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
This application filed on 12/04/2023, is a national phase application under 35 U.S.C. § 371 of International Application No. PCT/US2022/032707, filed on 06/08/2022, which claims benefit of U.S. Provisional Patent Application No. 63/208,923 filed on 06/09/2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 03/08/2024, 04/05/2024, 04/09/2024, 07/24/2025, 10/13/2025, 10/20/2025, and 03/04/2026, comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, these have been placed in the application file and the information therein has been considered as to the merits, except where noted.
Status of claims
The premilitary amendment filed on 12/13/2023, that amended claims 1, 14-15, 18-21, 23-27, 29-30 and 32, and canceled claims 2-13, 17, 22, 28, 31 and 33-42, is acknowledged.
Claims 1, 14-16, 18-21, 23-27, 29-30, and 32 are pending.
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.
Claim 32 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)”. The “use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
By way of background, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to “The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors” using a small genus of compounds. The Court decided that human testing “limited to one compound and two types of cancer” was not “commensurate with the broad scope of utility asserted and claimed”.
In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to “the treatment of certain specified cancers in humans” by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted “affidavits, publications and data” for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to “A therapeutic method for reducing metastasis and neoplastic growth in a mammal” using a single species. The decision notes that such utility “is no longer considered to be “incredible””, but that “the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence.” Note also that there is also a dependent claim 5 which specified “wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma.” The decision notes that “even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy.”
In Ex parte Stevens, 16 USPQ2d 1379 a claim to “A method for therapeutic or prophylactic treatment of cancer in mammalian hosts” was refused because there was “no actual evidence of the effectiveness of the claimed composition and process in achieving that utility.”
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required:
(1) The breadth of the claims
(2) The nature of the invention
(3) The state of the prior art
(4) The level of one of ordinary skill
(5) The level of predictability in the art
(6) The amount of direction provided by the inventor
(7) The existence of working examples
(8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(1) The breadth of the claims:
The presently claimed invention is directed to a method for the treatment of cancer comprising administering to a mammal with cancer an effective amount of a compound of Formula (I), wherein NP is Formula (X), L is a linker that covalently connects NP and Q, and Q is cytotoxic drug, kinase inhibitor or both, or a pharmaceutically acceptable salt thereof.
Cancer is not a single disease, or a cluster of closely related disorders. There are hundreds of proliferative diseases, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain, and salivary glands. They can occur in every part of the body. The specification and the art of record fail to disclose a validated marker or method for predicting a benefit from the instantly claimed compounds. Therefore, the scope of the diseases covered is deemed very broad, and cannot be considered enabled by the instant specification. In addition, treating a cancer encompasses thousands of anti-cancer/antitumor agents under the classes such as small molecular chemotherapy, antitumor antibiotic substance, a platinum-based agent, etc. is deemed very broad, and cannot be considered enabled by the instant specification.
(2) The nature of the invention:
The present claims describe a method for treating every cancer. That is; in order to be enabled to practice the present invention, the skilled artisan would have to accept that by administering a compound of Formula (I) to a cancer patient that such therapeutic objectives could actually be achieved. However, in light of the fact that the specification fails to provide the skilled artisan with any direction or guidance as to how the treatment of cancer in general could be achieved, or how the compound of Formula (I) dose or regimen will be selected for treating any particular kind of cancer, and how to select a compound of Formula (I) that comprises Q, any chemotherapeutic agent, L, cleavable or non-cleavable linker, and non-peptide ligand, Formula (X) that include substituted or unsubstituted variables, the present specification is viewed as lacking an enabling disclosure of the entire scope of the claimed invention.
