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
STATUS OF THE CLAIMS: Claims 11-12, 14-18, 20-23, 34-36, 38-41 are pending in this application.
Election/Restrictions
Applicant's election of species in the reply filed on November 6, 2025 is acknowledged. All claims were examined.
Claim Rejections - 35 USC § 112, first paragraph
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 11-12, 14-18, 20-23, 34-36, 38-41 (including claims dependent thereon and claims that relate back to independent claim) are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. 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 to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for specific compounds disclosed in the specification, does not reasonably provide enablement for rotamers and tautomers of those compounds and composition containing same. 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 and use the invention commensurate in scope with these claims.
Claims 11-12, 14-18, 20-23, 34-36, 38-41 are rejected because the claims recite specific rotamers and tautomers of said compounds. However, the specification fails to teach the preparation or identity of rotamers and tautomers. Therefore, the specification is not adequately enabled for making and/or using tautomer.
Identifying a rotamer and tautomer requires knowledge of in vivo regeneration pathways of instant compounds and short of extensive experimentation, would be the skilled artisan would need much more data to determine rotamers and tautomers of the instant compounds and compositions.
Applicants have not provided any clear guidance that would provide rotamers and tautomers of the instant compounds that will regenerate in vivo to the instant compounds by one or more biological processes or methods for prepartion. It is not the norm that one can predict with any accuracy whether a particular ester form of an active compound will be more soluble, more easily handled in formulations or more bioavailable without art recognized data to support same. The specification provides no guidance as to what type(s) of prodrugs are suitable for the instant compounds. Generally, rotamers and tautomers themselves are not considered to be therapeutically active but only to provide the active compound in vivo.
For rejections under 35 U.S.C. 112, first paragraph, the following factors must be considered (In re Wands, 8 USPQ2d 1400, 1404 (CAFC, 1988)):
1) Nature of invention.
2) State of prior art.
3) Quantity of experimentation needed
4) Level of predictability in the art.
5) Amount of direction and guidance provided by the inventor.
6) Existence of working examples.
7) Breadth of claims.
8) Level of ordinary skill in the art.
Nature of the invention
The nature of the invention is the preparation of compounds and compositions under the genus of a structural formula. As stated, however, rotamers and tautomers are also intended. The nature of rotamers and tautomer is not set forth nor is the manner in which it is to be prepared or the core compounds modified.
State of the prior art
The state of the prior art is that tautomer are known in the pharmaceutical industry. Rotamers and tautomer in related compounds are not modified.
Quantity of experimentation needed
The quantity of experimentation needed is undue. The skilled artisan would need to regenerate in vivo the instant compounds by one or more biological processes. All of which require undue experimentation. Applicant has not postulated a metabolic pathway or mechanism, which facilitate conversion of the tautomer into an active agent.
Level of predictability in the art
The art pertaining to the preparation and use of tautomers are compound specific and not all tautomers have the ability to regenerate in vivo. (See “Wolff, M.E., “Burger’s Medicinal Chemistry”, pp. 975-977, and Banker et al., “Modern Pharmaceuticals”, p. 596).
Amount of direction and guidance provided by the inventor
There is no guidance provided as all the examples in the specification are drawn to the preparation of compounds disclosed in the specification and not to tautomer. The lack of guidance to prepare any tautomer is not provided by the inventor.
Existence of working examples
As discussed above, working examples are drawn to the preparation of compounds disclosed in the specification and not to rotamers and tautomers. The lack of guidance to prepare any tautomer is telling. There is no direction or guidance provided by Applicant to prepare rotamers and tautomer of the instant invention.
Breadth of claims
The breath of the recited compounds and compositions in the claims includes tautomer for which there have been provided no specific examples or procedural steps to prepare rotamers and tautomers. Failure to teach how to make the instant compounds makes teaching how to use the compounds unduly difficult, if not impossible.
Level of ordinary skill in the art
The level of ordinary skill in the art is high due to the unpredictability in the chemical art.
