DETAILED ACTION
Examiner acknowledges receipt of the reply filed 4/02/2026, in response to the non-final office action mailed 1/02/2026.
Claims 5-12 are pending. claims 10-12 are newly added.
Claims 5-12 are being examined on the merits in this office action.
Examiner acknowledges receipt of the supplemental specification filed 4/02/2026.
The PPH petition was approved 10/28/2025.
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 .
Claim Objections- withdrawn
The objection of claims 5-9 is withdrawn in view of the amendment filed 4/02/2026.
Response to Arguments
Applicant's arguments and amendment filed 4/02/2026 with respect to the above objection have been fully considered and are persuasive. The objection have been withdrawn.
Applicant's arguments and amendment filed 4/02/2026 have been fully considered but they are not persuasive with respect to the maintained rejection.
Upon further consideration of the claims and claim scope, a new objection and rejections are set forth herein.
An action on the merits is set forth herein.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
ST.26 sequences guidelines became effective 7/1/2022. ST.26 sequences are required for applications filed under 35 USC 371, if the international filing date is July 1, 2022 or later. The instant application has priority to PCT application, PCT/CN2022/112763, international filing date August 16, 2022. Thus, ST.26 sequence guidelines apply to the instant application.
The claims and specification contain amino acid sequences comprising four or more amino acids not associated with a SEQ ID NO.
WIPO Standard ST.26, paragraph 28, specifies that disclosed amino acid sequences separated by internal terminator symbols, represented for example by "Ter" or asterisk "*" or period "." or a blank space, must be included as separate sequences for each enumerated amino acid sequence that contains at least four specifically defined amino acids and is encompassed by the description of sequences found in MPEP § 2412.03. Each such separate sequence must be assigned its own sequence identifier (SEQ ID NO; MPEP § 2412.05(a)).
Examiner notes that under st.26 guidelines, chemical structures, including cyclic structures, containing amino acid sequences require a SEQ ID NO. Enumerated amino acids that must disclosed in a Sequence Listing under st.26 guidelines further include non-natural amino acids and/or D-amino acids.
Assistance with st.26 guidelines can be obtained through the PTO Sequence Help Desk at 571-272-2510 or email SequenceHelpDesk@uspto.gov.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
The specification is objected to for disclosing amino acid sequences (and chemical structures comprising amino acid sequences) comprising four (4) or more amino acids not associated with a SEQ ID NO.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 7 and 8 remain/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 [alleviating/ameliorating/reducing] lung cancer, ovarian cancer, prostate cancer, does not reasonably provide enablement for preventing/inhibiting onset/occurrence of EphA2 overexpressed solid tumors, e.g., lung cancer, ovarian cancer, prostate cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. This rejection is maintained from the office action mailed 1/02/2026, but has been amended to reflect claims filed 4/02/2026.
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 make and 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)” (emphasis added). The “make and 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 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). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
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, 418 F.2d 540, 163 USPQ 689 (CCPA 1969), 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 (Bd. Pat. App. & Inter. 1981) 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 (Bd. Pat. App. & Inter. 1986) 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 types are known to respond quite differently to various modes of therapy.”
In Ex parte Stevens, 16 USPQ2d 1379 (Bd. Pat. App. & Inter. 1990) 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: (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. 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) Breadth of claims.
Claim 7 is drawn to a method for treating EphA2 overexpressed solid tumors in a subject in need, comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 5, which recites a compound of formula V.
Claim 8 is drawn to method for treating EphA2 overexpressed solid tumors in a subject in need, comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 6, which recites 5 specific compounds of formula V.
The specification states at pp. 12-13:
The term “treatment” refers to the administration of the compounds of the present invention or formulations to ameliorate or eliminate diseases or one or more symptoms associated with the diseases, including:
(i) inhibiting the diseases or disease states, i.e., controlling the development of the diseases or disease states;
(ii) alleviating the diseases or disease states, i.e., causing regression of the diseases or disease states.
