DETAILED ACTION
Status of Claims
Receipt is acknowledged of the Applicants’ Amendments and Remarks, filed September 8, 2025 which have been entered on the record.
Claims 1, 3, 6, 13, 15, and 22-26 are pending
Claims 2, 4-5, 7-12, 14, 16, and 18-21 were previously cancelled by Applicant.
Claim 17 is presently cancelled by Applicant.
Claims 1,13, 15, 22 are amended.
Claims 24-26 remain withdrawn as detailed in the Office Action dated June 18, 2024 and described in the Election/Restriction section below.
Claim 23 is rejoined as described in the Election/Restriction section below.
Claims 1, 3, 6, 13, 15, and 22-23 are pending and currently under examination.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 8, 2025 has been entered.
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
This application is a 371 National Phase Application of PCT/US19/56537 that claims benefit to US provisional applications 62/746283 filed October 16, 2018 and 62/884410 filed August 8, 2019.
Information Disclosure Statement
One additional information disclosure statement (IDS) submitted on September 8, 2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restriction
Applicant’s election of Group I (Claims 1-3 and 5-22) in the reply filed on May 23, 2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01/(a)).
Applicant further election of the following species (compound 9) is also acknowledged.
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Since the species was originally found free of prior art, the examination was expanded to the remaining species of formula (I) as in claim 1.
However, new rejections were provided based on the discovery of new art and Applicant amendments to address compound 9 in addition to the expanded search regarding species of formula (I) as in claim 1.
The Examiner has reconsidered the Requirement for Restriction/Election, and for the purposes of compact prosecution, Group II, claim 23 directed to a pharmaceutical composition of the bifunctional compound of claim 1, is rejoined and fully examined for patentability under 37 CFR 1.104.
Group III, claims 24-26 remain 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. Election was made without traverse in the reply filed on May 23, 2024.
Claims 1, 3, 6, 13, 15, 22-23 are currently under examination and are the subject of this office action.
WITHDRAWN REJECTIONS
The examiner withdraws rejections to Claims 1, 6, 13, 17, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Crews in view of Miller based on claim amendments by Applicants to the degrons recited and cancellation of claim 17.
The examiner withdraws rejections to 17 on the ground of nonstatutory double patenting based on the cancellation of claim 17.
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 6, 13, 15, and 22-23 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Bradner et al. (USPN 9,694,084 B2) (herein known as Bradner), in view of Miller et al. (USPN 9,493,440 B2) (herein known as Miller), and further in view of Scott et al (Scott, Jack D., Duane E. DeMong, Thomas J. Greshock, Kallol Basu, Xing Dai, Joel Harris, Alan Hruza et al. "Discovery of a 3-(4-pyrimidinyl) indazole (MLi-2), an orally available and selective leucine-rich repeat kinase 2 (LRRK2) inhibitor that reduces brain kinase activity." Journal of medicinal chemistry 60, no. 7 (2017): 2983-2992), and Fell et al (Fell, Matthew J., Christian Mirescu, Kallol Basu, Boonlert Cheewatrakoolpong, Duane E. DeMong, J. Michael Ellis, Lynn A. Hyde et al. "MLi-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibition." The Journal of pharmacology and experimental therapeutics 355, no. 3 (2015): 397-409).
Regarding claim 1, Bradner teaches compounds similar to the instant application that are “bifunctional compounds which act as protein degradation inducing moieties (Abstract), also known in the art as PROTACs consisting of a targeting ligand, linker and degron, matching the framework outlined in instant claim 1 and shown below.
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Bradner also teaches bifunctional compounds of Formula X, I-11 that are comprised of (column 3, lines 25-50): a) an E3 Ubiquitin Ligase binding moiety aka a Degron (column 2, lines 18-23), b) a linker, which “is a group that covalently binds to the Targeting ligand” (column 2, lines 18-23), and c) a targeting ligand….which “is a small molecule which is capable of binding to or binds to a target protein of interest” (column 3, lines 50-56),” where the target protein can be a kinase such as “a leucine-rich repeat kinase (i.e.: LRRK2)” (column 48, lines 5-6).
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Consequently, Bradner teaches the key functional components required to build a PROTAC that can be simply modified in a highly modular fashion based on the target protein through substituting the targeting ligand for an inhibitor selective for the protein of interest and specifically identifies target proteins that would be suitable for such experimentation (i.e.: LRRK2).
