DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application claims status as a 371 (National Stage) of PCT/EP2021/087374 filed December 22nd 2021, and claims priority under 119(a)-(d) to European Application No. 20216764.9 filed on December 22nd 2020.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for European Application 20216764.9, which papers have been placed of record in the file. Please note that the European application is in English and therefore no further action is needed.
Information Disclosure Statement
The Information Disclosure Statement filed on 06/22/2023 has been considered by the Examiner.
Sequence Interpretation/Claim Interpretation
Regarding claim 1, the Examiner is interpreting the scope of the OP tetrapeptidic moiety as requiring 100% identity to SEQ ID NO: 1 (i.e., ALLP) or to SEQ ID NO: 2 (i.e., APKP), with any N-/C- terminal additions.
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 1, regarding the scope of “capping group”, the specification defines the term as a protecting or capping moiety C, usually covalently linked to the N-terminal side of the oligopeptide (see instant specification, pg. 15, lines 1-2). As such, the Examiner is interpreting the scope of “capping group” as any moiety covalently linked to the N-terminal side of the tetrapeptidic moiety (i.e., SEQ ID NO: 1 or SEQ ID NO: 2).
Regarding the scope of “drug”, it is noted that the instant specification does not define what constitutes a “drug”. Rather the instant specification provides examples of types of drugs by reciting that the drug in particular is a cytostatic, cytotoxic or anti-cancer drug (see pg. 1, lines 6-7). Pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. Merriam-Webster Dictionary defines “drug” as a substance used as a medication or in the preparation of medication (see Merriam-Webster at pg. 1, retrieved from https://www.merriam-webster.com/dictionary/drug, on 02/04/2026). As such, the Examiner is interpreting the scope of “drug” as any substance used as medication or in the preparation of medication.
Regarding claim 3, the instant specification does not define what constitutes a “linker or spacing group”. Rather the instant specification describes the function of a linker (see pg. 10-11). Pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. Chichili et al. define “linkers or spaces” as short amino acid sequences created in nature to separate multiple domains in a single protein (see Chichili et al., Protein Sci. 2012, 22(2):153-167 at pg. 153, Abstract). Chichili adds that the advent of recombinant DNA technology made it possible to fuse two interacting partners with the introduction of artificial linkers (see pg. 153, Abstract); and that he lengths of linkers vary from 2 to 31 amino acids, optimized for each condition so that the linker does not impose any constraints on the conformation or interactions of the linked partners (see pg. 153, Abstract). Therefore, the Examiner is interpreting the scope of “linker or spacing group” as a natural or synthetic amino acid sequence ranging in length from 2 to 31 amino acids which separates two domains or components.
Regarding claim 10, it is noted that the instant specification refers to “treatment/treating” as to any rate of reduction, delay or retardation of the progress of the disease or disorder, or a single symptom thereof, compared to the progress or expected progress of the disease or disorder, or single symptom thereof, when left untreated (see instant specification, pg. 21, lines 18-20). The specification also recites that the terms treatment/treating also refers to achieving a significant amelioration of one or more clinical symptoms associated with a disease or disorder, or of any single symptom thereof (see instant specification, pg. 21, lines 27-29). As such, the Examiner is interpreting the scope of “treatment” of a cancer, as any rate of reduction delay or retardation of the progress of a cancer symptom, wherein the rate of reduction, delay or retardation, or progress of the cancer symptom does not encompass 100% prevention (i.e., as in to stop from happening or existing) of the cancer or the cancer symptom.
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.
1. Claims 1and 3-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.
Independent claim 1 recites “a compound having the general structure C-OP-D, wherein C is a capping group; DP is the tetrapeptidic moiety ALLP (SEQ ID NO:1) or APKP (SEQ ID NO:2); D is a drug…” As discussed in the “Sequence Interpretation/Claim Interpretation Section”, the Examiner interprets the tetrapeptidic moiety as requiring 100% identity to SEQ ID NO: 1 or to SEQ ID NO: 2 with any N-/C- terminal additions and a drug as any substance which has a cytostatic, cytotoxic or anti-cancer effect. As such, the scope of the claimed compound or pharmaceutically acceptable salt of said compound, pharmaceutically acceptable crystal or co-crystal comprising said compound, or a pharmaceutically acceptable polymorph, isomer, or amorphous form of said compound encompasses any capping group and any drug or substance with a cytostatic, cytotoxic or anti-cancer effect. Therefore, the scope of claim 1 and dependent claims 3-15 encompass a vast array of compounds of general structure C-OP-D without a necessary core structure that would be needed for the capping group to exhibit the function of protecting the oligopeptide and the drug to be the substance used in the preparation of the instantly claimed compound.
Applicants reduced to practice 4 compounds which comprise the general structure C-OP-D and have PhAc (phosphonoacetyl) as the capping group, and MMAE (monomethyl auristatin E) or Doxorubicin as the drug. (see instant specification, pp. 34-36).
