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 .
Current Status of 18/286,037
This Office Action is responsive to the amended claims of 04/08/2026 and the Applicant Remarks of 04/08/2026. Claims 1-4, 8, 11, and 12 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/IB2022/053253, filed 04/07/2022, which claims priority to KR-10-2021-0046134, filed 04/08/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/06/2023, 11/29/2023, 11/12/2024, and 03/18/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Election/Restrictions
Applicants’ election without traverse of the species of Compound 19
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in the reply filed on 04/08/2026 is acknowledged. The elected species was free of the prior art. The search was expanded to additional species of the compounds of instant claim 3 and no art was found on these compounds. The previous election of species is withdrawn and the full scope of the Markush genus of claim 1 was searched.
Claim Rejections - 35 USC § 112
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 8, 11, and 12 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating or preventing a histone deacetylase (HDAC)-mediated disease comprising administering a therapeutically effective amount of a compound of Formula I. Thus, the claims taken together with the specification imply that the administration of any compound encompassed by the genus of Formula I, including those not expressly identified in the disclosure, is capable of treating or preventing any HDAC-mediated disease. Thus, the scope of the claims is extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The state of the prior art is that the pharmacological art involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific disease by what mechanism). There is no absolute predictability even in view of the high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent the artisan from accepting any therapeutic regimen on its face.
The instant claimed invention is highly unpredictable as discussed below:
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is the more specific enablement is necessary to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable because the artisan would recognize that in regards to therapeutic effects of any condition mediated by HDAC6 inhibition, whether or not the condition is affected by the instant compounds’ activity would make a difference.
For example, Applicants’ claims are drawn to a pharmaceutical composition for preventing or treating cancer. It is well known in the art that neoplasms includes cancer. The state of the prior art is that cancer therapy remains highly unpredictable. The various types of cancers have different causative agents, involve different cellular mechanisms, and consequently differ in treatment protocol. Cancer is a disease characterized by a population of cells that grow and divide without respect to normal limits, invade and destroy adjacent tissues, and may spread to distant anatomic sites through metastasis (see http://en.wikipedia.org/wiki/Cancer>). Most cancers are named for where they start. For example, lung cancer starts in the lung, and breast cancer starts in the breast. Symptoms and treatment depend on the cancer type and how advanced it is (see <http://www.nlm.nih.gov/medlineplus/cancer.html>).
It is known that the challenge of cancer treatment has been to target specific therapies to pathogenetically distinct tumor types, that cancer classification has been based primarily on morphological appearance of the tumor and that tumors with similar histopathological appearance can follow significantly different clinical courses and show different responses to therapy (Golub, pg. 531). Treatment may include surgery, radiation, chemotherapy, immunotherapy, monoclonal antibody therapy, etc.
It is known that chemotherapy is most effective against tumors with rapidly dividing cells and that the cells of solid tumors divide relatively slowly and chemotherapy is often less effective against them. It is also known in the prior art (Lala, pg. 91) that the role of NO in tumor biology remains incompletely understood with both the promotion and inhibition of NO mentioned for the treatment of tumor progression and only certain human cancers may be treated by selected NO-blocking drugs. These examples show that there are different cellular mechanisms, the unpredictability in the art and the different treatment protocols. Because “cancer” refers to a class of diseases, it is unlikely that there will ever be a single “treatment of cancer.”
There is no absolute predictability even in view of the high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge of the art would prevent the artisan from accepting any therapeutic regimen on its face.
(5) The relative skill of those in the art:
The artisan would have experience in the field of organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would have experience in the design, synthesis, and evaluation of small-molecule therapeutic agents, including HDAC inhibitors and would be familiar with methods for assessing their biological activity.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for in vitro HDAC enzyme activity inhibition for compounds 1-46 (pg. 94, line 18- pg. 97, line 5).
However, the specification does not provide any in vivo data, disease model data, or any other evidence demonstrating a reasonable correlation between the disclosed in vitro HDAC inhibitory activity and the treatment or prevention of diseases through the full scope of the claimed method. The specification does not provide a working example demonstrating treatment or prevention of any claimed disease.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the lack of disease model data involving the claimed compounds and the high unpredictability associated with translating in vitro HDAC inhibition into therapeutic efficacy, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
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 1 and 2 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.
Regarding claim 1, the phrase "may be substituted" 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).
The recitation that certain hydrogens “may be substituted” renders the scope of the allowed substitutions of several variables unclear. R2 is defined as being -NR1RB, -ORC, -heteroaryl,
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. The claim goes on to recite that at least one H of
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may be substituted with a group selected from those of page 2 of the claim set. As written, it is unclear whether additional hydrogens of these rings are required to bear the same substituent or a different substituent selected from the recited group. This ambiguity is particularly apparent because other substitution clauses of claim 1 expressly recite that the hydrogen “may each independently substituted,” whereas the R2 limitation does not. This issue persists throughout the claims for variables RA, RB, RC, RD, RE, and RF. Each of the indicated variables contain similar language regarding the allowed substitutions of at least one hydrogen. It is unclear in each of these limitations if these limitations are applied to each of the substitutions or if they are only required for a single instance. In other words, if more than one hydrogen is substituted, is each substituted hydrogen independently selected from the recited group, or must the same substituent be used at each substituted position?
The claim recites that Z1 to Z4 are each independently N or CRZ and goes on to specify that at least three of Z1 to Z4 may not be N at the same time. This language allows for two possible interpretations. The first interpretation is that three or more of Z1 to Z4 may not simultaneously be N, meaning that the molecule can contain at most two N atoms. The second is that at least three of Z1 to Z4 must not be N, meaning that at least three positions must be CRZ and at most one N atom is present in the ring. These interpretations are materially different and render the metes and bounds of the claim indefinite.
For the allowed substitutions of R1, the claim recites “–(C2-C6 cycloheteroalkyl)” which is not defined in the specification. It is unclear whether “–(C2-C6 cycloheteroalkyl)” is a typographical error intended to recite“–(C2-C6 heterocycloalkyl)”, which is expressly defined in the specification, or whether “–(C2-C6 heterocycloalkyl)” denotes some different class of substituent.
Claim 2 contains similar indefinite language regarding the permitted substitutions of R1. For R1, claim 2 recites that at least one H of –(C1-C4 alkyl) may be substituted with T or OH, and that at least one H of the recited aryl or heteroaryl groups may be each independently substituted with T, CF3 or CF2H. These limitations create ambiguities similar to those discussed above. It is unclear whether substitution is optional or whether at least one substitution is required, and, where the substitutions are not expressly stated to be independently selected, whether multiple hydrogens may bear different substituents selected from the recited group.
Close Art
An STN search of the Markush compound of Formula I did not provide any compounds reading on the instantly claimed compound. The closest structure retrieved was
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from US 9566284 B2. The compound differs from the instantly claimed compounds in regard to the methyl substitution on the central phenyl ring, which is not allowed by the instant claims. The compounds of ‘284 are disclosed as TRPM7 modulators. The reference does not disclose that the claimed compounds are capable of HDAC6 inhibition. The compound of the reference belongs to a different class of compounds and are directed to different biological activity than those of the instant invention. The reference does not disclose that the compounds could serve as HDAC inhibitors and would not have provided the artisan with a reason to select the disclosed compound as a starting point for the development of HDAC inhibitors. Additionally, the compound above is structurally distinct from those of the instantly claimed compounds due to the substitution of the central phenyl ring. These features distinguish the instantly claimed compounds from those found in the prior art.
Conclusion
Claims 1, 2, 8, 11, and 12 are rejected.
Claims 3 and 4 are objected to for being dependent upon a rejected base claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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