Bradner teaches the linkers that meet the limitations recited in instant claim 1 where “the linker comprises an alkylene chain….which may be interrupted by, and/or terminate…in at least one of -O-, N(R’)COR….3-12-membered heterocyclene” as exemplified by dBET18 shown below (column 203-204, top molecule).
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Bradner additionally teaches that the linker between the degron and targeting ligand can be of Formula L1 or L2, where TL is the targeting ligand; W is independently absent, CH, O, S, NH or NR5; Z is absent, CH, O, NH or NR5 (column 37-39).
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Bradner also teaches linkers such as:
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Consequently, Bradner’s teaching meet the limitation of claim 13 shown below:
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Regarding selecting a linker, Bradner further teaches that “The Linker is a bond or a carbon chain that serves to link a Targeting Ligand with a Degron (column 37, lines 41-42).
Bradner further teaches preferred embodiments using PEGylated linkers “the Linker may be a polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units (column 47, 30-36),” as used in elected species SB1-G-185.
Bradner further provides guidance for optimizing the linker, specifically that “In certain embodiments, the Linker is designed and optimized based on SAR (structure-activity relationship) and X-ray crystallography of the Targeting Ligand with regard to the location of attachment for the Linker.
In certain embodiments, the optimal Linker length and composition vary by target and can be estimated based upon X-ray structures of the original Targeting Ligand bound to its target. Linker length and composition can be also modified to modulate metabolic stability and pharmacokinetic (PK) and pharmacodynamics (PD) parameters.
In certain embodiments, where the Target Ligand binds multiple targets, selectivity may be achieved by varying Linker length where the ligand binds some of its targets in different binding pockets, e.g., deeper or shallower binding pockets than others (column 37,lines 36-51).”
Consequently, Bradner provides specific guidance for ranges of linker lengths specifically using ethylene glycol units and how to optimize the linker length to achieve the desired pharmacological profile and compound properties.
Bradner also teaches the degrons recited in instant claim 1 (column 16-37).
By example only, Compound dBEt18 of Bradner incorporates the D1-b moiety of instant claim 15 (column 203-204, top molecule, shown below).
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Bradner does not explicitly teach the targeting ligands and/or compounds disclosed in the instant application or Claim 22.
Regarding Claim 1 and 6, Miller teaches potent inhibitors of LRRK2 kinase that are identical to the targeting ligand of instant application defined as (TL2-a) (by example only, see column 47, Table 2, Ex 47, shown below).
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Miller also teaches that “compounds and compositions effective at modulating LRRK2 activity may provide a treatment for neurodegenerative diseases such as Parkinson's disease, Lewy body dementia, neuroinflammation, and for disease such as Crohn's disease, leprosy and cancer (column 2, lines 8-14),” and that “the invention is also directed to medicaments or pharmaceutical compositions which may be useful for treating diseases or disorders in which LRRK2 is involved, such as Parkinson's Disease, which comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (column 2, “Summary of Invention” and column 6, lines 66-67, and column 7, lines 1-9).”
Consequently, Miller teaches similar and/or identical compounds to the targeting ligand of instant application with the identical purpose in treating neurodegenerative diseases such as Parkinson’s disease.
Miller does not teach the aforementioned components of the PROTAC or explicitly discloses the compounds in the instant application.
Fell teaches MiLi-2 as a potent LRRK2 kinase inhibitor investigated for potential treatment for Parkinson’s disease (PD) similar to instant invention’s targeting ligand, differing only by the morpholine substituent.
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Specifically, Fell teaches that “MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC50 = 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC50 = 1.4 nM), and a radioligand competition binding assay (IC50 = 3.4 nM). MLi-2 has greater than 295-fold selectivity for over 300 kinases in addition to a diverse panel of receptors and ion channels. Acute oral and subchronic dosing in MLi-2 mice resulted in dose-dependent central and peripheral target inhibition over a 24-hour period as measured by dephosphorylation of pSer935 LRRK2. Treatment of MitoPark mice with MLi-2 was well tolerated over a 15-week period at brain and plasma exposures >100× the in vivo plasma IC50 for LRRK2 kinase inhibition as measured by pSer935 dephosphorylation. Morphologic changes in the lung, consistent with enlarged type II pneumocytes, were observed in MLi-2-treated MitoPark mice. These data demonstrate the suitability of MLi-2 as a compound to explore LRRK2 biology in cellular and animal models.”
Fell also teaches that “the development of LRRK2 selective kinase inhibitors has been a dominant therapeutic focus for the treatment of PD.”
