PARP5b, PARP-6, PARP-7, PARP-8, PARP-9, PARP-10, PARP-12, PARP-13, PARP-14, PARP-15, and PARP-16 (Alvarez et al., pg. 18, para. [00067]), which does have such a macro domain.
2. Applicant remarks (pg. 8, para. 1) that Han and Yoneyama-Hirozane simply disclose the evolutionary conservation of macro domains generally. Qin discloses that PARP14 has three macro domains but does not teach or suggest that PARP14 could be a regulator of NAD+ levels or a therapeutic target for aging-related disorders. Nguyen merely discloses potential inhibitors for the nsP3 macro domain of chikungunya virus. Similar to Alvarez, Sinclair fails to disclose any macro domain 1 inhibitors or PARP14 mutants comprising a mutation in macro domain 1. In fact, Sinclair does not disclose modulation of any specific PARP enzyme for the treatment of an aging-related disorder, let alone targeting PARP14.
However, in response to Applicant, the information cited by the secondary references with regard to macro domains shows that macro domains are facilitators of NAD regulation, specifically depletion. Qin et al. teaches that an intact PARP14 (also named ARTD8 or BAL2) is constructed by macro1, macro2, macro3, WWE, and the catalytic domain. PARP14 takes advantage of nicotinamide adenine dinucleotide (NAD+) as a metabolic substrate to conduct mono-ADP-ribosylation modification on target proteins, taking part in cellular responses and signaling pathways in the immune system (pg. 1, Abstract). Han et al. teaches that the macro domain proteins might be viewed as molecular bridges that bring together target proteins, via interactions with the variable domains, and metabolites of NAD+, including PAR, via binding to the conserved macro domain (pg. 88, column 2, lines 1-5).
3. Applicant remarks (pg. 8, para. 2 thru pg. 9, para. 2) that i) PARP1 lacks macro domain 1. Applicant reminds the Examiner that if a proposal for modifying the prior art in an effort to attain the claimed invention causes the art to become inoperable or destroys its intended function, then the requisite motivation to make the modification would not have existed. If a person of ordinary skill in the art were to combine Alvarez (disclosing PARP1) and Nguyen (showing potential inhibitors for the nsP3 macro domain of chikungunya virus), effective treatment of an aging-related disorder would not be expected because macro domain 1 inhibitors would have no binding or activity on PARP1 because it lacks any macro domain.
However, in response to Applicant, the 103 rejection does not suggest that the PARP1 protein incorporated into the PARP1 inhibitor experiments shown by Alvarez et al. could have been directly substituted with the PARP14 protein, but the reference does suggest that inhibitors could be generated against any member of the PARP family of proteins (including PARP14). Alvarez et al. teaches that compounds that increase NAD+ include inhibitors of the poly (ADP-ribose) polymerase (PARPs) family of proteins. Members of the PARPs family of protein include PARP-1, PARP-2, PARP-3, PARP-4, PARP-5a, PARP5b, PARP-6, PARP-7, PARP-8, PARP-9, PARP-10, PARP-12, PARP-13, PARP-14, PARP-15, and PARP-16 (pg. 18, para. [00066]-[00067]).
As noted above, the cited secondary references provide information as to the structure of PARP14 with regard to macro domains as well as the interaction of the macro domains with regard to NAD substrate use by the PARP protein. Again, all of the members of the PARP enzyme family share (minimally) the one function of transferring negatively charged ADP-ribose groups from donor NAD+ molecules onto their target proteins (again, see Schweiker et al., pg. 1, column 1, para. 1 (provided here)).
4. Applicant remarks (pg. 9, last para. thru pg. 10, para. 3) that ii) PARP proteins have diverse functions despite belonging to the same family, and even macro domain proteins demonstrate a diversity of functions despite some sequence homology. The Examiner repeatedly argues that the secondary references have a "nexus" to Alvarez since Alvarez discloses PARP14 as a PARP protein, seemingly to indicate that one would expect PARP14 to function in a similar fashion in PARP1. PARP proteins have diverse functions (and structures, as discussed above) despite belonging to the same family.
However, in response to Applicant, again, the 103 rejection does not suggest or describe that PARP1 can be literally substituted with the PARP14 protein within the specific context of Alvarez et al. It is well known that within the PARP family of proteins there are subfamilies which indeed have a variety of functions. Schweiker et al. includes a Table 1 which shows the various PARP superfamily members and their classifications and functions (pg. 2, Table 1). It is well known in the literature that PARP enzymes have different functions. However, as taught by Schweiker et al. and shown in Table 1, there is one function that the enzymes all share- i.e., they are all ARTDs (ADP-ribose transferase enzymes) which is the functionality involved in the utilization of NAD+ as a substrate. The nexus to Alvarez et al. is that Alvarez et al. teaches that some type of inhibitor can be generated to any member of the PARP family, including PARP14.
