DETAILED ACTION
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 .
Status of the Claims
Claims 1-3, 10-12, 14, 15, 17, 18, 22, 25, 26, 34, 36, and 38-40 are pending.
Domestic Benefit
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Instant application is a U.S. National Stage Entry of PCT/US2022/032690, filed 06/08/2022. PCT/US2022/032690 claims domestic benefit of U.S. Provisional Application No. 63/208,345, filed 06/08/2021. Therefore, the effective filing date is 06/08/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/27/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Restriction/Election Requirement
Applicant’s election without traverse of Group I, claims 1-3, 10-12, 14, 15, 17, 18, 22, 25, and 26, drawn to compounds of Formula (I), in the reply filed on 08/21/2026 is acknowledged. Applicant has further elected the species Formula 1314 (CG-3-066), shown below, which reads on instant claims 1-3, 10-12, 15, 17, 18, 22, 25, and 26. The scope of the examination has been limited to the elected species.
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Claims 14, 34, 36, and 38-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species or invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/21/2026.
Improper Markush Grouping
Claims 1-3, 10-12, 15, 17, 18, 22, 25, and 26 are rejected on the basis that they contain 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). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of formula (I), shown below, is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the various permutations of variables A, L, and B results in compounds that require no structural similarity. The varying permutations are not recognized to belong to the same physical or chemical class or to be the same art-recognized class.
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To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. The scope of formula (I) (inclusive of the elected species) that would form a proper Markush grouping would be where at least one of A or B is defined. There would appear to be several different ways in which a proper Markush grouping could be derived from the scope instantly claimed. However, defining at least one of A or B to constitute a common core structure would appear to be a minimum requirement, since the options for variables results in numerous dissimilar permutations.
Claim Rejections - 35 USC § 112
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 1-3, 10-12, 15, 17, 18, 22, 25, and 26 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter alter claimed. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus …”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed genus is sufficient. See MPEP § 2163.
In the instant case, the claims are drawn to compounds of formula (I) or “prodrugs” thereof. The claims are also drawn to compounds of formula (I) wherein the variables may be “substructures” thereof.
“Prodrugs” and “substructures” of compounds of formula (I) are not structurally defined. It is unclear what is encompassed by the terms “prodrug” and “substructure”. On page 13 of the specification, a definition of “prodrug” is given which does not disclose any specific prodrugs or provide guidance as to what constitutes a prodrug of the instant invention. The definition is also non-limiting, stating “[a]dditional types of prodrugs are also encompassed” (page 13). Similarly, “substructure” is not defined, and no examples of substructures are provided in the instant claims or specification. There is no guidance as to what would constitute a substructure that would be expected to function in the instant invention.
Applicant’s specification provides no examples of a “prodrug” or “substructure” of the compounds of formula (I). Additionally, no disclosure is provided which would guide a person of ordinary skill toward a particular prodrug strategy or design for the compounds of formula (I).
The compounds of formula (I) and “prodrug thereof” or “substructure thereof” are not described in the prior art. They appear to be a new set of proteolysis targeting chimeras, and thus, information about their properties which would guide a person of ordinary skill toward a particular prodrug or substructure is also not disclosed in the prior art.
Methods of synthesizing compounds are, in general, known to the person of ordinary skill, however methods of making the myriad of compounds embraced by the instant claims is beyond the skill of the artisan, particularly when certain elements, such as “a prodrug” and “substructure”, are merely described partially. As such, the instant specification and instant claims do not provide sufficient description such that one could anticipate what additional elements may be present in the prodrugs and substructures of formula (I).
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.” Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
Additionally, the claims recites the limitations “Mcl-1 protein indirect inhibitor moiety”, “linking group”, and “E3 ubiquitin ligase ligand moiety” in the definition for a PROTAC molecule, or a pharmaceutically acceptable salt, solvate, or prodrug thereof for which the specification does not provide an adequate written description to convey that the inventors were in possession of the full scope of the claimed invention.
The claims also contain additional functional language such as “wherein the Mcl-1 protein indirect inhibitor moiety comprises a CDK9 inhibitor, a dual PI3K/mTOR inhibitor, a MEK1/2 inhibitor, a FLT3 inhibitor, a JAK1/2 inhibitor, a STAT3 inhibitor, an ERK1/2 inhibitor, or any substructure thereof”, “wherein the E3 ubiquitin ligase ligand moiety comprises cereblon (CRBN) ligand, a mouse double minute 2 (MDM2) ligand, a Von Hippel- Lindau (VHL) ligand, or any substructure thereof”, and “wherein the CDK9 inhibitor is selected from…shRNAs against CDK9, anti-sense mRNA against CDK9 and anti-CDK9 antibodies, and any substructure thereof”.