(3) The state of the Prior Art:
The instant claims are directed to a method for treating cancer comprising administering to a mammal with cancer an effective amount of a compound of Formula (I), wherein NP is Formula (X), L is a linker covalently connects NP and Q, and Q is cytotoxic drug, kinase inhibitor or both, or a pharmaceutically acceptable salt thereof. However, as taught by Chakraborty (S. Chakraborty, et al. Ecancermedicalscience. 2012, 14;6:ed16. doi: 10.3332/ecancer.2012.ed16), “the cure for cancer is like the Holy Grail since most of the existing treatments are not effective enough to provide full protection from this disease”. Chakraborty teaches that “in recent years the burgeoning of sophisticated genomic, proteomic and bioinformatics techniques has made it possible for us to get a glimpse of the intricate interplay of numerous cellular genes and regulatory genetic elements that are responsible for the manifestation of cancerous phenotypes. With the use of modern genomic technologies, we are now beginning to understand the enormous complexity of cancer, however, there are few success stories as far as the treatment of cancer is concerned, [Abstract]. Chakraborty teaches that the non-specific nature of cancer symptoms makes diagnosis difficult (let alone treatment). Chakraborty teaches examples of cancer with diagnosis difficulties include esophageal cancer, prostate cancer, and pancreatic cancer. [Page 3-4]. Moreover, Zafar (A. Zafar, et al. Med Res Rev. 2021;41:961–1021, DOI: 10.1002/med.21750), teaches the challenges associated with neuroblastoma treatment. Zafar teaches that standard treatment in children all lead to relatively poor outcomes for NB treatment. It is also important to note that oncology drugs have the lowest LOA (likelihood of approval) from phase I (6.7%) compared with drugs used for other diseases (allergy, dermatology, urology, autoimmune disease, and ophthalmology). Complicating matters, the current treatments approved for NB have limited targeted specificity. [Page 964, 1st para.].
Numerous mechanisms have been proposed as methods of treating assorted cancers a selection of which follow. Cytotoxic agents could be applied directly to the tumor’s cells, directly killing them. Immunotherapy to stimulate the patient's immune system to attack cancer cells, either by immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Increasing the amount or activity of the body’s tumor suppressor genes, PTEN, APC and CD95, which can, for example, activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. Angiogenesis inhibitor strategies based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells.
A number of these approaches – and others as well – have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, these approaches have yet to produce a drug which can claim such a goal.
Specifically, the prior art demonstrates that there never has been a compound capable of treating cancers generally. “The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally.” A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to determine how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally, and the existence of such a single treatment for cancer is contrary to our present understanding in oncology. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from an exceptionally wide variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses, exposure to environmental chemicals (e.g. tobacco tars, alcohol, toxins), ionizing radiation, and unknown environment factors.
Accordingly, there is substantive “reason for one skilled in the art to question the objective truth of the statement of utility or its scope” (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
Similarly, In re Novak, 134 USPQ 335, 337-338, says “unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them.” There is no such evidence in this case. Likewise, In re Cortright, 49 USPQ2d 1464, states: “Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient” does what the specification surmises that it does. That is exactly the case here. Moreover, even if applicants’ assertion that cancer in general could be treated with these compounds were plausible, which it is not, that “plausible” would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.”
(4) The skill of those in the art:
The skill of those in the art is expected to be high, requiring advanced training in chemistry, medicine, or pharmacology.
(5) The level of predictability in the art:
With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] …anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
With this in mind the level of predictability in the art is sufficiently low that even with hundreds of successful examples of chemotherapy there has yet to be shown any single method of treating the vast scope of cancers known. The level of unpredictability in the art renders the scope of instant claim to be not enabled.
(6) The amount of direction provided:
While the treatment of cancer is discussed in broad terms, the necessary specifics, i.e. dosing, therapeutic index, contraindications, interaction between the claimed compound with other antitumor agents, toxicity etc., are completely absent. And while the anti-cancer agent therapy is discussed in broad terms, only in vitro assays of the claimed conjugates on Chinese hamster ovary cells (CHO-Kl, ATCC #CCL-61) was provided. [Specification, page 75]. The limited assays do very little to provide the necessary information, and, in light of the immense diversity of types of cancers and their varied reactions to treatment, the guidance provided is very limited.
