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 present application, filed February 8, 2022, is a national stage application of PCT/US20/46110, filed August 13, 2020, and claims the benefit of U.S. provisional applications 62/889376, filed August 20, 2019, and 62/886869, filed August 14, 2019.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 17, 2025 has been entered.
Election/Restrictions
Applicant’s previous election with traverse of the invention of Group I (drawn to a chemical compound and pharmaceutical composition thereof), as well as the species of compound as compound 4 (found in claim 6), in the reply filed December 12, 2024, is acknowledged.
However, after examination and consideration of the claims, the election of species requirement is withdrawn. Accordingly, all claims included in Group I (claims 1-4, 6-7, 10-11, 14-16, and 18) are examined herein.
Status of the Application
Claims 1-4, 6-7, 10-11, 14-16, 18, 23-26, 29, 34, 36, and 41 are pending in this application.
Claims 23-26, 29, 34, 36, and 41 are withdrawn from consideration as being drawn to a non-elected invention.
Claims 1-4, 6-7, 10-11, 14-16, and 18 are examined on the merits herein.
Regarding potential rejoinder of the withdrawn claims upon finding that the elected claims are allowable, the withdrawn claims are now indicated as withdrawn on the Office Action Summary (PTO-326).
Specification
The disclosure is objected to because of the following informalities:
The disclosure contains several chemical structures of sufficiently low resolution that they are difficult to interpret. Specifically, structures 1-5 on p. 20, structures 6 and 7 on p. 22, and structures 8 and 9 on p. 23 are of low resolution. Please replace these structures with higher resolution images of the same structures.
Appropriate correction is required.
Claim Objections
Claims 6, 10 and 14 are objected to because of the following informalities:
Claims 6, 10, and 14 include chemical structures of sufficiently low resolution that they are difficult to interpret. Specifically, structures 1, 2, 3, 4, and 5 of claim 6, structures 6 and 7 of claim 10, and structures 8 and 9 of claim 14 are of low resolution. Please replace these structures with higher resolution images of the same structures.
Appropriate correction is required.
The following are new grounds of rejection:
Claim Rejections - 35 USC § 112
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 1-4, 7, 11, 16 and 18 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 the structure of formula I with Ring A as shown in the claims with substituents R2, R3, and R4. Claim 1 also recites that ring A is a carbocycle or heterocycle, wherein said carbocycle or heterocycle is aromatic. However, as shown in the chemical structure of claim 1, Ring A appears to show six carbon atoms (based on conventional nomenclature of chemical compounds), with substituents R2, R3, and R4 substituted at five of the six carbons. Based on the structure and description of Ring A in the claim, it is unclear if Ring A must comprise a six carbon cycle as depicted by the structure, and that Ring A may only be a heterocycle if heteroatoms are introduced as part of heterocycles formed from R1/R2 or from R3/R4, or if heteroatoms are permitted within Ring A, in which case R2, R3, and/or R4 may be absent from the structure.
This uncertainty is present in claim 15. Claim 15 depends from claim 1 and includes compounds 25 and 31, wherein Ring A (as defined in claim 1) is a pyridyl group. The compound of claim 25 lacks one of the R3 substituents, and the compound of claim 31 lacks one of the R2 substituents. Based on the requirements of claim 1, it is unclear if these compounds recited in claim 15 fall within the scope of claim 1, because it is unclear if R2 and R3 may be absent.
Because claims 16 and 18 depend from claim 1 and does not cure the above deficiency, claims 16 and 18 are also indefinite.
For the purposes of examination, the scope of claim 15 is considered as definite, because it recites specific chemical structures.
Independent claim 2 claims a compound of Formula 2 as shown. However, claim 2 does not define variable groups X or R3 shown in the compound of Formula 2. Regarding R3, claim 2 only states that R4 may be taken together with R3 to form a carbocycle or heterocycle. Therefore, claim 2 is indefinite because the scope of substituents permitted by X and by R3 is not defined.
Claims 3, 4, 7, and 11 depend from claim 2 and further limit the compound of Formula 2. However, claims 3, 4, 7, and 11 do not define X, and thus the scope of groups permitted by X in these claims is also not known.
