DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-12 are pending.
Status of Priority
The present application is a continuation of International patent application PCT/CN2022/126581, filed on October 21, 2022. This application also claims the benefits of foreign priority to CN202111235046.8, filed on October 22, 2021.
Specification - Abstract
The abstract of the disclosure is objected to because of the following informalities:
The abstract discloses a compound represented by Formula (I), but does not provide a structure of Formula (I). Please add the structure of Formula (I) to the abstract.
Appropriate correction is required.
Specification - Disclosure
The disclosure is objected to because of the following informalities:
In the table on pg. 5, some of the compounds depicted are cut off on the edges (i.e., compounds 1, 2, and 4).
Appropriate correction is required.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Zhong (CN113227068A; published August 6, 2021).
Novelty:
Zhong teaches compounds of a formula (I):
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(see abstract of original Chinese document; herein referred to as formula (I)-Zhong) which are GLP-1R agonists (see English-translated document, last statement written on the 1st page of the description section). Formula (I)-Zhong encompasses the instant compounds (variables of formula (I)-Zhong are defined in claim 1 of Zhong). However, none of the explicit examples provided by Zhong anticipate the instant compounds. Therefore, the instantly claimed compounds and their corresponding methods of use are considered novel.
Nonobviousness:
Reasoning 1:
Since Zhong defines the permissible groups for each variable of Formula (I)-Zhong, theoretically, a POSITA could make the compounds encompassed by instant Formula (I) which includes the instant compounds. However, given the vast number of possible compounds represented by general Formula (I)-Zhong and no guidance directing a POSITA to the particular sub-combination corresponding to the instant compounds, selection of the specific compounds disclosed in the instant application would not have been obvious.
For example, even though compound 190 of Zhong:
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(para. 1729 of original Chinese document which is attached to English translated document as provided by Examiner in application file wrapper) is very similar in structure to instant compound 4:
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, Zhong does not teach nor suggest to specifically replace the phenyl group (bonded to piperazine in compound 190 of Zhong) with a pyridyl group to yield instant compound 4. Thus, the instant invention is considered nonobvious.
Reasoning 2:
Prior art referenced:
Aspnes et al. (Aspnes) (CA2988721A1; published June 16, 2018.)
Furthermore, the instant specification (pg. 37) compares the oral pharmacokinetics of instant compound 1:
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and reference compound (PF-06882961):
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(same as example 4A-01 on pg. 89 of Aspnes) in mice. While instant compound 1 may be expected to exhibit GLP-1R agonist activity given that the instant compounds share a core structure with the compounds disclosed in Aspnes, the degree of GLP-1R agonist activity and the pharmacokinetics of the instant compound is unexpected relative to the prior art compound as a comparative.
More specifically, it can be seen from pg. 37, Table 2 of the instant specification that instant compound 1 (which differs, in structure, from the compound of Aspnes solely in that the instant compound possesses an ethynyl group instead of a cyano group) have significantly longer half-lives (T1/2) and mean residence times (MRT) compared to the reference compound as well as a significantly lower Cmax compared to the reference compound. These significant changes in the pharmacokinetics could not have been predicted from the disclosure of Aspnes. Thus, the instant invention is further considered nonobvious.
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 1, 2, and 5-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A compound as shown in General formula (I) or a pharmaceutically acceptable salt thereof:
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wherein
R1 is (S)-oxacyclobutan-2-yl,
R2, R3, R5, X, Z, and Z1 are as defined in claim 1, and
R4 = H, C1-C6 alkyl, or C3-C7 cycloalkyl
wherein the C1-C6 alkyl is optionally substituted with OH;
A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to point (A) above and a pharmaceutically acceptable carrier, diluent, and/or excipient;
A method for activating a glucagon-like peptide-1 receptor in a subject in need thereof, which comprises a step of administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to point (A) above to the subject;
A method for treating diseases, conditions, or disorders related to glucagon-like peptide-1 activity in a subject in need thereof, which comprises a step of administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to point (A) above to the subject, wherein the diseases are type 2 diabetes mellitus or the following conditions related thereto: hyperglycemia, insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia or non-alcoholic fatty liver disease;
A method for treating diseases, conditions, or disorders related to glucagon-like peptide-1 activity in a subject in need thereof, which comprises a step of administering a therapeutically effective amount of the pharmaceutical composition according to point (B) above to the subject, wherein the diseases are type 2 diabetes mellitus or the following conditions related thereto: hyperglycemia, insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia or non-alcoholic fatty liver disease;
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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.