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. MPEP 2163 (I)(A). The compounds reduced to practice (i.e., compounds 1-4) are not a representative number of species of the claimed genus. In other words, the compounds reduced to practice are not representative of a compound having the general structure C-OP-D wherein C is any capping group and D is any drug. The compounds reduced to practice are representative of only a species of compound where C is PhAc and D is MMAE or Doxorubicin.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Isidro-Llobet et al. provide a concise yet deep analysis of the protection of amino acids, the review is divided into sections which cover the amino acid functionalities protected, methods for the introduction of the protecting groups as well as their removal (see Isidro-Llobet et al., Chemical Reviews, 2009, Vol. 109, No. 6, pp. 2455-2504 at pg. 2457, left column, second paragraph). In particular Isidro-Llobet et al. teach α-Amino-Protecting Groups (see Tables 1, 2 and 3; pp. 2459, 2461-2462 and 2464-2465); Lys-, Orn-, Dap-, and Dap-Protecting Groups (see Tables 5, 6 and 7; pp. 2467-2469); α-Carboxylic Acid-Protecting Groups (see Tables 8, 9 and 10; pp. 2470-2472); Asp and Glu-Protecting Groups (see Tables 11, 12 and 13; pp. 2474-2475); Amide Backbone-Protecting Groups (see Tables 14 and 15; pp. 2477-2478); Asn- and Gln-Protecting Groups (see Table 16, pg. 2479); Arg-Protecting Groups (see Tables 17, 18 and 19; pp. 2482-2483); Cys-Protecting Groups (see Tables 20, 21 and 22; pp. 2485-2488); His-Protecting groups (see Tables 23, 24 and 25; pp. 2490-2491); Ser, Thr, and Hyp-Protecting Groups (see Tables 26 and 27, pp. 2493); and Tyr-Protecting Groups (see Tables 28 and 28, pp. 2494-2496).
Similarly TherapySelect teaches that drugs used to fight cancer, traditionally fall into two types: cytotoxic and cytostatic drugs (see TherapySelect Doc1, “Drugs for Chemotherapy” first available online on 11/18/2019, retrieved from https://www.therapyselect.de/en/blog/chemotherapy-fight-against-cancer-information-and-diagnostics on 02/04/2026). TherapySelect also teaches the most commonly used classification of cytostatics, which include Alkylating agents, platinum analogues, DNA intercalating agents, some anticancer antibiotics which can act as DNA intercalators or prevent DNA repair, mitosis inhibitors, Taxanes, Topoisomerase inhibitors and antimetabolites (see TherapySelect Doc2, at pg. 1-2). As such, the teachings of Isidro-Llobet et al. and Therapy Select, provide compelling information which demonstrate a vast array of “capping group” and “drug” structures, which would exhibit the function of protecting the tetrapeptidic moiety (i.e., OP) and which confer cytostatic, cytotoxic or anti-cancer effect when used in the preparation of a compound.
Thus, the claims are directed to a compound comprising any capping group, a tetrapeptidic moiety (i.e., SEQ ID NO: 1 or SEQ ID NO: 2), and any drug, wherein the capping group and the drug exhibit a certain function (i.e., protection of the tetrapeptidic moiety and cytostatic, cytotoxic or anti-cancer effect) but no correlated structure associated with that function. Without such structures, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by providing a representative number of species of the genus. In the instant case, the specification teaches only teaches 4 compounds which comprise PhAc (i.e., phosphonoacetyl) as the capping group and MMAE (i.e., monomethyl auristatin E) or Doxorubicin as the drug. Thus, evidence of four positive integrant and replicative compounds of comprising only one species of capping group and two species of drug, are not sufficient for the skilled artisan to envisage what constitutes a necessary core structure and/or sequence of the claimed compound.
Therefore, claims 1 and 3-15 do not meet the written description requirement.
2. Claims 10-11 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 using the compound according to claim 1 for reducing, delaying or retarding the progress of a symptom of a cancer (e.g., tumor-causing cancer: colorectal cancer, melanoma and glioblastoma), does not reasonably provide enablement for the use of the compound according to claim 1, in the treatment of any 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 use the invention commensurate in scope with these claims.
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 Wriqht, 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 Cortriqht, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessarily needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The eight In re Wands factors are applied to claims 10-11 as follows:
The Breadth of the Claims and The Nature of the Invention
Although addressing the use of the salt, crystal, co-crystal, polymorph, isomer or amorphous form of the compound of claim 1 in the treatment of a cancer; Applicants do not provide any evidence in the specification that the compound of the invention can treat any type of cancer.
The specification recites that “treatment"/"treating" refers to any rate of reduction, delay or retardation of the progress of the disease or disorder, or a single symptom thereof, compared to the progress or expected progress of the disease or disorder, or singe symptom thereof, when left untreated (see pg. 21, lines 18-20). The specification also teaches that the treatment can result in regression of the disease [e.g., in terms of decreasing (primary) tumor volume or (primary) tumor mass and/or in terms of decreasing or inhibiting metastasis (e.g. number and/or growth of metastases), in decreased progression of the disease compared to expected disease progression, or in stabilization of the disease, i.e. neither regression nor progression of the disease. All these are favorable outcomes of the treatment (see instant specification, pg. 21, lines 7-11). Thus the scope of claim 10 encompass any rate of reduction delay or retardation of the progress of a cancer symptom, wherein the rate of reduction, delay or retardation, or progress of the cancer symptom does not encompass 100% prevention (i.e., as in to stop from happening or existing) of the cancer or the cancer symptom.
