DETAILED NOTICE
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 .
Priority
The present Application, filed June 22, 2023, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/US2022/018892, filed March 4, 2022, which claims the benefit of U.S. Provisional Patent Application Publication No. 63/156,880, filed March 4, 2021.
Status of the Claims
In the amendment filed May 27, 2026, claims 1-2, 5-7, 19, and 27 are amended. Claims 1-17, 19, 22-24, 27-28, 42-46, and 48-49 are currently pending.
Response to Amendments/Arguments
Rejections for Indefiniteness:
The amendments to claims 1 and 27 resolve the rejections to these claims under 35 U.S.C. § 112(b) for indefiniteness. For this reason, the rejections of claims 1, 19, and 27, and their dependent claims 2-17, 22-24; 28, and 42-46 are withdrawn.
Claim Rejections - 35 USC § 112(a) – In view of Applicant’s amendment
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, 6-17, and 42-46 fail to comply with the written description requirement:
Claims 1, 6-17, and 42-46 are rejected under 35 U.S.C. § 112, first paragraph, as failing to comply with the written description requirement. The claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Specifically, Applicant does not have written description support for a method of treating a disorder in a subject in need thereof comprising administering a compound of Formula (I) to a subject whose tumor cells are determined, from a biological sample obtained from the subject, to exhibit amplification or overexpression of cMYC, or a KRAS mutation. As discussed further below, the instant disclosure's stated rationale for patient selection, its characterization of the compound of Formula (I) as a CDK2 inhibitor with selectivity toward CDK2/cyclin E complexes, its dedicated biomarker-detection teachings, and its working examples are directed exclusively to CDK2 and cyclin E (CCNE1/CCNE2). Neither cMYC nor KRAS is discussed in the specification, nor does the state of the art make it clear that tumors with KRAS mutation or increased cMYC activity would be especially responsive to CDK2 inhibitors. As such, claims 1, 6-17, and 42-46, to the extent they read on selection of a subject based on cMYC amplification/overexpression or KRAS mutation status, lack sufficient written description. Claims 2-5, 19, 22-24, 27-28, and 48-49 are not subject to this rejection, as they are limited to the cyclin E and/or CDK2 embodiments.
The written description requirement is distinct from the enablement requirement; as was first pointed out by the court in In re Ruschig, 379 F.2d 990, 154 USPQ 118 (CCPA 1967), and clarified in Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111 (Fed. Cir. 1991). The issue of whether the claimed subject matter is adequately supported/described by the specification, is a question of fact. Id. at 1563, 19 USPQ2d at 1116.
When considering whether the claimed subject matter complies with the written description requirement, Applicants' disclosure should be read in light of the knowledge possessed by those skilled in the art.
"[T]he disclosure in question must be read in light of the knowledge possessed by those skilled in the art, and that knowledge can be established by affidavits of fact composed by an expert, and by referencing to patents and publications available to the public ... "
In re Lange, 644 F.2d 856, 863, 209 USPQ 288, 294. See also, In re Alton, 76 F.3d 1168, 37 USPQ2d 1578 (Fed. Cir. 1996).
Applicants enjoy the presumption that their patent application is valid and all statements contained therein are accurate; it is the PTO's burden to demonstrate why any of Applicant’s claims should be rejected or why any of Applicant's statements should be doubted.
"it is incumbent upon the Patent Office, whenever a rejection ... is made, to explain why it doubts the truth or accuracy of any statement in a supporting disclosure and to back up assertions of its own with acceptable evidence or reasoning which is inconsistent with the contested statement. Otherwise, there would be no need for the applicant to go to the trouble and expense of supporting his presumptively accurate disclosure."
In re Marzocchi, 439 F.2d 220, 224, 169 USPQ 367, 370. If successful in presenting such evidence and argument, the burden then shifts to the Applicant to provide evidence that would convince one to the contrary.
