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
The instant application is a 371 National Stage Entry of PCT/ KR2023/003810 filed on March 22, 2023 which claims priority to foreign application Nos. KR10-2023-0037068 filed on March 22, 2023 and KR10-2022-0040563 filed on March 31, 2022.
No English Translation
The Examiner notes that no certified translations of the Foreign Application KR10-2023-0037068 filed on March 22, 2023 and KR10-2022-0040563 filed on March 31, 2022 have been placed on record. If applicant wants the application to be accorded benefit of the non-English language application, a certified translation is required (see 35 U.S.C. 119(b)(3), 37 CFR 1.55(g)(1)-(4)). Applicant is advised that any showing of priority that relies on a non-English language application is prima facie insufficient if no certified translation of the application is on file.
Claim Objections
Claims 10, 12, 15 are objected to because of the following informalities:
Claim 10 in multiple instances has large spaces which appears to be a formatting error, and in some instances interfere with the compound naming e.g. “[large gap] Methyl [large gap] (rest of compound name)” (see #s 15-16, 18-20, 30, 33, 44):
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It is recommended the large spaces are amended to regular spaces.
Claim 12 recites “treating cancer disease” but should read “treating a cancer disease”.
Claim 15 recites “ameliorating cancer disease” but should read “ameliorating a cancer disease”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 12-15 are 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 treating a cancer disease susceptible to HDAC8 inhibition, does not reasonably provide enablement for preventing or treating any cancer disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the nature of the invention,
2- the breadth of the claims,
3- the state of the prior art,
4- the predictability of the art,
5- the amount of direction or guidance provided
6- the presence or absence of working examples,
7- the quantity of experimentation necessary, and
8- the relative skill of those in the art.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Undue experimentation is required by one skilled in the art to determine enablement of the instant disclosure as claimed due to the following:
The nature of the invention (1) and the breadth of the claims (2)
The nature of the invention and breadth of claims is the treatment or prevention of a cancer disease broadly (claims 12, 14-15) or those diseases specifically listed in claim 13.
The instant specification does not define treatment or prevention. The broadest reasonable interpretation of “prevention” would encompass prophylaxis.
The instant specification does not define subject. The broadest reasonable interpretation of “subject” would encompass humans, mammals, and cells.
Furthermore since subjects include cells and individuals and prevention includes prophylaxis the broadest reasonable interpretation of the claims includes a patient population of anyone.
The state (3) and predictability (4) of the art
MPEP § 2164.05(a) states if a publication demonstrates that those of ordinary skill in the art would not find that a particular invention was not enabled years after the filing date, the publication would be evidence that the claimed invention was not possible at the time of filing.
In regards to targeting HDACs and cancer, Chakrabarti et. al.1 states
“the targeting of one single enzyme seems to be superior to broad spectrum HDAC inhibition when applied in an appropriate tumor entity that displays oncogenic dependency on that particular HDAC family member. In neuroblastoma for example, HDAC8 expression correlates with the aggressive tumor stage 4 and thus, with poor outcome. Selective HDAC8 inhibition in neuroblastoma cell lines induces signs of differentiation, such as the outgrowth of neurofilament-positive neurite-like structures.” (emphasis added, see Chakrabarti at p. 1616 left col.)
Chakrabarti thus speaks to targeting HDAC8 expression is only useful for cancers in which HDAC8 plays a role.
In regards to targeting HDAC8 for treating cancer, Kim et. al.2 teaches inhibiting HDAC8 has been an effective strategy in ovarian cancer, hepatocellular carcinoma (HCC), and acute myeloid leukemia (AML) (see Kim at p. 6 “4.2.2 Tumor Suppressors”).
In regards to unpredictability in targeting HDAC8 for treating cancer, Lehman et. al.3teaches HDAC8 is deregulated in bladder cancer, but targeting inhibition or knockdown was therapeutically useful (see Lehman at Abstract “Conclusions”).
In regards to preventing cancer, Meyskens et. al.4 teaches with respect to the prevention of cancer,
“Establishing the benefit of new cancer preventive interventions will take years and possibly decades, depending on the outcome being evaluated. We also propose that comparative effectiveness research designs and the value of information obtained from large-scale prevention studies are necessary in order for preventive interventions to become a routine part of cancer management” (see Meyskens at Abstract).
Therefore, cancer prevention is not well-established in or predictable in view of the art. It is unclear how the claimed method would achieve prevention in the vast array of cancers listed when such a field is expected to require several more decades of research to bring forth practical predictable applications.
It would certainly require undue experimentation to discover the enabled embodiments encompassed by the claims.
The prior art provides enablement for treating a cancer susceptible to HDAC8 inhibition.
