DETAILED ACTION
Notice of AIA Status
The instant application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the Leahy-Smith America Invents Act (AIA ).
Status of the Claims
The listing of claims filed 19 January 2024 with a Preliminary Amendment has been examined. Claims 1–15 are pending. Claims 10 and 13 are amended.
Priority
The instant application was filed 19 January 2024; is a national stage application of PCT/KR2022/010745, filed 21 July 2022, and claims priority to KR 10-2021-0095823, filed 21 July 2021, and KR 10-2022-0089938, filed 20 July 2022. Applicant’s claim for foreign priority is acknowledged, and a copy of the priority document has been received.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 13 February 2024 is acknowledged and has been considered.
Objections to the Specification
(i) The abstract of the disclosure is objected to because it recites legal phraseology (“wherein,” “comprising”) and phrases that can be implied (“Disclosed is,” “Also disclosed”).
Appropriate correction is required.
For guidelines for the preparation of patent abstracts, see MPEP § 608.01(b) (Explaining: The abstract should be in narrative form and avoid legal phraseology (e.g., means, said), terms referring to purported merits of the invention (e.g., new, novel), and phrases that can be implied (e.g., The disclosure concerns, The disclosure defined by this invention). The language should be clear and concise, and not repeat information given in the title. It should not compare the invention with the prior art. The abstract is generally limited to a single paragraph within the range of 50 to 150 words in length.).
(ii) The specification is objected to because it is unclear whether the preliminary amendment submitted 19 January 2024 reciting a Cross-Reference To Related Applications paragraph is intended to be included in the specification because Applicant concurrently submitted a Substitute Specification (designated “CLEAN”) that does not include the Cross-Reference To Related Applications paragraph.
Appropriate correction or explanation is required.
Claim Interpretation
Claim 1 is directed to a compound of Formula (1) having a substructure according to Formula (2), which includes a carbonyl (C=O or C(O)) and a bond projecting therefrom to what appears to be a terminal carbon atom (C(O)—C*) with an asterisk designating the binding site, as shown below left.
Claim 5 depends on claim 1. Claim 5 is directed to a compound of Formula (3), which has a bond between the carbonyl in the Formula (2) and a nitrogen atom in the variable L, as shown below right.
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Because Formula (3) does not include a carbon atom at the binding site identified by the asterisk in Formula (2), the claim is interpreted to encompass only those compounds having a direct bond between the carbonyl carbon and an atom from variable L. In other words, there is no terminal carbon atom at the binding site adjacent to the carbonyl in Formula (2); rather the asterisk identifies where variable L is connected to the carbonyl.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation 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.
Claims 13–15 are rejected under 35 U.S.C. § 112(a) because 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 the claims.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” . . . These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Wands factors are analyzed with respect to the claimed invention in turn below.
The breadth of the claims includes a pharmaceutical composition for preventing or treating a neuroinflammatory disease (claim 13), which a class of diseases that includes, e.g., inflammatory neurodegenerative brain diseases (claim 14) such as Alzheimer’s disease or Parkinson’s disease (claim 15). The breadth of claim 13 is broad in scope as it covers preventing or treating any neuroinflammatory disease. The breadth of claim 14 is broad in scope as it covers preventing or treating any inflammatory neurodegenerative brain disease. The breadth of claim 15 is narrow, as it is directed to preventing or treating specific diseases.
The nature of the invention generally relates to the pharmaceutical art and more specifically to a compound of Formula (I) and pharmaceutical compositions thereof. Each of the claimed pharmaceutical compositions recites an intended use directed to preventing or treating a neuroinflammatory disease. Accordingly, the nature of the invention is sophisticated.
The state of the prior art is discussed in the specification, which states: “the most commonly used contrast agents in clinical practice is a contrast agent based on gadolinium (Gd) chelate.” (Substitute Spec., ¶7). The specification states, “most of the commercially available contrast agents are non-specific contrast agents distributed in the extracellular fluid (ECF). Only a liver-specific contrast agent is used as a specific contrast agent.” (Id.). The specification states: “Currently, sufficient results about MRI contrast agents specific to degenerative brain diseases have not been obtained.” (Id, ¶8). Accordingly, based on the disclosures in the specification, the state of the art is developed for gadolinium chelate contrast agents generally, but in its infancy for target-specific contrast agents.