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 evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
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, and
7) the quantity of experimentation needed to make and use the invention based on the content of the disclosure, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims compounds as shown in Formula (I):
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and uses thereof. The compounds shown in Formula (I) provided by the present application may serve as effective glucagon-like peptide-1 (GLP-1) receptor agonists. They have excellent GLP-1R receptor agonist activity and significant blood glucose-reducing effect, have better pharmacokinetic characteristics, represent more options for the prevention and/or treatment of GLP-1 activity-related diseases, conditions, or disorders, and thereby have better clinical application prospects. The variables of formula (I) are defined in instant claim 1.
State of the prior art and the predictability or lack thereof in the art
Prior art referenced:
Ishøy et al. (Ishøy) (Ishøy, P. L. et al. No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia. Acta Psychiatrica Scandinavica 2017, 136, 52-62.).
Mansur et al. (Mansur) (Mansur, R. B. et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: A pilot, open-label study. Journal of Affective Disorders 2017, 207, 114-120.).
Flintoff et al. (Flintoff) (Flintoff, J. et al. Treating cognitive impairment in schizophrenia with GLP-1RAs: an overview of their therapeutic potential. Expert Opinion on Investigational Drugs 2021, 30, 877-891.) (Published online: Jul 9, 2021)
Ishøy tested non-metabolic effects of exenatide once-weekly (Bydureon™; a known GLP-1R agonist) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder (see abstract). No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia was found (see title) and the “non-significant results of this first clinical trial exploring non-metabolic effects of a long-acting GLP-1RA in patients with schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment” (see abstract). Accordingly, the study did not establish that GLP-1R agonism was effective for treating the cognitive impairments associated with schizophrenia.
In the study conducted by Mansur, liraglutide (a known GLP-1R agonist) was administered at a dose of 1.8 mg/day to 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB) (see abstract). Note: liraglutide was added as an adjunct to existing pharmacotherapy (see abstract). Mansur concluded that “[l]iraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described” in Mansur (see abstract).
Flintoff states that there is a bias in the literature toward primarily focusing on models of diabetes and Alzheimer’s disease to observe the potentially beneficial effects of GLP-1R agonists on cognition. “Consequently, further studies are needed on the effects of GLP-1RAs in models of schizophrenia in order to demonstrate predictive validity of the drug for this patient population. Given the range of pathophysiological mechanisms that may be responsible for cognitive impairment, modeling combined metabolic and schizophrenia-related cognitive dysfunction using animal models to increase the translational relevance of the findings is essential” (last three sentences of conclusion section).
Collectively, the prior art demonstrates that cognitive impairment may be the result of a diverse set of diseases, conditions, and/or disorders including neurodegenerative diseases (e.g., Alzheimer’s disease), metabolic diseases (e.g., diabetes), and psychological disorders (i.e., schizophrenia). The available evidence (as provided by the prior art discussed above), did not establish that the effects of GLP-1 receptor agonism (related to improving cognitive function) observed in one disease setting would predict efficacy in another. Flintoff explicitly identified the need for additional schizophrenia-specific studies as the limited studies available (including Ishøy) does not demonstrate cognitive benefit in patients with schizophrenia when administered exenatide (a known GLP-1R agonist). Accordingly, a person of ordinary skill in the art would not have predicted, nor reasonably expected, GLP-1 receptor agonism by any small molecule GLP-1 R agonist to be broadly effective for treating cognitive impairment (explicitly listed in instant claims 8 and 11) across its full scope.