The amount of direction or guidance provided (5) and the presence or absence of working examples (6)
The specification provides the following embodiments:
HDAC8 inhibition assay, screened 18 compound species against HDAC8 with a variety of efficacy (see instant spec. at pp. 63-64 Experimental Example 1 and Table 2).
Selective HDAC assay, screened 1 compound species against HDACs 1-11, showing selective inhibition for HDAC8 (see instant spec. at pp. 64-66 Experimental Example 2 and Table 3).
Cancer cell inhibition study, tested 2 compound species against prostate and liver cancer cell lines (see instant spec. at pp. 66-67 Experimental Example 3 and Figure 6).
Mouse cancer model, tested 1 compound species against a mouse prostate cancer cell model (see instant spec. at p. 67 Experimental Example 4 and Figures 2, 4-5, 7A-D).
The specification provides enablement for treating a cancer susceptible to HDAC8 inhibition.
Nowhere in the specification is it explained how such cancers are to be prevented through the administration of the claimed compounds.
Therefore, the full scope of treatment in the methods of claim(s) 12-15 are not enabled.
The quantity of experimentation necessary (7) and the relative skill of those in the art (8)
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. Because of the unknown predictability in the art (as discussed above) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that compounds of Chemical Formula I could be used to treat any and all cancer diseases.
Brenner v. Manson states "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (Brenner v. Manson 383 U.S. 519, 536, 148 USPQ 689, 696 (1966), cited in Genentech Inc. vs. Nova Nordisk 42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, little experimentation provided is drawn to treatment of cancers not associated with HDAC8, or the prevention of any cancer. A review of the state of the art fails to HDAC8 inhibitors are useful as therapeutic treatment as claimed (i.e. all cancer diseases). Determining if compounds of Chemical Formula I would be therapeutic for any particular disease state would require careful analysis and replicability of a composition comprising a compound of Chemical Formula I, formulation into a suitable dosage form, assay testing to correlate clinical efficacy, identifying off-targets, subjecting to animal trials, and subjecting to clinical trials.
All this is undue experimentation given the limited guidance and direction provided by Applicants.
Conclusion
Accordingly, the inventions of claims 12-15 do not comply with the enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Suggested Amendment
Examiner suggests amending the claims as follows:
Claim 12. A method of a cancer disease susceptible to HDAC8 inhibition, comprising: administering a pharmaceutical composition comprising the compound according to claim 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject.
Claim 15. A method of a cancer disease susceptible to HDAC8 inhibition, comprising; administering a health functional food composition comprising the compound according to claim 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject.
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.
Claims 1-7, 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yuan et. al.5
Regarding claims 1-7 and a compound of Chemical Formula 1, Yuan teaches compound 3aa (see Yuan at p. 275 Table 1), also known as CAS# 950260-69-2.
Yuan Compound 3aa
CAS# 950260-69-2
Instant Chemical Formula 1
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CAS# 950260-69-2 reads on instant Chemical Formula 1 when L1 is a bond, R1 is a substituted C6-10 aryl specifically phenyl substituted with C1-10alkoxy specifically methoxy
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, R2 is H, R3 is H, and R4 is C1-8 alkyl specifically methyl.
Regarding claim 9 and a compound of Chemical Formula 3, Yuan teaches compound 3a3 (see Yuan at p. 276 Table 2), also known as CAS# 2726-72-9.
Yuan Compound 3ae
CAS# 2726-72-9
Instant Chemical Formula 1
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CAS# 2726-72-9 reads on instant Chemical Formula 3 when L13 is a bond, R13 is a substituted C6-10 aryl specifically phenyl substituted with a C1-10 alkyl specifically methyl, R23 is H, R33 is H.
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.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Yuan as applied to claims 1-7 above and in further view of Surrey et. al.6
Regarding instant claim 11 step 2, Yuan teaches conventional amide bond formation for quinoxaline-2(1H)-ones is the condensation of quinoxalinone-3-carboxylic acids and amines under basic conditions or with coupling reagents, which corresponds with the second reaction step of instant claim 11 (see Yuan at p. 274 Scheme 1a).
The prior art differs from the instant claims as follows, while Yuan teaches the instant synthetic strategy for convert a compound with the core of 1B to 1, Yuan does not discuss the synthesis of 1B.
However,
Regarding instant claim 11 step 1, Surrey teaches the hydrolysis of riboflavin in sodium hydroxide (reading on instant hydroxide ion) yields a quinoxalinone-3-carboxylic acid (see Surrey at p. 2336 left col. I to II an at p. 2337 right col. “Experimental”).
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Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious to an artisan to incorporate Surrey’s quinoxalinone-3-carboxylic acid synthesis step in Yuan’s amide bond formation synthesis with a reasonable expectation of success because the product core of Surrey’s synthesis correlates with the reactant core of Yuan’s synthesis, and all share a common quinoxaline core with the same reaction-involved functional groups (e.g. step 1 uracil and hydroxide ion to carboxylic acid, step 2 carboxylic acid and amine to amide).
