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
The preliminary amendment dated 2 January 2024, in which claims 8, 9, 33, 34 have been amended, and claims 10, 11, 29-31, 35-41 have been cancelled, is acknowledged.
Claims 1-9, 12-28, 32-34, 42 are pending in the instant application.
Claims 2-5, 12, 14-15, 17, 19, 22-23, 25, 32-34, 42 are withdrawn as being drawn to a nonelected invention or to a non-elected species.
Claims 1, 6-9, 13, 16, 18, 20-21, 24, 26-28 are being examined on their merits herein.
Priority
This application is a National Stage application, filed under 35 USC 371 of International Application PCT/US2022/073517, filed on 7 July 2022, which claims the benefit of U.S. Provisional Patent Application 63/219,629, filed on 8 July 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 2 January 2024 and 16 April 2026 are acknowledged and considered.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-9, 12-28, drawn to a bifunctional compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition comprising the bifunctional compound of claim 1, in the reply filed on 23 July 2026, is acknowledged. Claims 32-34, 42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Applicants’ election without traverse of compound (1) below (Specification, [0059]) below:
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as the species of a compound of formula (Ia) for initial examination, in the reply filed on 23 July 2026, is acknowledged. The examiner notes that the elected species compound (1) above is a compound of formula (Ia)
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to which the following definitions apply:
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; R is
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; Z is N;
the linker is
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where n = o = p = 1;
and the degron is
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.
Claims 1, 6-9, 13, 16, 18, 20-21, 24, 26, 27 read on the elected species.
Claims 2-5, 12, 14-15, 17, 19, 22-23, 25 are withdrawn, as being drawn to a non-elected species.
Since Applicant has set forth no arguments against the requirement for restriction, it is considered that the election was made without traverse, and the restriction requirement is maintained and is herein made FINAL.
Claims 1, 6-9, 13, 16, 18, 20-21, 24, 26-28 have been examined to the extent they read on the elected species: compound (1), and the following rejections and objections are made below.
Claim Objection
Claims 2-5, 12, 14-15, 17, 19, 22-23, 25, 32-34, 42, while currently withdrawn, are objected to because of the following informality: they are presented in a non-compliant form. Specifically, the status identifiers for claims 2-6, 12, 14-15, 17, 19, 22-23, 25, 32-34, 42 should read "(Withdrawn)" until such time as examiner rejoins the claims for examination. Appropriate correction is required. See MPEP 714(C).
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 8, 13, 16, 18, 20 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.
Claims 8, 13, 16, 18, 20 recite “carbocyclene”, “heterocyclene”. It is unclear what these terms refer to. There is no definition in the Specification for these terms. Based on the chemical structures in examples of the Specification, carbocyclene seems to be –carbocyclyl—, and heterocyclene seems to be --heterocyclyl--. Yet, if this was the case, it is unclear why Applicant would use names that are not part of the organic chemistry nomenclature.
Appropriate clarification is required.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6, 8, 9, 13, 16, 18, 20, 21, 26, 28 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the art that the inventors, at the time the application was filed, had possession of the claimed invention. See MPEP 2163. The MPEP states that the purpose of the written description requirement is to the ensure that the inventor had possession, as of the filling date of the application, of the specific subject matter claimed by him. Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
(1) The nature of the invention and (2) the breadth of the claims:
Claims 1, 6, 8, 9, 13, 16, 18, 20, 21, 26, 28 are drawn to a compound of formula (Ia or (Ib):
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, wherein the Linker is any linking group that provides a covalent attachment between the targeting ligand and the degron, connected to any moiety (“degron”) that binds an E3 ubiquitin ligase.
The Specification teaches that the instant compounds are PROTACs (proteolysis targeting chimeric molecules).