Generally, in order to treat a disease, one of skill in the art must identify a biological target for affecting the disease, demonstrate a first drug candidate some way modulates the normal processes of the biological target, and demonstrate that a subject would benefit from such modulation without detrimental side effects. Typically, the process includes in vitro laboratory screening, in vivo testing, and clinical testing. Once that process has been successfully completed by the first drug candidate, subsequent drug candidates can benefit from the established proof of concept if a substantial correlation can be established between the first drug candidate and the subsequent drug candidates. In order to prevent a disease, one of skill in the art would need to identify the subjects likely to acquire such as disease, carry out the claimed invention (e.g., administer the claimed compound/composition), and demonstrate the subject did not have any cells infected by the pathogen and/or demonstrate the subject did not develop the disease as a result of the administration of the compound/composition. With respect to treating or preventing a disease with gadolinium (Gd) chelate contrast agents, Examiner is unaware of evidence in the prior art showing gadolinium (Gd) chelate contrast agents are recognized for their use in treating or preventing a disease. Further, Examiner is not aware of any pharmaceutical agents that are capable of preventing Alzheimer’s disease and Parkinson’s disease.
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
The level of predictability in the art is generally unpredictable. The relevant art requires each potential drug candidate to be assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18, 24 (CCPA 1970). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. MPEP § 2164.02(II) explains that a correlation between the claimed invention and the evidence provided in an application, along with a correlation between the evidence and the models recognized in the art, are required:
“Correlation” as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications).
Further, treatments may be effective for some subjects and ineffective for other subjects. Thus, each candidate for pharmaceutical medicine must be evaluated on its own even when a nexus to an existing drug or class of drugs has been established.
The amount of direction provided by the inventor is generally directed to the synthesis of the compounds of Formula (I) and an evaluation of a composition comprising the same. (Id., ¶¶65–102).
The existence of working examples are directed to an in vitro cytotoxicity evaluation of specific embodiments of the claimed Formula I on astrocyte and microglial cells; and an in vivo efficacy evaluation to determine whether specific embodiments can reduce the accumulation of factors related to inflammation. (Id., ¶¶103–109).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure is extensive, as it includes in vitro and in vivo screening for each specific disease or disorder encompassed by the claims with each specific gadolinium chelate complex encompassed by the claims.
Scope of Enablement Conclusion
In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a person having ordinary skill in the art to use the full scope of the claimed invention. The breadth of claims 13–15 is broad enough to include a composition for preventing diseases like Alzheimer’s disease and Parkinson’s disease; the nature of the invention is sophisticated; the state of the prior art is in its infancy for preventing any disease encompassed by the claims, as well as in its infancy for treating inflammatory neurodegenerative brain diseases with a gadolinium chelate complex; the level of skill in the art is high; the pharmaceutical art is unpredictable; the direction provided by the inventor is limited to synthesis of the compounds of Formula (I) and an evaluation of a composition comprising the same; the working examples suggest a capability for compounds of Formula (I) to reduce an accumulation of factors related to inflammation; and the quantify of experimentation needed to practice the claimed invention is extensive. Thus, when the evidence is considered as a whole, undue experimentation would be required to practice the full scope of the claimed invention.
Examiner recommends amending the claims to delete the intended use language. In the alternative, the claims may be amended to recite treating specific diseases rather than a class of diseases.
Allowable Subject Matter
Claims 1–12 are allowed. The compounds of Formula (1) are free of the prior art based on the structure of substructure Formula (2), which includes a phenyl moiety linked via a carbonyl, a hydroxyl substituent para to the carbonyl, and a methoxy substituent meta to the carbonyl. Relevant prior art, such as Leone et al., Dalton Trans. (2021), 50, 5506 [IDS] discloses related compounds; however, none of those compounds include both the para-hydroxyl and meta-methoxy substituents on the phenyl moiety.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jason Nolan at (571) 272-2480. The examiner can normally be reached Monday through Friday between 9:00–5:00.
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The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.M.N./Patent Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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