Claims 6, 10, and 14 depend from claims 2, 7, and 11 and require the specific structures shown in these claims. Because each of claims 6, 10, and 14 require one of a specific chemical compound as shown in the claim, the scope of claims 6, 10, and 14 is clear and these claims are not indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
As discussed above, variable groups X and R3 recited in the structure of claim 2 are not defined by the claim.
Claims 6, 10, and 14 depend from claim 2 and recite specific compounds required by these claims.
Similarly, claims 3-4, 7, and 11 depend from claim 2 and further define groups that are not defined by the claim upon which they depend (e.g., variable group R3).
If claim 2 is amended to define the X and R3, as discussed in the above rejection under 35 U.S.C. 112(b), and the scope claims 3-4, 6-7, 10-11, and 14 falls within the amended scope of claim 2, then the rejections under 112(d) below will be withdrawn. However, as presently drafted, claims 3-4, 6-7, 10-11, and 14 introduce new limitations (in the form of defined variable groups and chemical structures) which do not fall within the scope of claim 2.
Claims 3-4, 6-7, 10-11, 14, and 15 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 3-4, 6-7, 10-11, and 14 depend, directly or indirectly, from claim 2 and further define R3 and/or X, either by limitations in the claim or by compounds recited in the claim.
However, because R3 and X is not defined by claim 2, it is unclear if the scope of R3 and/or X recited in claims 3-4, 6-7, 10-11, and 14 further limits the subject matter of the claim upon which it depends or fails to include all the limitations of the claim upon which it depends.
Claim 15 depends from claim 1 and includes compounds 25 and 31, each of which lack one of groups R2 or R3. Because claim 1 does not permit groups R2 and/or R3 to be absent, when, for example, a heteroatom is present at a specific position in Ring A, claim 15 fails to include all limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claims 1, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Sinclair (US pre-grant publication no. 20210371446 A1; cited in PTO-892).
Sinclair is the U.S. pre-grant publication associated with U.S. application 17/284,691, filed April 12, 2021, which is a national stage application of PCT/US19/56487, filed October 16, 2019, and claims the benefit of U.S. provisional application 62/746,251, filed October 16, 2018. Because Sinclair claims priority to an earlier effective filing date (October 16, 2018) than the present application, it is eligible as prior art under 35 U.S.C. 102(a)(2).
Each of the embodiments cited in the rejection below are supported by provisional application 62/746,251 (see for example, pp. 17, 20, and 35-36 of the specification of 62/746,251).
Sinclair teaches compounds and compositions for preventing or treating aging or aging related disorders, disorders associated with inflammation, and for modulating an immune response in a subject.
As one example, Sinclair teaches compound 32 (p. 26, Table 2, first compound shown; structure reproduced below). This compound has the structure of the compound of Formula I with ring A as aromatic carbocycle (phenyl), X as phosphate, R2 and R3 as H, and R4 as substituted non-aromatic heterocycle.
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As another example, Sinclair teaches compound 38 (p. 27, Table 2, third compound shown; structure reproduced below). This compound has the structure of the compound of Formula I of claim 1 with ring A as aromatic carbocycle (phenyl), X as H, R2 and R3 as H, and R4 as substituted non-aromatic heterocycle.
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Sinclair further teaches the general formula XIII (p. 10, [0038]) which describes the compounds above and indicates that X2, the position of the phenol oxygen group in the ester of compounds 32 and 38, may be O or NH (p. 10, [0038]).
Sinclair teaches that the compounds disclosed in Table 1 or 2, which includes compounds 32 and 38 above, may be depicted as complexes or salts with trifluoroacetic acid or hydrochloric acid, but the compounds in their corresponding free base forms or as salts with other acids are equally within the scope of the invention. This is taken as teaching that Sinclair contemplates salts of their compounds, such as trifluoroacetate or chloride salts.
Sinclair further teaches that pharmaceutical compositions for use in accordance
with the present methods may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and the compounds and compositions may be formulated for into pharmaceutical compositions for administration by, for example, injection (p. 30, [0060], lines 1-7).
Finally, Sinclair teaches the compounds of their invention may have more than one stereocenter, and consequently, compounds of the invention may be enriched in one or more diastereomer (p. 12, [0051], lines 6-9).
