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, 8, 12, 14, 21-23, 43, 44-45, 50, 56, 60-61, and 69 are pending in the instant application.
Claims 1, 8, 12, 14, 21-23, 43, 44-45, 50, 56, 60-61, and 69 are examined herein.
Priority
The instant application claims benefit of priority to U.S. Provisional Application No. 62/970465, filed on 05 February 2020 and PCT/US2021/016465, filed on 03 February 2021. The claims to the benefit of priority are acknowledged. As such, the effective filing date of the claims is 05 February 2020.
Information Disclosure Statement
The information disclosure statement (IDS), submitted on 13 December 2022, is acknowledged and considered. The submissions are in compliance with the provisions of 37 CFR 1.97.
Response to Arguments
The amendment filed on 10 November 2025 has been entered.
As Applicant sets forth no arguments or amendments all rejections and objections are maintained.
All rejections and objections not found below have been withdrawn.
MAINTAINED REJECTIONS
Claim Rejections - 35 USC § 112
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 60, 61, and 69 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 treatment of muscarinic receptor 4 (M4) mediated diseases fails to provide the required enablement for prevention of M4 mediated diseases. 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 instant claims are drawn to a method of treating or preventing a M4 mediated disease, disorder, or symptom in a subject comprising administering a compound of Formula (Ia). The specification fails to provide information that would allow the one skilled in the art to practice therapeutically preventing a M4 mediated diseases.
To be enabling, the specification of the patent 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 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
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 the 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).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC1988) 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:
the nature of the invention
the state of the prior art
the predictability of the art
the amount of direction or guidance provided
the presence or absence of working examples
the breadth of the claims
the quantity of experimentation necessary
the relative skill of those in the art
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 - is a method of treating or preventing a M4 mediated disease, disorder, or symptom in a subject comprising administering a compound of Formula (Ia).
The state of the prior art - 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.
In order to treat a disease: one would need to precisely identify what the disease is, identify what biological target is connected with the disease, demonstrate that the drug candidate in some way modulates the normal processes of the biological target, and demonstrate that a patient benefited from such modification without detrimental side effects. 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.
In order to prevent a disease: one would need to precisely identify those subjects likely to acquire such a disease, administer Applicant’s claimed invention, and demonstrate that the patient did not develop the disease as a result of the administration of the claim invention.
In the instant case, the prior arts recognize that therapeutic agents have potential to exhibit antagonistic property toward the muscarinic receptor 4, which can be used to treat M4 mediated diseases (Moehle et al. ACS Pharmacol Transl Sci. 2021;4(4):1306–1321 and Gould et al. Neuropharmacology. 2018; 128:492-502). However, the art does not support the prevention of M4 mediated diseases. Moehle et al. describes the improvement of motor function in mice with a genetic form of dystonia (page 1314). As this would be a genetic mutation, it is not recognized by the art as being able to be prophylactically treated.
The predictability or unpredictability of the art – the law recognizes the pharmaceutical art as an unpredictable art and requires each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970). Accordingly, the more unpredictable an area is the more specific disclosure is necessary in order to satisfy the statute. Section 2164.02 of the MPEP provides:
"[C]orrelation” as used herein refers to the relationship between in vitro and in
vivo animal model assays and a disclosed or a claimed method of use . . . if the
art is such that a particular model is recognized as correlating to a specific
condition, then it should be accepted as correlating unless the examiner has
evidence that the model does not correlate.
In light of these remarks, the Examiner finds that one of ordinary skill in the art would agree with the court; that is, the pharmaceutical art is unpredictable. Thus, a substantial correlation is necessary for establishing the potential of new therapeutics.
The amount of direction or guidance presented – the instant specification provides an explanation of the biological activity of muscarinic receptors on page 1, and discusses the implication of M4 receptor inhibitors in the treatment of M4 mediated diseases. There is no direction or guidance provided that supports a use of a M4 inhibitor as a drug for preventing a M4 mediated disease.
The amount of guidance or direction 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. MPEP § 2164.03 (quoting In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970)). As identified supra, the pharmaceutical art is recognized as unpredictable.
Thus, in order to support a claim for preventing a M4 mediated disease a vast amount of evidence is required because such a claim is not supported by the prior art or the instant specification.
The presence or absence of working examples - there are no working or prophetic examples in the specification that demonstrate that the instant compounds or compositions thereof may prophylactically treat and prevent a M4 mediated disease. The assays in the specification demonstrate that the instant compounds were tested for their ability to inhibit the receptor in vitro (page 202 of the instant specification).
