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 03/14/2023, is a national stage entry filing of PCT/US2021/052458, filed 09/28/2021, which claims domestic priority to U.S. provisional application 63/085,709, filed 09/30/2020.
Claim Status
The amendment filed on 02/12/2026 is acknowledged and entered.
Claims 1, 5, 9, 14, 20, 27, 33, 50, 58, 95, 96, and 107 are amended;
Claims 2-4, 5-8, 10-13, 15-19, 21-26, 28-32, 35-49, 51-57, 59- 89, 91-93, 97-106, and 108-118 are cancelled;
Claims 119 and 120 are added.
Claims 1, 5, 9, 14, 20, 27, 33, 34, 50, 58, 90, 94-96, 107, 119, and 120 are pending and are under prosecution.
Telephonic communication
A phone call was placed by Examiner to Applicant’s agent of record, Gabrielle Hoover, with final communication on 06/23/2026. A series of examiner’s amendment was proposed to claims in order to place them in condition for allowance. Furthermore, the examiner requested an amended specification addressing the objections made. However, Applicant’s agent was unable to receive a timely approval from Applicant, and requested an office action.
Response to arguments
Applicant’s arguments with respect to the objections the specification as well as the claims, in addition to the claim rejections under 35 USC § 112 are herein addressed:
The specification was objected to for improper abbreviation of HeLa cells. Applicant has not submitted a substitute specification. In addition, Applicant has neglected to include proper trademarking designations within the instant specification related to Alexa FluorTM and other likely improperly designated trademark instances. As such, the objection to the specification is hereby maintained. In addition, a new objection to the specification with regard to the use of trademarks used therein is detailed below.
Claim 34 was objected to for depending on a rejected claim (claim 2). This objection was made in error and intended to be an objection against Claim 33, which depended on claim 2. Claim 33 has been rewritten to depend on claim 1, and the rejections against claim 1, no longer stand. As such, Applicant’s amendment has overcome the objection (see below), and the objection is hereby withdrawn.
Claim 90 was objected to for depending on a rejected claim (claim 58). Applicant’s amendment has overcome the rejection on rejected claim 58 (see below). As such, the objection is hereby withdrawn.
Claims 1, 50, 54, and 56 were rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The cancellation of claims 54 and 56 render the rejection against these claims moot. The amendment to claim 1 specifying the photocaged dihydrotetrazine and tetrazine compounds, is sufficient to describe the instantly claimed subject matter supported within the instant specification. As such, the rejection is hereby withdrawn.
Claims 2, 5, 9, 10, 14, 15, 20, 27, 33, 58, 94-96, and 107 were rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The cancellation of claims 2 and 10 render the rejection against these claims moot. The amendment to the claims to depend on instant claim 1. The amendments to claim 1 as well as claim 58 to recite a subgenus of the compounds as exemplified in the specification based on the limited scope of variables L1, L2, R1, and R2 is sufficient to describe the instantly claimed subject matter supported by the instant specification. As such, the rejection is hereby withdrawn.
Claims 95 and 96 were rejected under 35 U.S.C. § 112 (a) for a lack of enablement for a method of treating cancer. Claim 95 continues to list cancer as the disease to be treated. The claim was previously rejected as being broad with respect to the treatment of cancer. According to the original rejection, as well as the remarks filed by applicant, the specification provides support only for liver cancer cells as treated. The specification continues to lack support for the broad treatment of cancer, as well as cervical cancer. As such, rejection is hereby maintained.
Claim 107 was rejected under 35 U.S.C. § 112 (b) as being indefinite for not specifying which compound should be irradiated with light. In view of Applicant’s amendments to claim 107, clearly specifying that the photocaged dihydrotetrazine compound should be irradiated with light, the rejection is withdrawn.
New claim 119 depends on allowable claim 50, and are also found in the specification to be supported.
New claim 120 recites a trademark/trade name in the claim and is hereinafter rejected as indefinite.
In view of the new objection to the specification, this action is made non-final.
Specification
The specification is objected to for the following informalities:
The specification includes improper abbreviation of Henrietta Lacks cells found in two instances on page 144 (lines 18 and 26). The specification recites “Hela” where it is well-known that the abbreviation for Henrietta Lacks cells is “HeLa”.