Thus, claims 1, 6, 8, 9, 13, 16, 18, 20, 21, 26, 28, taken together with the Specification, embrace millions of compounds of formula (Ia), or (Ib), where
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, connected via any linker to any known moiety (“degron”) that binds an E3 ubiquitin ligase.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
Buckley et al. (Angew. Chem. Int. Ed. 2014, 53, 2312-2330, cited in PTO-892) teaches (page 2320, right column, first paragraph) that proteolysis targeting chimeras, or PROTACs, are heterobifunctional molecules that contain a ligand for an E3 ligase, a linker, and a ligand for a protein that is to be targeted for degradation. The molecule can then bind to both the E3 ligase and the target and thus induce the formation of a ternary complex. This hijacking of the E3 ligase can lead to the polyubiquitination of the target protein, followed by its degradation by the proteasome.
Buckley teaches (page 2317, under 2.4) that there are over 600 E3 ligases, divided into 4 families. Buckley teaches that the first E3 ligase successfully targeted was MDM2. Buckley teaches that the inhibitor of apoptosis protein (IAP) family of E3 ligases has been extensively targeted (page 2318, left column, second paragraph) with structurally diverse inhibitors of IAP, as in Figure 6, page 2318. Buckley teaches that SCF E3 ligases, VHL ligases, have been targeted. Buckley teaches (page 2319, right column, first paragraph) that thalidomide (D11, D12 in claim 7) binds to and inactivates the E3 ligase cereblon (CRBN).
Buckley teaches the structural diversity of the known small molecule inhibitors of E3 ligases.
Buckley discloses (Figure 11) a number of PROTACs as heterobifunctional molecules that combine an E3-ligase ligand (shown on the right) with ligands for various proteins of interest (shown on the left).
Toure et al. (Angew. Chem. Int. Ed. 2016, 55, 1966-1973, cited in PTO-892) teach (page 1969, left column, first paragraph under 3.1) that in the first generation PROTACs, which used large peptides as E3 ubiquitin ligases, the peptidic E3 recruiting moiety of these PROTACs lacked cell permeability, thus limiting their utility as chemical probe. Toure teaches (page 1969, right column, under 3.2) that first generation peptidic PROTACs lacked traditional drug-like properties, and the next step in developing PROTACs focused on incorporation of small molecule ligands for several E3 ligases. Toure teaches (page 1970, left column, under 3.2.1) that the entirely small-molecule PROTAC employing MDM2 ligand nutlin as an E3 ligase recruting moiety proved less effective than its peptidic analogs.
Toure also teaches (page 1970, left column, under 3.2.2) that PROTACs incorporating bestatin esters which bind the cellular inhibitor of apoptosis protein 1 (cIAP1) suffer from several key limitations: numerous off-target effects were observed, attributed to the bestatin moiety; in addition, high concentrations were needed to effectively degrade targeted proteins; further, the IAP ligands used are known to often induce IAP autoubiquitination and degradation which could be a concern for their use in therapeutic PROTACs (page 1970, right column, first paragraph).
Toure further teaches (page 1970, right column, first paragraph under 3.2.3) thalidomide and its derivatives were used as starting ligands for PROTACs targeting the E3 ligase CRBN, however that results in PROTAC instability, a known liability of phthalimides (page 1971, left column, second paragraph)..
Toure teaches (page 1972, left column, second paragraph) that recruiting different E3 ligases (such as, for example VHL or CRBN E3 ligases) may lead to different selectivity profiles with PROTACs, and this may depend on the protein being targeted. Toure teaches that a head to head comparison of E3 ligases could help to better inform which E3 ligase to choose for PROTACs in order to gain increased potency and selectivity.
Thus, Buckley and Toure clearly teaches that not any ligand for an E3 ligase can be successfully combined with ligands for a specific protein of interest (such as LRRK2) in a PROTAC. Buckley and Toure teach that there is unpredictability in the field of PROTACs with respect to the chemical nature of ligand for an E3 ligase which will affect the cell permeability, drug-like properties, potency, selectivity, and/or stability of the PROTACs. Thus, Buckley and Toure teach the need for experimentation in order to find the optimum ligand for an E3 ligase that results in PROTAC-mediated protein degradation, for each protein target.