Fell also teaches that “Although multiple potent LRRK2 kinase inhibitors, from structurally distinct chemotypes, have been reported in the literature, their utility to probe the tolerability and therapeutic potential of LRRK2 kinase inhibition in vivo has been hindered by a combination of poor selectivity, suboptimal pharmacokinetic qualities and/or a lack of brain penetration.”
Fell teaches that “In summary, the current work describes a structurally novel, potent, and highly-selective LRRK2 inhibitor discovered from internal medicinal chemistry efforts with our indazole series of LRRK2 inhibitors. Here, we detailed the pharmacological and pharmacokinetic properties of MLi-2 in mice, which demonstrate its suitability for exploring LRRK2 kinase biology in cellular and animal models….As progress on these fronts has been hampered by the various limitations of currently available pharmacological tools, we hope access to MLi-2 will help advance preclinical efforts at understanding LRRK2 biology and, through collaborative efforts, shed light on novel pathways downstream of LRRK2 that may enrich the target space for PD therapeutics.”
Consequently, Fell teaches MLi-2 possesses desirable pharmacological properties for investigation of LRRK2, particularly over other LRRK2 inhibitors known in the art. Scott additionally teaches SAR studies leading to the discovery of MLi-2. Scott teaches that “Without access to an X-ray crystal structure of LRRK2, we constructed a homology model of the LRRK2 kinase domain based on the X-ray structure of an indazole inhibitor bound to ERK2. This allowed us to gain further insight into the binding of our indazole inhibitors in LRRK2 and rationalize the selectivity over other kinases. As shown in Figure 2, the model of 17 in LRRK2 shows that the indazole is bound to the hinge region of LRRK2 in a hydrogen bond donor/acceptor pair with the indazole NH and nitrogen. The morpholine is positioned adjacent to Leu1949 on the hinge and directed toward bulk water, and the isopropoxy resides in the region of the catalytic lysine (Lys1906).”
Consequently, Scott teaches that the morpholine unit is solvent exposed and not critical to target binding; therefore, is amendable to modifications without loss of activity.
Scott also teaches that incorporation of methylcyclopropyl increased potency: “The addition of the methyl group on the cyclopropane ring provided a striking improvement in LRRK2 potency considering the modest potency (41 nM) of the cyclopropoxy analogue 18.”
Scott also teaches that morpholine can be substituted for piperidine analogues as demonstrated by compound 28, “In this communication, we report a set of IC50s generated via a high throughput cellular assay that has been used to profile the advanced inhibitors. In comparison of the enzymatic and cellular readouts, generally the high ATP enzymatic evaluation was found to be a good surrogate for a cellular assay with our most potent inhibitors, such as 27, 28, and 1, exhibiting similar potencies across the three assays.”
Consequently, both Scott and Fell emphasize the critical features of MLi-2, and desirability of MLi-2 as an LRRK2 inhibitor for further investigation based on target binding, brain penetration, etc.
The specific components taught by Bradner and Miller are shown below using compound 9 from instant claim 22 as elected by Applicant for the species election, in addition to the conceptual framework established by Bradner for PROTACs as aforementioned.
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A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c). See MPEP § 2144.09.
Therefore, it would have been prima facie obvious for an ordinarily-skilled artisan in the field of medicinal chemistry before the effective filing date of the claimed invention to have combined the teachings of Bradner, Miller, Fell and Scott to develop a bifunctional compound known as a PROTAC to target LRRK2 because Bradner teaches the framework for making a bifunctional molecule for protein degradation (i.e.: PROTAC) consisting of a degron, linker and LRRK2 targeting ligand, that LRRK2 is a suitable protein target, the identical degrons, and the identical linker and because Miller teaches a potent and effective targeting ligand for selectively inhibiting LRRK2. Scott teaches that the morpholine moiety of MLi-2 can be substituted for piperidine based on SAR studies, and Fell teaches desirable properties of MLi-2. Bradner additionally teaches methods for optimization of the linker length and other key parameters in PROTAC design.
A person of ordinary skill in the art would have been motivated to modify the invention of Bradner to incorporate the LRRK2 targeting ligand taught by Miller, Scott and Fell to develop a library of PROTACs targeting LRRK2 for treating neurodegenerative dieases such as Parkinson’s disease because Bradner teaches kinases such as LRRK2 are suitable protein targets and it is known in the art that PROTACs offer unique advantages over conventional approaches including potential to control degradation of undruggable proteins, bypass toxic effects, improved specificity and need for low concentrations and because Miller, Scott and Fell teach similar compounds that are amendable for modification for use in treating LRRK2-related diseases such as Parkinson’s disease directed towards identical protein targets.
