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 35 USC 371 National Stage filing of international application PCT/EP2023/064735, filed June 1, 2023, which claims the benefit of an effective US filing date under 35 USC 119(e) from US Provisional application 63/347,708, filed June 1, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 8, 2025 was in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the IDS document was considered and a signed copy of the 1449 form is attached.
Status of the Claims
Currently, claims 1-3, 5, 7, 17-18, 29, 40, 42-43, 45, 47, 49, 54, 57, 59, 61, 63, 65, 68-69, 73, 83-84 and 87 are pending in the instant application and are under consideration herein.
Specification
The specification is objected to because all instances of compound 77, 77a and 77b as drawn do not clearly depict the cyclohexyl ring within the larger macrocyclic structure. In order to avoid printing issues, Applicant should redraw each instance to clearly show the cyclohexyl ring structure.
Claim Rejections - 35 USC § 112
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.
Claim 83 is 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 pre-AIA the applicant regards as the invention. In particular, the claims are indefinite because the compound
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do not clearly depict the cyclohexyl ring required by the claimed structure. In order to avoid printing issues, Applicant is advised that the compounds must be redrawn with a clearly depicted cyclohexyl ring within the larger macrocyclic structure.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
Claim 87 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for the method of preventing the diseases as claimed or treating the full scope of diseases or disorders “associated with one or more orexin receptors.” 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.
As stated in the MPEP 2164.01(a), “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."
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
1. The nature of the invention
2. The state of the prior art
3. The predictability or lack thereof in the art
4. The amount of direction or guidance present
5. The presence or absence of working examples
6. The breadth of the claims
7. The quantity of experimentation needed, and
8. The level of skill in the art
The Nature of the Invention and Breadth of the Claims
Instant claim 87 is drawn to a method of preventing, treating, ameliorating, controlling or reducing the risk of diseases or disorders selected from the group consisting of the extraordinary breadth of conditions, encompassed by those “associated with one or more orexin receptors.” As defined in the specification, this is intended to include any and all cognitive impairment, any and all immune-mediated diseases, Alzheimer’s disease, Parkinson’s disease, etc. (see paragraph [0162]).
The prophylaxis or “prevention” actually means to anticipate or counter in advance, to keep from happening, etc. and there is no disclosure as to how one skilled in the art can reasonably establish the basis and the type of subject to which the instant compounds and compositions can be administered in order to have the "preventive" effect for a patient suffering or susceptible to any of the claimed diseases/conditions.
Specifically, for example, cardiovascular diseases are specifically recited in the claim. The claimed “cardiovascular disease” is a term which is interchangeable with heart disease, which is defined as "a broad term used to describe a range of diseases that affect your heart, and in some cases, your blood vessels." The term encompasses a wide range of disorders, including diseases of the blood vessels (e.g. coronary artery disease), heart rhythm problems (arrhythmias), and congenital heart defects which an individual is born with. Additionally, other conditions such as infections or conditions affect the heart’s muscle, valves, or beating rhythm are considered to be forms of heart disease. Thus, the claimed term encompasses not only diseases associated with xanthine oxidase activity, but also conditions that an individual could be born with. It is established that there is no way to prevent a congenital heart defect and additionally, one class of compounds (e.g. orexin receptor modulators) could not reasonably be expected to be effective in the treatment of the wide variety of diseases encompassed by cardiovascular diseases, including not only diseases associated with arterial blockage but also congenital heart defects.
The Amount of Direction / Guidance Present and the Presence or Absence of Working Examples
The specification fails to set forth sufficient working examples of the claimed invention. That is, the specification does not show any examples where the compound of the instant invention was used to treat and prevent any diseases or provide evidence that the compound was even administered for the claimed use. See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed … Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”). The specification merely sets forth binding assays for xanthine oxidase, and a test for the hypouricemic effect of the claimed compounds, which are not “reasonably correlated” to the vast numbers of diseases encompassed by the claims. See MPEP 2164.02 (“The issue of “correlation” is related to the issue of the presence or absence of working examples. “Correlation” as used herein refers to the relationship between in vitro … assays and a disclosed or a claimed method of use. An in vitro … 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.” … For a claimed genus [e.g., cardiovascular diseases, kidney diseases, respiratory diseases, autoimmune diseases, etc.], representative examples together with a statement applicable to the genus as a whole will ordinarily be sufficient if one skilled in the art … would expect the claimed genus could be used in the manner without undue experimentation”). While Applicants do indeed make various statements in the specification that their claimed compound will effectively treat the genus of claimed diseases, such is not supported by conclusive examples. For instance, no in vivo data is provided for any of the claimed compounds in treating or preventing any of the claimed diseases except hyperuricemia. Based on the disclosure and examples, the claimed compounds were not administered to humans for their preventative or therapeutic effects on the myriad of claimed diseases. Thus, the disclosure and examples do not reasonably correlate with the large number of diseases that fall with the scope of diseases as claimed. That is, the limited testing set forth in the assays does not constitute a “working example” within the meaning of MPEP 2164.02 let alone a “representative” set of examples that would be required the describe this enormous genus.