Additionally, the breadth of the claim exacerbates the complex nature of the subject matter to which the present claim is directed. The claim is extremely broad due to the vast number of possible cancer types claimed. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, 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. Different cancers have different properties. There are many cellular and molecular factors, for example more than 100 oncogenes, associated with cancer. They can occur throughout in virtually every part of the body. Here are some assorted categories, all of which are claimed:
infiltrating breast cancer, pre-invasive breast cancer, inflammatory breast cancer, Paget's disease, metastatic breast cancer, recurrent breast cancer, appendix cancer, bile duct cancer, extrahepatic bile duct cancer, colon cancer, esophageal cancer, gallbladder cancer, gastric cancer, intestinal cancer, liver cancer, pancreatic cancer, rectal cancer, stomach cancer, adrenal cancer, bladder cancer, kidney cancer, penile cancer, prostate cancer, testicular cancer, urinary cancer, cervical cancer, endometrial cancer, fallopian tube cancer, ovarian cancer, uterine cancer, vaginal cancer, vulvar cancer, eye cancer, head and neck cancer, jaw cancer, laryngeal cancer, pharyngeal cancer, oral cancer, nasal cavity cancer, salivary gland cancer, sinus cancer, throat cancer, thyroid cancer, tongue cancer, tonsil cancer, Hodgkin's disease, leukemia, acute lymphocytic leukemia, acute granulocytic leukemia, acute myelogenous leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, multiple myeloma, lymphoma, b-cell lymphoma, lymph node cancer, bone cancer, osteosarcoma, melanoma, skin cancer, basal cell cancer, squamous cell cancer, sarcoma, Ewing's sarcoma, Kaposi's sarcoma, brain cancer, astrocytoma, glioblastoma, glioma, pituitary gland cancer, spinal cord cancer, lung cancer, adenocarcinoma, oat cell cancer, non-small cell lung cancer, small cell lung cancer, squamous cell cancer, mesothelioma, etc.
With respect to the scope of claim 11, and the combination chemotherapy treatment or a combined modality chemotherapy treatment; the specification recites that a therapeutic modality on its own may not result in a complete or partial response (or may even not result in any response), but may, in particular when combined with other therapeutic modalities, contribute to a complete or partial response (e.g. by rendering the disease or disorder more sensitive to therapy) (see pg. 21, lines 20-23). Moreover, Examples 5-8 in the specification as well as accompanying Figures 15-18 depict the reduction in tumor volume for mice, with colorectal tumors, melanoma tumors, and glioblastoma tumors, treated with the compound of claim 1, wherein the drug is doxorubicin or MMEA (i.e., Monomethyl auristatin E). As such, the scope of claims 10 and 11 encompass treating three species of cancer. Accordingly, claims 10-11 are unduly broad with respect to using the compound, salt, crystal, co-crystal, polymorph, isomer or amorphous form according to claim 1 in the treatment of a cancer (i.e., any type of cancer) wherein said treatment of cancer is a combination chemotherapy treatment or a combined modality chemotherapy treatment.
The State of the Prior Art
Although the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regard to treating cancer broadly is underdeveloped. In particular, there is no known anticancer agent that is effective against all cancer cell types; nor is there a known anticancer agent that treats any type of cancer. Therefore, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains (i.e., using the compound, salt, crystal, co-crystal, polymorph, isomer or amorphous form according to claim 1, in the treatment of a cancer), then there is a lack of predictability in the art. Moreover, it is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. The court has indicated that the more unpredictable an area is the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). This is because it is not obvious from the disclosure of one species, what other species will work. As such, the cancer treatment art involves a very high level of unpredictability.
With respect to cancer treatments, Reubi reviews peptide receptors as molecular targets for cancer diagnosis and therapy (see Reubi. J.E., Endocrine Reviews, vol. 24, issue 4, 2003, pp. 389-427, at pg. 389, Title). In particular, Reubi teaches that peptide receptors can be expressed in large quantities in certain tumors therefore peptides linked to cytotoxic agents are considered for therapeutic applications (see pg. 389, abstract). Reubi’s review is restricted to physiologically occurring peptides and focuses on the so-called regulatory peptides that include the neuropeptides present in the brain, the gut peptide hormones, as well as peptides present in the vasculature and peptides of the endocrine system (see pg. 390, right column, paragraph 3 and Table 1).
Reubi adds that cancer research on peptides is presently dominated by two active fields: one is the search for new peptide receptors overexpressed in specific tumors, i.e., suitable peptide targets (see pg. 413, left column, third paragraph). The second field consists of the search and discovery of new radiopeptides and cytotoxic peptides, their development for potential clinical use in the previously defined targets, and the resulting clinical efforts to optimize peptide receptor targeting (see pg. 413, left column, third paragraph). However, more basic information to be gathered on peptide receptor biology and pathobiology in cancer, allowing a better understanding of the molecular mechanisms underlying the in vivo peptide receptor targeting (see pg. 413, right column, first paragraph). Some of the questions that need to be answered are: 1) What are the mechanisms triggering the expression of peptide receptors in cancer tissue? Is the presence of peptide receptors in the tissue of origin a prerequisite for the expression of tumoral receptors? What is the importance of the mutated peptide receptors detected occasionally in tumors? (see pg. 413, right column, second paragraph); 2) Can we actively manipulate, in particular up-regulate, the peptide receptor expression in tumors? (see pg. 413, right column, third paragraph); 3) are the receptor dynamics identical in tumors and in normal tissues? (see pg. 414, left column, second paragraph); 4) Is the receptor expression comparable in primary tumors and metastases? (see pg. 414, left column, third paragraph); 5) What is known about the in situ function of tumoral peptide receptors? (see pg. 414, left column, fourth paragraph); 6) What is the function of the receptors (somatostatin receptors, substance P receptors, VIP receptors, GRP receptors) overexpressed in peritumoral vessels? (see pg. 414, left column, last paragraph); 7) Do cancers express significant concentrations of endogenous peptides? Do these peptides interfere with tumoral peptide receptors? Do they affect tumor binding? (see pg. 414, right column, second paragraph); 8) What is the significance of homo and heterodimerization of peptide receptors in primary human tumors? What will be the impact on receptor binding, on receptor internalization, on the development of new analogs, and, more generally, on receptor targeting strategies? (see pg. 414, right column, third paragraph); 9) Which kind of radioisotopes is the best choice for optimal peptide receptor radiotherapy? (see pg. 414, right column, last paragraph); and 10) Can we take advantage of multiple concomitant receptor expression in tumors? (see pg. 414, right column, last paragraph). Therefore, Reubi’s review demonstrates the unpredictability in using peptides linked to cytotoxic agents in the treatment of a cancer.
