DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/US2021/063984, filed 12/17/2021, which claims the priority benefit of PRO Application No. 63/273,365, filed 10/29/2021, PRO Application No. 63/218,458, filed 07/05/2021, PRO Application No. 63/164,243, filed 03/22/2021, and PRO Application No. 63/128,141, filed 12/20/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/28/2023 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-7 in the reply filed on 04/24/2026 is acknowledged.
In accordance with the MPEP 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended (see MPEP 803.02). If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined.
The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim.
In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
As per MPEP 803.02, the Examiner will determine whether the entire scope of the claims is patentable.
Applicants' elected species 5-(4-((S)-4-(6-((2'-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,S]pyrrolo[1,2-a]pyrazin-2-yl)-3'-(hydroxymethyl)-1-(methyl-d3)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-5-yl)amino)pyridin-3-yl)-3-methylpiperazin-1-yl) piperidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, makes a contribution over the prior art of record.
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Therefore, according to MPEP 803.02: should the elected species appear allowable, the search of the Markush-type claim will be extended. The Markush-type claim shall be rejected and claims to the nonelected invention held withdrawn from further consideration. It has been determined that the entire scope claimed is not patentable.
Status of the Application
Claims 1-20 are pending. Claims 1, 3, 6-9, 11, 14-17, and 19-20 have been amended. Claims 8-20 have been withdrawn from further consideration as being drawn to a non-elected species. Claims 1-7 are currently examined herein insofar as they read on the elected invention and species.
Specification
The lengthy specification (186 pages) has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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.
Claim 1 is 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.
Regarding claim 1, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Examiner notes the term “e.g.” is interpreted as “For example”, and renders the claim limitation indefinite. This rejection may be overcome by removing the claim limitation of “(e.g., molecular weight less than about 1,500 Da, 1,200 Da, 900 Da, 500 Da or less)” from the definition of R in claim 1.
The term “small molecule” in claim 1 definition for R group is a relative term which renders the claim indefinite. The term “small molecule” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. A skilled artisan would not be able to ascertain which small molecules of a prodrug would be capable of binding an E3 ubiquitin ligase.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: element “W1” in formula 1 is not defined and therefore the limitations of claim 1 are incomplete.
This rejection may be overcome by clearly defining what W1 is in formula 1 of instant claim 1.
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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (WO 2019/161152) in view of Arthur et al. pgs. 1-31, (Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors).
The instant claims are directed to a compound of Formula (1), or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (1) or N-oxide thereof wherein E3 ubiquitin ligase is Cereblon, Von Rippel-Lindau, mouse double minute homolog 2, or IAP.
Chen et al. teach inhibitors of Covalent Bruton's tyrosine kinase (BTK) compounds of formula I used for treating a neoplastic disease (Abstract). Chen teaches “A modified compound of any one of such compounds including a modification having an improved (e.g., enhanced, greater) pharmaceutical solubility, stability, bioavailability, and/or therapeutic index as compared to the unmodified compound is also contemplated. Exemplary modifications include (but are not limited to) applicable prodrug derivatives, and deuterium-enriched compounds” (pg. 4, 4th para.) Chen also teaches a method of treating a neoplastic disease, particularly acute myelogenous leukemia and chronic and acute lymphocytic leukemia by administering to a subject in need thereof an effective amount of one or more of the disclosed compounds, modifications, and/or salts, and compositions (pg. 5, 2nd para). Chen also discloses a biological test for BTK inhibitors with a compound of GDC-0853 and ibrutinib wherein the data of the WT BTK dialysis assay clearly shows that Ibrutnib, Example 2, Example 3, Example 11, Example 12 are irreversible inhibitors of WT BTK, while GDC-0853 is a reversible WT BTK inhibitor (Biological Example 2, pgs. 75-76). Chen also discloses a derivative of formula 1 as the compound of N-(5-((6-(2-(7,7-dimethyl-1-oxo-l,3,4,6,7,8-hexahydro-2H cyclopenta[4,5]pyrrolo [l,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-y l)amino )-2-(2-methyl-1-morpholinopropan-2-yl)phenyl)acrylamide (Below) in example 16, which satisfies the structural limitations of formula 1 of the instant claims where R is a small molecule of morpholine, L3-L6 are absent, L2 is CH2, L1 is a C substituted with two methyl’s, Q4 is phenyl wherein one R4 is H and one R4 is N(Rb)c(O)Rc (NHCOCHCH2), Z is NH, W1 is N, wherein the CH3 is deuterium-enriched, Q2 is an N substituted phenyl, R2 is CH3, Q1 is a N substituted heterocycle sharing bonds whit ring Q0 and ring Ro, A is C=O in Q1 and the 2 Rd in ring R0 are CH3.