The compounds of Sinclair differ from the compounds of claim 1 because they lack the N-R1 group of the amide bond, and they do not depict the specific stereochemistry between the ribose and pyridyl groups, each as required by claim 1.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify compound 32 or 38 disclosed by Sinclair and shown above by substituting the ester group with an amide group. One of ordinary skill in the art would have been motivated to modify compound 32 or 38 disclosed by Sinclair by substituting the ester group with an amide group because Sinclair teaches these compounds as useful for treating aging or aging related disorders, disorders associated with inflammation, and for modulating an immune response in a subject, and because Sinclair teaches that variable group X2, the position of the phenol oxygen group in the ester of compounds 32 and 38, may be O or NH. Accordingly, one of ordinary skill in the art, when considering the teachings of Sinclair, would have contemplated derivatives of compounds 32 and 38 with NH in place of the phenol oxygen, which would generate compounds that satisfy the limitations of a compound of Formula I of claim 1.
Regarding the stereochemistry of the ribose-nicotinamide bond, Sinclair is silent about the stereochemistry of this position, presenting structures that do not depict one stereoisomer or the other in their disclosure. However, because Sinclair acknowledges their compounds may have multiple stereocenters and states that their compounds may be enriched in one or more diastereomers, one of ordinary skill in the art, recognizing the position of the ribose group bound to nicotinamide is a stereogenic center, would have considered diastereomers of the compounds disclosed by Sinclair, including compounds 32 and 38 above, with each configuration at this position.
Therefore the invention taken as a whole is prima facie obvious.
The following rejection is modified from the previous office action, mailed April 18, 2025, with citations and arguments amended to improve clarity. The rejection also includes additional embodiments of Kim which render obvious additional compounds within the scope of claims 1 and 7.
Applicant’s arguments relating to the previous rejection are addressed following this rejection.
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.
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.
Claims 1-4, 6-7, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (WO 2017160116 A9; cited in applicant IDS filed 4 May 2022, English translation cited in office action mailed January 21, 2025) in view of Oh (Oh, A.; et al. ChemBioChem 2014, vol. 15, pp. 1121-1130; cited in the office action mailed January 21, 2025).
Kim is published in a language other than English. The original document of Kim was included with Applicant’s IDS filed May 4, 2022, and an English language machine translation of Kim was included with the office action mailed January 21, 2025. Citations below refer to either the original document or English translation, as indicated.
Claim 1 is drawn to a compound having a structure represented by Formula I as shown. Claim 2 is drawn to a compound having a structure represented by Formula 2 as shown, claims 3-4 and 7 further limit the structure of Formula 2, and claim 6 requires a specific compound of Formula 2 as shown.
Claim 16 depends from claim 1 and requires a specific salt form of the compound of claim 1. Claim 18 claims A composition comprising the compound according to claim 1, and a pharmaceutically acceptable excipient or carrier.
Kim teaches novel compounds for inhibiting nicotinamide phosphoribosyltransferase
(NamPT) (English translation, p. 1, Abstract).
As one example, Kim discloses compound B1380 (Original document, p. 49, first table entry; structure shown below). B1380 has a nicotinamide moiety (indicated below) which includes a nitrogen containing heterocycle. This structure is the aglycone species of compounds 1 and 4 recited in claim 6, and satisfies the requirements of the aglycone portion of compounds of claims 1-4 and 6.
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Kim further teaches additional compounds as inhibitors of NAMPT that are aglycone derivatives of compounds represented in the present claims. For example, Kim teaches compound B1416 (original document, p. 49), B1477 (original document, p. 49), B1479 (original document, p. 50), B1485 (original document, p. 50), and B1523 (original document, p. 51) (structures shown below). These compounds are all aglycones that satisfy the requirements of present claims 1-4 and 6.
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Kim teaches their compounds as useful for the treatment of NAMPT-related diseases, such as cancer (English translation, document p. 79, claim 27). Kim further teaches these compounds as active against cancer cells lacking NAPRT expression in vitro (original document, pp. 63-64, see Table). Many of these compounds show IC50 values of less than 10 μM (e.g., B1380, B1416, B1479, and B1523), with some IC50 values less than 1 μM (e.g., B1477, B1485).