The term “therapeutically effective amount” refers to an amount of the compounds of the present invention used to (i) treat a particular disease, condition, or disorder, (ii) relieve, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount constituting a “therapeutically effective amount” of the compounds of the present invention will vary depending on the compounds, the disease states and severity, the method of administration, and the age of the mammal to be treated, but it may routinely be determined by those skilled in the art based on their knowledge and the disclosure.
Emphasis added. The term “subject” is not defined.
Examiner acknowledges applicant’s arguments filed 4/02/2026 asserting that the subject is limited to humans. However, given the broadest reasonable claim interpretation, subject is construed any and all animal species that express EphA2 and are subject to EphA2 overexpression solid tumors (lung, ovarian, or prostate).
Thus, the scope of treatment encompasses inhibiting/preventing tumor formation subjects [of potentially any animal species].
(b) Scope of the diseases covered.
There are many different types of cancers, but all share one hallmark characteristic: unchecked growth that progresses toward limitless expansion (National Institute of Cancer- understanding and related topics, accessed 8/21/2014 at URL: cancer.gov/cancertopics/understandingcancer at p. 2). 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 pretty much every part of the body. Id. Examiner notes that the following prior art is a selection of the recited forms of cancer.
A. Lung carcinoma is the leading cause of cancer-related death worldwide (Merck Manuals Lung Carcinoma accessed 3/12/2017 at URL merckmanuals.com/professional/pulmonary-disorders/tumors-of-the-lungs/lung-carcinoma- previously cited). About 85% of cases are related to cigarette smoking. Id. Treatment varies by cell type and by stage of disease. Primary treatments include surgery (depending on cell type and stage), chemotherapy and radiation therapy. Id.
B. Prostate Cancer covers a variety of cancer types. See e.g., Merck Manual Prostate Cancer accessed 8/21/2014 at URL: merckmanuals.com/home/kidney_and_urinary_tract_disorders/cancers_of_the_kidney_and_genitourinary_tract/prostate_cancer.html?qt=prostate cancer&alt=sh- previously cited. Among men in the United States, prostate cancer is the most common cancer and one of the most common causes of cancer death. Id.
The great majority of types of prostate cancers are not treatable with pharmaceuticals. Id.
(2) The nature of the invention and 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).
(3) Direction or Guidance: The guidance provided is limited. The specification fails to provide guidance on how a claimed compound would be sufficient to inhibit/prevent a EphA2 overexpressed tumors (e.g. lung, ovarian, or prostate) and potentially encompassing all animals species [presuming EphA2 is expressed].
No examples of preventing/inhibiting cancer onset were reduced practice.
The skilled artisan does not have sufficient guidance to extrapolate from the limited teachings from one single peptide and three cancer cell lines relating to treating [ameliorating] cancer to methods of preventing/inhibiting cancer onset. In order to prevent cancer, the skilled artisan must first be able to identify patient populations at risk for developing cancer, much less much less know dosage amounts, routes of administration, and dosing regimen that would be needed to prevent/inhibit cancer onset. The as-filed specification fails to provide such information.
Accordingly, the specification provides little guidance over the scope of the presently pending claims, as relating to preventing/inhibiting cancer (lung, ovarian or prostate).
(4) State of the Prior Art:
Xiao et al (J Hemat. Oncol. 13:114 (2020)- previously cited) teach that Eph receptors and the corresponding Eph receptor-interacting (ephrin) ligands jointly constitute a critical cell signaling network that has multiple functions. The tyrosine kinase EphA2, which belongs to the family of Eph receptors, is highly produced in tumor tissues, while found at relatively low levels in most normal adult tissues, indicating its potential application in cancer treatment. After 30 years of investigation, a large amount of data regarding EphA2 functions have been compiled. Meanwhile, several compounds targeting EphA2 have been evaluated and tested in clinical studies, albeit with limited clinical success (abstract).