Therefore, an ordinarily-skilled artisan in the field of medicinal chemistry would have arrived at the structures of the instantly claimed invention as a predictable result with a reasonable expectation of success. PROTACs are known to be modular in design as further taught by Bradner; therefore, simply substituting the targeting ligand for the LRRK2 inhibitors taught by Miller, Fell and Scott and applying routine optimization through standard structure-activity relationship (SAR) studies as commonly done in the art and based on the guidance provided by Bradner for optimization and what was known in the art as of the effective filing date of the claimed invention would provide the claimed invention as a predictable result with a reasonable expectation of success based on the beneficial teachings of Bradner, Miller, Fell and Scott.
It would have been further prima facie obvious to obtain the instantly claimed compositions using the compounds in instant claim 1 since the compositions recited in claim 23 are highly predicable results that would have reasonable expectation of success based on the teachings of Bradner, Miller, Scott and Fell and what is known in the prior art for formulation of pharmaceutical compositions.
Claims 1, 3, 13, 15, and 22-23 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Bradner et al. (USPN 9,694,084 B2), (herein known as Bradner), in view of Baker-Glenn et al. (USPN 8,354,420 B2), (herein known a Baker-Glenn) and Estrada et al (Estrada, A.A., Liu, X., Baker-Glenn, C., Beresford, A., Burdick, D.J., Chambers, M., Chan, B.K., Chen, H., Ding, X., DiPasquale, A.G. and Dominguez, S.L., 2012. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. Journal of medicinal chemistry, 55(22), pp.9416-9433).
As aforementioned, Bradner teaches similar elements of claim 1, 13, 15 and 22 including identical degrons, linkers and that the targeting ligand can target LRR2.
Bradner does not explicitly teach the targeting ligand defined in Claims 1 and 3.
Regarding Claim 1 and 3, Baker-Glenn teaches inhibitors of LRRK kinase that are identical to the targeting ligand of instant application defined as (TL1-a and TL1-b) (by example only, see column 55, Table 4, Ex 25; column 61, Table 4, Ex 47 and column 63, Table 4, Ex 50 as shown below).
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Baker-Glenn also teaches that “compounds and compositions effective at modulating LRRK2 activity may provide a treatment for neurodegenerative diseases such as Parkinson's disease and Lewie body dementia, for CNS disorders such as Alzheimer's disease and L-Dopa induced dyskinesia, for cancers such as kidney, breast, prostate, blood, papillary and lung cancers, acute myelogenous leukemia and multiple myeloma, and for inflammatory diseases such as leprosy, Crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis (column 1, lines 61-67).”
Baker-Glenn also teaches that “ Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease (abstract).
Estrada teaches compound similar to instant invention such as GNE-7915 as shown below (Abstract).
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Estrada teaches that “High throughput in vivo rodent cassette pharmacokinetic studies enabled rapid validation of in vitro–in vivo correlations. Guided by this data, optimal design parameters were established. Effective incorporation of these guidelines into our molecular design process resulted in the discovery of small molecule inhibitors such as GNE-7915 (18) and 19, which possess an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species.”
Estrada also teaches docking studies using compound 1, also similar to the targeting ligand of instant invention, specifically that “small ortho-substituents, such as the methoxy group in 2,4-diaminopyrimidine 1, are well tolerated in LRRK2 but are disfavored in JAK2 and approximately 290 other kinases that contain a larger Phe or Tyr residue in this binding site region near the hinge. This finding allowed us to use structure-based drug discovery to successfully optimize a series of diaminopyrimidine inhibitors that led to the identification of 1 as a potent, selective, and brain penetrable LRRK2 small molecule inhibitor.”
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Tables 1 and 3 of Estrada shows additional SAR studies for the aminopyridmines similar to the targeting ligand of instant invention. Estrada also describes issues with the morpholine ring, particularly that “As a result of significant N-demethylation observed from in vitro metabolite identification studies, the aminoethyl analogue of 10 (11) was prepared and successfully reduced the total clearance while maintaining comparable brain penetration. Both 10 and 11 also demonstrated significant in vitro oxidative metabolism of the morpholine ring. Thus, in an attempt to further reduce the metabolic turnover, the morpholine-d8 analogue (12) of 11 was synthesized and reduced the clearance significantly, presumably because of kinetic deuterium isotope effects,” and that “Finally, several morpholine derivatives were targeted, as the morpholine ring had been identified as a major site of metabolism and an altered metabolic profile for unpredictable toxicity/genotoxicity could prove desirable.”