Moreover, the claims encompass both treatment and prevention of a wide variety of diseases, conditions, and disorders. While the prior art contains studies evaluating therapeutic effects of GLP-1 receptor agonists in subjects already diagnosed with certain diseases, conditions, or disorders, the prior art does not provide guidance regarding the complete prevention of disease, condition, or disorder onset. As such, the state of the prior art does not demonstrate that administration of a GLP-1R agonist would be expected to prevent the development of the full scope of the claimed diseases, conditions, or disorders.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples
In the instant case, the specification only provides 21 specific compounds as working examples. All 21 compounds were tested for GLP-1R agonist activity, 12 of the 21 were subjected to a pharmacokinetic test, and one (i.e., instant compound 2) was subjected to a glucose tolerance test in a mouse.
The instant specification does not provide evidence that any of the instant compounds can completely prevent the development of any disease, condition, or disorder (wherein the disease, condition, or disorder can be regulated or treated by activating a GLP-1 receptor).
There are also no working examples of a compound of instant formula (I) wherein R4 is a C1-C6 alkyl that is substituted with any substituent besides OH or wherein R4 is a C3-C7 cycloalkyl that is substituted with any substituent.
The breadth of the claims
The claims are broad insofar as the instant claims recite a compound of general formula (I) wherein the compound can possess a structurally diverse range of chemical groups for R4 (since R4 can be optionally substituted C1-C6 alkyl or optionally substituted C3-C7 cycloalkyl and the claims do not limit what these groups can be substituted with).
Also, the claims are broad insofar as the instant claims recite a method for preventing and/or treating any disease, condition, or disorder related to GLP-1 activity which includes many different classes of diseases (e.g., neurodegenerative disease, metabolic disease, psychological disorder, etc.) by administering to a patient in need thereof an amount of a compound of instant formula (I) or a pharmaceutical composition comprising a compound of instant formula (I).
The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure
The amount of direction and guidance provided in the specification is limited relative to the breadth of the claimed subject matter. Although the specification demonstrates that the 21 instantly claimed compounds possess GLP-1R agonist activity and provides pharmacokinetic data for a subset of these instant compounds, and demonstrates glucose-lowering activity for a single compound (i.e., compound 2) in a mouse glucose tolerance model, the specification provides little guidance regarding which compounds within the full scope of Formula (I) would be effective for preventing or treating the numerous diseases, conditions, and disorders encompassed by the instant claims.
In particular, the claims encompass treatment and prevention of a broad range of diseases, conditions, and disorders including neurodegenerative diseases, metabolic diseases, and psychological disorders, for example. However, the specification does not apply any of the instant compounds to disease-specific models. For example, the specification does not provide a schizophrenia animal model, Alzheimer’s disease model, or any cognitive impairment model that would demonstrate therapeutic efficacy of the claimed compounds in the context of improving cognitive function. Instead, the disclosure relies primarily on GLP-1R agonist activity and glucose-lowering data.
Furthermore, the specification provides limited structure-activity relationship guidance for the broad genus of compounds encompassed by instant formula (I). Although 21 compounds are exemplified, the claims encompass compounds in which R4 may be an optionally substituted C1-C6 alkyl or optionally substituted C3-C7 cycloalkyl group without meaningful limitations regarding the nature, number, or placement of substituents. The specification does not identify which substituents, substitution patterns, or combinations thereof are associated with therapeutic efficacy for the various claimed diseases, conditions, and disorders. Nor does the specification provide guidance sufficient to predict which members of the claimed genus would retain the desired biological activity while also exhibiting suitable pharmacokinetic therapeutic properties.
The prior art further demonstrates the unpredictability of the field. As discussed above, GLP-1R agonism did not consistently translate into therapeutic efficacy across different disease settings. Ishøy does not demonstrate cognitive benefit in patients with schizophrenia treated with a known GLP-1R agonist, whereas other studies reported different outcomes in other patient populations. Flintoff likewise recognized that additional schizophrenia-specific studies were necessary and that cognitive impairment may arise from diverse underlying diseases, conditions, and disorders. Accordingly, the prior art did not establish that GLP-1R agonism alone was predictive of efficacy across the broad range of diseases, conditions, or disorders including those explicitly listed in instant claims 8 and 11.
