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 .
Priority
The instant application, filed 06/30/2022, is a 371 filing of PCT/TR2019/051248, filed 12/30/2019.
Amendments and Claim Status
The following amendment filed on 11/12/2025 is acknowledged and entered.
Claims 1 and 3 are amended;
Claims 2, 4, and 5 are cancelled;
Claim 8 is added;
Claims 6 and 7 remain withdrawn according to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species;
Claims 1, 3, and 6-8 are pending.
Information Disclosure Statement
An Information Disclosure Statement has not been received.
Response to arguments
Applicant’s arguments filed 11/12/2025 with respect to the objections to the drawings, claim objections, and claim rejections under 35 U.S.C. §§ 112(a) and 112 (b) have been fully considered.
With respect to the objection to the drawings, the amendments to the drawings, filed 11/12/2025, are sufficient to overcome the objection. Accordingly, the objection to the drawings is hereby withdrawn.
With respect to the rejection of claims 1-3 and 5 under 35 U.S.C. § 112(a), for the lack of enablement of treating any disease or disorder associated with circadian rhythm, the cancellation of claims 2 and 5 is sufficient to render the rejection of said claims moot. Furthermore, the amendment to claim 1 is sufficient to overcome the specific grounds of the original rejection. However, Applicant’s amendment to the claims remains unsupported by the instant specification. As such, a new rejection is made under the same statute addressing the new limitations. The arguments made by applicant are herein addressed.
Applicant argues that the amended claims are enabled because the specification demonstrates CRY1 binding, destabilization, degradation, in vitro and in vivo target engagement, bioavailability, and apoptosis sensitization in cancer relevant genetic context (p53 null), and therefore enables treatment of CRY1-mediated cancer.
Applicant’s arguments are found unpersuasive because, while the specification demonstrates CRY1 binding, destabilization, and degradation, these data simply establish target engagement and pathway modulation, not the treatment of cancer as required by the instant claims. The specification does not disclose any in vivo cancer model, tumor burden reduction, tumor growth inhibition, or survival benefit. Accordingly, the specification does not reasonably enable a method of treating a CRY1-mediated cancer.
Applicant further argues that apoptosis sensitization of Ras-transformed p53-null mouse embryonic fibroblasts demonstrates therapeutic relevance, and support the claimed method of cancer treatment.
The argument made by applicant is found unpersuasive because the referenced data is limited to in vitro sensitization of p53-null MEFs in combination with oxaliplatin. These experiments demonstrate chemosensitization—not treatment of cancer. The claims do not recite a method of sensitizing cancer cells to chemotherapy, nor do they require coadministration with oxaliplatin. Absent evidence that Formula One alone treats cancer, the disclosure is not commensurate with the scope of the instant claims.
Applicant asserts that limiting the claims to “CRY1-mediated cancer” and reciting a mechanistic requirement that Formula 1 destabilizes and degrades CRY1 cures the previously identified enablement deficiency.
Applicant’s argument is found unpersuasive because, narrowing the claims to a CRY1-mediated mechanism does not substitute for demonstration of cancer treatment. The specification shows CRY1 modulation in normal mouse liver tissue, and circadian transcriptional effects. It does not demonstrate therapeutic efficacy in any cancer model. Mechanistic plausibility alone is insufficient to enable a method of treating cancer.
Applicant further argues that routine oncologic evaluation to identify CRY1-mediated cancers does not constitute undue experimentation.
Applicant’s argument is found unpersuasive, because the issue is not undue experimentation in identifying patients, but rather the absence of evidence of the claimed method treats cancer at all. Without data demonstrating cancer treatment, tumor inhibition, or therapeutic benefit, the specification fails to enable the full scope of the claimed method regardless of how patients are selected.
Applicant maintains that in vivo CRY1 reduction and bioavailability support practicing the claimed method without undue experimentation.
Applicant’s argument is found unpersuasive because the in vivo data relate to CRY1 levels in noncancerous mouse liver tissue and circadian rhythm effects. These data do not establish that administration of the compound of formula 1 treats cancer, nor do they reasonably predict therapeutic efficacy in cancer. Enablement of a cancer treatment requires more than demonstrating systemic exposure target modulation in healthy tissue.
Therefore, the specification demonstrates CRY1 binding, destabilization, and apoptosis sensitization under limited in vitro conditions. It does not demonstrate treatment of cancer as required by the instant claims. The amended claims remains broader than the teachings of the specification because the recited method of treating a CRY1-mediated cancer without evidence of cancer treatment or therapeutic efficacy.