In addition, Kim teaches the general formula of their compounds (original document, p. 3, [16]), and teaches variable group R2, a substituent on the amide, may be selected from a group that includes CH2 m-R4, wherein R4 is L2-R7, and L2 may be direct bond and R7 may be a C1-6 alkyl group, wherein m is an integer from 0-4 (English translation, document p. 4, lines 102-103, 111, and 116-117; document p. 5, line 143). Accordingly, one of ordinary skill in the art would have contemplated derivatives of the compounds disclosed by Kim, wherein the amide nitrogen may be a different substituent, including a C1-6 alkyl group.
Finally, Kim teaches a composition comprising the compound and a pharmaceutically acceptable excipient (English translation, p. 38, lines 1-2). Kim also teaches their invention provides pharmaceutically acceptable salts of their invention (English translation, document p. 35, line 1447) and include, for example, inorganic acids such as hydrochloric acid (English translation, document p. 35, line 1459).
Kim teaches only aglycone species of compounds that satisfy the present claims. Kim does not teach the ribosylated or phosphoribosylated derivatives, as required by claims 1-4 and 6-7. In addition, Kim does not teach the salt of the phosphoribosylated derivative, as required by claim 16.
Oh teaches that prolonged inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a strategy for targeting cancer metabolism, and many NAMPT inhibitors undergo NAMPT-catalyzed phosphoribosylation (pRib), a property often correlated with their cellular
potency (p. 1121, Abstract, lines 1-5).
Oh teaches that in cells, NAD is consumed through several processes, such as DNA repair and stress response, and accelerated NAD depletion is often characteristic in tumors, and to rapidly replenish the NAD pool, tumor cells rely heavily on a salvage pathway that converts an NAD metabolite, nicotinamide (NAM), back to NAD in two steps. The first step is catalyzed by the enzyme NAM phosphoribosyltransferase (NAMPT), which facilitates the conversion of NAM and phosphoribosylpyrophosphate (PRPP) into NAM mononucleotide (NMN) (p. 1121, left column, lines 9-17). Oh teaches that NMN is subsequently converted into NAD in a non-rate-limiting manner by another enzyme (NMN adenylyltransferase; NMNAT;
Scheme 1) (p. 1121, left column, lines 17-20).
Oh teaches that NAMPT is upregulated in various types of cancer and, given its importance in the NAD salvage pathway described above, the NAMPT protein is considered as an attractive target for the development of new cancer therapies (p. 1121, left column, line 20 to right column, line 4).
Oh teaches that NAMPT inhibitors often bear nitrogen containing heterocycles that mimic the natural nicotinamide substrate of the enzyme and form phosphoribosylated (pRib) adducts (paragraph bridging pp. 1122-1123). Oh teaches that these NAMPT inhibitors bearing nitrogen containing heterocycles can exert inhibitory effects both as the free heterocycle and as the pRib adduct, for example pRib-GNE-617 (Scheme 2 and Figure 1A), because the free heterocycle serves as a substrate for NAMPT to make the pRib adduct, and the pRib adduct may then provide strong product inhibition of NAMPT (page 1127, paragraph 3).
Oh further teaches that in addition to their tight binding to the enzyme that can prolong retention in cells, the polar pRib adducts might also increase intracellular accumulation, thereby enhancing anti-NAMPT effects (p. 1129, left column, first full paragraph, lines 15-22). Therefore, in view of Oh, one of ordinary skill in the art would have recognized that some NAMPT inhibitors are substrates of NAMPT and are converted into the pRib adduct by NAMPT. In addition, one of ordinary skill in the art would have recognized pRib adducts of NAMPT inhibitors as potentially providing strong inhibition of NAMPT.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to prepare the phosphoribosylated adduct of a compound useful for treating NAMPT-related diseases taught by Kim, such as compound B1380. One of ordinary skill in the art would have been motivated to prepare the phosphoribosylated adduct of a compound useful for treating NAMPT-related diseases taught by Kim, such as compound B1380, because Kim teaches the anti-cancer activity of several of their inhibitors, including compound B1380, as recited above, and because Oh teaches inhibitors of NAMPT may undergo NAMPT-catalyzed phosphoribosylation, in some instances providing superior inhibition of NAMPT compared with aglycone NAMPT inhibitor. Therefore, one of ordinary skill in the art would have considered the phosphoribosylated adducts of NAMPT inhibitors may offer superior inhibition of NAMPT compared with the aglycone inhibitor, and thus would have considered preparing these phosphoribosylated adducts for the purposes of inhibiting NAMPT.