(7) Working examples:
The examples of the treatment of cancer are limited to only one example of the biological activity of the claimed conjugate Formula (I), wherein Q is Auristatin, NP is the claimed Formula (X), and the linker is a PEG chain, [Specification, page 77, Table B 1st entry]. The other two assays include a Gq1u-coupled receptor assay using 30,000 Flpln T-Rex 293 Cells and various concentrations of fixed compound, and various dilutions of compounds tested on 5,000 Chinese hamster ovary cells (CHO-Kl, ATCC #CCL-61) and (data/results not described), [Specification, page 75-76]. The only type of cancer tested in these examples is Chinese hamster ovary cells in vitro testing. While the claims are directed to multiple conjugates of Formula (I) with cytotoxic agent, kinase inhibitor, or both, the specification only provides one example of the claimed NP ligand of Formula (X) and Auristatin without providing data on the effect of this conjugate on any type of cancer, let alone all types of cancer. The exceptional diversity of cancers, and the treatment of them, is not well represented by these examples. It is well known that there is no single treatment that works for all kinds of cancers, so the experimentation required, based on solely limited cell line assays to practice the instant invention would be egregious.
(8) The quantity of experimentation needed:
Given the fact that, historically, the development of new cancer drugs has been difficult and time consuming, and especially in view of the above factors, the quantity of experimentation needed is expected to be great. However, the quantity needed to expand limited cell line assays as a working example provided in the instant specification to a viable treatment for the claimed scope of cancer or tumor is untenable.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 nonobviousness.
Claims 1, 14-16, 18-20, 23-26, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over P. Limonta, et al., Endocrine Reviews, Volume 33, Issue 5, 1 October 2012, Pages 784–811, “Limonta” cited in the IDS dated 10/20/2025) in view of D., Olberg et al. Bioorganic & Medicinal Chemistry Letters, Volume 24, Issue 7, 1 April 2014, Pages 1846-1850, “Olberg“ cited in the PTO-892).
Limonta teaches a GnRH antagonist-based cytotoxic hybrids as targeted therapeutic strategies for treating cancer. [Abstract]. Limonta teaches non-peptide GnRH antagonist CMPD1 as one of the potent GnRH antagonists [page 790, col. 1, and Figure 1]:
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Limonta teaches that CMPD1 is an active GnRH-R antagonistic agents that block the GnRH-R in the nanomolar range, CMPD1 has been used for the treatment of sex hormone-related diseases, CMPD1 bind with high affinity to rat, mouse, and human pituitary GnRH-R, and administration of CMPD1, both iv and orally, dose-dependently suppresses testosterone levels and counteracts GnRH agonist-stimulated gonadotropin and testosterone release, which indicates utility for the treatment of androgen-dependent tumors. [page 790, col. 1, last para. -col. 2, 1st para.]. Limonta’s non-peptide GnRH receptor antagonist CMPD1 above reads on instant Formula (X), wherein T is absent, V and W are N, and X is O.
Limonta teaches that cytotoxic hybrids represent one of the most promising targeted therapeutic strategies for tumors expressing the GnRH-R. linking a GnRH analog to a traditional cytotoxic compound would allow its specific targeting to GnRH-R-expressing cancer cells. The. more efficient conjugates wherein the GnRH analog binds GnRH-R with high affinity is linked to the cytotoxic drug. [page 797, col. 2, last para.]. Limonta teaches that in cancer cells of the female reproductive system, the conjugate may overcome the mechanisms of chemoresistance because the cytotoxicity of the hybrid was found to be independent of the multidrug resistance-1 system. The multidrug resistance together with the low toxicity of the conjugated compound, strongly support the clinical utility of conjugate targeted chemotherapy. [page 798, col. 1, 2nd para.]. Limonta also teaches a study when the hybrid conjugate includes chemotherapy taxane-based regimen. The primary outcome of this study was the clinical benefit of the treatment defined by non-progression of the disease as well as by no dose-limiting toxicity or other toxicity elements requiring termination of the treatment. Secondary outcome measures included time to overall disease progression, PSA response, time to PSA progression, and overall survival. [page 798, col. 1, last para.].