With regard to new claim 8, the claim remains unsupported being drawn to a method of treating CRY1-mediated cancer. The claim further recites administration of oxaliplatin and that Formula 1 sensitizes apoptosis as indicated by increased cleaved PARP. However, the specification only discloses in vitro apoptosis sensitization in engineered p53-null embryonic fibroblasts, and does not demonstrate that such sensitization results in the treatment of cancer. Furthermore, the presence of increased PARP cleavage under combination treatment does not establish therapeutic efficacy, tumor inhibition, or cancer treatment in vivo. Applicant has not demonstrated that these data will lead to any practical advantage in the treatment of cancer. As such, the rejection is applied to new claim 8.
Accordingly, the rejection of claims 1 and 3 under 35 U.S.C. § 112 (a) is hereby amended to address the new claim limitations as well as new claim 8, and is therefore maintained.
With respect to the rejection of claims 1-3 and 5 under 35 U.S.C. § 112(a), for the lack of enablement for the claims directed to preventing a disease or disorder associated with circadian rhythm, the cancellation of claim 2 and 5 is sufficient to render the rejection of said claims moot. Furthermore, Applicant’s amendment striking “prevention” from the claim is sufficient to overcome the specific grounds of the rejection.
With respect to the rejection of claims 1-3 and 5 under 35 U.S.C. § 112(b), for lack of antecedent basis, omitting essential elements, and the use of relative terms, the cancellation of claim 2 and 5 is sufficient to render the rejection of said claims moot. However, Applicant arguments as well as the amendments are insufficient to overcome the specific grounds of the rejection. The amendments are herein addressed:
Claim 1 continues to recite the limitation “a method of preparing” following the compound of Formula 1. However, the preamble of claim 1 recites a method of treatment, and not a method of preparing a medicament. Therefore, there is insufficient antecedent basis for this limitation in the claim, and the specific grounds for the rejection are maintained.
Further regarding claim 1, the claim amendments to include the subject to which the medicament is administered, and removing the relative terms “associated with” and “related to” sufficiently overcome the indefiniteness created by the claim language. As such, specific grounds for the rejection are withdrawn.
Further regarding claim 1, the claim amendments adding the language “CRY1-mediated cancer” remain indefinite, as a person of ordinary skill in the art would not be able to ascertain the level to which the cancer is mediated by CRY1. As such, a new rejection under the same statue is made, addressing the new claim limitations.
With regard to claim 3 and to new claim 8, the claims fail to cure the indefiniteness created by the amended claim language. As such, the claims are deemed indefinite.
Accordingly, the rejection of claims 1 and 3 under 35 U.S.C. § 112 (b) is hereby amended to address the new claim limitations as well as new claim 8, and is therefore maintained.
Thus, all arguments presented by Applicants have been addressed and are found unpersuasive for the reasons presented herein and in the previous non-final rejection.
Status of Claims
Claims 1, 3, and 6-8 are pending in the instant application. Claims 6 and 7 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention. Therefore, claims 1, 3, and 8 read on an elected invention and are therefore under consideration in the instant application.
Drawings
The drawings filed on 11/12/2025 are found to be in compliance with 37 CFR §§ 1.121 and 1.84, and are hereby accepted.
Claim Rejections - 35 U.S.C. § 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, and 8 are rejected under 35 U.S.C. § 112 (a), or 35 U.S.C. § 112 (pre-AIA ) first paragraph, because the specification, while being enabling for a method of selectively binding to and destabilizing CRY1 comprising the administration of a medicament of claim 1, it does not reasonably provide enablement for treating CRY1-mediated cancer. In the instant case, the claims are being examined for the elected species, cancer, and the specification does not enable the treatment of cancer.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 1, 3, and 8 of the instant application are drawn a method of treatment of a cryptochrome 1 (CRY1)-mediated cancer, comprising the administration of the medicament recited in claim 1. The claims are further drawn the administration of oxaliplatin, and wherein the compound of Formula 1 sensitizes apoptosis in the cells as indicated by an increase in cleaved PARP. Therefore the invention encompasses treating disorders such as cancer.
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that the claimed compounds can be used to treat a subject having cancer mediated by CRY1, comprising the administration of the medicament recited in claim 1. Thus the cited claims are deemed very broad since these claims read on essentially treating any cancer mediated by CRY1 , which includes subjects having a broad range of cancers, in any tissue or tumor type, and in any subject.