Additionally, Alas et al., are in the field of peptide-drug conjugates with different linkers for cancer therapy (see Alas et al., J Med Chem. 2021, 64(1):216-232 at pg. 1, title). Alas et al. teach that drug conjugates are chemotherapeutic or cytotoxic agents covalently linked to targeting ligands such as an antibody or a peptide via a linker (see pg. 1, abstract). Active targeting using a ligand allows a higher concentration of the drug to reach the tumor by targeting a specific cell-surface receptor or biomarker at the tumor site (see pg. 2, paragraph 1). The targeting ligands, such as antibodies or peptides, can be covalently conjugated to the drug or to the surface of a drug carrier system like liposomes, micelles, etc. for site-specific delivery (see pg. 2, paragraph 1). Thereby, the teachings of Alas et al. suggest that the peptide drug conjugates are not universal for the treatment of any cancer, instead the antibodies or peptides covalently linked to the cytotoxic agent directs the payload to a specific cell-surface receptor or biomarker at the tumor site.
Therefore, the level of predictability in the art is dependent on many factors including the efficacy of a representative number of claimed compounds having specific tetrapeptidic moieties that target a representative number of cancers. Although, finding a compound useful in the treatment of cancer broadly is important, the state of the art requires vast amounts of data, including analysis of a representative number of claimed compositions on a representative number of cancers, producing animal models based on representative numbers, in vitro and in vivo experiments, and phase 0, I, II, III, and IV clinical trials.
The Level of Skill in the Art
Practitioners in this art (medical clinicians, pharmacists, doctors and/or pharmaceutical chemists) would presumably be highly skilled in the art of compounds for use in the treatment of a cancer.
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable. If one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains (i.e., the compound, salt, crystal, co-crystal, polymorph, isomer or amorphous form according to claim 1 for the use in the treatment of cancer), then there is a lack of predictability in the art. Moreover, it is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. The court has indicated that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). This is because it is not obvious from the disclosure of one species, what other species will work.
In the instant case, Applicants do not demonstrate that using the compound, salt, crystal, co-crystal, polymorph, isomer or amorphous form according to claim 1 treats any cancer. Rather, Applicants appear to rely on the assumption that by providing evidence of the evaluation of ALLP- and APKP-tetrapeptide-comprising prodrug compounds of doxorubicin or MMAE in vitro (see instant specification, Examples 2-4) as well as by administering the instantly claimed compound to mice and evaluating its effect on a single symptom (i.e., tumor reduction) on colorectal cancer induced mice, melanoma induced mice and glioblastoma induced mice, would likely treat any cancer (see instant specification, Examples 5-8). Thus, Applicants appear to rely on the assumption that by providing evidence based on in vivo and in vitro results on only three species of cancers (i.e., colorectal, melanoma and glioblastoma) that the claimed compound would treat any cancer in a subject. However, such an assumption cannot be made because there is no indication that administering the claimed compound to subjects suffering from any cancer would function as intended.
Furthermore, 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). Thus, given highly unpredictable nature of prevention and/or treatment of cancer broadly and given that the Specification fails to demonstrate any data or evidence that the claimed compound treats any type of cancer, there would be no way of determining without undue experimentation whether the claimed compound exhibits such a desired result. Without more experimentation demonstrating the efficacy of a representative number of claimed compounds on a representative number of claimed cancers, the level of unpredictability remains high. Therefore, it is unpredictable that the claimed compound will treat any type of cancer in a subject.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
The specification does not enable any person skilled in the art to which it pertains (i.e. using the compound, salt, crystal, co-crystal, polymorph, isomer or amorphous form according to claim 1 in the treatment of any cancer) to make and/or use the invention commensurate in scope with the claims. There is a lack of adequate guidance from the specification or prior art with regard to the actual treatment of any cancer by using the claimed compound. Applicants fail to provide the guidance and information required to ascertain whether the claimed compound will be effective against treating any type of cancer without resorting to undue experimentation. Applicants' limited disclosure is noted but is not sufficient to justify claiming the treatment of all cancers broadly.
Absent a reasonable a priori expectation of success for using the claimed compound to treat any type of cancer, one skilled in the art would have to extensively test many various tumor types/cancer types. Since each prospective embodiment, and indeed future embodiments as the art progresses, would have to be empirically tested, and those which initially failed tested further, an undue amount of experimentation would be required to practice the invention as it is claimed in its current scope, because the specification provides inadequate guidance to do otherwise.
The amount of direction or guidance presented in the specification is limited to the in vivo an in vitro models. The Specification only discloses models for the treatment of colorectal cancer, melanoma and glioblastoma (see instant specification, Examples 2-8). However, these models are not inclusive of any type of cancer. Moreover, as noted in “Breadth of the Claims and Nature of the Invention" and “The Level of Predictability in the Art” Sections, cancers are highly heterogeneous at both the molecular and clinical level. Different cancers have different properties. There are many cellular and molecular factors, for example more than 100 oncogenes, associated with cancer. They can occur throughout in virtually every part of the body. As such, the predictive models described in the Specification are based on only three specific cancers (i.e., colorectal cancer, melanoma and glioblastoma), and even these specific cancers are difficult to treat.
