DETAILED ACTION
Status of Claims
Receipt is acknowledged of the Applicants’ Amendments and Remarks, filed February 20, 2026.
Claims 1, 3, and 5 are pending.
Claims 2, 4, and 6-34 are cancelled by Applicant.
Claims 1, 3, and 5 are under consideration in the instant office action as explained below in the Election/Restriction section
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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-7, drawn to a method of treating cancer comprising administering an effective amount of an GITR/GITRL agonist, in the reply filed on May 28, 2024 is acknowledged.
A telephone call was additionally made to Applicant October 9, 2024 pertaining to species election. Applicant elected without traverse species (a) the method wherein the GITR/GITRL agonist is represented by a compound of Formula I.
In Applicant’s reply, Applicant argues search burden as a rationale for why they believe
the restriction requirement to be improper. Applicant is reminded that the application under
examination is a 371 of PCT/US19/45742, and is not filed under 35 U.S.C. 111(a); therefore, “unity of invention” analysis, not “independent and distinct” analysis is applied. Please refer to MPEP § 1893.03 (d).
The examiner respectfully required restriction based on the lack of unity of invention on
grounds that the technical feature is not a special feature as it does not make a contribution over
the prior art in view of Molinero et al.. (US PG-PUB 2017/0260594 A1) as supported by the Written Opinion of the International Searching Authority.
The requirement is still deemed proper and is therefore made FINAL.
The examiner notes that claims 2 and 6 are cancelled by Applicant.
The examiner notes that claims 4 and 8-17, previously withdrawn are presently cancelled by Applicant.
Claims 1, 3, and 5 are currently under examination and are the subject of this office action.
Information Disclosure Statement
No additional information disclosure statements were submitted.
MAINTAINED OBJECTIONS
Drawings
The drawings remain objected to because Figure 6C is illegible. The graphs are blurry and text cannot be read, including on the title, and axis labels.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Applicant is reminded that in order to avoid an abandonment of this application, the drawings must be corrected in accordance with the instructions set forth in the paper mailed on November 12, 2024.
The examiner notes that corrected drawings have still not been provided nor received by the Office despite Applicant’s claim to provide corrected drawing sheets under separate cover.
Specification
Abstract Objections
Applicant is once more reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because the abstract is less than 50 words. Correction is required. See MPEP § 608.01(b).
The examiner notes that the abstract submitted is still not in compliance and less than 50 words and invites Applicant to once more submit an appropriate abstract following the guidelines provided in MPEP § 608.01(b).
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 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 1, 3, and 5 remain 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 melanoma in mice does not reasonably provide enablement for all cancers in all subjects. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01 (a).
Upon consideration of the factors discussed below, the examiner concludes that one skilled in the art would be unable to practice the invention as disclosed without being burdened with undue experimentation based on the information provided by the applicant.
A discussion of these factors in relation to the pending claims follows.
The breadth of the claims
The breadth of instant claims 1, 3, and 5 encompasses methods for treating melanoma in a subject in need thereof through administering a GITR/GITRL agonist, which is a compound of formula I. Applicant has narrowed the scope for cancer to melanoma.
Applicant defines subject as “a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal (page 17, paragraph [0066]).”
Consequently, it is reasonable to conclude that claims 1, 3, and 5 are broad with respect to subject, which is not limited to being a human, vertebrate, or mammal.
The nature of the invention
The nature of the invention is methods to treat cancer using a GITR/GITRL agonist and methods to treat cancer where the GITR/GITRL agonist is a compound of Formula (I).
The state of the prior art
The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). See Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021).
The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification. See MPEP § 2164.05 (a).
The development and study of GIR/GIRT agonists for treating cancer has been highly active area and candidates have been part of clinical studies.
As Davar comments, “Multiple GITR agonists have been advanced into the clinic, although the experience with these agents has been disappointing (Davar, D., & Zappasodi, R. (2023). Targeting GITR in cancer immunotherapy–there is no perfect knowledge. Oncotarget, 14, 614).
Additionally, there are still challenges when translating murine models to humans and other animals.