5. Applicant remarks (pg. 10, para. 4 thru pg. 11) that Applicant's Data Demonstrates the Unexpected Properties of Modulation of PARP14 on NAD+ levels. As previously discussed, Applicant has shown that PARP14 is a previously unrecognized regulator of NAD+ levels. FIG. 2 of the instant application shows that PARP14, uniquely among other PARP knockouts, is necessary for LPS-induced NAD+ destruction. Applicant has shown not only that PARP14 represents an undescribed regulator of NAD+ levels but can act in NAD+ pathways independently from other PARP enzymes.
However, in response to Applicant, as noted above, the common biophysiological property of all PARP enzymes is that they utilize NAD as substrate to transfer ADP-ribose onto their target proteins. In addition, Mehrotra et al. ((2011) J. Biol. Chem. 286(3): 1767-1776 (provided here)) shows that the PARP catalytic domain found in PARP-14 is enzymatically active, and it uses NAD as a substrate to transfer ADP-ribose onto itself and p100 (pg. 1767, column 2, para. 1). Iwata et al. (WO 2015/073818 A1 (provided here)) teaches that poly ADP-ribose polymerase 14 (PARP14) is also known as ADP-ribosyltransferase diphtheria toxin-like 8 (ARTD8), and PARP9/ARTD9 (pg. 52, para. [0295]). An experiment was performed which included PARP14 incubated with STAT1a and NAD to demonstrate the ribosylation of STAT1 (pg. 59, para. [0344] thru pg. 60, cont. para. [0344]). Yoneyama-Hirozane et al. teaches that PARP14 has three macro domains and may interact with ADP-ribose (pg. 626, column 1, lines 5-6). That is, it is evident from the literature that PARP14 regulates NAD levels and its macro domains have been implicated in the biological process involving utilization of NAD.
Further in response to Applicant, it is not clear that PARP14 is unique in its necessity for LPS-induced NAD+ destruction, because other PARP proteins have not been compared to PARP14 with regard to this property. In addition, whether or not PARP14 can act in NAD+ pathways independently from other PARP enzymes (and this may have some credence in the fact that PARP14 comprises macro domains not shared with some other PARP subfamilies), its activity is responsible for the same decrease in NAD+ levels shared by all other PARP proteins. The subject matter of instant claim 1 only describes a method with the intended use of increasing NAD+ serum levels by administering an inhibitor of/or inhibited PARP14 (whether by administering an actual small molecule inhibitor to the subject or administering a mutant/lack of function PARP14 protein). Again, therefore, inhibitors to or mutants of any PARP protein would potentially increase NAD+ levels in the serum of a subject with an age-related disorder.
6. Applicant remarks (pg. 11, para. 2-4) that the Examiner relies improperly on hindsight to arrive at the pending claims. A person or skilled in the art, without the benefit of Applicant's disclosure, would not arrive at a method according to the amended claims based on the cited references, either alone or in combination. Alvarez does not disclose any PARP14 inhibitors but instead discloses PARP1 inhibitors and "PARP inhibitors" generally. Nothing in Alvarez, especially in disclosing PARP1, a protein that lacks any macro domain, points a person of skill in the art to target macro domain 1 of PARP14 for treating aging-related disorders. Applicant has shown that PARP14 is a previously unrecognized regulator of NAD+ levels, and, in addition, is capable of regulating NAD+ levels in pathways where other PARP enzymes do not. None of the secondary references cited by the Examiner cure the deficiencies of Alvarez.
However, in response to Applicant, it is obvious from the cited prior art (and supported by the supplied evidentiary references) that PARP proteins, including PARP14, use NAD as a substrate to perform ADP-ribosylation activities. As noted above, the primary reference of Alvarez et al. exemplifies PARP1 inhibitors, but also teaches that inhibitors can be prepared "against" any protein in the PARP family, including PARP-14. Because all PARP proteins utilize NAD as a substrate, one of ordinary skill in the art would recognize from the information provided by Qin et al., Han et al., Yoneyama-Hirozane et al., and Nguyen et al. that the macro domains in those PARP proteins which have them (e.g., PARP9, PARP14 and PARP15) are potential targets for inhibiting PARP with regard to its utilization of NAD as a substrate. In addition, Nguyen et al. shows the crystal structure of a(n) nsP3 macro domain which exposes the docking location for ADP-ribose. In addition, it is proposed, as noted above, that the macro domain regions of PARP bind NAD. Whatever the biological function of the macro domain(s), it is evident that this/these region(s) are involved in a physiological reaction in which PARP14 utilizes NAD and ADP-ribose as substrates.
Conclusion
No claims are allowed.
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/SMP/ Examiner, Art Unit 1651
/MELENIE L GORDON/ Supervisory Patent Examiner, Art Unit 1651