Consequently, Estrada highlights key features of the compounds based on SAR studies, and additionally, provides motivation to modify the morpholine ring based on issues with metabolic profile.
The specific components taught by Baker-Glenn and Bradner are shown below using compound 4 from instant claim 22 in addition to the conceptual framework established by Bradner for PROTACs as aforementioned.
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Baker-Glenn does not teach the aforementioned components of the PROTAC or explicitly discloses the compounds in the instant application.
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c). See MPEP § 2144.09.
Therefore, it would have been prima facie obvious for an artisan in the field of medicinal chemistry before the effective filing date of the claimed invention to have combined the teachings of Bradner Baker-Glenn and Estrada to develop a bifunctional compound known as a PROTAC to target LRRK2 because Bradner teaches the framework for making a bifunctional molecule for protein degradation (i.e.: PROTAC) consisting of a degron, linker and LRRK2 targeting ligand, that LRRK2 is a suitable protein target, the identical degrons, and the identical linker and because Baker-Glenn teaches a potent and effective targeting ligand for selectively inhibiting LRRK2, and Estrada teaches SAR studies, desirable properties of similar and/or identical compounds to Baker-Glenn and motivation to modify the morpholine ring to improve the metabolic profile.
A person of ordinary skill in the art would have been motivated to modify the invention of Bradner to incorporate the LRRK2 targeting ligand taught by Baker-Glenn to develop a library of PROTACs targeting LRRK2 targeting LRRK2 for treating neurodegenerative dieases such as Parkinson’s disease because it is known in the art that PROTACs offer unique advantages over conventional approaches including potential to control degradation of undruggable proteins, bypass toxic effects, improved specificity and need for low concentrations and because Baker-Glenn and Estrade teach similar compounds that are amendable for modification for use in treating LRRK2-related diseases such as Parkinson’s disease directed towards identical protein targets.
By combining the components and fundamentals taught by Baker-Glenn, Bradner and Estrada an ordinarily-skilled artisan in the field of medicinal chemistry would have arrived at the structures of the instantly claimed invention as a predictable result. PROTACs are known to be modular in design; therefore, simply substituting the targeting ligand for Baker-Glenn’s LRRK2 inhibitors and applying routine optimization through standard structure-activity relationship (SAR) studies as commonly done in the art and based on the guidance provided by Bradner for optimization and what was known in the art as of the effective filing would provide the claimed invention as a predictable result with a reasonable expectation of success based on the beneficial teachings of Bradner, Baker-Glenn and Estrada.
It would have been further prima facie obvious to obtain the instantly claimed compositions using the compounds in instant claim 1 since the compositions recited in claim 23 are highly predicable results that would have reasonable expectation of success based on the teachings of Bradner, Baker-Glenn and Estrada and what is known in the prior art for formulation of pharmaceutical compositions.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 6, 13, 15, and 22-23 are/remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-9 and 13 of copending Application No. 18576068 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both applications disclose identical bifunctional compounds of formula (I) targeting LRRK2.
Claim 1 of ‘068 recites a bifunctional compound of formula (Ia) for targeting LRRK2, consisting of a targeting ligand that covers TL2-a of instant claim 1 (see comparison between TL2-a and Formula Ia below), any degron which maps to instant claims 15, 17, 19, 21, and any linker, which maps to instant claim 13, and consequently, also reads on bifunctional compounds 8-12 of instant claim 22.
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Claims 6-7 of ‘068 recite “wherein the degron binds cereblon (CRBN),” which maps directly to instant claims 1, and 15.
Claims 8-9 and 13 of ‘068 recite linkers that map directly to instant claims 1 and 13, specifically, “wherein the alkylene chain comprises 1-6 alkylene units or wherein the polyethylene glycol chain comprises 1-6 PEG units.”
Therefore claims 1, 6-9 and 13 of ‘068 are clearly anticipated by instant claims 1, 6, 13, 15, and 22-23
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The Remarks of September 8, 2025 have been fully considered but are not fully persuasive for the reasons below. The Examiner notes that arguments from Office Actions dated June 18, 2024; December 19, 2024, and and July 8, 2025 are additionally incorporated by reference herein.
