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 32-54 are currently pending and are examined on the merits herein.
Priority
Receipt is acknowledged of certified copies of papers submitted under 35 U.S.C. 119(a)-(d) for foreign priority based on an application EP 21171769.9 filed in Germany on 05/03/21, which papers have been placed of record in the file.
IDS
The information disclosure statements (IDS) submitted on 01/11/2024 are acknowledged and have been entered. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 USC § 112
Claims 32-43 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for making solvates and salts of the claimed compounds, does not reasonably provide enablement for making solvates and complex of the claimed compounds of formula (I). The claim(s) contains subject matter, which was not described in the specification in such a way as to enable one skilled in the art of medicinal chemistry to use the invention.
"The factors to be considered [in making an enablement rejection] have been summarized as a) the quantity of experimentation necessary, b) the amount of direction or guidance presented, c) the presence or absence of working examples, d) the nature of the invention, e) the state of the prior art, f) the relative skill of those in that art, g) the predictability or unpredictability of the art, h) and the breadth of the claims",
In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Exparte Formal, 230 USPQ 546. a) Finding a solvate or a crystal such as a polymer is an empirical exercise. Predicting if a certain crystal , for example, is in fact a single entity crystal or a molecular adduct, that produces the active compound metabolically, in man, at a therapeutic concentration and at a useful rate is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science.
For a compound to be a solvate and effectively work, it must meet three tests. It must be bioavailable and able to avoid drug interactions. It must be metabolized in such a way so that it is soluble and possess physiologically meaningful concentration. Thirdly, it must be physically and chemically stable in order to be clinically effective. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large quantity of experimentation.
b) The direction concerning solvates is lacking in the instant as applicant failed to provide any information as to how these purported novel compounds are prepared wherein the prepared form remain stable after obtaining the more stable form. Likewise, applicant provided no thermodynamic and kinetic properties to ascertain dissolution rates or packing properties to predict the particle morphology. Given the purported novelty of such compound the examiner maintains that applicant has not enabled the breadth of the claims.
c) There is no working example of a solvate or complex form of the compounds of formula (I). While examples are not required and one can look to the prior art for enablement support, the examiner contends that formation of crystals such as solvates and hydrates are unpredictable as stability at various temperatures can differ across structures or in the case of polymorphs wherein different polymorphs of the same compounds can possess contrasting slip planes wherein a defined slip plane provides greater plasticity, compressibility and tabletability as taught by Datta et al. on pg. 43.
d) The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body.
e) Datta et al. summarize the state of the crystal art. Datta et al. Crystal structures of drugs: Advances in determination, prediction, and engineering; 2004, Nature Reviews, Vol. 3, pgs. 42-57. The table on the left side of page 43 outlines all the differences that exists among various crystal forms, many of which are important in drug performance. Datta et al. further teach that while polymorphism, for example, and solid-state solvation are common among chiral drugs, the existence of polymorphism of a dug will not only affect its pharmaceutically relevant properties but may also result in interconversion between different types of racemates (see pg. 45, right col.) and this would indicate the low expectation of success. In that paragraph the difficulties of extrapolating between species are further developed. Since, solvents and polymorphism concept is a pharmacokinetic issue, the lack of any standard pharmacokinetic protocol or unpredictability within drugs discussed in the page of this paragraph is particularly relevant.
f) Datta et al. in the first paragraph on page 42 describes how the shape and particle size of a drug can affect its performance making Applicants' crystals which thus indicates the need of a collaborative team of synthetic pharmaceutical chemists and metabolism experts. All would have a Ph. D. degree and several years of industrial experience.
g) 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 ln re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970).
h) The breadth of the claims includes all of the compounds of formula (I) as well as the presently unknown list of potential solvates embraced by claim 1. 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 determine if any particular compound can, in fact, be made as a solvate or a polymorph.
Claim Rejections - 35 USC § 112
Notice of AIA Status
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.