The Invention in General
A component of Applicant's invention is directed to a compound of Formula (I),
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The compound of Formula (I) is presently shown to be a CDK2 inhibitor, and more particularly, a selective inhibitor of CDK2, CDK2/cyclin E1, or CDK2/cyclin E2. An additional component of Applicant’s invention is a method for treating cancer involving administration of the compound of Formula (I). In particular, the method can involve selection of subjects based on tumor biomarkers such as overexpressed cyclin E or CDK2.
The Background section explains that overexpression of CDK2/cyclin E is associated with abnormal cell-cycle regulation, and that CDK2 inhibitors "may be useful in treating CCNE1 or CCNE2 amplified tumors" (paragraphs [0002]-[0004]).
The Claimed Invention
Claim 1 is directed to a method of treating a disorder in a subject in need thereof, wherein tumor cells of the subject exhibit amplification or overexpression of cyclin E, amplification or overexpression of CDK2, amplification or overexpression of cMYC, or a KRAS mutation, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the amplification or overexpression (or, for the KRAS embodiment, the mutation) is determined from a biological sample obtained from the subject. Claims 6 and 7 depend from claim 1 and are directed, respectively, to the cMYC and KRAS-mutation embodiments individually. Claims 8-17 and 42-46 depend, directly or indirectly, from claim 1 without narrowing the biomarker limitation to fewer than all four recited alternatives, and therefore retain claim 1's full biomarker-related scope, including the cMYC and KRAS-mutation embodiments.
Non-rejected dependent claims 2-5, depending from claim 1, limit the biomarkers for patient selection to amplified or overexpressed cyclin E or CDK2. Non-rejected independent claims 19 and 27 (and their dependent claims) recite methods of treating cancer, involving treating the subject with the compound of Formula (I), where the subject is selected on the basis of having elevated CDK2 or cyclin E expression in tumor cells, as determined from a biological sample from the subject.
The Supporting Disclosure
Applicant's supporting disclosure describes a mechanistic and clinical rationale specific to CDK2 and cyclin E. The Background section states that “[o]verexpression of CDK2/cyclin E is associated with abnormal regulation of the cell-cycle,” describes the role of the CDK2/cyclin E complex in the G1/S transition, and states that “CDK2 inhibitors may be useful in treating CCNE1 or CCNE2 amplified tumors” (paragraphs [0002]-[0004]). Consistent with this rationale, the disclosure characterizes the claimed compound as a CDK2 inhibitor and as a compound with demonstrated selectivity for CDK2/cyclin E1 and CDK2/cyclin E2 complexes relative to other enzymatic targets (paragraphs [0036], [0053]). The disclosure provides dedicated subsections teaching methods for detecting CDK2, CCNE1, and CCNE2 expression in patient tumor material, including by immunohistochemistry and immunofluorescence, and comparison of the measured expression level to a suitable reference, standard, or normal adjacent tissue (paragraphs [0037]-[0051]). The disclosure further provides working examples reporting enzymatic inhibition data for the claimed compounds (identified therein as compounds 1a and 1b) against CDK2/cyclin A1, A2, E1, E2, and O complexes, showing greatest potency against the CDK2/cyclin E1 and CDK2/cyclin E2 complexes (Example 2, paragraphs [0104]-[0106]), and cellular target engagement data specific to the CDK2-CCNE1 complex (Example 4, paragraphs [0109]-[0110]).
The disclosure does not provide any examples indicating any particular utility for the compound of Formula (I) in treating cancers having amplification or overexpression of cMYC or a KRAS mutation.
The State of the Art
The compound of instant Formula (I) was known in the art prior, as was its general use for the treatment of cancer. It does not appear to have been known in the art that the compound of Formula (I) operated by inhibition of the CDK2/cyclin E interaction.
U.S. Patent No. 5,811,420 to Dhingra et al. (hereinafter, “Dhingra”), discloses compounds of Formula (I)
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in which the variables are as defined (col. 1, lines 1-25), and further discloses compound A and its epimer Compound B, where R1=H, R2=H, X=CO, and Z=O. Compound A of Dhingra is the compound of instant Formula (I), and Compound B of Dhingra is its enantiomer. Dhingra tests the anti-proliferative activity of Compounds A and B, and discloses that:
Compounds A and B have inhibitory activity on proliferation of transformed cell lines. Therefore, compounds of formula I provided by the present invention are useful as an antitumor agent against breast cancer, colo-rectum cancer, lung cancer, osteosarcoma cancer and the like for appropriate administration to a mammal, both human and non-human.