Moreover, these models fail to address whether administration of the compound as claimed can treat any type of cancer. Thus, the models described in the Specification (i.e., Examples 2-8) are not indicative of valid results (i.e., treatment of any type of cancer). In the absence of such information, a person of ordinary skill in the art would reasonably require an undue quantity of experimentation.
The Quantity of Experimentation Necessary
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. One wishing to practice the presently claimed invention would have to produce additional data and experimentation to determine whether administering the claimed compound is useful in the treatment of any type of cancer.
Furthermore, a person of skill in the art would require an undue quantity of experimentation even to select which of the broad array of cancers claimed in claim 10 could be treated [see “Breadth of Claims” and “The Nature of the Invention” sections] where treating cancer encompasses all types of cancer, given the complexity and diversity of the types of cancers, as well as the lack of established benchmarks in the art known at the time of this application where cancer was treated by an compound as claimed, alone or in combination with the additional agents.
Additionally, given that there is a myriad of cancers and the Specification is silent as to the how a compound according to claim 1, functions so as to treat such a diverse group of cancers, a person of skill in the art would be required an undue quantity of experimentation to select which of the broad array of cancers could be treated. Moreover, a person of skill in the art would also be required to conduct numerous animal models for each type of cancer and then clinical trials to ensure safety and efficacy of the compound according to claim 1.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
MPEP §2164.01(a), 4th paragraph, provides that, “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 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 10-11, in view of the Applicants’ entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the invention as claimed in claim 10 would not be enabled by the written disclosure for the treatment of any cancer excluding the treatment of colorectal cancer, melanoma and glioblastoma by administering a compound according to claim 1. Therefore, claims 10-11 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art in treating any type of cancer excluding the treatment of colorectal cancer, melanoma and glioblastoma by administering the compound according to claim 1.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
3. Claims 3-5 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 3 depends from parent claim 1, which is drawn to a compound having the general structure C-OP-D, wherein C is a capping group; OP is SEQ ID NO: 1 or SEQ ID NO:2 and D is a drug. Claim 3 recites the limitation "wherein the linkage between OP and D is direct or indirect via a linker or spacing group" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Similarly, claim 5 recites the limitation “wherein the linkage between C and OP is direct, or is indirect via a linker or spacing group” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 4 is also rejected because it depends upon claim 3.
4. Claim 14 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 14, further defines the method of claim 12 by further comprising forming a salt, amorphous form, crystal or co-crystal of the compound C-OP-D. However, it is ambiguous and/or unclear whether the claim limitations recited in claim 14 apply to the compound produced in claim 12 (i.e., C-OP-D), since claim 12 depends from parent claim 1 which is drawn to a compound having the general structure C-OP-D or a or a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable crystal or co-crystal comprising said compound, or a pharmaceutically acceptable polymorph, isomer, or amorphous form of said compound. Thus, instant claim 14 fails to further limit the claims from which it depends.
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.
5. Claims 1-15 are rejected under 35 U.S.C. 102 as being anticipated by WO 2014/102312 A2 with International Publication Date of July 3rd 2014 (cited in the IDS filed on 06/22/2023) (herein after “Trouet”), as evidenced by Morgensztern et al., 2009 Journal of Thoracic Oncology, vol 4, issue. 11, supplement 3, pp. S1082-S1083 (herein after “Morgensztern”).
For Claims 1, 3 and 5, Trouet discloses a method of screening candidate prodrugs having the general structure [Cx-OP]y-D, wherein C is a capping group; OP is a peptide with a minimum length of 4 consecutive amino acids (tetrapeptide) and a maximum length of 8 amino acids (i.e. a peptide with a length of 4, 5, 6, 7 or 8 consecutive amino acids) which comprises carboxy-terminally a proline comprising dipeptide selected from the group consisting of glycine -proline (GP), alanine-proline (AP), and lysine-proline (KP); D is a drug; x is an integer being at least 1 when y = 1; y is an integer being at least 1, if y is greater than 1, then at least 1 OP is carrying a capping group; and wherein the linkage between C and OP and the linkage between OP and D is direct or via a linker or spacing group, and wherein, if y is greater than 1, the multiple OP moieties are individually linked to each other directly or via a linker or spacing group and/or are individually linked to D directly or via a linker or spacing group (see pg. 88, claim 19). Thereby Trouet’s general structure of the prodrug [Cx-OP]y-D anticipates the instantly claimed general structure C-OP-D (i.e., capping group, SEQ ID NO: 2 (i.e., APKP), D is a drug). Trouet’s Cx is a capping group where x is at least 1 when y = 1, OP is a peptide with a minimum length of 4 consecutive amino acids (tetrapeptide) which comprises alanine-proline (AP) and lysine-proline (KP) and D is a drug. Trouet also discloses that the OP is carrying a capping group, thereby constituting wherein the linkage between C and OP is direct, as recited in instant claim 5, and also constituting wherein the linkage between OP and D is direct or is indirect via a linker or spacing group as recited in instant claim 3.
For claim 2, Trouet’s discloses that the drug D is selected from the group consisting of maytansine, geldanamycin, paclitaxel, docetaxel, campthothecin, vinblastine, vincristine, methothrexate, aminopterin, amrubicin, or a derivative of any thereof (see pg. 93, claim 25, lines 1-3).