35 USC § 103
Applicant’s Argument:
“Applicant traverses the rejection with respect to the presently amended claims.
The collective teachings of Bradner and Miller provide no scientific or legal rationale for making a bifunctional compound as presently claimed with a reasonable expectation that it would initiate degradation of LRRK2. Contrary to the position articulated on page 24,the properties of the claimed compounds, namely their capability of initiating degradation of LRRK2, must be considered as part of the obviousness determination. See, e.g., Eli Lilly & Co. V. Zenith Goldline Pharms., Inc., 471 F.3d 1369, 1378 (Fed. Cir. 2006) (affirming decision of the district court that the patent at issue was valid and infringed) patentability for a chemical compound does not depend only on structural similarity. This court will not ignore a relevant property of a compound in the obviousness calculus. When claimed properties differ from the prior art, those differences, if unexpected and significant, may lead to nonobviousness." (citations omitted)). In Eli Lilly, the compound claim of the patent at issue (U.S. 5,229,382) does not contain a recitation regarding function.”
Examiner’s Response:
The Examiner appreciates Applicant’s arguments; however, respectively disagrees.
As outlined in the previous Office Actions and above, Bradner teaches the framework for PROTACs that are comprised of (column 3, lines 25-50): a) an E3 Ubiquitin Ligase binding moiety aka a Degron (column 2, lines 18-23), b) a linker, which “is a group that covalently binds to the Targeting ligand” (column 2, lines 18-23), and c) a targeting ligand….which “is a small molecule which is capable of binding to or binds to a target protein of interest” (column 3, lines 50-56),” where the target protein can be a kinase such as “a leucine-rich repeat kinase (i.e.: LRRK2)” (column 48, lines 5-6).
Consequently, Bradner suggests that LRRK2 is a feasible target protein for design of a suitable degrader molecule.
Bradner additionally teaches the linkers and degrons as described previously, and teaches a person of ordinary skill how to optimize the linker as explained above.
This rebuts Applicant’s assertion that Bradner fails to provide any scientific or legal rationale to make a bifunctional degrader to target LRRK2.
Bradner additionally teaches that the targeting ligand is a small molecule, which is capable of binding to a target protein of interest (i.e.: an inhibitor).
It is well-known in the prior art that inhibitors capable of binding target proteins of interest are used in designing PROTACs.
As supporting evidence, the examiner previously cited Patterson and Crews: “To date, most of the reported PROTACs have been developed starting from a well-characterized ligand, often an inhibitor, as the POI recruiting moiety. The crystal structure of the POI ligand bound to its target and/or available POI ligand structure activity relationship (SAR) information has been used to guide PROTAC design, e.g. to identify linker attachment point on the POI ligand (Pettersson, Mariell, and Craig M. Crews. "PROteolysis TArgeting Chimeras (PROTACs)—past, present and future." Drug Discovery Today: Technologies 31 (2019): 15-27).” The examiner notes this review was published online February 13, 2019, which is before the effective date of filing for instant application, and this also parallels the guidance provided by Bradner for how to perform the optimization.
As aforementioned, the degron is well-known in the art and taught by Bradner and Miller and Baker-Glenn teaches LRRK2 inhibitors, similar and/or identical ones to instant invention. The Examiner has provided further evidence from Fell, Scott and Estrada who also teach the similar and/or identical inhibitors used as targeting ligands in instant invention, and further details regarding biological activity and SAR studies employed in molecule development, all which support the use of the inhibitors in treating neurodegenerative diseases such as Parkinson’s disease.
Bradner has provided the framework and motivation for the degron and targeting ligand to be linked (i.e.: to access PROTACs targeting LRRK2). The examiner has provided reasonable rationale for why a person of ordinary skill in the art would be motivated to make such a substitution and Bradner has indicated that the targeting ligand is primed to be substituted specifically for a compound that can bind LRRK2 (i.e.: an inhibitor).
Hence, contrary to Applicant’s assertion regarding the prior art, based on what was known at the time for PROTACs, a person of ordinary skill in the art would have been motivated to combine the teachings of Bradner with the inhibitors described by Miller, Scott, Fell, Baker-Glenn and Estrada to access PROTACs targeting LRRK2. Additionally, the artisan would have had a reasonable expectation of success in accessing such compounds as a predictable result through routine optimization as part of the drug discovery process common to the field of medicinal chemistry. It is not unexpected that the resulting compounds would be applicable to treating neurodegenerative diseases such as Parkinson’s based on the beneficial teachings of Miller, Scott, Fell, Baker-Glenn and Estrada.
