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 of Group 1, encompassed by claims 1-14, drawn to compounds and compositions of Formula II, in the reply filed on June 26, 2026, 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 has not pointed to any errors in the Examiner' s analysis of the classification of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Applicant further elected, without traverse, the following species (Compound 1), shown below:
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Applicant asserts that claims 1, 3-8 and 11-14 encompass the elected species. Applicant has not pointed to any errors in the Examiner’s analysis of the species. The requirement is still deemed proper and is therefore made FINAL.
Claims 1-20 are currently pending and claims 1, 3-8, and 11-14 are under examination. Claims 2, 9-10, and 15-20 are withdrawn from consideration based on the species election.
Priority
The instant application claims the benefit of priority to U.S. Provisional Patent Application No. 63/387,759, filed 12/16/2022.
Specification
The lengthy specification 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 of the errors of which applicant may become aware of in the specification.
The Applicant is reminded of the content of the Specification, which include:
(b) CROSS-REFERENCES TO RELATED APPLICATIONS: See 37 CFR 1.78 and MPEP § 211 et seq.
The specification is objected to because it lacks a section that cross-references to related applications.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 7/1/2024 is in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action.
Claim Objections
Claim 6 is objected to because of the following informalities: the term “diazaspirodecan-1-only” is misspelled. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 4, 5, 6 and 11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 is rejected as vague and indefinite in its usage of the undefined variable of “B” in the structures of claim 4. The variable appears among the diagrammed compounds, but no such variable is defined in the text of other limitations in claim 4, or in the independent claim from which it derives.
With regards to claim 5, the term “absent” is vague in the definitions of “B” and “C”. If the variables are absent, then the rest of the linker would not be attached. If Applicant intends a “bond,” replace the term “absent” with “bond” to overcome the rejection. Thus, claim 5 is vague and indefinite. Also, for consistency, Examiner recommends, in the limitation of “D” in claim 5, to move “a bond” from the end of the definition to the beginning of the definition, so as to be consistent with the definitions of “B” and “C” if they get amended to “bond”, as well.
Claim 6 recites the limitation "(C3-C6)cycloether" in the limitation of B. There is insufficient antecedent basis for this limitation in the claim.
Claim 11 is rejected as vague and indefinite for its usage of the term “dihydropyrimidine-dione”. There is no standard meaning for this term in the art, no definition is provided in the specification, and furthermore, a few “dihydropyrimidine-dione” can immediately be envisioned (see below), so it is unclear what the Applicant is claiming.
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Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 11 broadens the scope of independent claim 1 in the limitation “…wherein E comprises…” (emphasis added). Claim 1 is written in proper closed Markush format, while dependent claim 11 uses the open-ended “comprises”. The limitation “comprises” does not clearly convey the scope of the Markush grouping of alternatives encompassed by the claim and leaves the claim open to include other unknown and unspecified compounds. In order to overcome the rejection, Applicant may amend to replace the term “comprises” with “is” in the limitation. Relevant guidance can be found in the MPEP § 2173.05(h), titled “Alternative Limitations,” which deals with claims that list alternatives.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
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, 3-8, 11-12, and 14 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 is drawn to a compound of Formula II and recites a structure containing a Linker (L), and E3 ubiquitin ligase binder (E). Applicant does not have possession for all substances capable of binding to hydroxysteroid 17β-dehydrogenase13 (HSD17B13) tethered through a “linker” to all molecules capable of binding to all “E3 ubiquitin ligase binders”. Neither the ubiquitin ligase nor the linker are given any structure in claim 1. The specification teaches numerous, nonlimiting embodiments of linker groups (page 17-22) and generically states (page 17, lines 18-26):
ln certain embodiments, the Linker is designed and optimized based on structure-activity relationship (SAR) 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 b 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.
Additionally, the specification teaches numerous, non-limiting embodiments of degrons (page 22- 26), which is component of E of Formula II (see specification, page 22, line 14). The non-limiting definitions of both degrons and linkers in the specification and claims do not convey to one skilled in the art that the inventors had possession of the invention as claimed, since the possible compounds included in the definitions are not finite or given structure apart from the representative structures.
The compounds recited in the claims are “functionally” defined and a functional description is not sufficient to represent the genus claimed. As stated by the Federal Circuit in Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1405-06 (Fed. Cir. 1997), “A written description of an invention involving a chemical genus, like a description of a chemical species, “requires a precise definition, such as by structure, formula, [or] chemical name,” of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (Cust. & Pat.App.1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus․”).” Thus, said claims are rejected for inadequate written description.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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, 3-8, 11-12, and 14 are rejected under 35 U.S.C. 103 as being obvious over Adams et al. (WO 2024/075051 A1, published April 11, 2024, effectively filed October 7, 2022)(hereinafter, ‘Adams’).
The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The present application claims bifunctional compounds of Formula (II), wherein a targeting HSD17B13 ligand is tethered to an E3 ubiquitin ligase binder (E, also referred to as degron) through a linker (L), see claim 1 and below. A representative species, Compound 3 (Specification, page 2, 220; claim 13 – fifth compound), N-{[4-(5-{2-[4-(3-{1-[(3R S)-2,6-dioxopiperidinn-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide is also shown below:
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In the above example A is the 1,2,4-oxadiazole; and Linker L is shown below, represented by B-C-D, as defined in instant claim 5, and E is described in instant specification as Formula II-IIIab (page 23), shown below:
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Adams teaches a genus of compounds represented by Formula 1, shown below (see reference page 2) with a specific embodiment, Example 21, page 109, shown below:
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Furthermore, Adams teaches, on page 9-10, that the “invention includes compounds of the present invention that are targeted protein ligands covalently linked to E3 ligase ligands or ligands known to interact with ubiquitin proteasome system (Degrons) through a Linker of varying length and functionality”. Furthermore, Adams teaches compounds of Formula II (page 10, shown below) that include a linker (L), and a degron (D), where the “degron is a compound that is capable of binding to or binds to a E3 Ubiquitin Ligase, including cereblon, wherein the Degron is a thalidomide, lenalidomide, pomalidomide, or iberdomide, or newer IMiDs CRBN ligands disclosed in WO2019/060693, WO2019/140387, WO2019/236483 or analogs thereof” (page 10). These are the same degrons enumerated in instant specification (page 22). The reference provides definition for the term ‘linker’, followed by numerous examples at pages 11-12.
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Further, the reference discloses pharmaceutical compositions of said compounds (reference claim 20). Last, the reference teaches, on page 1, the same pharmaceutical use as instant application, that is, as HSD17B13 inhibitors and/or degraders.
Therefore, it would have been prime facie obvious to arrive at instantly claimed compounds in light of the teachings of Adams. Adams teaches the same target binding moiety for the same target (HSD17B13) and for the same use (inhibitor and/or degrader). Furthermore, Adams teaches inhibitor species that read on the target binding moiety of instantly claimed compounds. Lastly, Adams teaches that the reference invention includes a targeted protein ligand covalently linked to an E3 ligase through a linker of varying length (reference Formula (II) above). Adams specifies the same linkers and degrons as those specified in the instant application. Therefore, it would have been obvious to select any of the species taught by Adams to make a species of the instant application since Adams teaches both: species that read on target binding moiety as well as a suggestion to make compounds of reference formula II from those species.
Thus, said claims are rendered obvious.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Allowable Subject Matter
Claim 13 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1, 3-8, 11-12, and 14 are rejected.
Claim 13 is objected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 am.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey H Murray can be reached at 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.A.B./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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