Applicant has only provided screening data for murine models for melanoma and however, has provided no experimental data or support from the prior art suggesting such results would be translational across the diverse subjects claimed, including humans and animals and that such results would be generalizable across the full genus of compounds for the melanoma claimed.
Riccardi notes “The preferential/selective effect of different agents (mAbs, receptors or ligand fusion proteins) on conventional or suppressor components of the immune response needs to be clarified for the establishment of effective therapeutic approaches. Further, since human GITRL has a different molecular structure and assembly from murine GITRL (Table 3), biologicals agents such as anti-human GITR mAbs and human GITR fusion proteins can behave differently from the corresponding murine anti-GITR mAbs and GITRL fusion proteins… Therefore, caution is recommended when translating the findings of experimental murine models to human diseases (Riccardi, Carlo, Simona Ronchetti, and Giuseppe Nocentini. "Glucocorticoid-induced TNFR-related gene (GITR) as a therapeutic target for immunotherapy." Expert opinion on therapeutic targets 22, no. 9 (2018): 783-797).”
Riccardi further comments on the difficulty with preclinical trials and scarcity of data pertaining to clinical trials, “Human GITR is structurally different from murine GITR. Therefore, it is not easy to conduct preclinical studies. The most appropriate are humanized mice model, but the model is expensive and not well characterized. Since in vivo ADCC of Tregs is observed in tumor microenvironment, the activity of anti-hGITR Abs cannot be tested by in vitro assays. Moreover, most of the anti-human GITR mAbs available on the market are weak agonists, and this may be attributable to the trimeric structure of human GITR. Multimeric GITRL appears to have much stronger co-stimulatory activity. Several companies have patented anti-hGITR Abs and published the related data, but the information provided is not sufficient to evaluate their agonist activity. One of these companies has prepared an engineered antibody that is unable to bind the Fc receptor, and has shown that the antibody has co-stimulatory effects on CD8+ T cells. Another company has prepared an antibody that cause tumor growth inhibition through increased immune activation, attenuated Treg frequency and a decreased suppressive phenotype in humanized mice. However, no data from the phase I and phase I/II studies are available” (Riccardi, Carlo, Simona Ronchetti, and Giuseppe Nocentini. "Glucocorticoid-induced TNFR-related gene (GITR) as a therapeutic target for immunotherapy." Expert opinion on therapeutic targets 22, no. 9 (2018): 783-797).
Additionally, to the best of the examiner’s knowledge, based on prior art, there have been no reported clinical successes using GITR agonists to treat cancer.
As Davar explains, “Overall, the clinical results obtained so far with GITR agonist agents have demonstrated specific immune effects in the expected immune cell populations based on preclinical studies. However, these effects have not produced substantial therapeutic activity in cancer patients. Furthermore, these results underscore the mechanistic differences of critical immunotherapeutic pathways between preclinical animal models and humans. This suggests that advancing translational science for transformational impact in patients requires dedicated reverse translational efforts and the use of improved preclinical models (Davar, Diwakar, and Roberta Zappasodi. "Targeting GITR in cancer immunotherapy–there is no perfect knowledge." Oncotarget 14 (2023): 614).
Therefore, it is reasonable to conclude that the current state of the art is highly unpredictable, indicating that more details, working examples and guidance would be required to practice the invention as disclosed for all types of cancer in all subjects as claimed.
The level of one of ordinary skill
The person of ordinary skill in the art is a hypothetical person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the level of ordinary skill in the art may include: (A) "type of problems encountered in the art;" (B) "prior art solutions to those problems;" (C) "rapidity with which innovations are made;" (D) "sophistication of the technology; and" (E) "educational level of active workers in the field. In a given case, every factor may not be present, and one or more factors may predominate." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP § 2141.03 (I)
The invention described pertains to the biomedical and pharmaceutical arts. One of ordinary skill would be a person with considerable training in medicine, veterinary medicine, pharmacology, medicinal chemistry, biochemistry or a related technical discipline.
The level of predictability in the art
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling.
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. See MPEP § 2164.03.