As evidenced by Morgensztern, amrubicine is a third-generation synthetic anthracycline for the treatment of both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (see pg. S1083, left column, paragraph 2). Its metabolite, amrubicinol, has 5 to 200 times higher growth inhibitory activity against tumor cell lines compared with doxorubicin, and the principal mechanism of action seems to be through topoisomerase II inhibition (see pg. S1083, left column, paragraph 2). Thus, Trouet’s drug anticipates the claim limitations recited in instant claim 2, wherein D is a cytotoxic drug.
For claim 4, Trouet discloses that when present said linker or spacing group is a self-eliminating linker or spacing group (see pg. 93, claim 26, lines 5-6), thereby anticipating instant claim 4.
For claims 7 and 8, Trouet discloses that a prodrug or salt thereof of the invention can further be present in a composition comprising besides the prodrug or salt thereof one of a suitable solvent (capable of solubilizing the prodrug to the desired extent), diluent (capable of diluting concentrated prodrug to the desired extent) or carrier (any compound capable of absorbing, adhering or incorporating the prodrug, and of subsequently releasing at any rate the prodrug in the extracellular compartment of the subject's body) (see pg. 24, lines 16-21). Thereby corresponding to the instantly claim limitations recited in claims 7 and 8.
For claim 6, Trouet discloses that the drug or therapeutic agent conjugated to the oligopeptide of the invention may be useful for treatment of cancer (e.g., by exerting cytotoxic or antiangiogenic activity, inflammatory disease, or some other medical condition (see pg. 22, lines 29-30) Thus, the therapeutic agent may be selected from a number of classes of compounds including macrocyclic polyethers such as halichondrin B, eribulin (see pg. 23, lines 1-2; and pg. 24, line 6).
For claims 9 and 10, Trouet discloses a method for treating a tumor or cancer in a subject, said method comprising administering to a subject having cancer an amount of prodrug or salt thereof according to any one of claims 1 to 8 or of composition according to claims 9 or 10 sufficient to provide a therapeutically effective amount of drug in the vicinity of the tumor or cancer, said administering resulting in the treatment of said tumor or cancer (see pg. 87, claim 14, lines 29-33). Since Trouet’s claim 1 is drawn to a prodrug having the general structure: [Cx-OP]y-D, wherein C is a capping group; OP is an oligopeptidic moiety; D is a drug; x is an integer being at least 1 when y = 1 (see pg. 86, claim 1). As evidenced by the Oxford English dictionary, a medicament is a substance used for medical treatment (see pg. 1). Therefore, it must follow that Trouet’s method for treating a tumor or cancer in a subject comprises administering the prodrug anticipates instant claim 9, wherein the claimed compound is used as a medicament; and wherein the compound is used in the treatment of cancer as recited in instant claim 10.
For claims 11 and 14, Trouet claims that the prodrug or salt thereof according to any one of claims 1 to 8 or the composition according to claims 9 or 10 for use in the treatment of a cancer (see pg. 87, claim 11); and also claims that that the prodrug or salt thereof, or composition according to claim 11, wherein said treatment of cancer is a combination chemotherapy treatment or a combined modality chemotherapy treatment (see pg. 87, claim 12). Thereby anticipating the claim limitations recited in instant claims 11 and 14.
For claims 12 and 13, Trouet’s claim 18 is drawn to a method for producing the prodrug, wherein said method comprises the steps of: the steps of: (i) obtaining the drug; (ii) linking the drug to a capped oligopeptidic moiety, resulting in the prodrug; or, alternatively, (ii’) linking the drug to an oligopeptidic moiety followed by linking the capping group to the oligopeptidic moiety, resulting in the prodrug; and (iii) purifying the prodrug obtained in step (ii) or (ii') (see pg. 88, claim 18, lines 11-18).
For claim 15, Trouet claims a kit comprising a container comprising the prodrug or salt thereof according (see pg. 93, claim 27).
Accordingly, Trouet’s disclosure anticipates the claim limitations recited in instant claims 1-5 and 7-15.
6. Claims 1, 3, 5 and 7-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Barcenas et al., 2014. Analytical Chemistry, vol 86, issue 15, pp. 7962-7967 (herein after “Barcenas”), as evidenced by Weber Scientific., Phosphate Buffers, first available online on 11/15/2019, retrieved from https://www.weberscientific.com/phosphate-buffers-here-s-what-you-need-to-know#:~:text=The%20Many%20Uses%20of%20Phosphate%20Buffers%0A%0AHow%20you,of%20product%20you%20happen%20to%20be%20using on 02/04/2026 (herein after “Weber Scientific”).
For claim 1, Barcenas discloses the PPT1 substrate N-Ac-Ala-Leu-Leu-Pro-Phe-Gly-Cys-S-COC11H23 (see pg. 7964, right column, last paragraph), which reads on the instantly claimed compound having the general structure C-OP-D, wherein C is a capping group; OP is the tetrapeptidic moiety ALLP (SEQ ID NO:1) and D is a drug or any substance used as medication or in the preparation of medication, as discussed in the “Claim Interpretation” section above. Barcenas’ capping group consists of acetylation of the N-terminus (i.e., N-Ac), which protects the substrate (see pg. 7694, left column, last paragraph). The tetrapeptidic moiety in Barcenas’ disclosure is Ala-Leu-Leu-Pro, which corresponds to a sequence 100% identical to instant SEQ ID NO: 1 (i.e., ALLP) with any N-/C- terminal additions; and Barcenas’ drug or substance is the S-palmitoyl group (i.e., S-COC11H23). As such, Barcenas’ disclosure anticipates the claim limitations as recited in instant claim 1.