In addition, because Oh teaches that inhibitors of NAMPT undergo NAMPT-catalyzed phosphoribosylation, and because Kim teaches their compounds as inhibitors of NAMPT, one of ordinary skill in the art would have contemplated the phosphoribosylated adducts of these compounds as being formed intracellularly by NAMPT-catalyzed phosphoribosylation. Although Oh discloses that not all NAMPT inhibitors undergo NAMPT-catalyzed phosphoribosylation, because the compounds of Kim include nitrogen containing heterocycles that mimic the natural nicotinamide substrate of the enzyme and may form phosphoribosylated adducts, as taught by Oh, one of ordinary skill in the art would have considered that phosphoribosylated adducts of the inhibitors of Kim may be formed intracellularly by NAMPT, and may be the form of the inhibitor that is effective in slowing cancer cell growth in the experiments disclosed by Kim.
Regarding claim 7, because Kim suggests that the amide group of their compounds may be substituted by a substituent, one of ordinary skill in the art would have considered derivatives of the compounds disclosed by Kim with these substituents, which includes C1-6 alkyl groups. Therefore, these derivatives of the inhibitors of Kim, when considered as phosphoribosylated adducts prepared for the purposes of improving their affinity for NAMPT of when formed intracellularly by NAMPT-catalyzed phosphoribosylation, would render obvious the compounds of claim 7, wherein R1 is C1-C6 alkyl.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s arguments: With respect to the previous rejection of claims 1-4, 6-7, 16 and 18 under 35 U.S.C. § 103 over Kim in view of Oh, Applicant presents the following arguments:
1. Applicant argues that Kim discloses nearly fifty test compounds and expressly identifies the oxazole-bearing "A4" series (e.g., A4265, A4276) as the lead candidates. Kim attributes the superior potency of these lead compounds to the presence of an oxazole ring, which purportedly engages in n-n stacking with aromatic residues, donates and accepts hydrogen bonds within the nicotinamide phosphoribosyltransferase (NAMPT) pocket, and contributes hydrophobic contacts that stabilize the inhibitor-enzyme complex. Applicant argues that compound B1380, the molecule the Office Action identifies as the "lead" starting point, exhibited substantially poorer activity, manifesting higher IC50 values than both the oxazole-containing leads and the reference drug, FK866.
Applicant argues that given Kim's explicit structure-activity guidance and comparative data, one of ordinary skill in the art would have had no motivation to select the under-performing B1380 from a collection that clearly steers practitioners toward oxazole-substituted molecules. Applicant argues that Kim therefore teaches away from B1380, much less from investing additional synthetic effort to elaborate B1380 with a bulky, highly polar phosphoribosyl group. (Applicant’s remarks, p. 14)
2. Applicant argues that Oh discloses NAMPT inhibitors that spontaneously undergo enzymatic phosphoribosylation in situ. The paper underscores that adduct formation is an NAMPT-catalyzed event integral to potent, sustained inhibition. Applicant argues that Oh candidly reports that attempts to isolate or crystalize synthetic phosphoribosyl adducts were
largely unsuccessful because such species adopt high-energy conformations that distort NAMPT
crystals and compromise structural integrity. Oh expressly notes the difficulty of chemically
synthesizing pure pRib adducts and states that prior efforts produced only partially purified
material (Applicant’s remarks, pp. 14-15).
3. Applicant argues that the combination of Kim and Oh represents impermissible hindsight. Applicant states that Kim is silent regarding phosphoribosylation and never contemplates attaching a ribose-5-phosphate to B1380, and Oh fails to mention B1380, nor does it provide a generalized directive to phosphoribosylate all NAMPT inhibitors. Instead, Oh confines its mechanistic insight to inhibitors that share a specific substrate-mimicking scaffold, many of which already exhibit superior potency relative to B1380, thus the conclusion that it would have been obvious to select the pRib adduct is an example of impermissible hindsight (Applicant’s remarks, pp. 15-16).
