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 14 April 2025 has been examined.
Claims 1–16, 18–20, 25, and 26 are pending. Claims 17 and 21–24 are canceled.
Claims 4, 7, 8, 15, 16, 18, and 19 are amended. Claims 25 and 26 are new.
Priority
The instant application was filed 24 July 2024; is a national stage application of PCT/EP2023/051723, filed 25 January 2023, and claims priority to EP22153215.3, filed 25 January 2022, and EP2203186.6, filed 24 October 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 14 April 2025 is acknowledged and has been considered.
Objections to the Specification
The abstract of the disclosure is objected to because it recites language referring to the purported merits (“new”) and phrases that can be implied (“The invention provides”).
Appropriate correction is required.
Examiner recommends amending abstract to state, “Heterocyclic compounds having . . .”
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.).
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 19, 20, 25, and 26 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 claim is broad in scope, as it extends to the treatment or prophylaxis (e.g., preventing) of neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, and inflammatory bowel diseases.
The nature of the invention generally relates to the pharmaceutical art and more specifically to a compound of formula I, pharmaceutical compositions thereof, methods of making the compounds, and methods of administering the compound to a mammal to treat or prevent a disease via the inhibition of monoacylglycerol lipase (MAGL). Thus, the nature of the invention is sophisticated.
The state of the prior art has been ascertained by searching the database in www.clinicaltrials.gov for monoacylglycerol lipase (MAGL). The search revealed no studies for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, and inflammatory bowel diseases—other than migraine, multiple sclerosis, multiple sclerosis spasticity, hyperparathyroidism, and Alzheimer’s disease. Examined drugs include elcubragistat (ABX-1431; Lu-AG06466) and irafamdastat (BMS-986368; CC-97489).
Additional information is provided from documents cited in Applicant’s Information Disclosure Statement (IDS). Qin et al., Cell Biochem Biophys (2014), 70, 33–36 (“Qin”) and Nomura et al., Cell (2010), 140, 49–61 present data showing a correlation between MAGL and cancer. The latter published Qin concludes that MAGL inhibitors have potential to impair cancer progression but further investigation is needed regarding MAGL in tumor cells. (Qin, p.35).
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.
Based on the above-referenced evidence, the state of the prior art is ascending for the treatment of the certain diseases in claims 20 and 26.
Based on the above-referenced evidence, the state of the prior art is in its infancy for preventing any diseases with a MAGL inhibitor.
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 or veterinary 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 includes assay data that shows the compounds of formula (I) as MAGL inhibitors. (Spec., pp.164–180). The specification states the compounds are useful for treating diseases associated with MAGL. (Id., pp.180–182).
The existence of working examples relate to the in vitro screening of the compounds of formula (I). There are no examples demonstrating in vivo activity against a specific disease with the compounds.
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. As claimed, the quantity of experimentation needed is extensive.
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 the claims is broad in scope; the nature of the invention is sophisticated; the state of the prior art is in its infancy for preventing any disease and ascending for treating certain diseases; the level of skill in the art is high; the pharmaceutical art is unpredictable; the direction provided by the inventor is limited to an in vitro evaluation; there are no working examples demonstrating in vivo activity against a specific disease; 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 treating multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and migraine.
Allowable Subject Matter
Claims 1–16 and 18 are allowed. The compounds of formula (I), pharmaceutical compositions thereof, and methods of making the compounds are free of the art. The closest prior art compounds include elcubragistat (ABX-1431; Lu-AG06466) and irafamdastat (BMS-986368; CC-97489) because they are being studied for the same biological target, but those compounds have chemical structures that are distinct from the instant compounds.
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
/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621
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