The breadth of the claims – is incommensurate in scope with the disclosure because a fair reading of the specification fails to support a finding that the compounds of instant formula (Ia) may prevent a M4 mediated disease in a patient.
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. 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, Schafer et al. discloses: "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 to identify the lead compound (i.e. one among many in a Markush-type claim), to establish which preclinical tests are predictive of clinical success, and to establish which diseases are the best to target for each lead compound.
There is generally a vast amount of experimentation to take a drug from bench to the clinic. See e.g., 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.") The Examiner finds that one of ordinary skill in the art would agree with the statements in these articles; that is, the amount of experimentation required to enable a pharmaceutical drug is extensive.
The level of skill 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. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). 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 the active workers in the field of pharmaceuticals and/or medicine, 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 a field related to medicine and/or the pharmaceutical art and at least four years of work experience, i.e. a masters or doctorate level scientist/clinician.
Therefore, claims 60, 61, and 69 are rejected because the Examiner finds that the Wands factors suggest a conclusion that the skilled artisan would not be able to make and use the instant invention without undue experimentation, although the level of skill for an ordinary person in the art is high. That is, due to the breadth of the claims, the unpredictability of the art, the lack of guidance or direction from the disclosure, the lack of any working examples, and the amount of experimentation needed illustrate that a person having ordinary skill in the art would not be able to prevent a M4 mediated disease.
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, 8, 1, 21-23, 43-45, 56, 60, 61, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-4, 33, and 37 of co-pending Application No. 18293329 in view of Patani et al. (Chemical Reviews. 1996;96(8):3147-3176).
This is a provisional nonstatutory double patenting rejection.
Regarding claims 1 and 21-23, the co-pending Formula (Ia) encompasses species of the instant Formula (Ia) when X is CR8 or N, wherein R8 is H, C1-4 alkyl, halogen, C1-4 alkoxy, or cyano; Y is CR8 or N, wherein R8 is H, C1-4 alkyl, halogen, C1-4 alkoxy, or cyano; Z is CR8 or N, wherein R8 is H, C1-4 alkyl, halogen, C1-4 alkoxy, or cyano; R3 is H or C1-4 alkyl; R4 is H or C1-4alkyl; X1 is O or NH; X2 is H; R5 is H; R6 is H; and R7 is H, halogen, or C1-4- -alkyl; and m is 0 or 1 or 2 (claim 1).
The co-pending application discloses R1 to be sulfonyl, whereas the instant application discloses the aryl or heteroaryl ring of the instant R1 can be substituted with sulfanyl or sulfinyl (this corresponds to the co-pending R1).
Patani teaches that oxidation of sulfides leading to sulfinyl and sulfonyl groups increases the potency of a potential drug (page 3167, Table 40).
It would be obvious to one of ordinary skill in the art to substitute the sulfanyl or sulfinyl taught in the instant application with an oxidized state in light of the teaching of Patani.
Regarding claim 8, the co-pending application discloses X, Y, and Z can be CR8 or N, which corresponds to the instant R1 being phenyl, pyrazine, pyridazine, pyridine, and pyrimidine (claim 1).
Regarding claim 14, the co-pending application discloses the moiety corresponding to the instant R2 to be phenyl (claim 1).
Regarding claim 43, the co-pending application discloses the stereochemistry of the C(2) carbon in the piperazine ring to be (R) and the C(6) carbon to be (R) (claim 4).
Regarding claim 44, the co-pending application discloses optional stereochemistry of the C(2) and C(6) carbon in the piperazine ring, which would encompass both being (S) (claim 2).
Regarding claim 45, the co-pending application discloses the stereochemistry of the C(2) carbon in the piperazine ring to be (R) and the C(6) carbon to be (S) (claim 3).
Regarding claim 56, the co-pending application discloses a pharmaceutical composition of Formula (Ia) and a pharmaceutically acceptable carrier (clam 33).
Regarding claims 60-61 and 69, the co-pending application discloses a method of treating or preventing a M4 receptor mediated disease comprising administering a compound of Formula (Ia) (claim 37).
Claim Objections
Claim 12 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Allowable Subject Matter
Claim 50 is allowed.
The compounds of claim 50 are free from the prior art.
Conclusion
Claims 1, 8, 14, 21-23, 43-45, 56, 60, 61, and 69 are rejected.
Claim 12 is objected to.
Claim 50 is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jerica K Wilson whose telephone number is (703)756-4690. The examiner can normally be reached Monday-Friday 9:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571)270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.K.W./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621