For claims 3, Barcenas’ substrate comprises a three amino acid sequence (i.e., Phe-Gly-Cys) present between N-Ac-Ala-Leu-Leu-Pro (i.e., OP) and the S-palmitoyl group (i.e., drug) (see pg. 7964, right column, last paragraph). As discussed in the “Claim Interpretation” section above, the scope of a “linker or spacing group” is being interpreted as a natural or synthetic amino acid sequence ranging in length from 2 to 31 amino acids which separates two domains or components. Therefore, the Phe-Gly-Cys sequence that separates the N-Ac-Ala-Leu-Leu-Pro from the drug (i.e., S-palmitoyl group) anticipates wherein the linkage between OP and D is indirect via a spacing group as recited in instant claim 3.
For claim 5, Barcenas’ substrate comprises acetylation of the N-terminus (i.e., N-Ac-Ala-Leu-Leu-Pro-Phe-Gly-Cys-S-COC11H23), thereby corresponding to wherein the linkage between C (i.e., N-Ac) and OP (i.e., Ala-Leu-Leu-Pro-) is direct, as recited in instant claim 4.
For claims 7 and 8, Barcenas discloses that the PPT1 substrate (i.e., N-Ac-Ala-Leu-Leu Pro-Phe-Gly-Cys-S-COC11H23) was placed in a Eppendorf tube containing, died blood spot, polypropylene, phosphate buffer solution and Triton X-100 (see pg. 7964, left column, second paragraph). Thus, the Barcenas’ disclosure reads on a composition comprising the compound according to claim 1, as recited in instant claim 7.
As evidenced by Weber Scientific, phosphate buffers are sometimes used to dilute substances (see pg. 2, last paragraph); however, the use of phosphate buffer solutions ultimately depends on the application and the type of product being used (see pg. 3, first paragraph). As such, Barcenas’ composition comprising the PTT1 substrate and phosphate buffer solution anticipates the claim limitations as recited in instant claim 8, wherein the composition further comprises at least one of a pharmaceutically acceptable solvent, diluent or carrier.
Accordingly, Barcenas’ disclosure anticipates instant claims 1, 3, 5 and 7-8.
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 nonobviousness.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
7. Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/102312 A2 with International Publication Date of July 3rd 2014 (cited in the IDS filed on 06/22/2023) (herein after “Trouet”) and Barcenas et al., 2014. Analytical Chemistry, vol 86, issue 15, pp. 7962-7967 (herein after “Barcenas”).
Regarding Claim 1, Trouet teaches minimally toxic prodrugs having the general structure: [Cx-OP]y-D, wherein C is a capping group; OP is an oligopeptidic moiety; D is a drug; x is an integer being at least 1 when y = 1; y is an integer being at least 1 , if y is greater than 1 , then at least 1 OP is carrying a capping group; and wherein the linkage between C and OP and the linkage between OP and D is direct or via a linker or spacing group, and wherein, if y is greater than 1, the multiple OP moieties are individually linked to each other directly or via a linker or spacing group and/or are individually linked to D directly or via a linker or spacing group; or a pharmaceutically acceptable salt thereof (see Trouet, Title and pg. 86, claim 1).
However, Trouet does not expressly teach wherein the OP is the tetrapeptidic moiety ALLP (i.e., SEQ ID NO: 1), as recited in instant claim 1.
Barcenas teaches PPT1 substrate is a cysteine terminated heptapeptide carrying an S-palmitoyl group, N-Ac-Ala-Leu-Leu-Pro-Phe-Gly-Cys-S-COC11H23 (see pg. 7964, right column, last paragraph). Barcenas adds that the amino acid residues in the substrate were designed with two features in mind: one was to produce peptides that would be sufficiently lipophilic to be readily extracted on the C18 solid-phase support; and the other feature was to promote residue-selective ion fragmentation upon collisional activation that would focus most of the fragment ion signal into a single dominant dissociation channel (see pg. 7964, right column, last paragraph). Barcenas’ N-terminus acetylated Ala-Leu-Leu-Pro peptide is 100% identical to the instantly claimed OP tetrapeptide moiety ALLP (SEQ ID NO: 1), with any N-/C- terminal additions. Thus, the teachings of Trouet when combined with the teachings of Barcenas are suggestive of the instantly claimed compound having the general structure C-OP-D.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art to substitute Trouet’s oligopeptidic moiety with Barcenas’ cysteine terminated heptapeptide (i.e., N-Ac-Ala-Leu-Leu-Pro-Phe-Gly-Cys) in order to arrive at the instantly claimed compound. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do it because the N-terminus acylated tetrapeptide ALLP was known to be sufficiently lipophilic to be readily extracted on the C18 substrate, and because the peptide designed was known to promote residue-selective ion fragmentation upon collisional activation that would focus most of the fragment ion signal into a single dominant dissociation channel. One of ordinary skill in the art would have had a reasonable expectation of success given that Barcenas’ substrate also comprises an S-palmitoyl group linked to the known N-Ac-Ala-Leu-Leu-Pro-Phe-Gly-Cys; and given that Trouet’s minimally toxic prodrugs have the general structure [Cx-OP]y-D, wherein C is a capping group; OP is an oligopeptidic moiety; D is a drug. Therefore, substitution of Trouet’s OP with Barcenas’ cysteine terminated heptapeptide would support the instantly claimed compound by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, pursuant to KSR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
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.
