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 1-17 are currently pending.
Claim Warning
Applicant is advised that should Claim 6 be found allowable, Claim 11 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Both claims recite duplicate structures wherein R4, R6, and W are of the same scope: Claim 6 -
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and Claim 11 -
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. The warning applies insofar as the limitation regarding “formula (II’-3)” is not limiting. The term “preferably” is not limiting in Claim 5; see Claim Rejections - 35 USC § 112(b) below.
Claim Objections
Claims 2, 4, 9, 13, and 17 are objected to because of the following informalities:
Claims 2, 4, and 17 read as follows: “ The compound of [Formula] or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the hydrate thereof according to claim [#], wherein, the compound or the pharmaceutically acceptable salt, the stereoisomer, the solvate or the hydrate thereof is selected from…[structures] or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a hydrate thereof.” It is suggested that the claim be reworded as follows to preserve the same claim scope and employ more direct language: “The compound of [Formula] according to [Claim #](, wherein the compound is) selected from…[structures] or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof” or similar more concise language.
Claim 9 should recite “insulin resistance or hepatic insulin resistance” instead of “insulin resistance and hepatic insulin resistance”
Claim 13 recites “R4 is from” rather than “R4 is selected from”.
Claim 17 is objected to because “an y” should instead read “any”.
Appropriate correction is required.
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.
Claims 8-9 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 treating or preventing the following diseases recited in Claim 9:
type I diabetes, type II diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, nonalcoholic fatty 20 liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance or hepatic insulin resistance,
does not reasonably provide enablement for the treatment of diseases not mediated by GLP-1 receptor agonism or the treatment or prevention of malnutrition-related diabetes. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
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 the skill in the art.
The nature of the invention (1) and breadth of the claims (6)
The nature of the invention and breadth of Claims 8-9 is the treatment of a subject in need thereof with a GLP-1 receptor agonist (Claim 8, see Claim Rejections - 35 USC § 112(b) below for interpretation) and the treatment and/or prevention of the assorted diseases of Claim 9 comprising administering a compound of Claim 5.
The state of the prior art (2) and the predictability or lack thereof in the art (3)
Regarding Type I diabetes, which is an autoimmune disorder with an etiology that is not necessarily metabolic, Scholten (Diabetologia (2021) 64:1037–1048) teaches “Recent evidence from rodent models indicates a role for GLP-1 RAs in protecting beta cells from apoptosis and in promoting beta cell replication and mass. As such, although this remains to be confirmed, it is conceivable that GLP-1Ras may offer a way to prevent the ‘unmasking’ of the beta cell to immune effector cells, for example, by downregulating expression of MHC class I proteins” (Page 1042, Right Col.). At the very least, it is suggested that GLP-1 agonism may play a role in the preservation of beta cells and delay the onset of Type I diabetes if not prevent the development in susceptible populations outright.
Regarding the neurodegenerative disorders like Parkinson’s and dementia, GLP-1 agonism may also be implicated in the respective pathogenetic mechanisms. Manfready (Current Neurology and Neuroscience Reports (2022) 22:335–342) reports “GLP-1 can prevent or reverse neurodegeneration in animals, and is being tested to treat humans with Parkinson’s disease” and suggests “medications used to treat diabetes increase levels of GLP-1, and so may be repurposed to prevent or treat Parkinson’s disease” (Page 339, Take-Home Points). Further, Norgaard (Alzheimer's & Dementia: Translational Research & Clinical Interventions 8 (2022):e12268. 1-9) teaches “Our results suggest that GLP-1Ras may provide a new opportunity to reduce dementia incidence” and that said results “support the need for a well powered randomized controlled trial to determine whether GLP-1Ras may have a broader role in preventing dementia” (Page 3, Research in Context, Interpretation and Future directions). Such results across the art implicate the role of the GLP-1 pathway in not only treating neurodegeneration but preventing the diseases of Claim 9.
Regarding malnutrition-related diabetes, the treatment and prevention of which is not enabled, Ahmed (F1000Research 2022, 11:777. 1-27) teaches “Evidence from a recent systematic review suggests pancreatic endocrine and exocrine functions may not recover fully after childhood or adult wasting malnutrition. Such long-term effects on the pancreas may contribute to the different phenotype of diabetes common in [low- and middle-income countries] LMICs with prevalent malnutrition, compared with the diabetes phenotype in high-income countries” (Page 4, Para 1). The art is unclear as to how chronic nutritional deficiencies resulting in damage to the pancreas is implicated in the GLP-1 pathway. Rather, the cause of this diabetes phenotype is explicitly said to be caused by wasting malnutrition. The GLP-1RA is not a remedy for severe nutrient deficiency.
The amount of direction or guidance present (4) and the presence or absence of working examples (5)
Applicant offers experimentation beginning on Page 165. In vitro experiments suggesting agonist activity of select compounds in Example 1. Example 2 of Page 167 demonstrate in vivo effects on blood glucose levels in animal models. What is not suggested by the examples or explicated in the disclosure is how one might determine what diseases, which may or may not be mediated by GLP-1, may be treated by the compounds or how such diseases are implicated in the GLP-1 pathway. The nexus between GLP-1 activity and the scope of treatment or prevention of the claimed methods has not been established. Particularly, no explanation of malnutrition-related diabetes is offered with respect to GLP-1 activity.
