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 .
Claims 1-18 and 19-20 are pending.
Claim Rejections – Improper Markush Group
The nonstatutory Markush grouping rejection is based on a judicially approved “improper Markush grouping” doctrine. Claims 1-2, 4-16, 18-20 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if:
(1) the species of the Markush group do not share a single structural similarity,”
OR
(2) the species do not share a common use.
Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The compounds do not even belong to a recognized class of compounds because every variable varies having complex meanings and endless permutations and combinations. Further, the compounds include many known and unknown structural motifs. The members of the recited Markush group are so disparate chemically as not to be members of a recognized chemical class of compounds. Further the point of attachment and how these are linked to each render the conceivable compounds structurally different. In view of these claimed elements and the divergent substitutions on the above groups, the physical and chemical properties of claimed compounds are going to be different. Applicants’ may have to establish the core structure for their claimed compound. It cannot be said that all members of the Markush group have a single structural similarity, based on the above described structural differences. Specifically, the species of the Markush group do not share a “single structural similarity” because there are no required structural features within each variable definition such that each member of the group would have at least one structural feature, which feature is essential to the activity/function of the claimed compounds, in common. In addition alternatively usable member of the Markush group for example, the inhibitors or binders of different enzymes, does not share a common use, absent evidence to the contrary.
The question of whether the lack of a specific statutory basis is a fatal flaw against a holding of an Improper Markush group was decided in In re Harnish, 206 USPQ 300, 305, where the court said, “…we think it should be clear from our actions in Weber and Haas II that we there recognized the possibility of such a thing as an "improper Markush grouping." We were and are aware that it does not have a specific statutory basis …” The court went on to reverse the rejection, (which had been made by the Board under Rule 196(b)) but not on the lack of a specific statutory basis but rather, “Clearly, they are all coumarin compounds which the board admitted to be "a single structural similarity." We hold, therefore, that the claimed compounds all belong to a subgenus, as defined by appellant, which is not repugnant to scientific classification. Under these circumstances we consider the claimed compounds to be part of a single invention so that there is unity of invention…” Thus, the rejection was overturned not because of any lack of a specific statutory basis, but because of the specific facts in the case. The Markush group was held proper in that case, as was the case also in Ex parte Price 150 USPQ 467, Ex parte Beck and Taylor, 119 USPQ 100, and Ex parte Della Bella and Chiarino 7 USPQ2d 1669. Cases where the Markush group was held improper include Ex Parte Palmer, 7 USPQ 11, In re Winnek, 73 USPQ 225, In re Ruzicka, 66 USPQ 226, Ex parte Hentrich, 57 USPQ 419, Ex parte Barnard, 135 USPQ 109, Ex parte Reid, 105 USPQ 251, Ex parte Sun and Huggins, 85 USPQ 516, In re Thompson and Tanner, 69 USPQ 148, In re Swenson, 56 USPQ 180, and In re Kingston, 65 USPQ 371. Note In re Milas 71 USPQ 212 in which the structural difference between vitamin A and D was sufficient to uphold the improper Markush rejection. Also see In re Winnek 73 USPQ 225 and In re Ruzicka 66 USPQ 226 in which structural differences were small and yet a similar holding was maintained. All these cases involved compounds in the pharmaceutical art known to be structure-sensitive. Of particular interest is Ex Parte Hozumi, 3 USPQ2d 1059, which reversed an improper Markush rejection “in view of the relatively large proportion of the structure of the compounds in the claimed class which is common to the entire class”. Here, by contrast, the amount in common is none.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
Claim Rejections - 35 USC § 112
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 1-16, 18 and 19-20 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for making few compounds, does not reasonably provide enablement for plethora of conceivable compounds of the formula. For example, it is not seen where in the specification enabling disclosure is found for B being pyridazine or pyrazine. Similarly enabling disclosure is not found for pyridine A with any and all possible fusions. See sections under Claim Rejections – Improper Markush Group. 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.