Consequently, technologies involving physiological activity as opposed to mechanical or electrical inventions are generally regarded as being unpredictable sciences.
As forementioned, cancer is a dynamic disease and additionally known to be highly unpredictable. In terms of the GITR/GITRL agonists, many challenges and unknowns are still ongoing investigation within the field in terms as aforementioned. Additionally, there are well-known challenges translating from murine models to humans. Consequently, this field is also highly unpredictable.
In this context, based on assessing the fields of study, the predictability in the art is very low.
Consequently, the applicant would need to provide more details, working examples and guidance in order for the claimed invention to be enabling based on the scope and nature of the claimed invention.
The amount of direction provided by the inventor
As aforementioned, the amount of direction provided depends on the prior art and predictability of in the art. Based on the scope of protection sought by the applicant and the discussion aforementioned, the inventor has failed to provide sufficient direction for one ordinarily skilled in the art to practice the disclosed invention as claimed.
The existence of working examples
The applicants’ working examples are directed towards:
Measuring the effect of the GITR agonist on T effector cells and Tregs (human blood).
T cell suppression assay (in vitro human cell)
Effect of RMGL171102 on T cell proliferation.
Effect of GITR agonist on melanoma growth via implantation of B16 murine tumor cells in mice.
However, there are no actual human cell lines screened or additional working examples.
There are also no working examples supporting administration of existing therapies as per claim 5. Applicant simply remarks that “Both of these groups showed increased PD-1 expression suggesting increased IFN gamma induced upregulation of PD-1 and invoking the potential synergy of this agent with PD-1 checkpoint blockade.”
Based on the prior art as aforementioned, it is also known that there are significant challenges translating murine models to humans in a clinical setting.
On this basis and the prior discussion, the working examples are both not commensurate with the scope of protection sought and are not enabling. One ordinarily skilled in the art would unable to simply translate the evidence provided by the applicant into methods encompassing the subjects claimed without undue experimentation.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
As aforementioned, the quantity of experimentation depends on the prior art, the predictability of the art, and the direction provided by the inventor, which are factors that were already discussed.
In order for one ordinarily skilled in the art to practice the invention as disclosed, some attributes one would require, but are not limited to:
In vitro & in vivo studies encompassing the diverse class of subjects listed (i.e.: humans, cows, mice, mammals, other animals) supporting translation of murine to human models. As mentioned, there are known challenges and issues with murine models and no human cell lines were screened.
Additional details on development of a treatment regime including how to determine effective dosage, timing, monitoring plan and administration method for the diverse class of subjects, cancers and disease progression.
Based on the preponderance of evidence and rationale put forth, the examiner concludes that one ordinarily skilled in the art would require undue experimentation in order to practice invention based on the details provided and scope of invention defined in Claims 1, 3, and 5.
Consequently, Claims 1, 3, and 5 remain rejected for lacking enablement.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 3 remain rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Schwartz et al. (US 20100297046 A1) (herein referred to as Schwartz).
Regarding claims 1 and 3, Schwartz teaches “A method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a GITR/GITRL agonist,” and “wherein the GITR/GIRL agonist is represented a compound of Formula I:
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Schwartz specifically teaches a compound of Formula I with anti-cancer properties, which is identical to the compound of instant claim 3 (see below, and claims 48-49) and methods for treating skin diseases or disorders including skin cancer and melanoma (see page 29, column 1 , paragraphs [0304] and [305]).
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Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). See MPEP § 2112.01, I.
"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. See MPEP § 2112.01, II.
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. See MPEP § 2112, I.
Consequently, although Schwartz does not teach that the compound of Formula I is specifically a GITR/GITRL agonist, Swartz does teach the anti-cancer properties of the compound of Formula I and methods for treating skin cancer. It is therefore reasonable to conclude that as the compounds are identical, the properties disclosed (i.e.: GITR/GITRL agonist) are also inherently present.
Therefore, claims 1, and 3 remain rejected as being anticipated by Schwartz.
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, 3, and 5 are provisionally rejected on the ground of anticipation-type nonstatutory double patenting as being unpatentable over claims 10-12, 14-15, 17, and 20-21 of copending Application No. 17/633,505.