The use of the term Alexa Fluor, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112(a)
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 95 and 96 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 treating liver cancer cells, it does not reasonably provide enablement for a method of treating cancer broadly, or cervical cancer in a subject comprising administering a photocaged dihydrotetrazine compound, irradiating it with light to form a tetrazine, and reacting the tetrazine with a dienophile linked to an anti-cancer agent. The specification does not provide sufficient information to support the invention as claimed.
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 95 and 96 of the instant application are drawn to a method of treating cancer broadly, or cervical cancer in a subject comprising administering a photocaged dihydrotetrazine compound, irradiating it with light to form a tetrazine, and reacting the tetrazine with a dienophile linked to an anti-cancer agent. The claims encompass treating any cancer, including hepatocellular carcinoma, cervical carcinoma, kidney cancer, or skin 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 any cancer including cervical cancer, which is unsupported by the instant specification. Thus the cited claims are deemed very broad since these claims read on treating a large number of cancers.
State of the Prior Art: There are no art recognized methods that could be used to establish that the instantly claimed diseases can be commonly addressed using the claimed therapeutic method. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method using the claimed agents. Additionally, there are no art recognized methods that could be used to identify subjects who would have predictably developed the broad spectrum of the aforementioned cancers in order to determine that the cancers were treated using the claimed methods.
Regarding common disease mechanisms and biomarkers, McKean et al. (Biomarkers in precision cancer immunotherapy: Promise and challenges. American Society of Clinical Oncology – Educational Book (2020), 40, p.e275-e291), hereinafter McKean, teach that although ongoing studies and trials investigate the use of multiple biomarkers predictive of patient response or harm, none of these are comprehensive in predicting potential benefit (of treatment). This unmet need for validated biomarkers is largely secondary to a prohibitive complexity within tumor parenchyma and microenvironment, dynamic clonal and proteomic changes to therapy, heterogenous host immune defects, and varied standardization among sample preparation and reporting (abstract). McKean also teach that treatment failures occur even in ICI patient cohorts, despite respective prescreening with biomarkers such as PD-L1 tumor proportion scores (p.e275). Regarding gene expression profiles specifically, McKean teaches that an important concept within gene expression profiles is that the predictive utility of such algorithms may be dependent on individual therapy plans. Data suggest that signaling and transcriptomic patterns may correlate only with response to therapy of directly related targets (p.e280). Unrelated immune pathways may require separate and individualized gene expression assays for different therapies (p.e280). Therefore, the selection of a particular therapy for any specific type of cancer is unpredictable, and requires individualized assays that are fully described to achieve correlation.
In a contemporary disclosure, Chen et al. (Acta Pharmaceutica Sinica B, Volume 13, Issue 6, pages 2736-2746, published December 28, 2022), hereinafter Chen, teaches that while light controllable therapeutic systems can offer precise spatial and temporal control over drug activity, they face significant practical limitations in cancer treatment. Specifically, their effectiveness is confined to cancer types with plate accessible tissues, since light— particularly UV— has poor tissue penetration, and can cause undesirable tissue damage (pages 2741 and 2742). As a result, these methods are not suitable for deep or internal tumors. The authors emphasize that such drawbacks limit the broader applicability of light-based activation, which is motivated the development of non-light, bioorthogonal click-release systems that achieve similar localized control over drug activation without relying on external light exposure (Abstract).
Predictability/Unpredictability in the Art: It is noted that the pharmaceutical art 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 encompasses administering a compound of claim 58 to a subject having cancer, and thus encompass the treatment of a vast number of cancers including hepatocellular carcinoma, cervical carcinoma, kidney cancer, or skin cancer. Thus, the skilled artisan would view that the treatment of all cancers encompassed by the claims, by administering a compound of claim 58 is highly unpredictable.
Moreover, one of skill in the art would recognize that it is highly unpredictable in regard to therapeutic effects, side effects and toxicity generated by administering a singular class of compounds for treating all the disorders and diseases encompassed by the claims.