London et al (Mol. Biol. Reports 47:8037-8048 (2020)- previously cited) teach Eph (erythropoietin-producing human hepatocellular) receptors form the largest known subfamily of receptor tyrosine kinases. These receptors interact with membrane-bound ephrin ligands via direct cell–cell interactions resulting in bi-directional activation of signal pathways (abstract). The Eph receptors also display properties of both tumor promoters and suppressors depending on the cellular context. Characterization of EphA2 receptor in regard to EphA2 dysregulation has revealed associations with various pathological processes, especially cancer. The analysis of various tumor types generally identify EphA2 receptor as overexpressed and/or mutated, and for certain types of cancers EphA2 is linked with poor prognosis and decreased patient survival. Id. Cyclic peptides represent are a promising class of EphA2 receptor-targeting agents. These are peptides that contain cysteine groups that form disulfide bonds and enable peptide cyclization. Most importantly, these cyclic peptides are Molecular Biology Reports (2020) 47:8037–8048 8045 1 3 favored over conventional peptides due to their constrained conformations; these offer potential for enhanced binding affinity and specificity, protection against proteolytic degradation, passive transcellular absorption, and improved metabolic stability (pp. 8044-45).
The connection between Eph receptors and cancers has been reinforced through many studies. However, the defined role of individual Eph receptors in specific cancers is currently poorly understood, as Eph receptors have been suggested to be oncogenic in certain situations, and tumor suppressing in others. There are many factors that confound the analysis of this family of receptors. For example, the roles of the tumor microenvironment and stroma, the different cell types involved, the cell surface molecules expressed, and the different homo- versus hetero-multimer Eph receptor interactions are all variables that can differ from one study to the next. Additionally, almost all Eph receptor studies to date have focused on single roles of Eph receptor activities (p. 8045).
(5) Working Examples: Examples 1-8 disclose synthesis of specific compounds of formula V. Test Example 1 discloses binding of the compounds to EphA2 protein on a chip. Test Example 2 discloses in vitro assessment of tumor cell lines NCI-H1975 and SK-OV-3 in which cell proliferation decreased. Test Examples 3 and 4 discloses an animal model of prostate and ovarian cancer, respectively, xenograft expressing PC-3 or SK-OV-3 Cells in which tumor growth was reduced.
Test Examples 5-7 disclose pharmacokinetic assessments of compounds in mice, rats, and monkeys. Test Examples 8 and 9 disclose stability of the compounds in plasma or blood from different species. Test Example 10 discloses metabolic stability of the compounds in hepatocytes from monkeys and humans.
There are no examples in which onset or initial growth of a EphA2 solid tumor was inhibited/prevented. Examiner expressly notes that Examples in the specification teach administering PDC8 to an existing cancer cells line [in vitro Ex 2], or an existing tumor [Exs 3-4: xenografts]. Thus, the cancer cell growth was reduced. There are no examples where initial onset of tumor was actually prevented/inhibited.
(6) Skill of those in the art: The relative skill of those in the art is high. An ordinary artisan in the area of drug development would have experience in screening peptide compounds for particular activities. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against particular biological target is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems such as cancers/tumors.
Determining how a particular compound will impact a particular form of cancer is not routine. There is no chemical targeting system at this time that can directly stimulate or block only a highly divergent cancer(s), while avoiding effects on other parts of the cells, where the same signal may have a different and unwanted effect. Further, the functioning of many networks and the pathology of many cancers involve complex systems involving more than one network. Thus, the level of ordinary skill in the art needs specialized knowledge of the complex nature of cancers/tumors.
Examiner expressly notes that in order to inhibit onset or prevent a EphA2 solid tumor, the skilled artisan must first be able to identify a subject(s) that is at risk for developing a EphA2 solid tumor, much less amounts/routes of administration, and treatment regimen of the claimed compound to inhibit onset or prevent a EphA2 solid tumor in a given subject.
(7) The quantity of experimentation needed: Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of factors 1-6, the quantity of experimentation needed is expected to be undue.
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.
