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 .
Restriction requirement is moot in view of amendments to claims.
Pending claims 4-18 are examined together.
Claim Rejections - 35 USC § 103
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.
Claims 4-18 are rejected under 35 U.S.C. 103 as being unpatentable over, US 20090143371, further in view of Jensen, PLOS ONE February 2014 | Volume 9 | Issue 2 | e88456, Hurley, Neurology Today. (2013). 13 (17): 14–15, and Froestl J. Alzheimers Dis. 2012, 32 (4): 793–887 is maintained for reasons of record.
Buettelmann teaches
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(Cas Reg.Nos. 1159600-99-3, 1159601-01-0, 1159601-02-1, 1159601-03-2, 1159601-04-3).
Buettelmann teaches, page 1 column A last paragraph, that these above compounds as
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The above pointed out compounds are close structural analogs of the active ingredients of the instantly claimed methods, wherein the base instant claim 1 recites
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The difference (more on this below) is in
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portion in the above formula wherein R1 is defined in the instant case is not H, while the exemplified compounds of Buettelmann shown above is limited to H for the corresponding positions in the formula of the instant claims. The core (red colored portion in Buettelmann compounds) template of the active ingredients is the same in the prior art and the instant case. In the instant case, H is one of the plethora possibilities included in the definition of all the other R variables decorating the periphery on the core template in both cases.
Buettelmann teaching with respect to this specific position of instant R1, includes halogens (see page 3 column A [0022]). Halogens are included in the recited for the instant formula for the same position of the core template. Buettelmann at page 75, column B, teaches Cas RN 1159600-41-5 teach
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which differs from the claimed compounds in the replacement of C for N, at the position shown above with arrow. As per the claim limitations the interchangeability of C for N is an option in the recited active ingredients for optimization of structure for desired function. See definition of X, Y and Z of instant formula. This modification therefore is a result effective variable. Note that instant disclosure is limited with respect to the allegedly critical R1; see Table 2 and discussion relating to this in pages 46-48; large majority of the compounds drawn to one possibility with regards to R1, that is R1= methyl. Substituents R1-R6 such as H, alkyl, halogen etc., are obvious variants of each other, routinely used interchangeably in the medicinal chemistry art for the optimization of previously known core templates to arrive at compounds with improved physical and or biochemical properties. The instant recitation of the laundry list of possibilities for the R1-R6 groups, in itself is supportive of this commonsense practice in the medicinal chemistry art (the exercise known in as isosteric replacements), and is tacit acknowledgement that such modifications are result effective variables. See MPEP § 2144.05(II)(B) discusses result-effective variables.
Limitations of dependent claims (including those of claims 7-17) relate to different possibilities of the R variables of the pictured formula. Limitations of dependent claim 18 is found in the summary of the cited art noted above.
Buettelmann compound (RN 1159600-41-5) is also known as Basmisanil or RG 1662: Basmisanil (developmental codes RG-1662 and RO5186582) is a highly selective inverse agonist/negative allosteric modulator of α5 subunit-containing GABAA receptors which is under development by Roche for the treatment of cognitive impairment associated with Down syndrome as per the teachings of
Jensen, page 2, column A, first full paragraph “Roche’s RG-1662 currently
in Phase I trials…”; Hurley, page 18 Insert column B, second full paragraph …”GABA-A receptor inhibitor RG 1662, developed by Roche” and Froestl, page 813, column A, last paragraph.
Again with respect to the active ingredients, the difference is, presence or absence of substituents which decorate the invariable structure moieties in the prior and the claimed formulae. Compare the first pictured Buettelmann compound with the first pictured compound of dependent claim 6, the difference is methyl group on the pyridine). Substituents are art recognized as result-effective variables and as such are routinely used in the medicinal chemistry art to modify properties.
In this case, it is well-known in the art and as disclosed in the generic formulae in the instant specification and cited references, the interchangeable use of H, alkyl and positional isomers to optimize previously known structural templates. H and methyl are obvious variants and suggestive of one another. With regards to biological activity, the claims are not limited to in vitro property, rather actual diseases (see below 112-1), that could be treated with large number of structurally similar compounds. For example, cognitive impairment (compare instant claim 18) is explicitly taught by 20090143371 (see abstract) for structurally similar compounds (except for unsubstituted, that is with H and substituted with methyl). On top of this, there is no data in the disclosure for secondary consideration whether the alleged difference (see Tables 1 and 2) in biochemical property (either present in the cited references or the prior art is/art silent about such inherent properties), has any bearing on the diseases being claimed for example as in claim 18.
