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 U.S. National Phase filing of PCT application PCT/IB2022/053367, filed April 11, 2022, which claims the benefit of and priority to U.S. Provisional Application No. 63/173,592, filed April 12, 2021, and claims the benefit of and priority to U.S. Provisional Application No. 63/308,843, filed February 10, 2022, and claims the benefit of and priority to U.S. Provisional Application No. 63/323,401, filed March 24, 2022.
However, the limitations of the instant claims are not adequately supported or enabled in the manner provided by 35. U.S.C. 112(a) or pre-AIA U.S.C. 112, first paragraph by 63/173,592. In claim 1 of the instant application, in the description of the R4 limitation, it reads “…are each optionally substituted with 1, 2, or 3 groups independently selected from C1-3 alkyl, halo, CN, NO2, OR4A…” The C1-3 alkyl is not claimed or present in the provisional applications 63/173,592 or 63/308,843. In a similar manner, the limitations of R5 and R5’ in instant claim 1 include this C1-3alkyl term, which is not claimed or present in ‘592 or ‘843. Last, the limitation of R4a, R4b, R4c, and R4d of instant claim 1 reads “…groups independently selected from C(O)OR4A, -OH and halo…” The C(O)OR4A group is not claimed or present in the provisional applications ‘592 or ‘843. All of the above limitations are first claimed or described by applicant in provisional application 63/323,401, filed March 24, 2022. Thus, claim 1 and all of its dependent claims 2-19, 23-24 of the instant application have been awarded the effective filing date of provisional application 63/323,401, filed 03/24/22.
Application and Claims Status
Applicant’s preliminary amendments filed on October 10, 2023 are acknowledged and entered.
Claims 1-24 were pending. In the amendment as filed on October 10, 2023, applicants have amended claims 3-15, 18, 19, 23; cancelled claims 20-22; and added no new claims. Therefore, claims 1-19, 23-24 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) filed on January 5 ,2024 is in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action.
Specification
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 of the errors of which applicant may become aware of in the specification.
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
The abstract of the disclosure is objected to because: the abstract does not commence on a separate sheet (the WIPO publication cover sheet was submitted instead). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 1 is objected to because of the following informalities:
in the definition of R4, the “S(=NR4g)(O)NR4cNR4d” term is missing a valence around the last nitrogen. There should be an additional substituent. A similar issue occurs later in the definition of R4 with the S(=NR4G)(O)NR4CNR4D” term. Again, this issue is repeated twice more in the definition of R5 and once in the definition of R5’. Appropriate correction is required.
in the definition of R5’, there is an extra ‘and’ separating C3-6-cycloalkyl and 4-10 membered heterocycloalkyl that should be removed. Appropriate correction is required.
Claim 6 recites “wherein R4 is selected from…” and proceeds to list potential selections. It then continues with “wherein R4 has the structure of” and proceeds to list more potential selections. The examiner suggests removing this second “wherein” phrase as it is redundant and confusing.
Claim 8 recites “wherein R5 is selected from…” and proceeds to list potential selections. It then later continues with “wherein R5 is selected from” and proceeds to list more potential selections. The examiner suggests removing this second “wherein” phrase as it is redundant and confusing.
Claim 9 is objected to because of the following informalities: in the definition of R5, there are
multiple duplicates listed, for instance, F, -CH2CH3, and fluorophenyl. Appropriate correction is required.
Claim 13 is objected to because it lacks a period at the end of the claim. Appropriate correction is required.
Claim 14 is objected to because it lacks a period at the end of the claim. Appropriate correction is required.
Claim 15 is objected to because it lacks a period at the end of the claim. Appropriate correction is required.
Claim 17 is objected to because it has an unnecessary period at the end of the list of compounds. The claim currently ends, “and 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1- yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1 H-imidazol-5-yl)oxazole-5-carboxylic acid. or a pharmaceutically acceptable salt thereof.” The period following “acid” should be removed. Appropriate correction is required.
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 1-19, 23-24 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 the limitation of m in formula (I). There is insufficient antecedent basis for this limitation in the claim, as m is not defined anywhere in independent claim 1.
Claim 1 recites “the point of attachment”. There is insufficient antecedent basis for this claim and it should properly read “a point of attachment”.
Claim 24 recites “one or more diabetic complications,” and the specification (page 45, l. 7-13) provides a definition as “problems caused by persistently high blood glucose levels that damage other organs including kidneys, peripheral limbs, and eyes (e.g., retinopathies) or induce vascular disease and neuropathy. Impaired vascular function contributes to erectile dysfunction and can lead to increased risk of skin infections. Diabetes also increases the risk for heart disease and bone and joint disorders. Other long-term complications of diabetes include excess risk of cancer including hepatocellular carcinoma, endometrial cancer, breast cancer, and pancreatic cancer.” The disclosure provides no guidance as to the metes and bounds of “persistently high” blood glucose levels such that the requisite degree cannot be ascertained. Further, it is unclear what the metes and bounds are for a single diabetic complication or multiple diabetic complications. Is the Applicant suggesting that their GLP1 agonists can treat erectile dysfunction, or skin infections, or even forms of cancer?
