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 .
Claim Objections
Claims 4-39, 46-51, 61-63, 67, 68, 72-107, 111-118, 124-127, 132-140 are objected to under 37 CFR 1.75(c) as being in improper form. The claims are multiple dependent claims that depend from multiple dependent claims. See MPEP § 608.01(n).
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 1-118 and 120-127 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for using the compounds of claim 119, does not reasonably provide enablement for using the compounds with the substitution pattern as depicted in the rejected claims. The specification is not adequately enabled for the scope of diverse functional groups and rings as positions R2a, R2b, R3a, R3b, R4a, R4b, R5, R6, R7, R11a, R11b, R15a, R15b, R16, R17. Compounds made and tested represent the scope of claim 1 where the positions recited above are Hydrogen or Methyl group. The specification does not enable any skilled pharmacologist or physician to use the invention commensurate in scope with these claims. The factors to be considered in making an enablement rejection have been summarized above.
a) Determining if any particular claimed compounds within the scope of the rejected claims would be active would require synthesis of the substrate and subjecting it to testing with Applicants' Inhibition of TSP binding assay. Considering the large number of compounds to be made this is a large quantity of experimentation.
b) The direction concerning the claimed compounds is found in the specification, which merely states Applicants' intent to make and use such compounds.
c) In the instant case none of the working example on page 174 contains any radical other than a hydrogen or methyl. None of these working examples contain a basic or acidic group or cyclic groups. None of these contain electron deficient hetero aromatic rings.
d) The nature of the invention is modulation of TBPS binding and treatment of human diseases with Applicants' compounds. This involves physiological activity. The nature of the invention requires an understanding of the receptor, the binding activity of small ligands to that receptor, and the ability of those compounds to modulate TBPS binding. In view of the unpredictability of receptor binding activity and claimed divergent substituents with varied polarity, size, and polarizability, the skilled physician would indeed question the inclusion of such diverse substituents, commensurate in scope with these claims. Also see the MPEP § 2164.03 for enablement requirements in the structure sensitive arts of pharmacology and medicinal chemistry.
e) The state of the art with regards to binding mechanism of the currently claimed compounds is lacking. It’s unclear which parts of the claimed compound participates in the binding to TBPS and therefore potentially find therapeutic applications
In re CAVALLITO AND GRAY, 127 USPQ 202 (claims covering several hundred thousand possible compounds, of which only thirty are specifically identified in appellants' application, not enabled unless all of the thirty specific compounds disclosed had equal hypotensive potency because that fact would strongly indicate that the potency was derived solely from the basic structural formula common to all of them. A wide variation in such potency would suggest that it was due in part to the added substituents and might be eliminated or even reversed by many of the possible substituents which had not been tried.)
Compounds made and tested represent the scope of claim 119 not the rejected claims.
f) The artisan using Applicants' invention to treat diseases with the claimed compounds would be a physician with a MD degree and several years of experience. He would be unaware of how to predict a priori how a changing any of the claimed substituents would affect biological activity. In view of the divergent groups with varied basicity, steric hindrance, and polarisability, the skilled physician would indeed question the inclusion of such a diverse group of substituents, commensurate in scope with these claims.
g) Physiological activity, is well-known to be unpredictable, In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
h) The breadth of the claims includes all of millions of compounds of formula (I-1, I-4 and X]). Thus, the scope is very broad. The present claims embrace various radicals, which are not art-recognized as equivalent. The specific compounds made are not adequately representative of the compounds embraced by the extensive Markush groups instantly claimed.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here. Thus, undue experimentation will be required to practice Applicants' invention.
Claims 134-140 are rejected under 35 U.S.C. 112, first paragraph, because the specification, does not reasonably provide enablement for treatment or prevention of CNS-related disorders recited in claims 134-140. The specification enables treatment of the disorders of claims 136-140 in subjects who are suffering from the depression comprising administration of a compound of claim 119, but does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to prevent said disorders or treat the full scope of disorders encompassed by the term “CNS-related disorder”.
A conclusion of lack of enablement means that, based on the evidence regarding each of the factors below, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation.
These factors include:
(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 breadth of the claims
Claims 134-140 are directed to a method of treating a CNS related disorder and further limited to various types of depressive disorders in claims 135-140. The term treatment is defined in the specification on page 44, paragraph [0142]:
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The definition encompasses administration before a subject begins to suffer from the disease, which is prophylactic administration to prevent development of disease or condition.
Claims 134-135 are directed to a very large range of diseases.
The state of the prior art
With regards to prevention of CNS-related disorders, specifically depression, the examiner notes that the art does not recognize preventive therapeutic agents for depression. Therapeutic agents are administered only after a subject has been diagnosed with the disorder. Applicants are invited to provide evidence to the contrary. In any event, the examiner notes that there is no art provided of record, evidence set forth in the disclosure, or correlation establishing some nexus to support preventive administration or therapy between the art and the instant disclosure to support the alleged disease preventing applicability of the claimed compounds.