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications recite claims directed to methods treating cancer using identical compounds.
It is also noted that both sets of claims use “comprising,” to describe the claimed methods for treating cancer. The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements, or method steps.
Consequently, both sets of claims permit the presence of additional method steps and/or unrecited elements. See MPEP § 2111.03.
Claim 1 of ‘505 teaches “A method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of T cells that have been activated ex vivo with an antigen presenting cell.”
Claim 10 of ‘505 teaches “The method of claim 1, further comprising contacting the T cells with GITR/GITRL agonist.”
Claims 11-12 of ‘505 teaches “The method of claim 10, wherein the GITR/GITRL agonist is represented by a compound of Formula I.”
Instant claim 1 teaches a method for treating cancer through administering a GITR/GITRL agonist, which directly maps to claim 1 of ‘505.
Instant claim 3 teach the identical compound of Formula I as the GITR/GITRL agonist, which directly maps to claims 11-12 of ‘5050.
As aforementioned, the transitional term “comprising” does not exclude the unrecited elements of claim 1 of ‘505.
Claim 14 of ‘505 teaches “The method of claim 1, further comprising administering existing therapies for cancer to the subject either co-administered or sequentially,” which directly maps, including using identical language to instant claim 5.
Claim 15 of ‘505 teaches methods for teaching identical cancers to the instant application, directly mapping to instant claim 1.
Claim 17 of ‘505 teaches methods for treating cancer using a GITR/GITRL agonist, which directly maps to claim 1.
Claim 20-21 of ‘505 teaches that the GITR/GITRL agonist is identical to a compound of Formula 1 in instant application, directly mapping to claims 3.
As aforementioned, the transitional term “comprising” does not exclude the unrecited elements of claim 1.
Consequently, claims 1,3, and 5 are rejected on grounds of anticipation-type nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection because the patentably
indistinct claims have not in fact been patented.
NEW REJECTIONS
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claims 1, 3, and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Schwartz et al. (US PG-PUB 2010/0297046 A1) in view of Mokhtari et al. (Mokhtari, Reza Bayat, Tina S. Homayouni, Narges Baluch, Evgeniya Morgatskaya, Sushil Kumar, Bikul Das, and Herman Yeger. "Combination therapy in combating cancer." Oncotarget 8, no. 23 (2017): 38022).
The teachings of Schwartz are set forth as applied above.
Schwartz does not explicitly teach the elements of claim 5 “further comprising administering existing therapies for cancer to the subject either co-administered or sequentially.”
Mokhtari teaches that “Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis (abstract).”
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have modified Schwartz’s invention to incorporate combination therapy in treating skin cancer because Schwartz teaches compounds and methods for treating skin cancer and because Mokhtari teaches that combination therapy is a cornerstone of cancer therapy and provides numerous benefits including enhanced efficacy, reduced drug resistance, etc.
Consequently, a person of ordinary skill in the art would have arrived at instant invention as a highly predictable result with a reasonable expectation of success in developing an effective and comprehensive treatment plan for a patient with skin cancer as the use of combination therapy is routine practice the field of oncology.
Therefore, claims 1, 3, and 5 are rejected on grounds of obviousness.
Response to Arguments
The Remarks of February 20, 2026 have been fully considered but are not fully persuasive for the reasons below.
35 USC 112(a)
Applicant’s Arguments:
“The Examiner has indicated that the present claims directed to treating melanoma are enabled but not treatment of other types of cancer. Applicant vigorously disagrees with this statement. However, in order to expedite prosecution of the present application, the claims have been amended to refer to treatment of melanoma.”
Examiner’s Response:
The Examiner acknowledges Applicant’s claim amendments to narrow the scope towards melanoma; however, as aforementioned, the claims are also broad towards subject. Applicant’s working examples are solely directed towards murine models. No human cell lines or other animal models or studies were performed.