4. Applicant argues that there are significant structural, physical, and biological differences that would have discouraged one of ordinary skill in the art from combining the teachings of Kim and Oh to arrive at the present claims. Applicant argues that converting B1380 to its phosphoribosylated form increases its molecular weight significantly, introduces a dianionic phosphate at physiological pH, and adds multiple stereogenic centers, and that such dramatic modifications would have been expected to significantly affect cellular uptake and alter binding orientation, which are key physiologic considerations absent from Kim's and Oh' s teachings. Furthermore, one of ordinary skill in the art would have understood that the
highly polar pRib group would confer a net negative charge, contrasting sharply with the lipophilic profile of Kim's aglycones. Kim's rationale and experimental results indicate that maintaining or enhancing hydrophobic interactions in the NAMPT tunnel is key for NAMPT inhibition. Accordingly, grafting a large hydrophilic appendage to a lead compound runs counter to Kim's guidance. Applicant further argues that Oh's failed crystallography attempts caution that pre-formed pRib adducts can strain the NAMPT structure, and accordingly, one of ordinary skill in the art, in view of these observations, would have been dissuaded from preparing such adducts, particularly with a scaffold (B1380) already penalized for sub-optimal potency (Applicant’s remarks, p. 16).
5. Applicant further argues the claimed compounds exhibit unexpected effects.
Applicant provides a declaration showing that Figures IA and 1B demonstrate that the claimed compounds maintain NAD(H) levels in non-cancerous HEK293 cells while depleting NAD(H) in HepG2 hepatocellular carcinoma cells, and in contrast, the natural substrate NMN elevates NAD(H) indiscriminately in both healthy and cancerous cells. Applicant argues that neither Kim nor Oh reports, predicts, or even contemplates such cell-selective NAD modulation, and thus this unexpected, tissue-selective pharmacology translates directly into a superior therapeutic window, which is an advantage not suggested in the cited art and is therefore indicative of non-obviousness (Applicant’s remarks, pp. 16-17).
Applicant’s arguments have been fully considered but they are not found persuasive.
Regarding Applicant’s first argument, Kim discloses IC-50 values for approximately 50 compounds against cancer cell lines in vitro. As Applicant acknowledges, oxazole-substituted molecules of Kim show strong inhibitor activity, as shown in Table 7. However, other compounds that fall within the scope of present claim 1 show similar activity to the oxazole-substituted compounds (e.g., B1477). In this instance, one of ordinary skill in the art would have considered the full disclosure of Kim, and although Kim acknowledges the activity the oxazole-substituted compounds, one of ordinary skill in the art would have recognized the oxazole-substituted compounds are not the only other potent inhibitors disclosed by Kim, and would have considered other potent inhibitors for phosphoribosylation as well.
Regarding specifically compound B1380, although it is not the most active compound disclosed by Kim, this compound is not inactive, showing IC50 values of 6.25 and 2.5 μM against cancer cell lines lacking NAPRT (Table 7). Medicinal chemists routinely evaluate compound sets of the size disclosed by Kim or larger, and because Oh teaches phosphoribosylation may improve its affinity for NAMPT and improve its anti-cancer activity by promoting cellular accumulation, one of ordinary skill in the art would have considered the phosphoribosylated derivative of B1380.
Moreover, because Kim teaches these compounds as administered to cancer cells in vitro, one of ordinary skill in the art, in view of Oh, would have recognized this compound may undergo phosphoribosylation catalyzed by NAMPT intracellularly, and would have contemplated that the phosphoribosylated adduct of this compound may be the form of the inhibitor providing NAMPT inhibition when administered to cancer cells.