Furthermore, it is well-within the ordinary skill in art to identify and incorporate relevant synthetic steps for achieving a known product.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Yuan as applied to claims 1-7, 9 above and in further review of Remington7.
Yuan teaches quinoxalines moieties often have biological properties such as anticancer, antimicrobial, benzodiazepine receptor agonists, or protein kinase inhibition (see Yuan at p. 273 left col. ¶1).
The prior art differs from the instant claims as follows: While Yuan teaches a species of instant Chemical Formula 1, Yuan does not specify a pharmaceutical composition.
However,
Remington teaches methods of formulating pharmaceutical and medicinal agents for various modes of administration, including with pharmaceutical excipients (see Remington at Table of Contents).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious to an artisan to formulate a compound such as CAS# 950260-69-2 (Yuan) with a known biologically active moiety as a pharmaceutical composition because the prior art suggests compounds with quinoxaline moieties have medicinal properties (as taught by Yuan) and guides artisans in formulating pharmaceutical compositions (as taught by Remington). In order to test any potential benefit a quinoxaline such as CAS# 950260-69-2 would have on a subject, an artisan would need to first formulate CAS# 950260-69-2 as a pharmaceutical composition.
Furthermore, it is well-within the ordinary skill in art to formulate a known compound as a pharmaceutical composition according to known methods.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Allowable Subject Matter
Claims 8 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.
Claim 10 is currently objected to, and dependent upon a rejected base claim, but if corrected would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The closest prior art to Chemical Formula 2 of claim 8 and the species of claim 10 is WO 2020117974 A1 to Hill et. al.8
Hill teaches Compound 161 Example 57 (see Hill at p. 233) also known as CAS# 2438202-63-0.
Hill Compound 161
CAS# 2438202-63-0
Instant Chemical Formula 2
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CAS# 2438202-63-0 corresponds with instant Chemical Formula 2 when L1 is a C1-10alkylene specifically ethylene and R22 and R23 are H. CAS# 2438202-63-0 differs in that R12 is not a cycloalkyl, aryl, or heteroaryl as permitted by the claim. Rather, CAS# 2438202-63-0’s R12 is a heterocycloalkyl. No reasonable suggestion or motivation was found to alter CAS# 2438202-63-0 heterocycloalyl to a cycloalkyl, aryl, or heteroaryl. Moreoever an artisan would not have a reasonable expectation of success making such a change because the different cyclic groups have different properties (e.g. aromaticity, polarity, opportunities for H-bonding etc.).
Conclusion
Claims 8, 10, 12, 15 are objected to.
Claims 1-7, 9, 11-16 are rejected.
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/SOPHIA REILLY/Examiner, Art Unit 1627
1 Chakrabarti et. al. "Targeting Histone Deacetylase 8 as a Therapeutic Approach to Cancer and Neurodegenerative Diseases" Future Medicinal Chemistry 2016, 8, 13, 1609-1634. DOI: 10.4155/fmc-2016-0117. Hereinafter Chakrabarti.
2 Kim et. al. "Pathological Role of HDAC8: Cancer and Beyond" Cells 2022, 11, 19, 3161, 1-22. DOI: 10.3390/cells11193161. Hereinafter Kim.
3 Lehman et. al. "Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment" J Exp Clin Cancer Res 2014, 33, 1, 59, 1-14. DOI: 10.1186/s13046-014-0059-8. Hereinafer Lehman.
4 Meyskens et. al. “Cancer Prevention: Obstacles, Challenges, and the Road Ahead” J Natl Cancer Inst 2016, 108, 2, djv309, 1-8. DOI: 10.1093/jnci/djv309. Hereinafter Meyskens.
5 Cite No. 1 in the IDS filed 9/29/24. Yuan et al. Transition-metal free direct C-H functionalization of quinoxalin-2(1H)-ones with oxamic acids leading to 3-carbamoyl quinoxalin-2(1H)-ones. Org. Chem. Front. 2020, 7, 273-285. DOI: 10.1039/c9qo01322a.
6 Cite No 1 in the IDS filed 8/31/25. Surrey et. al. "Alkaline Hydrolysis of Riboflavin" J. Am. Chem. Soc. 1951, 73, 5, 2336-2338. DOI: 10.1021/ja01149a128. Hereinafter Surrey.
7 Remington's Pharmaceutical Sciences (22nd Ed) London, UK: Pharmaceutical Press 2013 Select Pages. Hereinafter Remington.
8 Published June 11, 2020. Hereinafter Hill.
Prosecution Insights