Response to arguments
Applicant traversed the rejection at pp. 119-122 of the reply filed 4/02/2026. Applicant asserts that claims 7 and 8 have been amended to recite “ephrin A2 overexpressed solid tumor” and “lung cancer, ovarian cancer or prostate cancer” (reply at p. 120). Applicant asserts that the skilled artisan, based on the specification would clearly understand that the subject recited cited in the claims refers to a human. Examiner notes that the background the specification refers to cancer patients. In that the examples demonstrate binding affinity of 5 compounds to the EphA2 protein. Representative compound PDC_8 was used in in vitro assays against 2 different cancer types. Examples 3 and 4 assessed treating an existing xenograft of prostate or ovarian cancer cells, respectively. Examples 5-7 relate to pharmacokinetic assessments of compounds in mice, rats, and monkeys. Test Examples 8 and 9 disclose plasma stability of PDC_8. Example 10 discloses metabolic stability of PDC_8 in monkeys and humans. Applicant asserts that the experimental workflow follows a standard human drug development process progressing from molecular activity assays, in vitro and in vivo studies, and assessment of PK parameters. Applicant asserts that the amount of the application does not explicitly defined subject, the scope is directed to humans (reply at p. 120).
Applicant asserts that the claims group has been narrowed to “ephrin A2 overexpressed solid tumor” and “lung cancer, ovarian cancer or prostate cancer” (reply at p. 121). Applicant states: “Test Examples 2-4 provide ample evidence demonstrating that the compounds provided herein are useful for inhibiting the progression of these 3 types of tumors”. Id.
Regarding the nature of the invention, predictability in the art, and direction or guidance, Applicant asserts that test example 1 verified that the five compounds possess comparable affinity for the EphA2 protein. Id. Applicant asserts that the compounds have similar structures and properties and are therefore analogous. Applicant further asserts that the specification provides computations to specific cells/animals and specific cancer types, thus the skilled artisan would accept that other compound sharing similar structures and exhibiting comparable affinity for the Aph!2 protein would also possess similar biological activities, as provided by the representative compound PDC_8 (reduced to practice). Id.
Regarding the state of the prior art and working examples, applicant asserts that the claims have been narrowed to lung, ovarian, and prostate cancer and that Test Examples 2-4 “advantageously demonstrate the inhibitory effects of the compounds recited herein against these three types of tumors” (reply at p. 121).
Regarding skill of those in the art and the number experiments, applicant refers to examples 2-4 for the assertion that in vitro and in vivo the compounds provided “are effective in inhibiting lung cancer, ovarian cancer and prostate cancer resulting from EphA2 protein overexpression, thereby demonstrating the efficacy of the therapeutic method” (reply at pp. 121-122). Applicant asserts that the specification provides sufficient technical reasoning necessary for patentability, further referring to specification teaching peptide preparation, compound affinity, cellular and animal level activity validation, PK perimeter determination, plasma stability assays, and metabolic stability evaluations. Id. Applicant asserts that claims 7 and 8 satisfy the enablement requirement.
Examiner has reviewed and considered applicants arguments, but is not persuaded.
Examiner first notes that the scope of enablement has been revised to correlate with the findings of the instant specification, e.g., enabling for treating [specifically alleviating/ameliorating/reducing] lung cancer, ovarian cancer, prostate cancer, but
does not reasonably provide enablement for preventing/inhibiting onset/occurrence of EphA2 overexpressed solid tumors, e.g., lung cancer, ovarian cancer, prostate cancer.
There are no examples in which onset or initial growth of a EphA2 solid tumor was inhibited/prevented. Examiner expressly notes that Examples in the specification teach administering PDC8 to an existing cancer cells line [in vitro Ex 2], or an existing tumor [Exs 3-4: xenografts]. Thus, the cancer cell growth or tumor progression was reduced. There are no examples where initial onset of tumor was actually prevented/inhibited.