As aforementioned in the enablement rejection, the Examiner cites to Riccardi who notes “The preferential/selective effect of different agents (mAbs, receptors or ligand fusion proteins) on conventional or suppressor components of the immune response needs to be clarified for the establishment of effective therapeutic approaches. Further, since human GITRL has a different molecular structure and assembly from murine GITRL (Table 3), biologicals agents such as anti-human GITR mAbs and human GITR fusion proteins can behave differently from the corresponding murine anti-GITR mAbs and GITRL fusion proteins… Therefore, caution is recommended when translating the findings of experimental murine models to human diseases (Riccardi, Carlo, Simona Ronchetti, and Giuseppe Nocentini. "Glucocorticoid-induced TNFR-related gene (GITR) as a therapeutic target for immunotherapy." Expert opinion on therapeutic targets 22, no. 9 (2018): 783-797).”
Riccardi further comments on the difficulty with preclinical trials and scarcity of data pertaining to clinical trials, “Human GITR is structurally different from murine GITR. Therefore, it is not easy to conduct preclinical studies. The most appropriate are humanized mice model, but the model is expensive and not well characterized. Since in vivo ADCC of Tregs is observed in tumor microenvironment, the activity of anti-hGITR Abs cannot be tested by in vitro assays. Moreover, most of the anti-human GITR mAbs available on the market are weak agonists, and this may be attributable to the trimeric structure of human GITR. Multimeric GITRL appears to have much stronger co-stimulatory activity. Several companies have patented anti-hGITR Abs and published the related data, but the information provided is not sufficient to evaluate their agonist activity. One of these companies has prepared an engineered antibody that is unable to bind the Fc receptor, and has shown that the antibody has co-stimulatory effects on CD8+ T cells. Another company has prepared an antibody that cause tumor growth inhibition through increased immune activation, attenuated Treg frequency and a decreased suppressive phenotype in humanized mice. However, no data from the phase I and phase I/II studies are available” (Riccardi, Carlo, Simona Ronchetti, and Giuseppe Nocentini. "Glucocorticoid-induced TNFR-related gene (GITR) as a therapeutic target for immunotherapy." Expert opinion on therapeutic targets 22, no. 9 (2018): 783-797).”
Additionally, as aforementioned, the Examiner cites to Davar who explains “Overall, the clinical results obtained so far with GITR agonist agents have demonstrated specific immune effects in the expected immune cell populations based on preclinical studies. However, these effects have not produced substantial therapeutic activity in cancer patients. Furthermore, these results underscore the mechanistic differences of critical immunotherapeutic pathways between preclinical animal models and humans. This suggests that advancing translational science for transformational impact in patients requires dedicated reverse translational efforts and the use of improved preclinical models (Davar, Diwakar, and Roberta Zappasodi. "Targeting GITR in cancer immunotherapy–there is no perfect knowledge." Oncotarget 14 (2023): 614).
Consequently, Applicant is invited to address the points raised by Riccardi and Davar concerning issues translating murine models into other subjects including humans.
Therefore, the claims remain rejected for lack of enablement.
35 USC 102(a)(1) and (a)(2)
Applicant’s Arguments:
“Schwartz fails to anticipate the present claims because the reference fails to disclose or suggest or inherently disclose a method of treating melanoma in a human or mammal by administering the claimed GITRL agonist compound of Formula I. The presently claimed method requires administering a compound of Formula I as a GITRL agonist, which modulates the GITR/GITRL pathway to enhance T-effector cell activity and neutralize T-regulatory cell suppression for anti-cancer effects. In contrast, Schwartz's compounds are FN3K inhibitors, aimed at preventing glycation (See for example Schwartz, Fig. 1).
Further, even if Schwartz broadly mentions "skin diseases," this does not anticipate treating melanoma, a specific skin cancer, via immunotherapy. Anticipation requires every element to be described or inherently present. Also, a reference anticipates only if the allegedly inherent feature is necessarily and inevitably present, not merely probably or possibly present. See In re Robertson, 169 F.3d 743 (Fed. Cir. 1999); Continental Can, 948 F.2d 1264 (Fed. Cir. 1991). The prior art must inevitably include the claimed feature. It is not enough that it could, might, or probably does. Here, the GITRL agonist property and melanoma treatment do not "necessarily and inevitably" flow from Schwartz's teachings. The present application demonstrates the novel discovery of the Formula I as GITRL agonist, which is not recognized at all in Schwartz. Accordingly, Schwartz fails to anticipate the present invention.”