The determination that "undue experimentation" would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the relevant factual considerations.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). These include: (1) breadth of the claims; (2) nature of the invention; (3) state of the prior art; (4) amount of direction provided by the inventor; (5) the level of predictability in the art; (6) the existence of working examples; (7) quantity of experimentation needed to make or use the invention based on the content of the disclosure; and (8) relative skill in the art.
All of the factors have been considered with regard to the claims, with the most relevant factors discussed below:
The claimed formula
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is drawn to large number of possible ring fusions with respect to A and B. Depending on the fusion, there are large number of bicyclic possibilities. Further with different fusion possibilities, independently varying X and Y, there are large number of conceivable structures for the formula. With R1 and R3 substituents layered on substituents encompassing wide variety and number of structures there is little support in the specification for making and using for the breadth of the claims. These substituents and hence the compounds of given formula are drawn to species that vary widely in physical and chemical properties such as size, molecular weight, stereochemistry, logP, acidity, basicity, etc. These factors are known in the art (see multiple references cited below) to greatly influence biological properties, for example, binding interaction between target protein and small molecule and art recognized concepts relating to productive small molecule-macromolecule interaction.
There is no guidance on what to choose from these large number of structural moieties or where and how to link these moieties. Enablement is a two prong (make and use) requirement.
Consider for example fusion of A = pyridine. There is only one possibility disclosed in the specification on how to make (see page 52 [0043] and use. The specification does not teach starting materials needed to make isomeric compounds of 31.
For the fusion of A=benzene,, there is only one example wherein R1 is other than H, name R=methyl.
The comparative Example 1 from WO2015116663 disclosed at top of page 79 in the instant case has no substituents on the indole ring, that is A = benzene.
Applicants have not provided any competent evidence or disclosed tests that are highly predictive for the claimed method (of claims 19-20). Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Rodger, Int. J. Mol. Sci. 2023, 24, 11022 teaches the range of strategies to combat α-syn-aggregation are cause for optimism and the need for an improved understanding of the physiological function of α-syn and how that becomes disrupted to evoke neurotoxicity and neuropathology since this will help direct therapeutic approaches.
In this context the wide scope of the claimed compounds does not find support in the specification. Biological properties are unpredictable and are ultimately tide to the chemical structure. See “Role of the Development Scientist in Compound Lead Selection and Optimization” by Venkatesh, J. Pharm. Sci. 89, 145-154 (2000) (p. 146, left column). Likewise, J. G. Cannon, Chapter Nineteen in Burger's Medicinal Chemistry and Drug Discovery, Fifth Edition, Volume I: Principles and Practice, Wiley-Interscience 1995, pp. 783-802, teaches many caveats in analog design such as the following at page 799 column B:
Alteration of distances between portions of the pharmacophore of a molecule (or even' between other portions). may produce profound qualitative and/or quantitative changes in pharmacological actions.
Note that in University of Rochester v. G.D. Searle & Co., 68 USPQ2d 1424 at 1438, the screening for over 600 compounds was deemed to be undue. Applicant’s scope far exceeds this number. The specification must teach how to make and use the invention, not teach how to figure out for oneself how to make and use the invention. In re Gardner, 166 USPQ 138 (CCPA 1970). Therefore, one skilled in the art could not make or use the claimed invention without undue experimentation.
There is no structural guidance such as pharmacophore definition disclosed in the specification to guide one of skill in the art to choose from the plethora possibilities recited for the variables.
There is a substantial gap between what is taught in the specification and what is being claimed. For these reasons, one skilled in the art would be faced with undue amount of research. The specification lacks disclosure sufficient to make and use the invention, in predictable manner, commensurate with the scope of the claims.
MPEP 2164.01(a) states, “A conclusion of Iack 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. ln re Wright, 999 F.2d 1557,1562, 27 USPQ 2d 1510, 1513 (Fed. Cir. 1993).'' That conclusion is clearly justified here. Thus, undue experimentation would be required.
Claim 17 is objected to as being dependent upon a rejected base claim 1, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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