The quantity of experimentation needed (7)
The quantity of experimentation needed is extremely difficult, novel, and undue experimentation; the ability of the claimed agonists to treat let alone prevent diseases which are not suspected or known to be associated with the GLP-1 pathway is nearly impossible to determine and not at all enabled by the experiments disclosed in the specifications of the application. One of skill in the art would be unduly burdened by determining what patients are in fact “in need thereof” with respect to administration of the claimed compounds. Further, the genus of formula (II’) of Claim 5 encompasses a great deal of compounds with variation among several R groups, making the determination of what diseases may be treated via the particular agonists more burdensome. Regarding, malnutrition diabetes, the distinct and environmentally induced etiology of the particular phenotype is not contemplated in the specification nor is it clear what role GLP-1 may play. Therefore, the quantity of experimentation requires resolving which diseases, including those not necessarily mediated by GLP-1, may be treated with the compounds of the invention wherein the diseases and compounds are innumerable. Such experimentation is unduly burdensome.
The level of the skill in the art (8)
The level of skill in the art is high. However, even one of the highest skill in the pharmaceutical arts could not reasonably predict what diseases, mediated by GLP-1 or not, might be treated by the methods as claimed, nor would such an artisan at the time of filing the invention have readily understood the role of GLP-1 in the divergent diabetes phenotype which is linked to external nutritional stress rather than those GLP-1 involved pathways of Type I and II diabetes.
Thus, the specification fails to provide sufficient support of the broad use of the methods of the instant claims for the treatment of a patient “in need thereof” or the treatment or prevention of malnutrition-related diabetes.
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 5-12, and 15-16 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 regards as the invention.
Claims 5, 9-10, 12, and 15-16 recite the term “preferably”. The phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention or merely exemplary. See MPEP § 2173.05(d). The limitations which follow the term “preferably” are not interpreted as necessary claim limitations but rather exemplary embodiments. Those claims further limiting the preferable structure “II’-3”, namely Claims 6 and 16, are rejected for the same reason. Claims 6-8 and 11 are rejected by virtue of dependency.
Claim 8 recites “a method for preparing” GLP-1 agonists wherein the active method step is “administering” amounts of a GLP-1 agonists. It is unclear whether this claim is meant to be a method of preparation or administration to a patient for treatment/GLP-1 agonism. No method steps are recited so as to suggest the method is one of preparation as stated. For the purpose of compact prosecution, the claim is interpreted to be a method of treating comprising administering the agonists to “a subject in need thereof”.
Claims 8-9 recite “the pharmaceutical composition” according to Claim 5. Claim 5 does not recite a pharmaceutical composition. Therefore, the phrase lacks antecedent basis and it is unclear what “composition” is being referenced in either claim.
Claim 9 recites “treating and/or preventing”. It is unclear how one might treat and prevent a disease rather than treat or prevent. To treat a disease, one must be afflicted with said disease; however, to prevent a disease, one must not already be afflicted with said disease. The two states, diseased and not-yet-diseased are exclusive and it is unclear how one of skill in the art might treat a patient without the disease to be treated or prevent the disease in a patient who is already afflicted therewith.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2, 4, and 17 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 2, 4, and 17 recite compounds of their respective formulae of the respective independent claims, upon which the rejected claims depend, wherein the generic
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moiety is instead a poly-, hetero-, and/or (partially) saturated cycle rather than the C6aryl depicted in said respective formulae. For example,
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of Claim 2 possesses a piperidinylene:
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, and
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of Claim 4 possesses a partially saturated carbocyclylene:
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. The compounds which do not comport with the definitions of the independent claims broaden the scope of each respective independent claims and are therefore not properly limiting.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Allowable Subject Matter
The closest prior art to Claim 1, formula (II), is found in Ammann (WO2021081207, 7/29/2024 IDS). Ammann teaches Compound 152 on Page 477:
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, wherein Compound 152 differs from formula (II) in that 1) the oxygen-containing bicycle is partially saturated in Compound 152 and 2) the instant R2 position of Ammann Compound 152 is
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rather than the distinct alkylene-heterocycles permitted by the instant claims:
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. Regardless of whether each modification would be obvious to make alone, it would not be obvious to modify Compound 152 twice to render obvious a compound of examined formula (II) and reasonably expect success in doing so with such disparate functional groups.
Regarding the compounds specifically listed in the claims, the closest prior art is found in Cai (WO2023000834, 3/25/2026 IDS, with priority to 7/23/2021 through Chinese Application No. CN202110839013.8A). Cai teaches the following compound: on Page 105:
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which differs from examined compound 1:
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, in that the piperidinylene moiety is of the opposite orientation. The general formula of Cai does not teach variation in the position of the nitrogen or the simultaneous exchange of N for CH and CH for N at opposite positions. The formula is as follows:
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(Page 101). It would not be obvious to exchange the atoms or rotate the ring 180 degrees because not only does Cai not permit such variation in the above formula, but the piperidine nitrogen lone pair electrons are situated adjacent to the pyridinyl. Such proximity allows for delocalization of said lone pair around the heteroaryl ring which is not accounted for by the general formula of Cai. The contrasting electronics between the prior art and claimed compound and the rigid scope of the Cai formula would suggest the exchanges or rotation are not obvious let alone predictable with respect to synthesis and biological activity before the filing date of the examined invention.
Conclusion
Claims 2, 4, 9, 11, 13 and 17 are objected to. Claims 2, 4-12 and 15-17 are rejected. Claims 1, 3, and 14 are allowable.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Richard G. Peckham whose telephone number is (703)756-4621. The examiner can normally be reached 8:30am - 4:30pm EST.
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/RICHARD GRANT PECKHAM/Examiner, Art Unit 1627
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