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 .
Product claims 1-16, 22 17-18, process and intermediate claims 19-20 and pharmaceutical method of claims 23-25 are pending.
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, 22 17-18, process 19 and intermediate claims 19-20 and pharmaceutical method of claims 23-25 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for making and using some possibilities of the claimed formula I, does not reasonably provide enablement for plethora of conceivable compounds of these formula. For example, it is not seen where in the specification enabling disclosure compounds with R1 or R2 is D (more examples later) is found. 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 formulae are drawn to compounds of formula I, and using them in claims 23-25 and intermediates and process for making these in claim 19-20. The formula I has many variables with substituents layered on substituents encompassing wide variety and number of structures. With different combination of these variables the formula I is drawn to possibilities 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.
How to make compounds (claims 19-20) are found at generic chemistry schemes at pages 21, 22, 25, 26, 28 and 30. However, it is not seen where in the specification any working examples for making for making X = O or S and Y =CH2; no working examples are found for making compounds wherein R1 or R2 is D; R4 or R5 is F; R3” or R’; R5 is cyclopropyl; there is no working examples for R6 is heterocycle or bicycle or alkyl or phenyl-alkyl. For example, specification does not teach how to make the ketone needed to make X=NH or protected version of compounds in Scheme 1e at page 30. The specification is silent with respect to procuring starting materials that could be substituted in these generic schemes to make the above noted possibilities.
According to the U.S. Court of Customs and Patent Appeals in In re Argoudelis , De Boer, Eble, and Herr 168 USPQ 99 at 101, "[o]rdinarily no problem in this regard arises since the method of preparing almost all starting materials can be set forth in writing if the materials are not already known and available to the workers in the art, and when this is done the specification is enabling to the public". In re Argoudelis , De Boer, Eble, and Herr 168 USPQ 99 at 104, "it is essential that there be no question that, at the time an application for patent is filed, (emphasis in original) the invention claimed therein is fully capable of being reduced to practice (i.e., that no technological problems, the resolution of which would require more than ordinary skill and reasonable time, remain in order to obtain an operative, useful embodiment)."
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. Similarly, according to Sundaresan, Protein Science (2002), 11:1330–1339 ‘stereoselectivity in biological molecular recognition processes is extremely important for rational drug design’. The teachings of Sundaresan, Venkatesh and Cannon is consistent with the unpredictability in the art and disclosure in the specification. For example, at page 95 Table 2 discloses the biological data relevant for the use prong of the enablement requirement (claims 23-25). As noted in the top 4 compounds here show, one of the isomer (see bottom of base claim 1), is active the other one is not. Apparently the same situation is not true for other isomeric compounds with otherwise same structures.
Substituents do make a difference in the pharmacological properties is also evidenced in the teachings of the state of the art of SERD compounds taught in Ahmad, J.Med.Chem 2020, 63, 512-528. Ahmad teaches positional isomers of the instantly claimed formula compound, at Table 3 at page 515, which also teaches that substituents do make differences in potency and metabolic stability. For example, substituent meta-dichlorophenyl for R6 as in Ahmad compound 43d is what is found in majority of the compounds in the instant disclosure. See page 96.
Further the breadth of the claim 24 with respect to diseases treated finds little support in the specification. No animal model or in vivo assay is found in the disclosure. Enablement can be acknowledged for treatment of cancer, specific to ‘breast cancer’ based on the established use of SERD fulvestrant, not for any and all cancer.
Specification lacks data showing that the compounds are capable of treating all or every cancer. ERα is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone and white adipose tissue. Abnormal ERα signaling leads to development of a variety of diseases, such as cancers, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases and osteoporosis” The mechanism of shutting down the ERα signaling by removing ERα from the tumor cells using Selective Estrogen Receptors degraders (SERDs)is also disclosed See specification page 1. However, none of the prior art compounds are reported to completely prevent the onset of any or every cancer by removing ERα from the tumor cells using Selective Estrogen Receptors degraders (SERDs) mechanisms.
It is noted that pharmacological activity in general is a very unpredictable area. 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).
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.
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 1-16, 22 17-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 12545640 . Although the claims at issue are not identical, they are not patentably distinct from each other as explained below:
Compounds of claims of 12545640 are positional isomers of the compounds of the instant formula wherein X=CH2 and Y = O, R6 is Ar (phenyl); R2 = OH, all other Rs are Hs (see rejection under 112-1). According to MPEP 2144.09, [R-01.2024]: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.
Likewise, (Likewise means for the same rationale as above)
Claims 1-16, 22 17-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 12595230.
Claims of 12595230 (encompass the compounds of claims of 12545640) are positional isomers of instant compounds with the same intended use. Note in formula of 12595230, Y includes CH.
The art made of record and not relied upon is considered pertinent to applicant's disclosure. US 12157721.
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 at (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
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