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 .
DETAILED ACTION
Claims 21-23 and 73-88 are pending and are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/26/2024 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application is a continuation of International Application Number PCT/EP2022/052131 filed on January 28, 2022, which claims priority to U.S. Provisional Patent Application Nos. 63/142,876, and 63/196,902, respectively filed on January 28, 2021, and June 4, 2021.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 21-23 and 73-88 are rejected under 35 U.S.C. 112, first paragraph, first paragraph, as failing to comply with the enablement requirement. The claims 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. Applicants claim a method of treating Childhood-Onset Fluency Disorder (COFD), comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of Formula I:
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(I). and A method of treating Childhood-Onset Fluency Disorder (COFD) in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of: a compound of Formula III:
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III); and a compound of Formula I:
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or a pharmaceutically acceptable salt thereof.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention
The invention is drawn to a a method of treating Childhood-Onset Fluency Disorder (COFD), comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent RO5545965, formula I (recited in instant claims 21 and 79) alone or in combination with olanzapine , compound of formula III (recited in instant claim 79).
Claims relate treatment of childhood fluency disorders which includes stuttering and cluttering , and distinguishes between originary (neurogenic non-syndromal and neurogenic syndromal and acquired (neurogenic and psychogenic) stuttering..
Relative skill of those in the art
The level of ordinary skill in the art may be found by inquiring into: (1) the type of problems encountered in the art; (2) prior art solutions to those problems; (3) the rapidity with which innovations are made; (4) the sophistication of the technology; and (5) the education level of active workers in the field. Custom Accessories, Inc., 807 F.2d at 962. All of those 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 typical education level of active workers in the fields of Medicinal chemistry, biology, biochemistry, and pharmacology, as well as the high degree of sophistication required to solve problems encountered in the art, the Examiner finds that a person of ordinary skill in the art would have at least a college degree in one of the fields identified above and at least four years of work experience; i.e. a masters or doctorate level scientist.
State of the prior art/Predictability or unpredictability of the art:
The state of the prior art is such that it involves screening both in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. which compounds treat which specific amyloid associated disease). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The instant claimed invention is highly unpredictable as discussed below:
The present claims relate to the treatment of childhood fluency disorders (stuttering) by treating the patient with the specific compounds RO5545965, formula I (recited in instant claims 21 and 79) alone or in combination with olanzapine , compound of formula III (recited in instant claim 79).
The pharmacological art requires the screening of potential drug candidates in vitro and in vivo to determine if the drug candidates exhibit the desired pharmacological activities. Typically, this process includes in vitro laboratory screening, preclinical in vivo screening, and three phases of clinical trials. Once this arduous process has been successfully completed by a drug candidate, subsequent drug candidates will benefit from the established proof of concept. The subsequent drug candidates must demonstrate a substantial correlation between their biological activity and that of the known drug candidate. With regards to childhood fluency disorders or stuttering, the treatment of this condition is highly unpredictable and there are no approved agent or drugs which has proven to be effective in treating this.
Sander et al. (American Family Physician, 2019, Volume 100 (9), pages 556-560,cited in IDS dated 02/26/2024) recites that extensive studies, no pharmacologic agent has been shown to have a significant benefit for persistent stuttering at any age (Page 558, col.1, last para to col.2. para 1).
Maguire et al. (Frontiers in Neuroscience, 2020, Pages 1-8, cited in IDS dated 02/26/2024) discloses that currently there is no FDA-approved medication for the treatment of stuttering. Maguire et al. disclose that it is postulated that elevated dopamine levels are associated with stuttering and lower activity of the striatum, supported by a 1997 study showing significantly higher 6-FDOPA uptake in the ventral limbic cortical and subcortical regions leading to an overactive presynaptic dopamine system and that atypical antipsychotic medications such as olanzapine and risperidone block dopamine at the D2 receptor, thus leading to increased activity of the striatum and improved fluency (page 3, under pharmacologic treatment of stuttering). They further disclose that While olanzapine at doses between 2.5 and 5 mg has been more effective than a placebo at reducing stuttering, it is also correlated with an average of 4 kg weight gain. They recite that numerous medications for stuttering are have been studied, but until recently only those with dopamine blocking activity have confirmed efficacy (page 4, col.1 last para). Maguire et al. further discuss that there are two active medications, mentioned previously and under patent, ecopipam and deutetrabenazine, that are currently going through clinical trials with the hope of eventually being FDA approved for stuttering. They disclose that research is also needed to address stuttering in adolescents, since some FDA-approved medications do not include research in this population. Future research should also include improving the accuracy of assessing changes in stuttering severity. Although global scales are consistent with treatment effect, stuttering research needs standardization among quantitative measures of outcomes in order to improve comparisons between medications. As for now, there is no head-to-head comparative trials between speech therapy and pharmacologic treatment of stuttering, and with different raters and subject pools, comparative analyses cannot be adequately performed (page 6, under Discussion). It is noted that McGuire fails to disclose PED10 inhibitors as a potential drug choice in treating COFD.