-Dhingra, col. 10, lines 49-55
Dhingra further claims a method of treating various cancers, such as breast or lung cancer, comprising administering a compound of Dhingra formula I (claim 29). Dhingra does not disclose a mechanism of action of the compounds of formula I, and does not mention CDK2, cyclin E, cMYC, KRAS, or any biomarker-based patient selection.
Even if given the presently disclosed CDK inhibitory activity of the compound of instant Formula (I), the art suggests that any connection between CDK-family inhibition and KRAS-mutant cancer is tenuous at best. For example, the non-patent publication, Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models, Oncotarget, 7, pgs. 39595-39608 (2016) by Lee et al. (hereinafter, “Lee”) discloses that combination therapy involving coadministration of a MEK inhibitor and a CDK4/6 inhibitor is more effective than MEK inhibitor monotherapy against a KRAS-mutant colorectal cancer.
early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity" and "[c]ombined inhibition of both MEK and CDK4/6 is effective
-Lee, Abstract
This arguably suggests some role of CDK inhibition in KRAS-mutant cancer therapy, but Lee has no teaching specific to CDK2 and shows no effectiveness of CDK inhibitor monotherapy.
The art indicates a stronger, but still unresolved and tumor-type-dependent, connection between CDK2 activity and MYC-family overexpression. The non-patent publication, Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells, PNAS, 106, 12968-12973 (2009) by Molenaar et al. (hereinafter, “Molenaar”), reports that CDK2 inhibition (via the small-molecule CDK inhibitor roscovitine) induced MYCN-dependent apoptosis in MYCN-amplified neuroblastoma cells, and proposes CDK2 inhibitors as “potential MYCN-selective cancer therapeutics,” (Abstract). However, Molenaar addresses MYCN, a MYC-family member distinct from cMYC (MYC), and addresses only neuroblastoma.
The non-patent publication, Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells, BMC Cancer, 14, art. 32, pgs. 1-13 (2014) by Kang et al., tested CDK1, CDK4/6, and CDK2 inhibition specifically in MYC-dependent breast cancer cells and found that CDK1 inhibition, but not CDK4/6 or CDK2 inhibition, was selectively lethal to MYC-dependent cells.
These references suggest that CDK inhibition may be effective against some MYC-overexpressing cancer lines, but do not establish a general effectiveness of CDK2 inhibition against cMYC-overexpressing cancers.
Summary of Written Description Rejection
The presently claimed methods are understood as being distinguished by selection of a patient population based on a new mechanistic understanding of a previously known active pharmaceutical ingredient. Because the claimed invention is directed to a method of selecting a subject for treatment based on a specific, patient-confirmed molecular characteristic of that subject's tumor cells, and because the compound of Formula (I) and its general antitumor use were already known in the art (Dhingra), written description support for the claimed patient-selection method depends on the specification's disclosed mechanistic rationale for that selection — namely, the disclosed finding that the compound acts as a CDK2 inhibitor with selectivity toward CDK2/cyclin E complexes. The specification supplies this rationale for cyclin E and CDK2 through its disclosed mechanism, its characterization of the compound as a CDK2/cyclin E-selective inhibitor, its dedicated detection methodology, and its supporting biochemical data. It supplies no corresponding rationale for selection of patient populations based on amplification or overexpression of cMYC or mutation of KRAS. Knowledge in the art does not bridge this gap, as it does not clearly suggest a utility of inhibitors of the CDK2/cyclin E interaction in the treatment of cancers characterized by amplified or overexpressed cMYC or mutated KRAS. Accordingly, claims 1, 6-17, and 42-46 fail to comply with the written description requirement to the extent they encompass selection of a subject based on cMYC amplification/overexpression or KRAS mutation status.
Allowable Subject Matter
Claims 19, 22-24, 27-28, and 48-49 are allowable. Claims 2-5 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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