Regarding Applicant’s second argument, this argument appears to speculate that the method of Oh would not be effective in converting the inhibitors of Kim into their phosphoribosylated derivatives. However, absent a showing that these compounds are not phosphoribosylated by NAMPT in vitro or when administered to a cell or subject, speculation regarding these compounds in the synthesis method of Kim is not persuasive. Because Oh teaches phosphoribosylation of inhibitors of NAMPT, and Kim discloses their compounds as inhibitors of NAMPT, one of ordinary skill in the art would have considered that these compounds may be converted to the phosphoribosylated adduct by NAMPT for the purposes of improving NAMPT inhibition. In addition, one of ordinary skill in the art would have recognized these compounds may undergo NAMPT-catalyzed phosphoribosylation intracellularly, and accordingly, would have contemplated the product of that phosphoribosylation reaction as well.
Regarding Applicant’s third argument, each of Kim and Oh are drawn to the field of NAMPT inhibition. Kim discloses several compounds that potent inhibitors of NAMPT, as described above. Because Oh teaches that phosphoribosylation of NAMPT inhibitors may improve an inhibitor’s affinity for NAMPT and may increase intracellular accumulation, one of ordinary skill in the art would have considered the phosphoribosylated adducts of the inhibitors of Kim, because they may offer superior anti-cancer activity, absent evidence to the contrary.
Moreover, Oh teaches that NAMPT inhibitors may be substrates for phosphoribosylation reactions catalyzed by NAMPT. Accordingly, when administering the NAMPT inhibitors of Kim, one of ordinary skill in the art would have reasonably considered that these inhibitors may undergo a phosphoribosylation reaction intracellularly to generate the claimed compounds, and would have thus contemplated the products formed from this phosphoribosylation reaction.
Regarding Applicant’s fourth argument, this argument appears to speculate that one of ordinary skill in the art would not have had an expectation of success because the method of Oh would significantly change the physical and/or chemical properties of the inhibitors. Because Oh teaches the phosphoribosylated adducts may be superior inhibitors of NAMPT, one of ordinary skill in the art would naturally consider these adducts, because they may offer improved NAMPT inhibition.
In addition, because Oh teaches that nitrogen-containing heterocycles commonly present in NAMPT inhibitors tend to form covalent adducts with PRPP through a NAMPT-catalyzed process, one of ordinary skill in the art would have contemplated these adducts as forming intracellularly when the compounds of Kim are administered to cells to NAMPT. In this instance, one of ordinary skill in the art would not have considered the physical or chemical property changes that occurred to their inhibitor, because said changes the compound occur intracellularly. Moreover, even if one of ordinary skill in the art did consider these changes, they may have considered them as beneficial, because the changes may increase intracellular accumulation of these compounds, as taught by Oh.
Regarding Applicant’s fifth argument, persuasive evidence of non-obviousness in the form of unexpected results must include a comparison to the closest prior art. In this instance, the closest prior art is considered B1380 or other aglycone species disclosed by Kim. Applicant’s data and declaration only compare these compounds to the natural substrate NMN, showing NMN does not distinguish between healthy and cancer cell lines. Applicant does not demonstrate these unexpected results occur with the claimed compounds and do not occur with compound B1380 or other aglycone species disclosed by Kim.
Moreover, there is a reasonable expectation that the compounds disclosed by Kim would demonstrate the same effects. Kim discloses that their compounds are more potent in cell lines lacking NAPRT expression than in cell lines in which NAPRT expression is present (original document, p. 63, Table 7). Cell lines H322, H661, and H1115 all lack NAPRT expression, while cell lines H1299, H1975, H1993, H2030, H2122, and HBEC30 all have positive NAPRT expression (English translation, p. 54, lines 2341-2350).
The examiner notes that the machine translation of Kim translates negative expression of NAPRT as “voice.” If there is doubt that cell lines H322, H661, and H1115 lack NAPRT expression, publication no. EP3431472A2 (cited in PTO-892), which is the European Patent Office equivalent of Kim and eligible as prior art under 35 U.S.C. 102(a)(1), recites the same Table 7 and clearly shows H322, H661, and H1115 have negative NAPRT expression (pp. 45-46).
Kim also teaches that NAMPT is the rate-limiting enzyme in one of two pathways that restore NAD (English translation, document p. 2, lines 22-24), and that small molecule inhibitors of NAMPT cause depletion of intracellular NAD+ levels (English translation, document p. 2, lines 11-32). Therefore, administration of an NAMPT inhibitor is expected to deplete NAD+, as taught by Kim.