The State of the Prior Art and the Predictability or lack thereof in the art
Treatment of diseases associated with orexin receptors is challenging and highly unpredictable. Adding to the challenge is the fact that neither the art nor the specification provides any guidance as to how the onset of the entirety of this claimed scope could be prevented.
Parkinson's disease is a progressive neurodegenerative disorder (synucleopathy) diagnosed on the basis of characteristic motor disturbances, asymmetry of symptoms onset and response to levodopa (Litvan et al., 2003). Lewy bodies, neurofibrillary tangles and plaques are observed in nigral, limbic and neocortical regions. These degenerations are supposed to affect catecholaminergic (dopamine and norepinephrine) and cholinergic neurotransmission. In particular, an important part of cognitive deficits (executive function and working memory) have been related to a decreased prefrontal dopaminergic signaling in non demented patients (Nandakumar et al., 2013). With regard to the cognitive impairment, for which there is currently no treatment, patients with schizophrenia show significant deficits in specific cognitive domains, especially executive function, working memory, and episodic memory. Cognitive domains which are dysfunctioning in these two disorders are complex functions involving many neurotransmitters and brain regions; however, dopamine signaling in the dorsolateral prefrontal cortex (DLPFC) has been shown to play a critical role in these processes (Goldman-Rakic, Castner et al. 2004). One approach to rectifying cortical dopamine neurotransmission is to take advantage of the differential modes of clearance of dopamine from the different brain regions. In the midbrain, there is extensive expression of the dopamine transporter (DAT), which is thought to be primarily responsible for dopamine clearance from the synapse (Ciliax, Heilman et al. 1995). In contrast, cortical regions exhibit only low levels of DAT expression, and dopamine is cleared primarily by enzymatic catabolism of dopamine, with a contribution from the norepinephrine transporter (NET) (Yavich, Forsberg et al. 2007; Kaenmaki, Tammimaki et al. 2010). The primary enzymes responsible for dopamine catabolism in the prefrontal cortex ("PFC") are monoamine oxidase (MAO) and catechol-O-methyltransferase ("COMT").
Consequently, a person of skill in the art would not reasonably mere statements that the compounds as claimed are capable of inhibiting orexin receptors to reasonably translate to therapeutic or preventative effects in humans, or to “reasonably correlate” with the hundreds of disease treatments and preventions encompassed by the claims. That is, Applicants limited disclosure is not representative of this enormous genus especially when said genus encompasses a large amount of unpredictable art.
The level of the skill in the art
The level of skill in the art is high, with the skilled artisan typically having an advanced degree such as a Ph.D. or MD.
The quantity of experimentation needed
As a result of the broad and unpredictable nature of the invention and the lack of specific guidance from the specification, it is respectfully submitted that the quantity of experimentation needed to make and or use the invention would be great. Note that there must be sufficient disclosure, either through illustrative examples or terminology, to teach those of ordinary skill how to make and use the invention as broadly as it is claimed. In re Vaeck, 947 F.2d 488, 496 & n.23, 20 USPQ2d 1438, 1445 * n.23 (Fed. Cir. 19991). Also note that the amount of guidance or direction needed to enable the invention is inversely related to the degree of predictability in the art. In re Fisher, 839, 166 USPQ 24. Thus, although a single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements, in cases involving unpredictable factors, such as most chemical reactions and physiological activity, more teaching or guidance is required. In re Fisher, 427 F.2d 839, 166 USPQ 24; Ex Parte Hitzeman, 9 USPQ 2d 1823. Here, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated or prevented by the compound encompassed in the instant claims, with no assurance of success.
Conclusion
In conclusion, the specification fails to provide sufficient support of the broadly claimed therapeutic or prophylactic agent for the very broad scope of diseases as claimed, as a result necessitating one of skill to perform an exhaustive search for which conditions, if any, could be treated or prevented in order to practice the claimed invention. “A patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001.
Allowable Subject Matter
Claims 1-3, 5, 7, 17-18, 29, 40, 42-43, 45, 47, 49, 54, 57, 59, 61, 63, 65, 68-69, 73 and 84 are allowed.
The closest prior art to the instantly claimed compounds is, for example, WO 2022109117 (cited on 10/8/2025 IDS). The prior art teaches compounds of Formula (I) as orexin receptor inhibitors
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. While the art generically teaches similar macrocyclic compounds, the prior art compounds universally lack the required spirocyclic fused moiety required by instant Formula (I). Accordingly, since the art does not provide sufficient motivation to prepare the instantly claimed compounds, the claimed compounds are allowable.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alicia L. Otton whose telephone number is (571)270-7683. The examiner can normally be reached on Monday - Thursday, 8:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Fereydoun Sajjadi can be reached on 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699
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