Guidance of the Specification/Working Examples: Applicant has only provided working examples suggesting that compounds of claim 58 are capable of remodeling HeLa cell membranes by photoactivated tetrazine ligation (Figures 4A-G) single-cell photoactivation of tetrazine ligation on the cell membrane to treat HeLa cancer cells (Figure 4D). The specification details the imaging of the single cell membrane of living HeLa cancer cells by Alexa Fluor TM 568 dye (FIG. 4F). Finally, the specification details wherein Hep 3B human liver cancer cells were treated (paragraph [0435]). Thus, the specification fails to provide sufficient evidence in support of the broad treatment of cancer as recited in the instant claims. Through the disclosure, only liver cancer treatment has been enabled.
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 large range of cancers can be treated by the administration of the compounds claimed. 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 in a subject comprising administering a photocaged dihydrotetrazine compound, irradiating it with light to form a tetrazine, and reacting the tetrazine with a dienophile linked to an anti-cancer agent not enabled by the instant specification.
Claim Rejections - 35 U.S.C. § 112(b)
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.
Claim 120 is 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.
Claim 120 contains the trademark/trade name Alexa Fluor. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to describe the dyes included in the claim and, accordingly, the description is indefinite.
REASONS FOR ALLOWANCE
Claims 1, 5, 9, 14, 20, 27, 33, 34, 50, 58, 90, 94, 107, and 119 are allowed.
The following is a statement of reasons for the indication of allowable subject matter:
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The instant claims are drawn to a method of making a tetrazine compound of Formula (II) (right) comprising irradiating a photocaged dihydrotetrazine compound of Formula (I) (left) with light. the instant claims are further drawn to a drawn to the tetrazine compounds resulting from the method of making the compounds, limited to a subgenus supported by the instant specification. The claims are further drawn to a method of treating cancer comprising the administration the instantly claimed compounds, irradiated with light. Finally, the instant claims are drawn to a method of delivering a drug or probe by administering the instantly claimed compounds, irritated light. The following is considered to be the closest prior art:
Fox et al. (US 20180362504 A1, published December 20, 2018, cited in applicant IDS dated 07/18/2023), hereinafter Fox, teaches the conversion of dihydrotetrazine into a tetrazine compound (claim 1) in a reaction comprising a light-activated catalyst (claim 18). However, Fox fails to disclose a photocaged dihydrotetrazine compound, defined in the instant specification as “a dihydrotetrazine compound covalently bonded via a linker to a photolabeled moiety” (paragraph [0137]). No such photolabeled moiety is disclosed within the teachings of Fox. Similarly, Hilderbrand et al. (US 20190040021 A1, published February 2, 2019, cited on applicant IDS dated 07/18/2023), hereinafter Hilderbrand, teaches a method of synthesizing tetrazine from dihydrotetrazine using an oxidative process (paragraph [0232]), which fundamentally lacks the involvement of light as well as the photolabeled moiety. Thus Hilderbrand fails to meet the limitations of the instant claims.
Fox discloses a compound similar to a compound of Formula (I), wherein L1 and L2 are bonds, R1 is substituted heteroaryl and R2 is unsubstituted heteroaryl (paragraph [0159]: first compound listed). The compound disclosed lacks the photolabeled moiety instantly claimed as A-L3. Similarly, Hilderbrand discloses compound similar to a compound of Formula (I) wherein L1 and L2 are bonds and R1 is alkyl and R2 is substituted aryl (paragraph [0233]), but fails to disclose the photolabeled moiety instantly claimed as A-L3 as well as a dihydrotetrazine.
The teachings of these references do not encompass the scope of the instantly claimed processes, which are novel and nonobvious over the prior art, and do not encompass the scope of the instantly claimed compounds and methods. These references lack identical or obvious limitations of the claims. A person of ordinary skill in the art would not have expected that making modifications would retain an identical active as disclosed in the prior art.
Conclusion
The specification is objected to.
Claims 95, 96, and 120 are rejected.
Claims 1, 5, 9, 14, 20, 27, 33, 34, 50, 58, 90, 94, 107, and 119 are allowed.
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.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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