The prior art further acknowledges that NAMPT inhibitors are less effective against cell lines wherein NAPRT is expressed. Lee (Lee, J.; et al. Gastroenterology 2018, vol. 155, pp. 799-814; cited in PTO-892) teaches the selective cytotoxicity of the NAMPT inhibitor FK866 against gastric cancer cell liens that have lost NAPRT (p. 799, Title). Lee concludes that FK866 selectively kills gastric cancer cells with an epithelial-to-mesenchymal transition gene expression signature by inhibiting nicotinamide phosphoribosyltransferase in cells with NAPRT deficiency (p. 799-800; Abstract, Conclusions section, lines 1-4). Lee teaches their data suggest that the downregulation of NAPRT in a broad array of EMT-subtype gastric tumors contributes to EMT activation through stabilization of β-catenin and activation of its downstream
signaling and simultaneously makes them dependent on the function of NAMPT to maintain intracellular NAD levels, thereby providing a potential synthetic lethal target in the EMT-subtype gastric cancer and possibly other cancers (p. 811, right column, first full paragraph, lines 1-9) (emphasis added). Therefore, in view of Lee, one of ordinary skill in the art would have recognized that NAMPT inhibitors are more effective in cell lines deficient in NAPRT, consistent with the data presented by Kim. In addition, because Lee teaches that cells deficient in NAPRT are dependent on NAMPT to maintain intracellular NAD levels, one of ordinary skill in the art would have recognized that inhibiting NAMPT in an NAPRT-deficient cell line would reduce intracellular NAD levels.
Figures 1A and 1B, referenced in no. 23 (p. 6) of Applicant’s declaration, demonstrate the effect of the presently claimed compounds administered to HEK293 cells and to HepG2 cells. Applicant’s declaration states these data demonstrate that the compounds of Formula I maintain NAD levels and therefore cell viability in the healthy cells in Figure 1A while lowering the concentration of NAD(H)/number of viable cells in cancerous cells in Figure 1B (p. 7, no. 26), and concludes that the claimed compounds having an unexpected advantage of targeted efficacy (p. 7, no. 27) of cancerous cells (HepG2 cells in the above example) compared with healthy cells (HEK293 cells in the above example).
However, the examiner believes this effect to be mediated by NAPRT. As evidenced by Hara (Hara, N.; et al. The Journal of Biological Chemistry 2007, vol. 282, pp. 24574–24582; cited in PTO-892), the expression of NAPRT is not detected in HepG2 cells (p. 24576, right column, second full paragraph, lines 1-4). In addition, Hara teaches that HEK293 cells do express NAPRT, because knockdown of NAPRT expression with siRNA exhibited significant decreases in NAPRT enzyme activity as well as NAPRT protein (p. 24577, right column, second paragraph, lines 1-7; data shown on p. 24579, Figure 6).
Therefore, the unexpected selectivity of the presently claimed compounds for HepG2 cells compared with HEK293 cells in Figures 1A and 1B is believed to be due to the expression of NAPRT in HEK293 cell line compared with lack of NAPRT in the HepG2 cell line. Because the HepG2 cancer cell line lacks NAPRT expression, it should be dependent on NAMPT for production of NAD, as taught by Lee, and thus treatment of these cells with NAMPT inhibitors would be expected to reduce NAD levels compared with cells that express NAPRT, such as HEK293 cells.
Although Kim may not recognize this advantage of the claimed compounds, because the claims are drawn to the compounds of Formula I, and because the claimed compounds would have been obvious over Kim and Oh, as described above, the Applicant’s arguments of unexpected results fail to demonstrate a nexus between the present invention and the closest prior art. A showing that the compounds of Formula I demonstrate these superior or unexpected results and the compounds disclosed by Kim do not exhibit the same unexpected results would be persuasive evidence of non-obviousness sufficient to overcome this rejection.
Therefore, for the reasons stated above, the present rejection of claims 1-4, 6-7, 16, and 18 under 35 U.S.C. 103 as unpatentable over Kim in view of Oh is maintained.
Conclusion
No claims are allowed.
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/B.M.B./ Examiner, Art Unit 1693
/ANDREA OLSON/ Primary Examiner, Art Unit 1693