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Example 16 (Left) Formula 1 of the instant claims (Right)
Chen also teaches a warhead group on formula 1 of the reference (Below).
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Chen also teaches “[a]ny inert excipient that is commonly used as a carrier or diluent may be used in compositions of the present invention, such as sugars, polyalcohols, soluble polymers, salts and lipids. Sugars and polyalcohols which may be employed include, without limitation, lactose, sucrose, mannitol, and sorbitol.” (pg. 15, last para).
However, Chen et al. fail to explicitly disclose the small molecule is Cereblon, Von Rippel-Lindau, mouse double minute homolog 2, or IAP as a E3 ubiquitin ligase binding moiety for the R subgroup of formula 1.
Arthur et al. teach the current limitations of treatments for chronic lymphocytic leukemia (CLL) revolve around toxicity and resistance are major limitations and new treatment options are required and that Proteolysis targeting chimeras (PROTACs) are an exciting new approach for targeted inhibition based on event-driven rather than occupancy-based activity [2, 3]. Several BTK-targeted PROTACs have been described and these studies provide a powerful illustration of how PROTACs can address clinically relevant drawbacks associated with ibrutinib, including improved selectivity and retained activity in models of ibrutinib resistance (pg. 2, Introduction) Arthur also teaches E3 ligases commonly targeted by PROTACs include cereblon (CRBN), Von Hippel-Landau (VHL), and inhibitor of apoptosis protein (IAP) (pg. 2, last sentences to pg. 3, 1st para). Arthur also discloses the compound of formula DD-04-015 (Below) which satisfies the limitations of formula 1 of the instant claims where R0 is Halogen and epoxy, Qo and Q1 taken together form a fused-heterocyclic with two shared/border atoms between Qo and Q1, including G1 and G2, A is in Q1 and is C=O, Q2 is a 6 membered cycloalkyl, R2 is C(O), W1 is CH, Z is NH, ring Q4 is an N substituted heteroaryl, L1 is an heterocycle (pyrazine), L2 is CH2, L3 and L4 are alkoxy, L5 is alkylamino, L6 is NH substituted with 2 Rf with 2 =O, and R is heterocycle substituted with Nh and 2 =O.
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Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to combine Chens disclosures of treating the neoplastic disease of leukemia with an enhanced compound of formula 1 using deuterium for improving pharmaceutical effect to target BTK with Arthurs disclosures of DD-04-015 in treating leukemia with PROTACs and E3 targeting ligases of cereblon, Von Hippel-Landau (VHL), and inhibitor of apoptosis protein (IAP) because a skilled artisan looking to avoid the negative effects of toxicity and resistance using the BTK inhibitor ibrutinib would have found it obvious to combine Arthur’s E3 binding ligases with Chen’s disclosure of enhanced deuterium compounds in a treatment for leukemia by using deuterium in the compounds disclosed by Arthur. See MPEP 2144.05(II)
A person of ordinary skill in the art would have been motivated to use Arthurs teachings of PROTACs, DD-04-015 and E3 binding ligases with Chen’s deuterium enriched compounds with an excipient and/or carrier to administer a therapy to a patient with a neoplastic disease using a deuterium enhanced PROTAC compound DD-04-015 with a reasonable expectation of success in inhibiting BTK in a leukemia patient without the negative side effects of toxicity and drug resistance. See MPEP 2144.06.
Conclusion
All claims are rejected, no claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623
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