Examiner’s Response:
The Examiner respectively disagrees. As aforementioned, Schwartz teaches the identical compound as in instant invention and methods for treating melanoma as in the instant invention.
As per MPEP 2112.01: “"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”
Applicant is reminded as per MPEP 2112. II: “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).”
Additionally, as per MPEP 2112.02: “The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978).”
As the Examiner has presented evidence and reasoning to show inherency, the burden of production once more shifts to Applicant to demonstrate how the compounds and methods in instant invention are materially different from Schwartz. See MPEP 2112.V.
Consequently, claims 1 and 3 remain rejected as being anticipated by Schwartz.
35 USC 103
Applicant’s Arguments:
“However, Mokhtari fails to disclose or suggest the GITR/GITRL pathway, immune checkpoint modulation, or melanoma specifically. Mokhtari fails to disclose or suggest a link to FN3K inhibitors or Schwartz-like compounds. The combination of Schwartz and Mokhtari fails to render the present claims obvious because there is no motivation to modify Schwartz's oxidative stress inhibitors for use as GITRL agonists in treating melanoma, and no reasonable expectation of success in achieving the claimed immunomodulatory effects. As argued above, Schwartz teaches FN3K inhibitors for non-cancer conditions like oxidative stress and skin diseases, without mentioning cancer treatment or GITRL modulation. Mokhtari is a general review article of combination therapies, emphasizing synergies in targeting pathways like Nrf2-Keap1, HIF-1α, and CAIX to reduce resistance and toxicity. Mokhtari discusses repurposing non-cancer drugs (e.g., minocycline with sabutoclax) but provides no specific guidance on FN3K inhibitors, GITR/GITRL pathways, or melanoma. Mokhtari lacks any reference to GITR, GITRL, or related immune checkpoints, focusing instead on metabolic and hypoxic targets. Obviousness requires an articulated reason with a rational underpinning to combine or modify prior art (KSR Int'l Co. V. Teleflex Inc., 550 U.S. 398 (2007)). A skilled artisan would not be motivated to combine these references to arrive at the claimed method, as Mokhtari's disclosure is unrelated to Schwartz's mechanism or the GITRL agonism required by the claims. There is no reasonable expectation that Schwartz's compounds would act as GITRL agonists or treat melanoma via T-cell modulation, as this property is absent from both references. In addition, Applicant notes that the present application provides unexpected GITRL agonist activity in melanoma models, which further provides evidence of non-obviousness. Accordingly, the present invention is not obvious over the cited references.”
Examiner’s Response:
The teachings of Schwartz have been previously discussed. As aforementioned, Applicant themselves have provided no working examples pertaining to combination therapies. Mokhtari is cited as evidence discussing the importance and obviousness to use combination therapy in developing cancer therapies. Mokhtari discusses how combination therapy can help enhance efficacy. Therefore, Mokhtari establishes that it is routine in the art of cancer oncology to explore combination therapy as part of routine optimization to arrive at a suitable treatment plan for cancer patients and improve efficacy. Consequently, it would be prima facie obvious and highly predictable with reasonable expectation of success to modify Schwartz’s invention already directed towards the identical compound and method of treating melanoma to incorporate combination therapies and optimize the treatment plan for cancer patients.
Applicant is reminded that “in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).”
As per MPEP 2145, IV: Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually…This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012)
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the motivation originates from knowledge generally available to one of ordinary skill in the art as combination therapy is a well-known strategy used to optimize cancer treatments as supported by Mokhtari.
Therefore, Claims 1, 3, and 5 remain rejected as being obvious.
Double Patenting
Once more, no arguments were provided by Applicant against the nonstatutory double patenting rejection, and claim amendments remain insufficient to overcome this rejection.
Conclusion
Claims 1, 3, and 5 are under consideration and remain rejected.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) 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.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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