Claims 32-43 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 epilepsy comprising administering the compound of Formula (I) wherein R1 is a heteroaromatic ring or a phenyl ring, wherein X is C=O or C-OH and wherein R2 is phenyl, does not reasonably provide enablement for treating epilepsy comprising administering the compound of Formula (I) with R1 or R2 as both double 6 membered aromatic ring or R1 as H or alkyl and wherein X is CH2 or C=N. 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 epilepsy comprising administering a compound of formula (I) as delineated in claim 1. The instant specification fails to provide information that would allow the skilled artisan to practice the treatment of epilepsy comprising administering every single compound of formula (I).
[In re Sichert, 196 USPQ 209 (CCPA 1977)]
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).1
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 (CAFC 1988) 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:
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:
1. The nature of the invention, state and predictability of the art, and relative
skill level
The invention relates to a method of treating epilepsy comprising administering a compound of formula (I) as delineated in claim 1. The relative skill of those in the art is high, that of an MD or PHD. That factor is outweighed, however, by the unpredictable nature of the art. The specification teaches effective treatment or reducing seizure by administering compounds of formula (I) that are 3.1, 3.3, I.4, 1.22, 1.1 and 1.27 wherein X is CH-OH or X is C=O and both R1 and R2 are heterocyclic rings or alkyl. As illustrative of the state of the art, the examiner cites Kanner et al. (Academy of Neurology, 2018, pgs. 82-90) who teach various second and third generation anti-epileptic drugs (see abstract). Importantly, Kanner et al. teach various anti-epileptic drugs that are structurally divergent and further teach that head-to-head trials of anti-epileptic drugs (AEDs) are lacking including dosage regimens for pediatric patients (see pg.88). This suggests that treatment of epilepsy has yet to be advanced and additional research is still needed. Thus, the examiner maintains that treatment of epilepsy with every single compound of formula (I) is unlikely and unpredictable.
2. The breadth of the claims
The claims are thus very broad insofar as they recite that the “treatment of epilepsy” comprising administering every single compound of Formula (I). While “treatment of epilepsy” might theoretically be possible by administering the compounds of formula (I) wherein X is C-OH or C=O and R1 and R2 are phenyl and/or heterocyclic aromatic ring, as a practical matter it is nearly impossible to achieve the treatment of epilepsy with every single compound of formula (I). Moreover, nowhere in the specification did Applicant demonstrate treatment utilizing a compound of formula (I) wherein X is C=N or CH2 wherein R1 and/or R2 are either or both double 6-membered ring.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides no direction or guidance for the use of the compound of Formula (I) with X is CH2 or C=N in treating epilepsy. While specific guidance is provided concerning the use of said compounds of formula (I) treating epilepsy or reducing seizures (see tables 2-3 and figures 3 and 5), no treatment of epilepsy was shown utilizing X as CH2 or C=N and/or R1 and/or R2 as both double-6 membered ring.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence demonstrating the inhibitory effect of the compounds of formula (I) with X as CH2 or C=N and/or R1 and/or R2 as both double-6 membered ring, no one skilled in the art would accept the assertion that every single claimed compound of formula (I) could be predictably used for treating epilepsy as delineated in claim 1 as inferred by the claims and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 102
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.
Claims 44-45 and 48-49 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Kal et al. Arnoldi et al. (Pestic. Sci., 1983, Vol. 14, pgs. 191-198, abstract, cited by applicant and filed on an IDS 1449).
Arnoldi et al. teach acetylic and halovinyl heterocyclic compounds that have activity against pathogenic fungi (see abstract). Specifically, Arnoldi et al. teach fungicidal compounds of formula (IV):
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168
356
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(see fig. 2, pg. 192);
wherein R1 is delineated in table 1 (see pg. 193).
