DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of: Group I (drawn to a compound/pharmaceutical composition) and the species of formula (I) of: compound (45), in the reply filed on 09/13/2024 is acknowledged.
Claims 1-2, 5, 8, 10, and 12-19 are pending of which claims 10 and 15-16 (Group II) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention there being no allowable generic or linking claim. The restriction requirement is still deemed proper and is made Final.
Pending claims 1-2, 5, 8, 12-14, and 17-19 have been examined on the merits.
Please note, for clarity of the record, Applicant’s election of the species of compound 45 - as recited in claim 8, having the following structure:
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also corresponding to formula (I-6) (in claim 5) and to formula (I) (in claim 1) wherein X1 is -O-; X2 is -CH2-; R1, R2, R3, R4 are hydrogen; A is
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; and B is
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, and reading on claims 1, 2, 8, and 17-19.
During the course of examination, prior art was identified that relates to non-elected subject matter. In the interest of compact prosecution, that prior art has been applied to demonstrate the non-allowability of the generic claims, as discussed below.
Withdrawn Rejections
The rejection of claim 8 under 35 U.S.C. 112(d) is withdrawn in view of the Applicant’s argument.
New Grounds of Rejection due to Claim Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5, 12-14, 17 and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 describes ring A, wherein A1 is selected from C, N, O, S and NR5; however, the specification fails to provide any structural examples in which A1 is NR5, as an example. Similarly, although A3 and A4 are defined as C, N, O, or S, the specification does not provide representative compounds or guidance in which A3 and A4 are O or S. Furthermore, the claim encompasses a broad range of substitutions on the B moiety, including but not limited to cyano, nitro, and C1-C6 alkylsulfonyl substituents, and yet the specification lacks representative examples or description supporting such substitutions. Additionally, when A and B moieties are cycloalkyl, the claims allow variations at positions such as A7 (N, O, S) and n1 and n2 is 0, 1, 2, 3, but the specification does not provide adequate examples or description of compounds encompassing the combination of these variations. Similar deficiencies are also present in claims 5, 17 and 19; for example, claim 5 lacks support including but not limited to compounds of formula (I-6); claim 17 lacks support for the distinct A moiety such as thiophene; and claim 19 lacks supports for the wide range of substituents, including NR5. Therefore, the breadth of the claimed genus combined with the absence of representative structural features, suggest Applicant was not in possessing of the claimed invention at the time of filing.
Claim 13 recites “to produce synergistic effects in the prevention or treatment of specific diseases or dysfunctions, or to reduce or eliminate the toxic and side effects of one or more other ingredients.” While the specification discloses that compound of formula (I) may be combined with other ingredients, these are merely conclusory statements which do not necessarily convey possession of the claimed subject matter. This is because, the specification does not provide
any working examples or experimental data demonstrating that any specific combination achieves synergistic effects or reduces or eliminates toxicity or side effects. Moreover, the specification fails to describe any method, standard or criteria for determining or measuring “synergistic effects,” such as isobologram, combination index methods (e.g., Chou-Talalay), or comparative baselines. The specification also does not identify any particular combinations, ratios, or conditions under which such functional results would be achieved. Furthermore, the claim recites achieving these results in the prevention or treatment of “specific diseases or dysfunctions,” which encompasses a broad and heterogenous range of disease states, without identifying the diseases and dysfunctions. It is also important to note that each disease has distinct pathologies and therapeutic consideration. Yet the specification does not provide any description correlating particular combinations of treatment with any specific disease or class of diseases. Therefore, the specification clearly fails to demonstrate possession of composition capable of achieving the claimed synergistic effects or reduction or elimination of toxic or side effects across the full scope of the as claimed.
Claim 14 recites a pharmaceutical composition further comprising one or more therapeutic agents selected from the group consisting of dexamethasone, rituximab, as an example. The specification does not provide any working examples or experimental data demonstrating a composition comprising compound of formula (I) in combination with dexamethasone, rituximab, as an example. The specification also fails to identify any particular compositions, dosages, ratio, treatment regimens in which compound of formula (I) is administered together with any of the listed agents. It is important to highlight that the claimed therapeutic agents encompass a wide and heterogenous group of small molecules, biologics, immunotherapies, and cell-based therapies with diverse mechanism of action, and yet the specification does not provide any description correlating the compound of formula (I) and with any specific agent within the claimed group.
Therefore, a POSITA would conclude that Applicant does not possess the full genus of compounds defined and represented by formula (I) and respective substituents. This further supports the conclusion that the specification lacks adequate written description of the claimed subject matter.
New Grounds of Rejection due to claim amendment
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
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 1-2, 5, 8, 12-14, 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Phillips et al. (WO2017197051) in view of Thakurta et al., US PG-PUB 2015/0152511, Patani et al. (Chem Rev. 1996 Dec 19; 96(8):3147-3176), Man et al. (WO 2011/100380).