In order to inhibit onset or prevent a EphA2 solid tumor (lung, ovarian cancer, or prostate), the skilled artisan must first be able to identify a subject(s) that is at risk for developing a EphA2 solid tumor, much less amounts/routes of administration, and treatment regimen of the claimed compound to inhibit onset or prevent a EphA2 solid tumor (lung, ovarian cancer, or prostate) in a given subject (human).
The rejection is maintained for at least these reasons, and those previously made of record.
New Objections/Rejections
Claim Objections- New objection
Claims 5-12 are objected to because of the following informalities:
Claims 5, 6, 9, 10, 10, and 11 are objected to for disclosing amino acids sequences comprising four (4) or more amino acids not associated with a SEQ ID NO. See st.26 sequence guidelines.
Claims 7, 8, and 11 should be amended to recite “treating an ephrin A2 overexpressed solid tumor
Claims 10 should be amended to recite “The [[A]] compound according to claim 6:[[,]]
Claims 10 should be amended to recite: “The [[A]] compound :[[,]]”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 11 is 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 [alleviating/ameliorating/reducing] lung cancer, ovarian cancer, prostate cancer, does not reasonably provide enablement for preventing/inhibiting onset/occurrence of EphA2 overexpressed solid tumors, e.g., lung cancer, ovarian cancer, prostate cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. This is a new rejection necessitated by the amendment filed 4/02/2026.
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 make and 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)” (emphasis added). The “make and 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 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). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
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, 418 F.2d 540, 163 USPQ 689 (CCPA 1969), 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 (Bd. Pat. App. & Inter. 1981) 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 (Bd. Pat. App. & Inter. 1986) 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 types are known to respond quite differently to various modes of therapy.”
In Ex parte Stevens, 16 USPQ2d 1379 (Bd. Pat. App. & Inter. 1990) 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: (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. 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) Breadth of claims.
Claim 11 is drawn to a method for treating ephrin A2 overexpressed solid tumors in a subject in need, comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 10, wherein the ephrin A2 overexpressed solid tumor is lung cancer, ovarian cancer, prostate cancer.
The specification states at pp. 12-13:
The term “treatment” refers to the administration of the compounds of the present invention or formulations to ameliorate or eliminate diseases or one or more symptoms associated with the diseases, including:
(i) inhibiting the diseases or disease states, i.e., controlling the development of the diseases or disease states;
(ii) alleviating the diseases or disease states, i.e., causing regression of the diseases or disease states.
The term “therapeutically effective amount” refers to an amount of the compounds of the present invention used to (i) treat a particular disease, condition, or disorder, (ii) relieve, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount constituting a “therapeutically effective amount” of the compounds of the present invention will vary depending on the compounds, the disease states and severity, the method of administration, and the age of the mammal to be treated, but it may routinely be determined by those skilled in the art based on their knowledge and the disclosure.
Emphasis added. The term “subject” is not defined.
Examiner acknowledges applicant’s arguments filed 4/02/2026 asserting that the subject is limited to humans. However, given the broadest reasonable claim interpretation, subject is construed any and all animal species that express EphA2 and are subject to EphA2 overexpression solid tumors (lung, ovarian, or prostate).
Thus, the scope of treatment encompasses inhibiting/preventing tumor formation subjects [of potentially any animal species].
(b) Scope of the diseases covered.
There are many different types of cancers, but all share one hallmark characteristic: unchecked growth that progresses toward limitless expansion (National Institute of Cancer- understanding and related topics, accessed 8/21/2014 at URL: cancer.gov/cancertopics/understandingcancer at p. 2). 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 pretty much every part of the body. Id. Examiner notes that the following prior art is a selection of the recited forms of cancer.
A. Lung carcinoma is the leading cause of cancer-related death worldwide (Merck Manuals Lung Carcinoma accessed 3/12/2017 at URL merckmanuals.com/professional/pulmonary-disorders/tumors-of-the-lungs/lung-carcinoma- previously cited). About 85% of cases are related to cigarette smoking. Id. Treatment varies by cell type and by stage of disease. Primary treatments include surgery (depending on cell type and stage), chemotherapy and radiation therapy. Id.