As such, a POSITA seeking to identify compounds within the full scope of instant claim 1 that are capable of preventing or treating the numerous diseases, conditions, and disorders (as recited in instant claims 7, 8, 10, and 11) would need to synthesize and screen substantial number of additional compounds (with varying combinations/number of substituents), evaluate their pharmacological and pharmacokinetic properties, and conduct disease-specific efficacy studies across multiple distinct disease models. Such efforts would require undue experimentation.
Written Description
Claims 1, 2, and 5-12 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
The instant specification fails to provide an adequate written description of the full scope of the claimed invention. Although the claims encompass compounds of Formula (I) wherein R4 may be an optionally substituted C1-C6 alkyl or optionally substituted C3-C7 cycloalkyl group, the specification provides only a limited number of exemplified species. In particular, the working examples do not demonstrate the breadth of structural diversity encompassed by the claimed genus. For example, the exemplified compounds do not adequately represent compounds wherein R4 is a substituted alkyl or substituted cycloalkyl bearing the broad range of substituents encompassed by the claims (the instant specification only provides one example of R4 being a C1-alkyl that is substituted with OH and one example of R4 being a cyclopropyl that is unsubstituted). Thus, the disclosure does not provide representative species commensurate in scope with the breadth of the claimed genus.
Furthermore, the specification does not identify any structure-function relationship that would permit a person of ordinary skill in the art to recognize which members of the claimed genus possess the recited therapeutic activities. Although the specification reports GLP-1R agonist activity for certain compounds, it does not describe which structural features of the claimed genus are responsible for activity, nor does it provide guidance regarding which substitutions within the claimed genus are expected to retain the asserted biological properties. Accordingly, the disclosure does not provide a sufficient number of representative species that demonstrate possession of the full claimed genus and adequately reflect the structural diversity of the claimed genus.
The deficiency is further compounded by the breadth of the therapeutic claims. The claims encompass prevention and/or treatment of a large number of diseases, conditions, and disorders related to GLP-1 activity which includes metabolic diseases, neurodegenerative diseases, and psychological disorders. However, the specification provides only GLP-1 receptor agonism data, pharmacokinetic data for a subset of compounds, and a glucose tolerance study for a single compound. The specification does not provide any data, models, or examples demonstrating treatment of cognitive impairment associated with schizophrenia, for example.
As discussed above (see section “2. State of the prior art and the predictability or lack thereof in the art” section above under “Scope of Enablement”), the prior art recognized that cognitive impairment may arise from diverse underlying diseases and conditions and did not establish that GLP-1 receptor agonism predictably translated into therapeutic efficacy across all such conditions. Flintoff explicitly identified the need for additional schizophrenia-specific studies as the limited studies available (e.g., Ishøy) did not demonstrate cognitive benefit in patients with schizophrenia who were administered a known GLP-1R agonist. In view of this unpredictability, the disclosure of GLP-1 receptor agonism of the instant compounds alone does not reasonably convey to a POSITA that Applicant was in possession of compounds capable of treating the full scope of the claimed diseases, conditions, and disorders, including cognitive impairment associated with schizophrenia.
Accordingly, the specification does not reasonably convey to a POSITA that the instant invention was in possession of the full scope of the claimed compounds and methods at the time of filing.
Claim Rejections - 35 USC § 112(b)
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, 2, and 5-12 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.
Claim 1 recites “optionally substituted” without specifying what substituents are encompassed. Even though the specification discloses a list of preferred substituents (see pg. 4), this list is non-limiting and the permissible number of substituents, or the positions at which substitution may occur is not defined. Therefore, it is unclear what chemical structures are encompassed by the term “optionally substituted” as the term could include an unlimited range of functional groups and substitution patterns, including those that would significantly alter the chemical and physical properties of the claimed compound. As such, a POSITA would not be able to determine the metes and bounds of the claimed invention with reasonable certainty and claim 1 is rendered indefinite.
Claims 2 and 5-12, which are dependent on claim 1, are also rejected for further requiring and/or reciting the indefinite limitation of claim 1.
Allowable subject matter
Claims 3 and 4 are objected to as being dependent upon a rejected base claim, but would be allowable once the corresponding rejections have been overcome.
Conclusion
Claims 1, 2, and 5-12 are rejected. Claims 3 and 4 are objected to. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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