With regards to treatment of subjects who are suffering from CNS-related disorder, art recognizes neuroactive steroids zuranolone and brexanolone for rapid treatment of various types of depressive disorders. Zuranolone functions by inhibiting TBPS binding, which is the same activity as demonstrated for the currently claimed agents.
The level of one of ordinary skill
The skilled artisan in this field is that of an MD and/or a PhD skilled in treatment of depressive and CNS disorders.
The level of predictability in the art and amount of direction provided
The examiner acknowledges the probability and predictability that the compound of instant claim 119 can probably be utilized in treatment of disorders. This is derived from the experimental data provided by applicants which demonstrated TBPS inhibition by claimed compounds.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Indeed, in view of the information set forth supra, the instant disclosure is not seen to be sufficient to enable the prevention of any disease or conditions and the skilled artisan would not extrapolate preventive efficacy from the compounds instantly claimed. Nor is the in vitro TBPS binding inhibition data alone is recognized in the art, as sufficient data to assert compounds with this activity would be expected to prevent any CNS related disorder.
With regards to treating subjects who are already suffering from a disease, applicants are enabled for treatment of depression with compounds of claim 119. Whether any other compound would exhibit therapeutic efficacy in any other CNS-related disorder is highly unpredictable and the amount of experimentation required is most certainly undue. With regards to scope of compounds, a skilled artisan would have to design and execute synthesis of hundreds of compounds within the generic formulas of the claims and test the compounds in the applicants TBPS binding inhibition assay. However, the in vitro TBPS binding inhibition assay is not an art recognized model for any of the CNS-related disease. It is suitable for identifying potential candidates, but is not predictive of clinical efficacy. Whether any CNS-related disease can be treated by any of the compounds outside of scope of claim 119 is therefore highly unpredictable and would require considerable experimentation in order to determine which, if any of the claimed compounds can be used in clinical treatment of any disorder.
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.
Claim(s) 1-36, 38-39, 42, 61, 62, 67, 120-127 and 133 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Robichaud et al (WO 2018/013613).
Robichaud discloses compounds 7 and 36 (pages 53 and 59, respectively) which anticipate the rejected claims. In claim 48, page 287, Robichaud discloses a pharmaceutical composition comprising the compound and an excipient.
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Claim(s) 69-112 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Robichaud et al (WO 2019/126761).
Robichaud discloses compounds I-15 and I-27 (pages 99 and 102, respectively) which anticipate the rejected claims.
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Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Robichaud et al (WO 2018/013613).
Scope of prior art
Robichaud discloses compounds 7 and 36 (pages 53 and 59, respectively) which anticipate the rejected claims. In claim 48, page 287, Robichaud discloses a pharmaceutical composition comprising the compound and an excipient.
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Ascertaining the difference
In compounds of the art R19 is H, while in current claims R19 is Me
Obviousness
A person of ordinary skill in the art prior to the earliest effective filing date of the current application would have found it obvious to substitute H for Me in the compounds of the art. One would expect the resulting compound to retain the biological properties of the parent. 1) Throughout the document Robichaud teaches compound with both H and Me group in the R19 position. 2) It is well established that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Lincoln, 126 U.S. P.Q. 477, 51 U.S.P.Q. 40 (C.C.P.A. 1942); In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C.P.A. 1963); In re Lohr, 317 F.2d 388, 137 U.S.P.Q. 548 (C.C.P.A. 1963): In re Hoehsema, 399 F.2d 269, 158 US.P.Q. 598 (C.C.P.A. 1968); In re Wood, 582 F.2d 638, 199 U.S.P.Q. 137 (C.C.P.A. 1978); In re Hoke, 560 F.2d 436, 195 U.S.P.Q. 148 (C.C.P.A. 1977); Ex parte Fauque, 121 U.S.P.Q. 425 (P.O.B.A. 1954); Ex parte Henkel. 130 U.S.P.Q. 474. (P.O.B.A. 1960).
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 1-36, 38-39, 42, 61, 62, 67, 120-127 and 133-140 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 12-14 of U.S. Patent No. 11,396,525. Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 7 of the ‘525 patent recites compounds withint he scope of the currently rejected claims (column 299, line 50; column 305, line 15, 30; column 306, line 25; col 307, line5, 30, 45). Claim 12 is directed to pharmaceutical composition and claims 13-14 are directed to a method of treating a CNS-related disorder including depression.
Allowed claims
Claim 119 is allowed. Closest art is WO 2018/013613 which teaches compounds similar in structure to those of claim 119 but does not teach the aromatic heterocyclic ring as a Y substituent on the amide.
Conclusion
Claims 1-140 are pending
Claims 1-118 and 120-140 are rejected
Claim 119 is allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YEVGENY VALENROD whose telephone number is (571)272-9049. The examiner can normally be reached Mon-Fri 9am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/YEVGENY VALENROD/Primary Examiner, Art Unit 1628
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