B. Prostate Cancer covers a variety of cancer types. See e.g., Merck Manual Prostate Cancer accessed 8/21/2014 at URL: merckmanuals.com/home/kidney_and_urinary_tract_disorders/cancers_of_the_kidney_and_genitourinary_tract/prostate_cancer.html?qt=prostate cancer&alt=sh- previously cited. Among men in the United States, prostate cancer is the most common cancer and one of the most common causes of cancer death. Id.
The great majority of types of prostate cancers are not treatable with pharmaceuticals. Id.
(2) The nature of the invention and 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).
(3) Direction or Guidance: The guidance provided is limited. The specification fails to provide guidance on how a claimed compound would be sufficient to inhibit/prevent a EphA2 overexpressed tumors (e.g. lung, ovarian, or prostate) and potentially encompassing all animals species [presuming EphA2 is expressed].
No examples of preventing/inhibiting cancer onset were reduced practice.
The skilled artisan does not have sufficient guidance to extrapolate from the limited teachings from one single peptide and three cancer cell lines relating to treating [ameliorating] cancer to methods of preventing/inhibiting cancer onset. In order to prevent cancer, the skilled artisan must first be able to identify patient populations at risk for developing cancer, much less much less know dosage amounts, routes of administration, and dosing regimen that would be needed to prevent/inhibit cancer onset. The as-filed specification fails to provide such information.
Accordingly, the specification provides little guidance over the scope of the presently pending claims, as relating to preventing/inhibiting cancer (lung, ovarian or prostate).
(4) State of the Prior Art:
Xiao et al (J Hemat. Oncol. 13:114 (2020)- previously cited) teach that Eph receptors and the corresponding Eph receptor-interacting (ephrin) ligands jointly constitute a critical cell signaling network that has multiple functions. The tyrosine kinase EphA2, which belongs to the family of Eph receptors, is highly produced in tumor tissues, while found at relatively low levels in most normal adult tissues, indicating its potential application in cancer treatment. After 30 years of investigation, a large amount of data regarding EphA2 functions have been compiled. Meanwhile, several compounds targeting EphA2 have been evaluated and tested in clinical studies, albeit with limited clinical success (abstract).
London et al (Mol. Biol. Reports 47:8037-8048 (2020)- previously cited) teach Eph (erythropoietin-producing human hepatocellular) receptors form the largest known subfamily of receptor tyrosine kinases. These receptors interact with membrane-bound ephrin ligands via direct cell–cell interactions resulting in bi-directional activation of signal pathways (abstract). The Eph receptors also display properties of both tumor promoters and suppressors depending on the cellular context. Characterization of EphA2 receptor in regard to EphA2 dysregulation has revealed associations with various pathological processes, especially cancer. The analysis of various tumor types generally identify EphA2 receptor as overexpressed and/or mutated, and for certain types of cancers EphA2 is linked with poor prognosis and decreased patient survival. Id. Cyclic peptides represent are a promising class of EphA2 receptor-targeting agents. These are peptides that contain cysteine groups that form disulfide bonds and enable peptide cyclization. Most importantly, these cyclic peptides are Molecular Biology Reports (2020) 47:8037–8048 8045 1 3 favored over conventional peptides due to their constrained conformations; these offer potential for enhanced binding affinity and specificity, protection against proteolytic degradation, passive transcellular absorption, and improved metabolic stability (pp. 8044-45).
The connection between Eph receptors and cancers has been reinforced through many studies. However, the defined role of individual Eph receptors in specific cancers is currently poorly understood, as Eph receptors have been suggested to be oncogenic in certain situations, and tumor suppressing in others. There are many factors that confound the analysis of this family of receptors. For example, the roles of the tumor microenvironment and stroma, the different cell types involved, the cell surface molecules expressed, and the different homo- versus hetero-multimer Eph receptor interactions are all variables that can differ from one study to the next. Additionally, almost all Eph receptor studies to date have focused on single roles of Eph receptor activities (p. 8045).