Limonta teaches that novel cytotoxic hybrid conjugate includes docetaxel because docetaxel is, at present, the first-line chemotherapy treatment for castration-resistant prostate cancer patients [page 798, col. 2, 1st para.].
Limonta teaches a conjugate of anticancer drug paclitaxel and a synthetic GnRH analog, [page 799, col. 2, 1st para.]:
Tax-polyethylene glycol (PEG)-GnRH
In view of the forgoing discussion, Limonta teaches conjugates of cytotoxic and GnRH antagonist, wherein the cytotoxic agent is covalently linked to the GnRH. Limonta teaches CMPD1 as a potent GnRH antagonist. However, Limonta does not specifically teach CMPD1-linker-cytotoxic agent as described by claimed 1.
However, Olberg teaches small molecule non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonists and in vitro evaluation for the GnRH antagonist receptor binding affinities. Olberg’s GnRH antagonists are depicted below:
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Olberg teaches the benefits of using small molecule GnRH receptor antagonists include better pharmacokinetic properties, putatively increased metabolic stability and are good candidate for a small radio labeled molecule. Olberg teaches that for the development of a positron emission tomography ligand, the pyrimidine functionality is being highly activated system for SNAr type reaction as a convenient introduction point for a suitable linker. Olberg teaches that labeling can be introduced directly on the pyrimidine ring or through a linker. [page 1847, col. 2, 1st para.]. Olberg teaches that “an alkoxy or alkylamine linker in the pyrimidine 2-position is normally required to obtain GnRH antagonists with low nM affinity” [page 1848, col. 2, 2nd para.].
Olberg’s non-peptide GnRH receptor antagonist above reads on instant Formula (X), wherein T is absent, V and W are N, and X is O.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective fining date of instantly claimed invention to utilize Limonta’s GnRH antagonist-cytotoxic hybrid anticancer therapeutic strategy using GnRH antagonist taught by both Limonta and Olberg. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because: Limonta teaches that cytotoxic hybrids are one of the best targeted therapeutic strategies for tumors expressing the GnRH-R; the conjugate overcomes chemoresistance; low toxicity of the conjugated compound; the conjugate resulted in better outcomes and non-progression of the disease; and linking a GnRH antagonist to a traditional cytotoxic compound would allow its specific targeting to GnRH-R-expressing cancer cells. Moreover, Limonta teaches taxane-based conjugates as an example of the GnRH antagonist-cytotoxic conjugate: Tax-polyethylene glycol (PEG)-GnRH. One of ordinary skill in the art would have been motivated to use Limonta’s CMPD1 as the GnRH antagonist in Limonta’s GnRH antagonist-cytotoxic conjugate because: Limonta teaches that CMPD1 is an active GnRH-R antagonistic agents that block the GnRH-R in the nanomolar range; CMPD1 bind to GnRH receptor with high affinity; Limonta teaches that more efficient conjugates wherein the GnRH analog binds GnRH-R with high affinity is linked to the cytotoxic drug; Olberg teaches that the benefits of using the GnRH antagonist above include better Pharmacokinetic properties, putatively increased metabolic stability and are suitable for binding to linkers; the pyrimidine functionality is highly activated system for SNAr type reaction as a convenient introduction point for a suitable linker. Moreover, Olberg teaches that “an alkoxy or alkylamine linker in the pyrimidine 2-position are normally required to obtain GnRH antagonists with low nM affinity”. Furthermore, Olberg teaches the procedure of forming linker at the pyrimidine ring. Therefore, one of ordinary skill in the art would have been motivated to utilize Olberg’s GnRH antagonist above and the linker-forming procedure at pyrimidine 2-position, and Limonta’s hybrid, Tax-polyethylene glycol (PEG)-GnRH to prepare the conjugate below:
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The above conjugate reads on claimed formula (I) wherein NP is Formula (X); L is PEG; Q is taxane. Therefore, the combination of Limonta and Olberg teach each and every limitation of claim 1.