Therefore nothing unobvious is seen in the claims.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Nuwer, Long-term α5 GABA A receptor negative allosteric modulator treatment reduces NMDAR-mediated neuronal excitation and maintains basal neuronal inhibition Neuropharmacology, Volume 237, 1 October 2023, 1-12.
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Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 4-18 are rejected under 35 U.S.C. 112(a), because the specification, while being enabling for a method of modulating GABAAA α5 receptor does not reasonably enable for treating any disease or condition. 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.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
These factors include the following:
The Applicant has not demonstrated within the application how to treat certain GABAA α5 receptor-related diseases or conditions by administering a compound or composition of Formula (I) However, there are no working examples of any compound of formula (I) which can treat any and all GABAA α5 receptor-related diseases or conditions. These cannot be simply willed into existence. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However...there is no evidence that such compounds exist...the examples of the '881 patent do not produce the postulated compounds...there is...no evidence that such compounds even exist.” The same circumstance appears to be true here. Hence, Applicants must show that a compound or composition of formulae (I) or (II) can treat any and all GABAAA α5 receptor-related diseases or conditions, or limit the claims accordingly.
The nature of the invention and predictability in the art. The invention is directed toward medicine and is therefore physiological in nature. 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).
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.
The compound core depicted with specific substituents represents a narrow subgenus for which applicant has provided sufficient guidance to make and use; however, this disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed to treat a GABAAA α5 receptor-related disease or condition. This could cover an array of known and unknown diseases. For example, what of a disease or disorder discovered a few years from now which is “mediated by a GABAAA α5 receptor”? Can the applicant simply “reach through” and obtain patent protection for a disease which has either yet to be discovered, or a known disease, whose mechanism of action is discovered at a future date? Applicants have provided no working examples of any compounds, compositions or pharmaceutically acceptable salts which treat the diseases or disorders mentioned above in the present application.
Within the specification, "specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula." See MPEP 608.01(p).
The scope of the independent with respect to active ingredients is large (about 195). The large number of these compounds and any and all GABAA f5 receptor implicated diseases hitherto known or not render the scope of the claims wide.
Nature of the invention. The nature of this invention relates generally to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to GABAA α5 receptor positive allosteric modulators (PAMs) for the treatment or prophylaxis of GABAA α5 receptor related diseases and diseases or conditions which can be treated by the modulation of GABAA α5 receptor activity.
According to Rudolph, Vol. 54:483-507 (Volume publication date January 2014)
cognitive symptoms in schizophrenia are attributed to a cortical GABAergic deficit, and dysfunctional GABAergic inhibition is increasingly understood to contribute to the pathophysiology of autism spectrum disorders. Futher, GABA-Alpha receptor subtypes offer the promise of a new CNS pharmacology and with an increasingly subtype-specific pharmacology, the GABA system holds expanding therapeutic potential for CNS disorders. In a post filing Review, Solomon, Volume 171, 1 June 2019, Pages 434-461 teach that the selective GABAA α5 receptor subtype inverse agonists have significant potential for the treatment of memory and learning deficits without convulsant or anxiogenic side-effects. with intriguing pharmacological profiles and potential intellectual property. Also according to Kwakowsky, NEURAL REGENERATION RESEARCH｜Vol 16｜No. 8｜August 2021, 1550-1551 “In summary, our findings provided evidence that targeting α5GABAARs with α5IA reverses the Aβ- induced increase in ambient GABA levels, α5 subunit upregulation, and reduces cell death. These findings suggest for the first time that the
α5GABAARs might be important drug targets in AD. Targeting these receptors might enable us to ameliorate the imbalance in E/I neurotransmission, prevent cell death, and potentially have a disease modifying effect in AD”. Therefore, terms such as ‘promise’ ‘potential’ or ‘significant potential’ or “targeting these receptors might enable” while encouraging with respect to use of GABAA α5 receptor modulators, these are not substitutes for enabling disclosure. Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return”. Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.
An ordinary artisan in the area of drug development would have experience in screening chemical compounds for particular activities. 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.
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 that Applicant is not enabled for making these compounds or compositions or treating the diseases mentioned.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached on (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625