Consequently, Applicant’s assertion that: “The collective teachings of Bradner and Ishikawa provide no scientific or legal rationale for making a compound as presently claimed with a reasonable expectation that it would initiate degradation of LRRK2,” is inaccurate based on the teachings of Bradner pertaining PROTACs, targeting proteins, targeting ligands, linker and linker optimization, and Miller, Scott, Fell, Baker-Glenn and Estrada’ teachings regarding the specific inhibitors/targeting ligands and what was known in the prior art at the effective date of filing.
As previously explained, Applicant’s arguments are singularly focused on predictability for the PROTACs to actually degrade the targeting protein LRRK2, not whether the PROTACs would be predictable to make and access
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “degradation of LRRK2”) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Once more, Applicant’s claims are directed towards a compound of Formula (I).
Furthermore, Applicant cites Eli Lilly & Co. v. Zenith Goldline Pharms., Inc., 471 F.3d 1369, 1378 (Fed. Cir. 2006); however, the facts of this case are distinct from the present disclosure. Eli Lilly & Co. v. Zenith Goldline Pharms., Inc. is a case regarding small molecule drugs, specifically, olanzepine and clozapine, which differ based on a hydrogen vs. chloro moiety, which changes the electronic properties of the drug. This is not equivalent to the present case regarding bifunctional molecules which consist of degron, linker and targeting ligand: components that are all known in the prior art. The key point from the case cited is that the invention taught away from the substitution; therefore, the invention was rendered non-obvious. Particularly, rather than provide motivation, the prior art taught away from selecting the compound in question (page 12). Additionally, the prior art failed to suggest or teach other modifications to arrive at the compound in question. Finally, the strongest consideration was that Eli Lilly overcame the prima facie case of obviousness through providing extensive secondary considerations to rebut obviousness (page 14-15).
This is distinct from the issues presented in this application. Applicant cites the case which states that “patentability for a chemical compound does not depend only on structural similarity. This court will not ignore a relevant property of a compound in the obviousness calculus. When claimed properties differ from the prior art, those differences, if unexpected and significant, may lead to nonobviousness.”
The Examiner agrees that properties are considered as part of obviousness determination which is consistent with the statements in the previous Office Actions, which the Examiner clearly cites “ A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963).”
However, as aforementioned, it is improper to read limitations from the specification into the claims, and Applicant’s claims are directed towards a compound of Formula (I) with no requirement that the compounds possess any properties in particular.
Based on the prior art presented, the similarity in chemical structure and function does provide motivation for an ordinarily-skilled artisan to make a claimed compound based on the expectation of similar properties. As discussed, Bradner teaches a framework for developing PROTACs with applications towards treating diseases and/or conditions associated with the target proteins, and Miller, Scott, Fell, Baker-Glenn and Estrada teach inhibitors for applications in treating neurodegenerative diseases such as Parkinson’s directed towards LRRK2.
Applicant’s own data demonstrates that the resulting compounds show similar properties to MLi2 by example only. Based on Bradner’s guidance, and that all three components (i.e.: degron, linker and targeting ligand) are known in the art, it is also not unexpected that one would arrive at bifunctional compounds capable of promoting and/or degrading a kinase.
Applicant is once more reminded about reasonable expectations of success and predictable results, particularly that the expectation of success need only be reasonable, not absolute and that “conclusive proof of efficacy is not required to show a reasonable expectation of success.” See MPEP 2143.02 for further guidance.
Applicant has provided no support or suggestion that the prior art teaches away from arriving at instant invention nor has Applicant provided sufficient secondary considerations to rebut the prima facie obvious case.
Applicant is again reminded that the burden is on the Applicant to explain why results are significant and unexpected.
Applicant’s Argument:
“The present claim amendments create an even tighter nexus between the claims and the results, e.g., reasonable extrapolation of the structures of the compounds that degraded LRRK2 (compounds 1, 4, and 6-13 - contain cereblon degrons). Applicant's results illustrated in FIG. 1-FIG. 18D and disclosed on pages 77-81 of the specification, demonstrate that claimed compounds cause degradation of LRRK2. In the previous response, Applicant presented a number of representative publications that speak to the unpredictability in the PROTAC art. Applicant's results must be taken as "unexpected".