State of the Prior Art: The current state of the art recognizes that the circadian clock, and specifically the core protein CRY1, plays an important role in regulating cellular processes, relevant to cancer biology, such as proliferation, metabolism, DNA repair, and apoptosis (page 2, Huang et al. Cancer Biol Med Vol. 20, Iss 1, pg. 1-24, published January 12, 2023, hereinafter Huang). The mammalian circadian mechanism, CRY1 act as a negative regulator within the core transcription-translation feedback loop (TTFL), thereby controlling the expression of downstream circadian and cancer-related genes (page 1 and 2). Dysregulation of CRY1 expression has been observed in a variety of tumor types. For example, as detailed by Huang et al. (Figure 1, page 1 and 2), the expression levels of CRY1 differ between normal and tumor tissues, and these alterations can impact cell proliferation in tumor progression (page 3).
Furthermore, in breast cancer models, Ector et al. (Molecular Systems Biology, Vol 21, Iss 4, pg. 315-340, published February 24, 2025), hereinafter Ector, demonstrated that mutations and distributions in circadian clock genes, including CRY1, contribute to altered cancer cell phenotypes (pages 317 and 318) and may affect drug sensitivity (Abstract). Moreover, the reference literature highlights substantial heterogeneity and circadian phenotypes among cancer cells, and suggested cancer subtypes with disrupted or mutated CRY1 often exhibit increased instability, but do not consistently demonstrate responsiveness to clock targeting therapies (page 317). Thus, experimental evidence indicates that simply modulating CRY1 is not predictably effective for cancer treatment across diverse contexts in vivo. Accordingly, the state of the art does not bridge the gap between CRY1 modulation in cancer treatment, reinforcing the need for working examples demonstrating therapeutic benefit.
With respect to the instantly claimed compound found in the medicament of claim 1, the compound is known in the art as CAS Registry Number: RN 890808-56-7 [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 890808-56-7, Entered STN: 06 Jul 2006], supplied by Aurora Fine Chemicals according to Figure 1. Although the compound is known, the state-of-the-art is silent on said compound’s ability to treat circadian rhythm diseases or disorders, such as the elected cancer, as the compound has not been demonstrated to do so to date.
Figure 1. RN 890808-56-7
PNG
media_image1.png
167
409
media_image1.png
Greyscale
Figure 1. Aurora Fine Chemicals CAS Registry Number: RN 890808-56-7
The level of ordinary skill in producing a medicinal dose from a bioactive compound requires sufficient experience in pharmaceutical formulations and is considered to be sophisticated. Regardless, the level of skill cannot overcome the extreme unpredictability in cancer therapy.
With regard to the relationship of predictability of the art and the enablement requirement, the MPEP § 2164.03 states,
The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938).
In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). A need for greater disclosure derives from the fact it is not obvious from the disclosure of one species, what other species will work.
Generally speaking, then, the Courts recognize that predictability in chemical related arts is low enough to require a highly detailed disclosure. Unpredictability arises in chemical related arts because subtle changes in molecular structure may greatly impact a compound's structure-activity relationship, pharmacologic activity, and/or biologic profile. In drug development, the skilled artisan would not be able to easily extrapolate treatment for a medical use from a single example or limited disclosure without more instruction. These considerations support a requirement for a disclosure with a high level of detail. Predictability with regard to the claimed method of producing a medicinal dose from a raw plant is considered to be extremely low due to the lack of specificity regarding the type of plant, type of medicinal dose, and type of medical use. Considered in light of the general unpredictability of pharmacology, the predictability of practicing the claimed methods of is extremely low.
Therefore, at the time of filing, the prior art largely described CRY1 in mechanistic or correlated studies, rather than as a validated therapeutic target. The art does not establish that destabilization or degradation of CRY1 will reliably result in therapeutic efficacy against cancer, nor does it provide guidance for translating CRY1 into tumor treatment. In particular, the state-of-the-art art does not demonstrate that CRY1 inhibition alone is sufficient to treat cancer, as opposed to merely influencing cellular responses or sensitizing cells to other agents.
Predictability/Unpredictability in the Art: It is noted that the pharmaceutical art of cancer treatment is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the recitation includes treating any disease mediated by CRY1. Thus, the skilled artisan would view that successfully targeting the large number of diseases mediated by CRY1 encompassed by the claims comprising the administration of the compound, is highly unpredictable, as there are a large number of mutations and distributions in circadian clock genes, including CRY1, contributing to altered cancer cell phenotypes, as demonstrated in the teachings of Ector, above. CRY1 functions as a pleiotropic regulatory protein, and its modulation can produce context -dependent and tissue specific effects, which may vary based on tumor type, genetic background, circadian phase, and interaction with other oncogenic pathways. Because cancer therapy itself is an unpredictable field, and because circadian protein modulation introduces an additional layer of biological complexity, a person of ordinary skill in the art would not reasonably expect that CRY1 destabilization would consistently treat cancer without extensive empirical testing. Accordingly, mechanistic plausibility does not substitute for experimental evidence of therapeutic efficacy. This high degree of unpredictability weighs against enablement, especially where the specification lacks working examples demonstrating cancer treatment, tumor inhibition, or therapeutic benefit.