8. Claims 1-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-8, 12 and 14-15 of U.S. Patent No. 10,076,576 B2 (here in after “576”), in view of Barcenas et al., 2014. Analytical Chemistry, vol 86, issue 15, pp. 7962-7967 (herein after “Barcenas”) and Marti-Centelles et al., Chem. Rev. 2015, 115, 8736-8864 (herein after “Marti-Centelles”).
Regarding instant claims 1, 3 and 5; U.S. Patent No. 10,076,576 B2 claims:
A prodrug having the general structure: [Cx-OP]y-D, wherein C is a phosphonoacetyl group; OP is a tetrapeptide with the sequence ALGP (SEQ ID 30NO: 1 ), TSGP (SEQ ID NO: 4), or KLGP (SEQ ID NO:
6), and amino acids of the tetrapeptide are naturally occurring amino acids; D is a therapeutic drug; x is an integer of at least 1; x is 1 when y=1; y is an integer being at least 1, if y is greater than 1, then at least 1 OP is carrying a capping group; and wherein the linkage between C and OP and the linkage between OP and Dis direct, and wherein, if y is greater than 1, the multiple OP moieties are individually linked to each other directly and one of the multiple OP moieties is linked to D directly; or a pharmaceutically acceptable salt thereof (see ‘576, column 63, claim 1).
However, ‘576 does not expressly claim wherein the OP is the tetrapeptidic moiety ALLP (SEQ ID NO: 1) or APKP (SEQ ID NO: 2), as recited in instant claim 1.
As previously discussed, Barcenas teaches cysteine terminated heptapeptide, N-Ac-Ala-Leu-Leu-Pro-Phe-Gly-Cys (see pg. 7964, right column, last paragraph), which reads on the instantly claimed tetrapeptidic moiety ALLP with any N-/C-terminal additions. As such, an ordinary skilled artisan would have been motivated with reasonable expectation of success to substitute ‘576’s OP tetrapeptide sequence with the N-Ac-Ala-Leu-Leu-Pro sequence taught by Barcenas. One of ordinary skill in the art after reading Barcenas would have been motivated with reasonable expectation of success because Barcenas peptide was designed to be sufficiently lipophilic to be readily extracted on a C18 substrate; and because the peptide designed was known to promote residue-selective ion fragmentation upon collisional activation that would focus most of the fragment ion signal into a single dominant dissociation channel. Thus, after reading ‘576 and Barcenas, an ordinary skilled artisan would have been motivated to make the substitution in order to arrive at the instantly claimed invention.
Regarding instant claim 2, U.S. Patent No. 10,076,576 B2 claims:
The method according to claim 12 wherein said drug D is selected from the group consisting of maytansine, geldanamycin, paclitaxel, docetaxel, campthothecin, vinblastine, vincristine, methothrexate, aminopterin, amrubicin, or a derivative of any thereof (see ‘576, column 66, claim 14).
Regarding instant claim 4, U.S. Patent No. 10,076,576 B2 claims:
The method according to claim 12 wherein, when present, said linker or spacing group is a self-eliminating linker or spacing group (see ‘576, column 66, claim 15).
Regarding instant claim 6, U.S. Patent No. 10,076,576 B2 does not claim the compound, salt, crystal, co-crystal, polymorph, isomer or amorphous form according to claim 1 further complexed with a macrocyclic moiety.
However, Marti-Centelles teaches that macrocyclic structures are common synthetic targets in drug discovery and that peptidic macrocycles have been developed to restrict conformational flexibility (preorganization) and to increase stability (see pg. 8736, Abstract). Therefore, an ordinary skilled artisan would have been motivated with reasonable expectation of success before the effective filing date of the claimed invention to incorporate a macrocyclic moiety as part of ‘576’s prodrug. One of ordinary skill in the art would have been motivated to do it because it was known that macrocycles restrict conformational flexibility and increase stability. As such, further complexing a macrocyclic moiety to the ‘576’s prodrug would support the instantly claimed compound.
Regarding instant claims 7 and 14, U.S. Patent No. 10,076,576 B2 claims:
A composition comprising the prodrug or salt thereof according to claim 1 (see ‘576, column 65, claim 6).
Regarding instant claim 8, U.S. Patent No. 10,076,576 B2 claims:
The composition according to claim 6 further comprising at least one of a pharmaceutically acceptable solvent, diluents or carrier (see ‘576, column 65, claim 7).
Regarding instant claims 9-11, U.S. Patent No. 10,076,576 B2 claims:
A method for treating a tumor or cancer in a subject, said method comprising administering to a subject having cancer an amount of prodrug or salt thereof according to claim 1 sufficient to provide a therapeutically effective amount of drug in the vicinity of the tumor or cancer, said administering resulting in the treatment of said tumor or cancer. (see ‘576, column 65, claim 8).
Regarding instant claims 12-13, U.S. Patent No. 10,076,576 B2 claims:
A method for producing the prodrug according to claim 1, said method comprising the steps of: (i) obtaining the drug; (ii) linking the drug to a capped oligopeptidic moiety, resulting in the prodrug; or, alternatively, (ii') linking the drug to an oligopeptidic moiety followed by linking the capping group to the oligopeptidic moiety, resulting in the prodrug; and (iii) purifying the prodrug obtained in step (ii) or (ii'); wherein the oligopeptidic moiety is a tetrapeptide with the sequence ALGP (SEQ ID No 1), TSGP (SEQ ID NO: 4), or KLGP (SEQ ID NO: 6). (see ‘576, column 65, claim 12).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Conclusion
No claim is allowed.
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/CLAUDIA ESPINOSA/ Patent Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654