Claim 14 is met by the GnRH above; claims 15 and 16 are met because Q is a cytotoxic and PEG is a cleavable or a non-cleavable linker, see instant specification at [00134]; claims 18 and 19 are met because the cytotoxic of the conjugate is a taxane.
Claims 23, 24, 26 are met because PEG reads on the linkers described by the claims, wherein x is O, and claim 25 is met because Olberg teaches that the linker at pyrimidine 2-position can be Oxy or amino.
With regard to claim 20, one of ordinary skill in the art would have been motivated to substitute the taxane of the conjugate above with a kinase inhibitor, e.g., tyrosine kinase inhibitor because Limonta teaches the association of kinase and GnRH receptor in cancer cells; the kinase p38MAPK mediates the apoptotic effect of GnRH antagonist; the crucial effect of GnRH receptor on tyrosine kinase receptor at the membrane level of cancer cells; and in prostate cancer cells, GnRH analogs have been consistently shown to reduce the expression/activity of epidermal growth factor receptors and silencing their specific MAPK and PI3K/Akt intracellular signaling pathways. [page, 794, col. 2, last para.- page 795, col. 1, Figure 5].
With regard to claim 30, one of ordinary skill in the art would have been motivated with reasonable expectation of success to prepare a pharmaceutical composition of the above conjugate and pharmaceutically acceptable carrier because Olberg teaches in vivo testing using a composition of the GnRH above in DMSO. [page 1848, col. 2, 3rd para.]. moreover, Limonta teaches that the GnRH above is prepared in oral and intervenors composition. [page 790, col. 1, 3rd para.]. Furthermore, the conjugates taught by Limonta were in vitro and in vivo tested and are administrated in pharmaceutically acceptable composition. (whole document).
Reasons for Allowable
Claims 21, 27, and 29 are allowed.
The following is an examiner’s statement of reasons for allowance:
The closest prior art is considered to be P. Limonta, et al., Endocrine Reviews, Volume 33, Issue 5, 1 October 2012, Pages 784–811, “Limonta” cited in the IDS dated 10/20/2025) and D, Olberg et al. Bioorganic & Medicinal Chemistry Letters, Volume 24, Issue 7, 1 April 2014, Pages 1846-1850, “Olberg“ cited in the PTO-892).
The disclosures set forth above in the 103 Rejection over the same Limonta et al. and Olberg et al. references are herein incorporated by reference.
The combination of Limonta and Olberg teaches a conjugate comprises a non-peptide ligand of Formula X (wherein T is absent, V and W are N, and X is O or N); linker L (PEG); and a cytotoxic agent Q.
While the combination of Limonta and Olberg teaches that Q is an anti-cancer cytotoxic e.g., taxane, the combination of Limonta and Olberg does not teach the anti-cancer cytotoxic is the agent recited in claim 21 (claim 27 recites the -L-Q with Q is the cytotoxic agents of claim 21, and claim 29 recites conjugates of claim 21 cytotoxic agents).
In order to arrive at the claimed conjugates of claims 21, 27, and 29, one of ordinary skill in the art would have to replace Limonta’s taxane in the conjugate (Tax-PEG-GnRH antagonist) with the cytotoxic of claim 21, and replace PEG with the linkers of claims 27 and 29 to arrive at the claimed conjugates. However, Limonta’s and Olberg’s disclosures do not provide sufficient guidance and motivation to one of ordinary skill in the art to perform the functional modifications and replace the cytotoxic and linkers to arrive at instantly claimed conjugates. Therefore, Limonta and Olberg do not anticipate or render the conjugates of claims 21, 27, and 29 obvious.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 1, 14-16, 18-20, 23-26, 30 and 32 are rejected. Claims 21, 27 and 29 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MANAHIL MIRGHANI ALI ABDALHAMEED whose telephone number is (571)272-1242. The examiner can normally be reached M-F 7:30 am - 5:00 pm.
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/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622