DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s election without traverse of Group I, and species of compound 8, in the reply filed on July 27, 2026 is acknowledged.
3. Examination followed guidelines provided by MPEP 803.02. The elected species appeared to be novel and nonobvious over the prior art. Therefore, the search and examination was extended. Prior art was found that anticipates the Markush claims with respect to a nonelected species. The Markush claims were rejected and claims to nonelected species were withdrawn from further consideration. The claims were searched to the extent of the elected species and additionally to the nonelected species shown below.
4. Claims 6, 7, 10 and 12-18 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter. Election was made without traverse in the reply filed on July 27, 2026.
Priority
5. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
6. The information disclosure statement (IDS) submitted on July 12, 2024 was in compliance with the provisions of 37 CFR 1.97 and 37 CFR 1.98. The IDS was considered. A signed copy of form 1449 is enclosed herewith.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
7. Claims 1-5, 8, 9 and 11 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for compounds or the pharmaceutically acceptable salt, racemate, tautomer, enantiomer, diastereomer, isotope-substituted compound thereof, does not reasonably provide enablement for the prodrug thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 ITS, 261,270 (1918) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied, in re Wands, 858 F.2d 731, 737, 8USPQ2s 1400, 1404 (Fed. Cir. 1988). MPEP 2184.01(a) states “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue.” The factors are applied below to the instant claims.
The breadth of the claims and nature of invention
The claims are drawn to compounds of Formula (I) or a pharmaceutically acceptable salt, racemate, tautomer, enantiomer, diastereomer, isotope-substituted compound thereof, or prodrug thereof.
The state of the prior art, level of ordinary skill, level of predictability, amount of guidance provided
The state of the art and present specification provide guidance on how to make and use pharmaceutically acceptable salts, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative of the claimed compounds. However, neither the specification nor the state of the art provide specific guidance on how to predict and design prodrugs of the claimed compounds including what structural modifications result in these prodrugs.
Furthermore, the state of the art for designing prodrugs is unpredictable and challenging because structural modifications do not have a predictable effect on properties such as absorption, distribution, metabolism excretion or toxicity (ADMET).
“On the basis of this analysis, we discuss strengths and limitations of current prodrug approaches and suggest areas for future development.” Abstract
“As these modifications are likely to affect the physicochemical properties of the prodrug differently, we further investigated whether the distribution of the promoieties would differ depending on the purpose of the prodrug.” Fralish page 369, 1st column, second paragraph
“Release can be further impacted by the mode of administration; for example, through release by gastric enzymes or microbes in oral delivery....” Fralish, page 373, columns 1-2
“Granted, the prodrug approach adds considerable complexity to the molecular design and requires additional safety evaluations for not only the prodrug and the API, but all degradation products. Consequently, prodrug design has historically focused on overcoming ADMET issues...” Fralish, page 379, 1st column
Serendipity has a significant role in the design and careful optimization must be conducted to address each individual drug separately, vs. generic known structural modifications that yield predictable results.
“More recently, although there has been an immense gain in knowledge and a push for the rational design of more complex prodrugs, serendipity still often has a significant role during prodrug design.” Fralish, page 371, Box 1
“Conversely, small-molecule prodrugs are often easy to synthesize, purify, distribute and administer but can be more difficult to design because multi-objective optimization of synthesizability and ADMET properties is required for each project.” Fralish page 366, 1st column, second paragraph
The quantity of experimentation needed to make or use the invention
In the absence of working examples/direction, enablement rests on the existence of an art recognized predictable correlation. Evidence suggests that this requirement is not met for the present case. The amount of experimentation is undue. The experimentation required is to test all structural modifications of the claimed compounds and optimize the modifications relative to parameters such as ADMET in order to determine which modifications result in prodrugs of the claimed compounds. Furthermore, these tests will have to indicate that the modifications produce a prodrug of each of the claimed compounds. It is therefore determined that the present disclosure does not enable one of ordinary skill to practice the scope of the claimed invention.
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.
8. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 2, 3, 4 and 6 recite the broad recitation eg. “R8 and R9 are each independently selected from hydrogen, C1 to C6 alkyl, or C3 to C6 cycloalkyl”, and the claims also recite “preferably, R8 and R9 are each independently selected rom H or methyl”, which is the narrower statement of the range/limitation. Multiple occurrences of such broad/narrow language are recited. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 112
9. Claims 1-5, 8, 9 and 11 rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of Formula I is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the core structure is defined in terms of variables X1-X8. The definition of the variables result in different structures which include carbocycle or various hetereocycles determining the core structure.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
10. Claim(s) 1, 3, 4 and 11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by RN 2872587-59-0 (
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). The reference has a date of December 20, 2022 which antedate the present claims having an effective filing date of January 6, 2023 and priority claim to foreign application dated January 14, 2022. The earlier filing date cannot be granted. Applicants have not filed a certified translation of the foreign document such as support under 35 USC 112 for the claimed genus can be ascertained.
The compound corresponds to the present claims in the following manner: X1-X8=C(R7=H); C1=CON(R8/R9=H/Me); R2=R4=H; R3=Hal; R5 and R6 form condensed ring with Y/Z=CH2.
Conclusion
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/SUN JAE YOO/Primary Examiner, Art Unit 1621