Neumann et al. (Deutsches Ärzteblatt International | Dtsch Arztebl Int 2017; 114: 383–90) teaches that for treatment of originary neurogenic non-syndromic stuttering in children aged 6-12, there is no solid evidence for the efficacy of any treatment and the evidence does not support the efficacy of pharmacotherapy, rhythmic speaking, or breathing regulation as the sole or main form of treatment (abstract). They disclose that the efficacy of pharmaceuticals such as . antidopaminergics, MAO inhibitors, anticonvulsants, GABA receptor modulators, calcium antagonists, parasympathomimetic drugs or substances affecting the cardiovascular system, if reported is small with frequent adverse effects (Table 3, pharmaceuticals, page 388). It is noted that Newmann et al. also does not mention PDE10 inhibitors as potential pharmacotherapy agent in stuttering.
With regards to the instantly claimed compound, Fantasia et al. (US 2016/0046628) discloses the instantly claimed compound of formula (I) (Example 13) as phosphodiesterase (PDE) inhibitors, particularly PDE10 inhibitors which have the potential to treat psychotic disorders like schizophrenia (abstract). Lebel et al. (US 2003/0032579) discloses a method of treating anxiety or psychotic disorder in a mammal by administering a PDE10 inhibitor to said mammal which includes nerurodegenerative diseases [Claims 1-29]. However, there is no teaching in the art of using PDE10 inhibitors in the treatment of Childhood fluency disorders. As such the utility of these agents in the treatment of such conditions for which pharmacotherapy still lacks proper evidence is highly unpredictable.
It is noted in MPEP 2164.03 that the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. >See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) (“Nascent technology, however, must be enabled with a specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee' s instruction. .” The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability. Most often, additional factors, such as the teachings in pertinent references, will be available to substantiate any doubts that the asserted scope of objective enablement is in fact commensurate with the scope of protection sought and to support any demands based thereon for proof.
Amount of guidance/Existence of working examples:
The specification fails to provide adequate support for effectively treating the childhood fluency disorder with the instantly claimed compound which is a PED10 inhibitor. Applicant fails to provide any information sufficient to practice the claimed invention, absent undue experimentation.
In their examples, Applicants provide the method of synthesis of the instantly claimed compound and crystalline form of the compound (example 1-2). In terms of the use of compound of formula I in the treatment of COFD, they detail a prophetic study design to evaluate its treatment (example 3). This study is a suggested protocol and there is no data or results which shows that the compound is indeed useful for the treatment as claimed. With regards to the combination of the compound of Formula I with that of Olanzapine (formula III), applicants evaluate the combine effect on glucose tolerance which does not translate to successful treatment of COFD by this combination. The examples are speculative and lacks any evidence or rationale of a therapeutic of PDE10A inhibitors, specifically the claimed compound of formula (I) in the treatment of COFD.
.The quantity of experimentation necessary:
Generally speaking, the amount of experimentation to transform a molecule into medicine is vast and the success thereof is low. Recent statistics indicate that the attrition rates during drug development remain high. See Schafer et al. Drug Discovery Today 2008, 13 (21/22), 913-916. The article makes clear that there are many steps necessary to promote a new molecular entity toward its clinical use, any one of which is cumbersome. For instance, the authors found that "proof of concept trials have failed when the decision to enter clinical development was based on preclinical experiments using the wrong compound, the wrong experimental model, or the wrong endpoint.” It can be gleaned from this article that a plethora of experimentation is needed just to identify the best compound (i.e. one amongst many in a Markush-type claim), which preclinical tests are predictive of clinical success, and which diseases are the best to target. There is generally a vast amount of experimentation to take a drug from bench to the clinic. See, i.e., Horig et al. Journal of Translational Medicine 2004, 2(44) (“Successful drug development requires satisfying a matrix of domains from relevance to the disease and the drug-ability of the target through feasibility and convenience of drug delivery, demonstration of favorable benefit-risk profile in order to achieve a drug label that reflects physician and patent acceptance.") . As such in the instant case, with the high unpredictability in the art and the limited guidance and examples provided by the applicant, the quantity of experimentation is very high.
Conclusion:
Thus, the specification fails to provide clear and convincing evidence in sufficient support for practicing the invention as claimed. Thus, factors such as “sufficient working examples” “guidance' and “predictability”, etc. have been demonstrated to be sufficiently lacking in the instantly claimed methods. In view of the chemical nature of the invention, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate with the scope of the claims.
Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent 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”.
Therefore, in view of the Wands factors discussed above, to practice the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation to test the efficacy of the instantly claimed compound in the treatment of COFD, with no assurance of success. Thus, rejection of claims 21-23 and 73-88 under 35 U.S.C. §112, first paragraph, is deemed proper.
Conclusion
Claims 21-23 and 73-88 are rejected. No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Dierdre (Renee) Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAVITHA M RAO/ Primary Examiner, Art Unit 1691