Regarding the requirement for adequate written description of chemical entities, Applicant's attention is directed to the MPEP §2163. In particular, Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), holds that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, "not a mere wish or plain for obtaining the claimed chemical invention.” Eli Lilly, 119 F.3d at 1566. The Federal Circuit has adopted the standard set forth in the Patent and Trademark Office ("PTO") Guidelines for Examination of Patent Applications under the 35 U.S.C. 112.1 "Written Description" Requirement ("Guidelines"), 66 Fed. Reg. 1099 (Jan. 5, 2001), which state that the written description requirement can be met by "showing that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics," including, inter aria, "functional characteristics when coupled with a known or disclosed correlation between function and structure..." Enzo Biochem, Inc. v. Gen-Probe Inc., 296 F.3d 316, 1324-25 (Fed. Cir. 2002) (quoting Guidelines, 66 Fed. Reg. at 1106 (emphasis added)). Moreover, although Eli Lilly and Enzo were decided within the factual context of DNA sequences, this does not preclude extending the reasoning of those cases to chemical structures in general. Univ. of Rochester v. G.D. Searle & Co., 249 Supp. 2d 216, 225 (W.D.N.Y. 2003).
Medicinal chemistry and pharmacology are unpredictable areas. Even carefully designed PROTACs do not always function as expected. It is generally unpredictable whether a molecule would possess the specific functions, such as indirectly inhibiting an Mcl-1 protein. Some structure-activity-relationship may be ascertained from structurally similar derivatives; however, the degree of structural similar must be high in order to expect similar properties. For new or untested compounds, activity as a PROTAC is unpredictable.
Applicants have not described the genus of PROTACs having a Mcl-1 protein indirect inhibitor moiety, linking group, and E3 ubiquitin ligase ligand moiety, or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a manner that would allow one skilled in the art to immediately envisage all the compounds contemplated for use. Applicant also fails to structurally define the CDK9 inhibitors, dual PI3K/mTOR inhibitors, MEK1/2 inhibitors, FLT3 inhibitors , JAK1/2 inhibitors, STAT3 inhibitors, ERK1/2 inhibitors, cereblon (CRBN) ligands, mouse double minute 2 (MDM2) ligands, Von Hippel- Lindau (VHL) ligands, shRNAs against CDK9, anti-sense mRNA against CDK9, anti-CDK9 antibodies, and substructures thereof. As such, the claims lack adequate written description for the indefinite compounds embraced by the claimed molecules.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 10-12, 15, 17, 18, 22, 25, and 26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-3, 10-12, 15, 17, 18, 22, 25, and 26, the phrases "prodrug" and “substructure” renders the claims indefinite because the claims include elements not actually disclosed (those encompassed by "prodrug" and “substructure”), thereby rendering the scope of the claims unascertainable. On page 13 of the specification, a definition of “prodrug” is given which does not disclose any specific prodrugs or provide guidance as to what constitutes a prodrug of the instant invention. The definition is also non-limiting, stating “[a]dditional types of prodrugs are also encompassed” (page 13). Similarly, “substructure” is not defined, and no examples of substructures are provided in the instant claims or specification. This results in an indefinite number of compounds falling under the terms “prodrug” and “substructure”.
The inventor or joint inventor should note that claims 1-3, 10-12, 15, 17, 18, 22, and 26 are reach-through claims. The claim attempts to obtain protection for subject matter that is prophetic and/or has yet to be invented. This includes Mcl-1 protein indirect inhibitor moieties, linking groups, E3 ubiquitin ligase ligand moieties, CDK9 inhibitors, dual PI3K/mTOR inhibitors, MEK1/2 inhibitors, FLT3 inhibitors , JAK1/2 inhibitors, STAT3 inhibitors, ERK1/2 inhibitors, cereblon (CRBN) ligands, mouse double minute 2 (MDM2) ligands, Von Hippel- Lindau (VHL) ligands, shRNAs against CDK9, anti-sense mRNA against CDK9, and anti-CDK9 antibodies. Similarly, the metes and bounds of the above listed moieties are not defined by the claim, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. Neither the specification, nor the claim, explicitly limits the invention to any specifically disclosed or recited embodiments of Mcl-1 protein indirect inhibitor moieties, linking groups, E3 ubiquitin ligase ligand moieties, CDK9 inhibitors, dual PI3K/mTOR inhibitors, MEK1/2 inhibitors, FLT3 inhibitors , JAK1/2 inhibitors, STAT3 inhibitors, ERK1/2 inhibitors, cereblon (CRBN) ligands, mouse double minute 2 (MDM2) ligands, Von Hippel- Lindau (VHL) ligands, shRNAs against CDK9, anti-sense mRNA against CDK9, and anti-CDK9 antibodies. Consequently, the PROTAC compounds of formula (I) have been rendered indefinite by the use of the reach-through protocol.
Conclusion
Claims 1-3, 10-12, 15, 17, 18, 22, 25, and 26 are rejected are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RILLA M SAMSELL whose telephone number is (703)756-5841. The examiner can normally be reached Monday-Friday, 7-3.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/R.M.S./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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