(5) Working Examples: Examples 1-8 disclose synthesis of specific compounds of formula V. Test Example 1 discloses binding of the compounds to EphA2 protein on a chip. Test Example 2 discloses in vitro assessment of tumor cell lines NCI-H1975 and SK-OV-3 in which cell proliferation decreased. Test Examples 3 and 4 discloses an animal model of prostate and ovarian cancer, respectively, xenograft expressing PC-3 or SK-OV-3 Cells in which tumor growth was reduced.
Test Examples 5-7 disclose pharmacokinetic assessments of compounds in mice, rats, and monkeys. Test Examples 8 and 9 disclose stability of the compounds in plasma or blood from different species. Test Example 10 discloses metabolic stability of the compounds in hepatocytes from monkeys and humans.
There are no examples in which onset or initial growth of a EphA2 solid tumor was inhibited/prevented. Examiner expressly notes that Examples in the specification teach administering PDC8 to an existing cancer cells line [in vitro Ex 2], or an existing tumor [Exs 3-4: xenografts]. Thus, the cancer cell growth was reduced. There are no examples where initial onset of tumor was actually prevented/inhibited.
(6) Skill of those in the art: The relative skill of those in the art is high. An ordinary artisan in the area of drug development would have experience in screening peptide compounds for particular activities. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against particular biological target is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems such as cancers/tumors.
Determining how a particular compound will impact a particular form of cancer is not routine. There is no chemical targeting system at this time that can directly stimulate or block only a highly divergent cancer(s), while avoiding effects on other parts of the cells, where the same signal may have a different and unwanted effect. Further, the functioning of many networks and the pathology of many cancers involve complex systems involving more than one network. Thus, the level of ordinary skill in the art needs specialized knowledge of the complex nature of cancers/tumors.
Examiner expressly notes that in order to inhibit onset or prevent a EphA2 solid tumor, the skilled artisan must first be able to identify a subject(s) that is at risk for developing a EphA2 solid tumor, much less amounts/routes of administration, and treatment regimen of the claimed compound to inhibit onset or prevent a EphA2 solid tumor in a given subject.
(7) The quantity of experimentation needed: Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of factors 1-6, the quantity of experimentation needed is expected to be undue.
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.
Closest Prior Art
Chen et al (U.S. 2019/0184025- previously cited) disclose polypeptides which are covalently bound to non-aromatic molecular scaffolds such that two or more peptide loops are suspended between attachment points to the scaffold. The reference discloses peptides which are high affinity binders of the Eph receptor tyrosine kinase A2 (EphA2), as well as methods of treatments comprising the peptides (abstract). Page 9 of Chen et al disclose compound BCY6136:
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Of note, the cleavable linker contains: Pabc-Val-Cit-Glutaryl. Per the instant specification at page 17,
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and
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. R1 is the methyl side chain of alanine. R2 is -CH2-COOH, the side chain of aspartic acid. Compound BCY6136 of Chen further includes Sar10 and the same recited peptide ring structure, wherein xi, xii, and xiii are each Cys. However, Chen et al do not teach of suggest the claimed structure of formula V for R1 and R2
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which forms a specific bridge structure between two amino acid side chains (R1 and R2). Examiner notes that this structure is also part of the compounds recited in claims 6 and 9. Claim 9 recites the compounds of claim 6, but lacking the MMAE-PABC-Val-Cit-Glutaryl. Compounds of claim 9 have β-Ala at the N-terminus.
Accordingly, compounds of claims 5, 6, and 9 are free of the closest prior art.
Conclusion
Claim 5, 6, and 9 are allowed.
Claims 5-12 are pending. Claims 7, 8, and 11 are rejected. Claims 7, 8, and 10-12 are objected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654
/JULIE HA/Primary Examiner, Art Unit 1654
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