Regarding claims 1-2, 5, 8 and 17-19, Phillips (page 19, line 24- 27, at (p-q)) teaches “[a] compound of Formula I, Formula II, Formula III, Formula IV, or Formula V as described herein, and pharmaceutically acceptable salts, isotopic derivatives and prodrugs thereof that are useful in the treatment of an abnormal cellular proliferation such as cancer.” Phillips (pages 75) also teaches the following:
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Phillips (pages 86-136) further describes various components of Formula I, Formula II, Formula III, Formula IV, or Formula V, which combine to produce, for example, compound 261 (see page 466). Compound 261 corresponds to the instant Formula (I) wherein R1, R2, R3, R4,
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are hydrogen; X2 is -CO-; X1 is -NH-; n is 1; A is
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when A2, A3, A4 are nitrogen; A1 and A5 are carbon; A and B moieties are directly linked, where B is a pyridine. While compound 261 displays X2 is -CO-, however, Phillips (page 107, 117-118; page 122) teaches general formula wherein X2 is either CH2 or -CO-; as exemplified by Phillips (page 487, compound 300).
Moreover, Phillips (page 484) also teaches compound 292, wherein X1 is -O-; resulting in a modified compound that is comparable to the instant claim. As disclosed supported by
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Thakurta (abstract; page 65), lenalidomide bearing an oxygen substituent is known in the art; therefore, the claimed concept of Formula (I) is not novel. Therefore, it would have been obvious with a reasonable expectation of success to a POSITA before the effective filing date of the claimed invention to modified Phillips’ teachings in view of Thakurta to arrive at the claimed invention, because the concept is already known in the art.
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Phillips does not explicitly teach A2 is carbon.
However, a POSITA would recognize that the combined teaching of Phillips (a triazole with nitrogen at A2) and Thakurta (furan, thiazole or imidazole with carbon at A2) teach alternative 5-memebered aromatic system, demonstrating that substitution among heteroaromatic cores is known in the art. Thus, given their shared aromaticity and connectivity, a POSITA would contemplate replacing triazole with a furan, as an example, because such substitution would reasonably be understood in the art as a bioisosteric replacement, employ to further optimize the chemical compound library by introducing variation in a 5-memebred heteroaryl core, as disclosed by Thakurta. Additionally, a POSITA would have also considered rearranging nitrogen positions within the triazole to generate regioisomers as part of routine structure-activity exploration. Thus, such modification would reasonably yield variants where positions like A2 is occupied by carbon, as an example, rather than nitrogen. This is supported, for example, by Patani (page 3148) disclosing CH2, NH, S and O represent a group of isosteres repositioning within the ring. As exemplified by Patani (page 3163), disclosing the repositioning and replacement of divalent bioisosteres:
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Dick (page 3) also provides evidence of such, disclosing the following:
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Dick (page 8) provides further evidence by disclosing the following:
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Therefore, because CH2, NH, S and O are common divalent bioisosteres that preserve valency while modulating polarity, hydrogen bonding, and metabolic property, thus a POSITA would be motivated to explore regioisomeric rearrangements of the 1,2,3-triazole core as taught by Phillips in view of Thakurta and Patani. Thus, substituting ring atoms with O or S and varying the divalent linkers is a routine, predictable strategy to diversify a compound library to arrive at the claimed compound. (Malik et al. RSC Med Chem. 2020 Jan 29;11(3):327-348.)
Regarding claim 12-13, Phillips at page 230, line 19- 21 teaches “pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any of the uses described herein.” Additionally, Man (page 32, ([130]) further teaches at “A compound provided herein, or a pharmaceutically acceptable salt, Solvate, prodrug, clathrate, or stereoisomer thereof, can be combined with other pharmacologically active compounds (“second active agents’) in methods and compositions provided herein. Certain combinations may work synergistically in the treatment of particular types diseases or disorders, and conditions and symptoms associated with Such diseases or disorders.” Given that Man and Phillips teach the same core structure and utility, and Phillips (page 212, line 18- 20) also teaches compound can be used in combination with another compound to treat a disease, this suggests a potential for synergistic effect. Therefore, it would have been obvious to a POSITA to consider combining the teachings of Phillips and Man on using compounds in combination, with the expectation that this effect may lead to synergistic outcomes, significantly impacting treatment efficacy.
Regarding claim 14, Phillips (page 221-223) teaches additional therapeutic agents can include, but not limited to an HDAC inhibitor, pemetrexed, gemcitabine, vincristine, adriamycin, melphalan, and cytarabine.
Response to Applicant’s Argument
Applicant argues that the amended claims specify that moieties A and B are directly connected, and further appears to argue that the claim language requires that B moiety to be substituted. Applicant’s argument is not persuasive, because the new ground of rejection above clearly presents a compound in which moieties A and B are directly connected. With respect to substituted B moiety, the claim language does not support Applicant’s own interpretation. Because as disclosed below (the text was highlighted for emphasis), the claim explicitly encompasses both substituted or unsubstituted options.
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Applicant argues that the claimed variable X2 differs from the prior and therefore the 103 rejection is not proper. Applicant’s argument is not persuasive, because Phillips explicitly teaches that X2 may either be CH2 or C(O). In view of Thakurta’s disclosure that X2 is CH2, thus the nature of X2 is not nonobvious. Therefore, the new ground of rejection meets the claim limitations.
Applicant further argues that the claimed compounds exhibit unexpected results, relying on IC50 data presented as ranges to demonstrate improve activity over the prior art. Applicant’s argument is not persuasive, because the IC50 data presented as ranges prevents precise comparison with the prior art and also fails to establish a clear improvement. Additionally, the data is internally inconsistent, as some cycloalkyl compounds (A moiety) show more favorable IC50 values than the aryl or heteroaryl compounds emphasized by the instant claim as allegedly the effective compounds. Thus, the evidence for unexpected results is inconclusive in view of the claimed invention.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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