Further, Toure teaches (page 1968, right column, last paragraph, page 1969, left column, first paragraph) that PROTACs position the protein of interest (POI) in a spatially favorable presentation to facilitate substrate poly-ubiquitination, thereby selectively knocking down levels of the targeted protein (Figure 3). Thus, Toure implicitly teaches that the length and nature of the linker connecting the E3-ligase ligand and the protein of interest in the PROTAC are essential for achieving the desired therapeutic effect. Toure provides specific examples showing that linker optimization may result in improved potency with PROTACs (page 1970, left column, first paragraph under 3.2.1.), that the structure of the linker may have an effect on the extent of protein degradation (page 1971, left column, third paragraph), and that various linker lengths as well as linker attachment points influence the extent of PROTAC-mediated protein degradation (page 1972, left column, third paragraph).
Toure teaches (page 1972, second paragraph, lines 7-8) that linker composition and length are crucial variables in determining the potency of PROTACs. Toure teaches (page 1972, left column, third paragraph) that studies have addressed the role that the linker plays in optimal PROTAC-mediated protein degradation by successfully determining the linker length and attachment point that results in the best protein degradation.
Toure teaches that, while this exercise generated a very potent PROTAC, optimal linker lengths of future PROTACs are expected to be highly target dependent and will therefore need to be determined on a case-by-case basis (page 1972, left column, third paragraph).
Thus, Toure teaches the need for experimentation in order to find the optimum linker that results in PROTAC-mediated protein degradation, such linker being highly target dependent. Toure teaches that linkers need to be determined on a case-by-case basis. It follows, based on the teachings of Toure, that not any linker as recited in instant claim 1, may result in PROTAC-mediated LRRK2 protein degradation.
Toure teaches that there is unpredictability in the field of linkers with respect to linker structure, length, point of attachment, used in PROTACs.
(5) The relative skill of those in the art:
The level of skill in the art is that of the authors of the references cited to support the examiner’s position (MDs, PhDs, or those with advanced degrees and the requisite experience in drug discovery research).
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
A disclosure should contain representative examples which provide reasonable assurance to one skilled in the art that ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed by him. The applicants have broadly claimed millions of compounds of formula (Ia or (Ib):
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, wherein the Linker is any linking group that provides a covalent attachment between the targeting ligand and the degron, connected to any moiety (“degron”) that binds an E3 ubiquitin ligase.
MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that claims 1, 6, 8, 9, 13, 16, 18, 20, 21, 26, 28 are broad and generic, with respect to all possible compounds encompassed by the instant claims. There is a very large number of structural variations encompassed by formula (Ia) or (Ib). The claims lack in written description because there is no disclosure of a representative number of species within the very broad claimed genus. Moreover, the specification lacks sufficient variety of species to reflect this variance in the genus. The specification provides guidance to a number of specific PROTACs (in claims 24, 25, 27) in which indazole-pyrimidines are connected via specific linkers, to thalidomide (which binds to and inactivates the E3 ligase CRBN).
(8) The quantity of experimentation necessary:
There are millions of combinations of elements Linker-degron embraced by claim 1. Generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See Enzo Biochem, 323 F.3d 956, 966, 63 USPQ2d 1609, 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (Fed. Cir. 1997). Applicant has disclosed the synthesis of a number of specific PROTACs of indazole LRRK2 inhibitors, all said PROTACs sharing a common structural feature: a specific linker and thalidomide as specific moiety that binds E3 ligase CRBN.
Applicant has claimed millions of PROTACs having any combination of elements Linker-degron.
Considering the state of the art and the high unpredictability in the art, as evidenced by Buckley and Toure, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of claims 1, 6, 8, 9, 13, 16, 18, 20, 21, 26, 28.
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 6-9, 13, 16, 18, 20, 26, 28 are rejected under 35 U.S.C. 103 as being unpatentable over Gray et al. (WO 2020/081682, published 23 April 2020, cited in IDS).