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371
1210
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Such compound reads on instant formula (I) wherein R2 is a phenyl; X is C=O; and instant R1 is either a 6-membered aromatic ring or phenyl/IVa; a 5-membered aromatic ring or thienyl/IVb or IVc; 6-membered aromatic ring or 3-pyridinyl; or double-6 membered ring benzopyran or IVd.
Accordingly, the teachings of Arnoldi et al. anticipate claims 44-45 and 48-49.
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:
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 46 is rejected under 35 U.S.C. 103(a) as being unpatentable over Arnoldi et al. (Pestic. Sci., 1983, Vol. 14, pgs. 191-198, abstract, cited by applicant and filed on an IDS 1449).
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
The Arnoldi et al. reference is as discussed above and incorporated by reference herein. However, Arnoldi et al. do not specifically a substituted phenyl group.
However, Arnoldi et al. teach compound of formula Iva which teaches a phenyl with only hydrogen substituent.
While Arnoldi et al. does not teach a methyl group attachment and is not disclosed by Arnoldi et al., it is generally noted 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, 53 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 U.S.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.PA.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). Given that applicant did not provide unexpected or unobvious results of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to substitute the “H” group to a “methyl”.
Thus, to one of ordinary skill in the art at the time of the invention would have found it obvious to substitute a methyl for a hydrogen since Arnoldi et al. teach that the compounds of the invention were effective anti-pathogenic fungi compounds. Given the teachings of Arnoldi et al., one of ordinary skill would have been motivated to substitute a methyl for a hydrogen with the reasonable expectation of providing a compound that is effective and has activity against phytopathogenic fungi.
Claims 32, 37, 43-44, and 49 are rejected under 35 U.S.C. 103(a) as being unpatentable over Chen et al. (WO 2004/029044 A1, cited by applicant and filed on an IDS 1449).
Chen et al. teach pyrimidine compounds as therapeutic agents and pharmaceutical compositions comprising said compounds for treating compounds of Formula (I) including compound Formula IIa or AAA:
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436
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wherein A is C=O or CH2; n is 0; p is 0; wherein when A is CH2 then R2 is phenyl (see pgs. 6-7). This compound renders obvious instant formula (I) wherein instant R2 is phenyl; X is CH2; and R1 is a 6-membered aliphatic ring which is further substituted by a substituent (i.e. pyrimidine). Chen et al. further teach that the compounds of the invention can be formulated as a composition comprising a pharmaceutically acceptable carrier or excipient (see pg. 8). Additionally, Chen et al. teach that the pyrimidinylpiperazine compounds of the invention are useful in treating epilepsy including partial seizures, convulsive seizures, etc…(see pg. 217, lines 6-10 and pg. 221).
The Chen reference is as discussed above and incorporated by reference herein. However, Chen does not specifically teach solely the treatment of epilepsy.
Chen et al. teach that the pyrimidine compounds are useful to treat a variety of disorders including epilepsy (see pg. 221).
Thus, to one of ordinary skill in the art at the time of the invention would have found it obvious to utilize the compounds of Chen et al. to treat epilepsy since Chen et al. teach that the compounds of the invention are useful for treating a variety of disorders including epilepsy. Thus, one of ordinary skill would have been motivated to utilize the method of Chen to treat epilepsy with the reasonable expectation of success since Chen et al. teach effective use of the pyrimidinylpiperazine compounds.
Objections
Claims 33-36, 38-42, 47, and 50-54 are objected to because of the following informalities: Claims are dependent upon rejected claims. Applicant is required to incorporate all of the limitations of the independent claims into the objected claims. Appropriate correction is required.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Samira Jean-Louis whose telephone number is 571-270-3503. The examiner can normally be reached on 7:30-6 PM EST M-Th.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sreeni Padmanabhan can be reached on 571-272-0629. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMIRA JEAN-LOUIS/
Primary Examiner, Art Unit 1627
09/12/2016
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Director Patricia Mallari whose telephone number is 571-272-4729. The Supervisory Primary Examiner can normally be reached on 12:00-8:00 PM EST M-F at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
1 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”.