Hence, as discussed above, to practice the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation to test which tautomer can be used in the instant claim, with no assurance of success. Therefore, applicant must show that the specification teach the preparation of rotamers and tautomers, or limit the claims accordingly.
Claims 11-12, 14-18, 20-23, 34-36, 38-41 (including claims dependent thereon or relate back to independent claim 1) are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for unlabeled subgenus of compound of formula I or pharmaceutically acceptable salt thereof, does not reasonably provide enablement for and subgenus of compound of formula I labeled with deuterium (deuterated compounds) at various position or pharmaceutically acceptable salt thereof as recited in instant claims. 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 and use the invention commensurate in scope with these claims.
In evaluating the enablement question, following factors are considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed.
1. The nature of the invention and the state of the prior art:
The invention is drawn to a compound of formula (I-2):
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wherein the variable groups, include besides other variable groups a deuterium isotope or a pharmaceutically acceptable salt thereof. The scope of the genus of the compound of formula I-2 shown above includes besides other various variable groups, D. E, F C, Rs thereof at many positions of the variable groups
Even a cursory calculation of the number of compounds embraced in the instant formula I based on the generic definition of alkyl, aryl, heteroaryl, heterocyclyl, substituted aryl, heteroaryl, cycloalkyl and other optional substituents of substituents etc. would result in trillions and trillions of compounds if not more. This is of course not the accurate number and the true number of compounds would far exceed this number of compounds. Thus, the genus embraced in these claims is too large and added to that any pharmaceutically acceptable salt thereof would further expand the scope of compounds. Adding deuterium as isotopic variation of H would result in trillions or more compounds. In addition, the core rings are variously substituted with both reactive groups and non-reactive groups and claim 1 merely recites D thereof of such a genus of compounds which by itself would now include at least trillions of compounds multiplied by trillions of compounds for the salts and then multiplied by trillions of compounds based on the deuterium compounds.
As recited, instant claim 1 is reach thorough claim wherein based on the fact that the number of compounds of formula I disclosed in the specification, it is claimed that any compound of the genus of formula I depicted above can be labeled with atoms of deuterium isotope at any variable groups for which there is no enabling disclosure.
Isotope labeling, in general, is a specialized art. Careful design and performance of synthesis of suitable precursor is needed not only to rapidly make the labeled compound but also to separate starting precursor from the desired final product. A reaction, which works for a particular precursor, may not work for another precursor. The art is not predictable. Thus, the breadth of the instants claims which is broad to include any available position for isotope labeling and use of the resultant compound lacks adequate support in the specification. The same is true for various other radiolabels or isotope where one need to design a suitable precursor and develop a process for each compound. See Atzrodt et al. Angew. Chem. Int. Ed. 2007, 46, 7744-7765 and Hulikal, V. Deuterium Labeled Compounds in Drug Discovery Process-Abstract, www.hwb.gov.in/htmldocs/nahwd2010/L15.pdf.
For example, if the process involves replacement of a halogen with deuterium by catalytic deuteration with D2 then presence of halogen in various variable groups of a compound of formula I will also undergo such a replacement reaction. In addition, the presence of unsaturated groups will also undergo deuteration. Similarly direct exchange of H with D will occur any available position not necessary or specifically. The Specification merely suggests deuterium isotopic variant for H but does not teach or suggest how to perform such an isotopic labeling process. Likewise, in instant specification, there is no teaching of making deuterium labeled compound in compounds of the genus shown in Tables and others as well as Examples. In addition, there is no single example in the specification showing how to perform the deuterium labeling. Given the general nature of the isotopic labeling embraced, it would not be possible for one trained in the art to redeem such an isotopic labeling as a routine process.
Careful design and performance of synthesis of suitable precursor is needed not only to rapidly make the labeled compound but also to separate starting precursor from the desired final product. A reaction, which works for a particular precursor, may not work for another precursor. The art is not predictable. Specification offers no teaching or suggestion for labeling with deuterium isotope.