Guidance of the Specification/Working Examples: The instant specification provides evidence that RN 890808-56-7 is capable of selectively binding to CRY1 (page 67-68), established through docking studies and pulldown assays. Furthermore, it is shown in the specification that the half-life of CRY1 is reduced in a dose-dependent manner in vitro (page 66-67) using RN 890808-56-7. The specification further demonstrates that RN 890808-56-7 shows no cytotoxicity in basic animal studies (page 69). The specification further indicates that RN 890808-56-7 is detectable in plasma and brain tissue, and can reduce CRY1 levels in mouse liver nuclei (page 71), demonstrating that RN 890808-56-7 is bioavailable in vivo. Finally, the specification reports that the compound sensitized p53 mouse embryonic fibroblasts to apoptosis in vitro (page 72).
Although the specification demonstrates that RN 890808-56-7 is capable of selectively binding to and destabilizing CRY1 in vitro, and in animal tissues, and shows an effect on circadian gene expression and protein levels, there is no data provided demonstrating that the administration of RN 890808-56-7 leads to the treatment of any disease or disorder in any relevant disease model.
The specification provides no evidence that the use of the compound will lead to success in treating a cancer, or a disease or disorder associated with a circadian rhythm or related to CRY1. The in vivo studies are limited to measurements of off-target engagement, and lack of overt toxicity . They do not show any effect on disease or disorder treatment, or survival in animal models of cancer or circadian rhythm disorders. The present data merely demonstrates that the compound increases apoptosis in a highly specific and artificial cell system. The studies do not demonstrate any preventative treatment measure in an animal model of cancer.
The specification fails to provide working examples demonstrating the treatment of cancer as required by the instant claims. Although the specification includes biochemical and cellular experiments showing that Formula 1 binds CRY1, reduces CRY1 stability,, alters circadian transcription, and sensitizes Ras-transformed p53- no mouse embryonic fibroblasts to oxaliplatin- induced apoptosis in vitro, these disclosures do not constitute working examples of cancer treatment. The in vivo data is limited to CRY1 modulation and circadian effects in noncancerous mouse liver tissue, and no experiments are provided in tumor bearing animals, cancer derived cells, or clinically relevant cancer models. Moreover the apoptosis data relies on combination treatments with oxaliplatin and does not demonstrate that Formula 1 alone produces therapeutic benefit. As such, the specification fails to provide sufficient evidence in support of a method of treatment of cancer mediated by CRY1 as recited in the instant claims.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the claimed medicament could be administered to treat a subject having cancer mediated by CRY1. The population of subjects could include any subject, and thus the quantitation of experimentation is unreasonably large. The skilled artisan would need to design and perform cancel model selection, tumor bearing animal studies, dose optimization for efficacy, and a determination of whether or not Formula 1 alone or in combination is actually effective. These experiments go well beyond routine optimization. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In conclusion, Genentech, 108 F.3d at 1366, 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”. A method of treating cancer associated with a circadian rhythm, and related to CRY1 is not enabled by the instant specification.
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, and 8 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 claim 1, the term “CRY1-mediated cancer” recited in the claim, is a relative term which renders the claim indefinite. The term “mediated” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The claim is unclear about the degree to which a cancer may be mediated by CRY1, and whether or not that mediation is direct or indirect.
Further regarding claim 1, the claim recites the limitation “a method of preparing” following the compound of Formula 1. However, the preamble of claim 1 recites a method of treatment and/or prevention, and not a method of preparing a medicament. Therefore, there is insufficient antecedent basis for this limitation in the claim. Accordingly, claim 1 is deemed indefinite.
Regarding claims 3 and 8, the claims depend on a claim rejected as being indefinite (claim 1) and does not remedy the indefiniteness of the claim on which it depends, and is therefore also rejected as indefinite.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sophia P. Hirakis whose telephone number is +1 (571) 272-0118. The examiner can normally be reached within the hours of 5:00 am to 5:00pm EST, Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached on +1 (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is +1 (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call +1 (800) 786-9199 (IN USA OR CANADA) or +1 (571) 272-1000.
/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623