Examiner’s Response:
The Examiner agrees that the claim amendments have narrowed the scope of invention; however, Applicant’s results merely support that it would have been prima facie obvious to arrive at the instant invention for the rationale provided previously.
It is not unexpected that the instant invention’s compounds would be capable of inhibiting LRRK2 based on the prior art. As aforementioned, not all compounds were capable of degradation nor were all compounds claimed capable of superior inhibition of LRRK2 compared to MLi2 analog (comparative study) based on Applicant’s own data. Consequently, such results cannot be taken as unexpected.
Applicant’s Argument:
To reiterate its position set forth in the prior response, the determination of obviousness is unsupported by and in fact, contrary to the extant state of the art. Applicant provided representative examples of publications, in the previous response, that emphasized that the "concept" and "design" of PROTAC/bifunctional compounds are known, but the art remains empirical and unpredictable. Even after two decades of development, it readily concedes that a sizeable gap remains between concept/design and reality/success. To the contrary, the art indicates there are many challenges with PROTACs. Developing PROTACs molecules is known to be a labor-intensive and challenging process. Each PROTAC compound comprises three essential components: a ligand that binds to the protein of interest (POI), an E3 ubiquitin ligase ligand, and a linker connecting the two and the synthesis of these complex structures often requires multiple chemical steps. Modifying any of these three components (POI ligand, E3 ligase ligand, or linker) can significantly impact the PROTAC's efficacy, selectivity, and pharmacokinetic properties. Optimizing the linker, in particular, involves exploring various lengths, compositions, and attachment points, all of which are crucial for ensuring proper ternary complex formation and target protein degradation. This necessitates extensive experimental validation and iterations of design, synthesis, and biological testing to identify the most promising candidates, which can be both time-consuming and resource- intensive.”
Examiner’s Response:
The Examiner agrees that there are many challenges in the field of PROTACs; however, as presented, this in itself does not mean an invention in the field is by default patentable and rendered non-obvious.
As previously explained, based on the state of the art at the effective date of filing and the facts presented, it would have been prima facie obvious for an ordinarily-skilled artisan to arrive at the invention through routine optimization. It is standard to engage in iteration and optimization in the field of medicinal chemistry as part of SAR studies, and the state of the art provides limited options including limited number of degrons that work and limited number of linkers that work, as taught by Bradner. Based on Bradner’s teachings and framework to design a PROTAC and that the three components: degron, linker and targeting ligands are all known in the art, it would be obvious to arrive the instant invention as explained.
As presented, Bradner provides guidance on how to optimize the parameters mentioned, and based on the evidence presented, such choices would not be a pick-and-choose exercise, but would be achievable by a person of ordinary skill in the art as a predictable result with a reasonable expectation of success.
Applicant is again reminded that “Applicant is reminded that “"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. See MPEP 2141.03.”
Applicant’s Argument:
Nandave supports statements in Han regarding the importance of the linker. Han's disclosure would have directed persons skilled in the art in a direction other than the presently recited linkers. Thus, the PROTAC art has appreciated its complexity and the importance of all 3 structural moieties. Viewed from this broader and more complete perspective, the collective teachings of Bradner and Miller would not have directed a person of ordinary skill in the art to arrive at the claimed compounds, at least with a reasonable expectation that they would initiate degradation of LRRK2.
Examiner’s Response:
The Examiner respectfully disagrees and has provided detailed analysis to set forth a reasonable prima facie case of obviousness as per MPEP 2143 in this Office Action and previous Office Actions.
As previously mentioned, Applicant has failed to provide support suggesting synthesizing the compounds claims would be an insurmountable challenge and additionally, limitations from the specification are not read into the claims; therefore, the compounds are not required to achieve degradation of HCK.
As per MPEP 716.02 (c): Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978)
Additionally, as per MPEP 716.02: “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Consequently, the burden once more shifts to Applicant to provide additional evidence and/or support of nonobviousness and unexpected results.
Applicant is further reminded that arguments do not take the place of evidence on the record and the burden is on Applicant to demonstrate that such results are truly unexpected.
The examiner appreciates Applicant’s remarks; however, for the reasons set forth, they are not fully persuasive.
Conclusion
Claims 1, 3, 6, 13, 15, and 22-23 are under consideration and remain rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN L. LADD whose telephone number is (703)756-5313. The examiner can normally be reached M-Th, 7:00 am to 5:30 pm EST.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622