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 with traverse of Group I, and species of compound 26, in the reply filed on June 5, 2026 is acknowledged. The traversal is on the ground(s) that the full scope of the claims can be examined without undue burden. This is not found persuasive because the present application is a national stage entry case for which the consideration of burden does not apply.
The requirement is still deemed proper and is therefore made FINAL.
3. Examination followed guidelines provided by MPEP 803.02. The elected species was found 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. Therefore, the claims were rejected and claims to nonelected species were withdrawn from further consideration.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 the nonelected species shown below.
4. Claims 16-21 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter. Applicant timely traversed the restriction (election) requirement in the reply filed on June 5, 2026.
Priority
5. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
6. The information disclosure statements (dated December 13, 2024 and May 6, 2024) were in compliance with the provisions of 37 CFR 1.97 and 37 CFR 1.98. The statements were considered. Signed copies of form 1449 are 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, 15, 21, 50-53, 55, 57 and 131 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 a stereoisomer, a tautomer, and N-oxide, a solvate, a metabolite, or a pharmaceutically acceptable salt 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 stereoisomer, a tautomer, and N-oxide, a solvate, a metabolite, or a pharmaceutically acceptable salt, 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
8. Claims 1-15 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 compounds do not share a single structural similarity due to the presence of variables
PNG
media_image1.png
74
70
media_image1.png
Greyscale
, R2 and Y-R4 which can be single atoms, different functional groups, cyclic or non-cyclic.
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.
9. Claim(s) 1-11 and 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dai et al. (caplus an 2022:541561). The reference has a publication date of March 3, 2022 which antedate the present claims having an effective filing date of October 14, 2022. Priority claim to foreign applications dated October 15, 2021 and January 26, 2022 and June 2, 2022 is noted. However, the earlier date(s) cannot be granted because an English language translation of the documents showing support under 35 USC 112 of the present genus has not been provided.
The reference teaches compounds such as
PNG
media_image2.png
378
710
media_image2.png
Greyscale
that corresponds to the present claims in the following manner: R1=alkenyl; R2=naphthyl substituted with R8=alkyl or alkoxy substituted with alkoxy; R3=F; R4=alkyl; R5=COO(R61=alkyl); Y=S.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUN JAE YOO whose telephone number is (571)272-9074. The examiner can normally be reached Mon-Fri 8-5.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SUN JAE YOO/Primary Examiner, Art Unit 1621
Prosecution Insights