2. The predictability or lack thereof in the art:
Hence the process as applied to the above-mentioned deuterium labeled compounds claimed by the applicant with a huge genus of variously substituted compounds of formula I to be labeled is not art-recognized process and hence there should be adequate enabling disclosure in the specification with working examples to make the compound of formula I with deuterium isotope claimed.
The amount of direction or guidance present:
Examples illustrated in the experimental section or written description offer no guidance or teachings as to the process of making variously substituted compound of formula I labeled with deuterium. Examples of unlabeled compounds shown therein cannot be deemed as objective enablement for any isotope and one needs guidance for precursor selection and labeling as there is no guidance provided in the specification for labeling with deuterium and the process of making them.
The presence or absence of working examples:
Although examples show the process of making instant compounds, as noted above, they are limited to process of making unlabeled compound of formula the subgenus not the corresponding compounds labeled with deuterium. There are no representative examples showing the viability of the process for plurality of variable groups labeled with deuterium isotope generically embraced in the instant claims.
The breadth of the claims:
Specification has no support, as noted above, for all deuterium labeled compounds of formula I and there is no guidance as to what precursor is suitable for process of making deuterium labeled compounds of formula I with various variable groups and there is also no valid chemical reasoning for one trained in the art to expect that all isotopes would be applicable and share the same use embraced.
The quantity of experimentation needed:
The quantity of experimentation needed would be an undue burden on skilled art in the chemical art since there is inadequate guidance given to the skilled artisan for the many reasons stated above. Even with the undue burden of experimentation, there is no guarantee that one would get the product of desired structure, namely l compound of formula II labeled with deuterium isotope at various position embraced in the instant claims.
Thus, factors such as “sufficient working examples”, the “level of skill in the art and predictability, etc. have been demonstrated to be sufficiently lacking in the case for the instant claims.
Also note MPEP 2164.08(b) which states that claims that read on "... significant numbers of inoperative embodiments would render claims nonenabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative.". Clearly that is the case here.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that "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 for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable".
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 and undue experimentation will be required to practice Applicants' invention.
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 11-12, 14-18, 20-23, 34-36, 38-41 (including claims dependent thereon or relate back to other claims) are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CN102203100.
This reference discloses compounds and methods in paragraphs [0472]-[0474], I-6, I-7, I-25 and embodiments 6-7, 24 and 25. (See Abstract and entire documents). These compounds and methods read on the instant claim. Since this reference teaches the exact compounds, Applicant’s claims are anticipated, and thus, rejected under 35 U.S.C. 102.
Claims 11-12, 14-18, 20-23, 34-36, 38-41 (including claims dependent thereon or relate back to other claims) are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CN102203100.
This reference discloses compounds and methods in paragraphs [0566]-[0567], pages 101-121, and Tables 4, 8, 14 and 19. (See Abstract and entire documents). These compounds and methods read on the instant claim. Since this reference teaches the exact compounds, Applicant’s claims are anticipated, and thus, rejected under 35 U.S.C. 102.
Claims 11-12, 14-18, 20-23, 34-36, 38-41 (including claims dependent thereon or relate back to other claims) are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Euro. J’nal of Med. Chem.’2018.
This reference discloses compounds and methods in paragraphs [222] (compound c),pages 851, and Table I. (See Abstract, Figures 1-3, and entire documents). These compounds and methods read on the instant claim. Since this reference teaches the exact compounds, Applicant’s claims are anticipated, and thus, rejected under 35 U.S.C. 102.
Conclusion
Claims 11-12, 14-18, 20-23, 34-36, 38-41 are pending. Claims 11-12, 14-18, 20-23, 34-36, 38-41 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL V WARD whose telephone number is (571)272-2909. The examiner can normally be reached M-F 9am to 5pm.
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/PAUL V WARD/Primary Examiner, Art Unit 1622