Gray (WO 2020/081682) discloses [0082] a bifunctional compound of formula (I)
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wherein the targeting ligand (TL) is an indazole TL-2a below [0086]:
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;
the linker is (page 33), for example,
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which are linkers of instant claims 8, 9, 13, 16, 18,
or the linker is alkylene terminating with or interrupted with 6-membered heterocyclene,
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as in instant claims 8, 9, 13, 16, 18, 20, 26;
and the degron is a degron that binds cereblon ([0111], page 43-44), as in instant claims 6-7, for example,
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.
Gray also teaches the following bifunctional compounds:
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, where the linker comprises a PEG chain comprising 1-6 PEG units, which may terminate with at either or both termini with C(O).
Gray also teaches the following bifunctional compounds:
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where the linker is alkylene chain terminated in -C(O)-, as in instant claim 8.
Such bifunctional compounds disclosed by Gray are bifunctional compounds of formula (Ia) of instant claim 1, wherein -W-N-Y is -C=N-NH; R is
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; q = r = 1; .
It would have been obvious to a person of ordinary skill in the art to use the teachings of Gray to arrive at the instant invention, by combining the elements disclosed in Gray in a bifunctional compound of the instant claims. The person of ordinary skill in the art would have used degrons D1-n, D1-o in bifunctional compounds TL2a-L10a to TL2a-L10k disclosed by Gray, to arrive at a compound of the instant claims, with a reasonable expectation that said bifunctional compound belonging to the genus disclosed by Gray would retain therapeutic effect.
Further, it would have been obvious to synthesize a PROTAC by linking together LRRK2 target ligand TL2a, a linker L2a, L2b, L2c or L4, and a degron which is D1-n, or D1-o, to arrive at a compound of the instant claims, with a reasonable expectation that said bifunctional compound belonging to the genus disclosed by Gray would retain therapeutic effect.
As such, claims 1, 6-9, 13, 16, 18, 20, 26, 28 are rejected as prima facie obvious.
Claims 1, 6-9, 13, 16, 18, 20-21, 24, 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Araujo et al. (WO 2021/194879, international filing date 19 March 2021, priority from U.S. Provisional Patent Application 62/992,952, filed 21 March 2020, cited in PTO-892).
Araujo (WO 2021/194879) discloses [0016]-[0017] a bifunctional compound
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wherein the PTM is, for example, ([0147], page 119)
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, where the PTM is covalently bound to the linker L via an atom of the heterocycloalyl A;
linker L is, for example,
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or
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, ([0111], page 64), where N* is a nitrogen atom that is covalently linked to the ULM, each of m, o is independently 0-20,
or the linker
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(page 68, last structure, page 70, third line), which is the linker in the instant elected species, and is a linker of instant claims 8, 9, 13, 16, 18, 20, 21 (n = p = o = 1), 24, 26 (L11), 27,
or the linker is
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, as in instant calims 8, 9, 13, 24;
and ULM is [0094]
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W = CO, as in instant claims 6-7.
Arujo also teaches [0093], page 51-52, the following CLM and linker attachment point:
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.; linker can be alkylidene [0110] .
Such bifunctional compounds disclosed by Araujo are bifunctional compounds of formula (Ia) of instant claim 1, wherein -W-N-Y is -C=N-NH; R is
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; q = r = 1; .
It would have been obvious to a person of ordinary skill in the art to use the teachings of Araujo to arrive at the instant invention, by combining the elements disclosed in Araujo in a bifunctional compound of the instant claims. The person of ordinary skill in the art would have
assembled a PROTAC by linking together LRRK2 target ligand PTM which is
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, where the PTM is covalently bound to the linker L via an atom of the heterocycloalyl A; with the linkers L taught above, and the degron CLM above, or with the degron-linker combinations above, to arrive at a compound of the instant claims, with a reasonable expectation that said bifunctional compound belonging to the genus disclosed by Araujo will retain therapeutic effect.
As such, claims 1, 6-9, 13, 16, 18, 20-21, 24, 26-28 are rejected as prima facie obvious.
Conclusion
Claims 1, 6-9, 13, 16, 18, 20-21, 24, 26-28 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S. LUNDGREN can be reached at (571)272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629