Claims 2-19, 23-24 are rejected to for being dependent upon a rejected claim.
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 - Compounds
Claims 1-15, 18-19, 23-2 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 the following:
A compound having a formula (I), as recited in claim 1
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or a pharmaceutical composition comprising a compound having a structure represented by formula (I), as recited in claim 18, or a combination comprising a compound having a structure of formula (I) and one or more therapeutically active agents, as recited in claim 19:
wherein R1, R2, and R3 are as defined in claim 1
wherein m = 1
wherein A is as defined in claim 1
wherein X = O and W = O, CH2
wherein R4, R4a, R4c, R4d, and R4A are defined as in claim 4, with the further limitation of 5-6 membered heterocycloalkyls and 5-6 membered heteroaryls, not the 4-10 and 5-10 membered ringed systems, respectively, as currently claimed
wherein R5 is defined fully by claim 9, the structures only of claim 8, and H.
wherein R5’ and R6’ are H, C1-6alkyl only, as the claims and specification lack any working examples of R5’ and R6’
wherein R6 is defined as in claim 1, with the further limitation of 5-6 membered heterocycloalkyls and 5-6 membered heteroaryls, not the 4-10 and 5-10 membered ringed systems, respectively, as currently claimed
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 the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention:
The nature of the invention relates to compounds of formula (I) in claim 1. Such compounds are useful for treating obesity and related diseases through GLP1R agonism. This invention is also directed to compositions comprising said compounds, as well as a combination comprising said compound with one or more therapeutically active agent.
Predictability of the art:
The compounds synthesized in the instant specification appear novel. However, the hypothetical compounds in claim 1 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 1. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
The breadth of the claims:
The scope of the claims involves compounds of formula (I), shown below.
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Claim 1 is very broad in the number of variables and the options of substituents for each variable. There is an extremely large amount of hypothetical compounds included in claim 1.
The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary:
The specification only provides the synthesis of 45 compounds.
Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. For example, there are no working examples of a compound of formula (I) wherein X and W of the fused ring system are both carbon atoms. As another example, there are no working examples of R4 as C(O)NR4c(S(O)2R4b), as claimed in claim 1. It could also be possible that some combinations of compounds may not be able to be synthesized due to their instability (e.g., where R5’ is CN). It would require one skilled in the art, such as a chemist, to perform thousands of reactions to determine which compounds of formula (I) can be prepared and would likely require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claims 2-15, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
Scope of Enablement - Prevention
Claims 23-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph, because the specification, while being enabling for treatment, does not reasonably provide enablement for prevention. 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.
The following Wands factors have been considered if not explicitly discussed: (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 term “treatment” is defined on page 39, l. 18-23 of the specification. Said definition does not embrace prevention, and in fact, prevention is explicitly defined separately. However, the term “therapeutically effective amount” as defined on page 38, l. 31-37 and page 39, l. 1-11, embraces the term prevent. The specification states, “‘a therapeutically effective amount’ of a compound of the present invention refers to an amount of a compound…that will elicit the biological or medical response of a subject, for example…prevent a disease, disorder, or condition. In one embodiment, the term “a therapeutically effective amount" refers to the amount of a compound of the present invention that, when administered to a subject, is effective to at least partially alleviate, prevent, and/or ameliorate a condition.”
It is presumed “prevention” of the claimed condition would require a method of identifying those individuals who will develop the claimed condition before they exhibit symptoms.
The factors to be considered in making an enablement rejection were summarized above. 1) Preventing diseases requires identifying those patients who will acquire the condition before the symptoms occur. This would require extensive and potentially open-ended clinical research on healthy subjects. 2) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical pharmacology and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will develop obesity before the fact. 6) The artisan using Applicants invention would be a Board Certified physician. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of obesity. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable for any agent to be able to prevent obesity. 7) It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved" and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed conditions.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-19, 23-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Meng et al. (WO 2022/028572 A1, published February 10, 2022, claims priority to PCT/CN2020/107437, filed August 6, 2020, and PCT/CN2021/073958, filed January 27, 2021, hereinafter Meng).
Meng discloses compounds 131 – 144 (Table C1, page 55 – 60) in ‘958. All of these species anticipate the genus of formula (I) in instant claim 1, as well as formula (IIa) and (IIIa) of instant claims 13 and 14, respectively. In fact, Meng specifically discloses species 135 (page 57) in ‘958, shown below:
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This above species of Meng is anticipated by dependent claim 16 of the instant application, as applicant claims the same compound. Meng further discloses the administration of an additional therapeutic agent (claims 322-329), thereby anticipating claim 19 of instant application. Last, Meng discloses a method of treating GLP-1 associated diseases, disorders, or conditions (Claims 301-303, 334-337) with reference compounds, thereby anticipating claims 23-24 of instant application.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-19, 23-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20, 24-25 of copending Application No. 18/836,800 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of 18/836,800 substantially overlap with the instant claims such that it would be prima facie obvious for one of ordinary skill in the art to arrive at the instantly claimed compounds by routine experimentation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
All claims are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 am.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey H Murray can be reached at 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.A.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624