DETAILED ACTION
Election/Restrictions
Applicant’s election of
PNG
media_image1.png
200
400
media_image1.png
Greyscale
, an aptamer targeting moiety, no modification and cancer cell in the reply filed on December 23 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). In light of the lack of prior art of the elected compound the species election was expanded to include:
PNG
media_image2.png
164
300
media_image2.png
Greyscale
(second compound in line 9 of claim 1).
Claims 1-12 are pending in the application. Claims 7-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (species), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 23 2025. Accordingly, claims 1-6 are being examined on the merits herein.
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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 and 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/110153, PCT/IB2016/050495 and 15/547069, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Prior filed 62/110153 fails to provide support for any of the claimed compounds. Prior filed ‘153 fails to provide written description support for the compound inhibiting TCF/LEF transcriptional activity or expression. Prior filed ‘153 fails to provide written description or enablement support for the small molecules treating or preventing a condition in a subject.
Prior filed PCT/IB2016/050495 and 15/547069 while providing written description support for the specific small molecules claimed fail to provide written description support for the inhibition of TCF/LEF transcription activity or expression. The only occurrence in these documents for TCF/LEF is in the teachings of additional cancer therapies which can be used with the compound. The prior filed documents fail to provide written description or enablement support for treating or preventing a condition in a subject.
The instant application is correctly identified as CIP of 15547069.
Therefore, the effective filing date of the instant claims is February 25 2022.
Information Disclosure Statement
No IDS has been provided.
Drawings
The drawings are objected to because some of the drawings are illegible. In figure 3, the 3rd compound has some writing which cannot be read. It is isn’t clear what is being references with the one group attachment (it might be Abs but no indication is given as to what that stands for).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities: many of the structures are illegible. Due to the size and shape, it is difficult to read the structures recited in the claim. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: the abbreviations TCF/LEF need to be spelt out the first time they occur. The recitation TCF is interpreted as T-cell factor. The recitation LEF is interpreted as lymphoid enhancer binding factor. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: a word is missing between preventing and condition in line 1. Currently claim 1 is ungrammatical and recites “A method for treating or preventing condition”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-6 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 1 as written is vague and indefinite. The first recited structure, the elected species, contains a N with only 2 bonds. See:
PNG
media_image3.png
125
82
media_image3.png
Greyscale
. The structure of the claimed compound is unclear. It isn’t clear if an H is missing, the claim is supposed to have a negative charge or if a double bond is missing between the N and C. The specification does not clarify the scope. As taught in westfield.ma.edu: Nitrogen will usually have 3 bonds, occasionally 4; however, if the N has 4 bonds it will be positively charged. Nitrogen can also have 2 bonds if the nitrogen atom is negatively charged. Here the nitrogen has two bonds but does not include a negative charge. Therefore, the scope of the structure is unclear. The examiner note there are several other compounds in which there are only two bonds to nitrogen which would also be considered indefinite, specifically 5th in first line; 2nd , 3rd and 5th in second line; 2nd, 3rd, 4th and 6th in 3rd line; 3rd, 4th and 6th in 4th line; 1st, 2nd, 3rd and 4th in 5th line; 1st, 2nd, 3rd, 4th in 6th line; and 1st, 2nd, 3rd in 7th line.
Claim 2 as currently written is vague and indefinite. The claim recites “said agent comprises a targeting moiety”. Claim 2 depends from claim 1. The antecedent basis support for “said agent” is associated with the specific small molecules claimed. However, claim 2 now recites that the agent also has a targeting moiety. Since the claims include aptamers (as elected) and none of the small molecules are aptamers, this targeting moiety must be an additional component. But claim 2 never recites that the agent “further comprise” a targeting moiety. Nor do the claims or the specification contemplate how these targeting moieties are attached to the small molecules. While additional functionality could potentially be added to the small molecules to connect the targeting moiety, this would then change the structure of the small molecule and thus the scope of “said agent”. This creates uncertainty as to the scope of the claimed agent.
Claim 4 as currently written is vague and indefinite. Claim 4 recites said agent inhibits cancer growth or cancer stem cell growth. However, claim 4 depends from claim 1 and claim 1 recites treating or preventing any condition in a subject. Therefore, it isn’t clear if in claim 4 applicants are limiting the subject to be one with cancer or if the subject is still a subject with any condition. Claims 5 and 6 suffer from similar issues. The claims require agents which are for treating/preventing cancer but they depend from claim 1 and claim 1 is to treating or preventing any condition.
Claim 3 is included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Improper Markush Grouping
Claims 1-6 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of small molecule is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: looking to claim 1, there are 58 specific compounds recited. None of the compounds share single structural similarity. They all include different functional groups (rings, S, N, O, halogens (i.e. Cl, F)) and in different arrangements. While some include phenyl rings, other compounds do not. Thus, the structure cannot be said to possess a common use that flows from the substantial structural feature. While the claim purports, and figure 4 shows an IC50 less than 1 µM, that the compounds inhibit TCF/LEF transcriptional activity, the instant specification provides no working examples nor any useful protocol for how the inhibition, reported in the Figure 4, is 1) measured or 2) relates to the instantly claimed scope. Foldesi (Biomol, 2020) teaches that use of the IC50 is a common way to denote inhibitor potency. But this is just one parameter that should be considered. Jansson-Lofmark et al. (Clin Pharmacol Ther. 2020) teaches that taught that high in vitro drug potency does not necessarily predict in vivo benefit, partly because of poorer pharmacokinetic properties (page 299, left column, first paragraph). Since the art does not recognize the compounds as belong to a particular class of compounds, the lack of a common structure and a common use, the Markush grouping is improper.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 2 and 5 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 claim(s) 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 2 is directed to a targeting agent which is capable of binding to the surface of a cancer cell.
Claim 5 is directed to a targeting which treats or prevents cancer.
The instant specification does not disclose a single aptamer which is capable of binding to the surface of a cancer cell as required by the instant claims or which can treat or prevent cancer. The instant specification does direct the readers’ attention to Ray et al. which does teach aptamers such as anti-TN-C aptamers which target glioma, breast and colon cancer; anti-PSMA aptamer which targets prostate-specific membrane antigen in prostate cancer cells, AS1411 which targets breast cancer cells; anti-mucin-1 aptamers in epithelial cancer cells (breast, ovary, colon, pancreas, lungs and prostate) but this reference just merely states targets to which the aptamers may target. It appears that AS1411 is the only specific aptamer taught and which meet the written description and enablement provisions of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. However, claim(s) 2 is(are) directed to encompass any aptamers, peptides, biodegradable materials, antibody-derived epitope binding domains, cellular ligands, and combination thereof which only correspond in some undefined way to specifically instantly disclosed chemicals. None of these targeting moieties meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, due to lacking chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above specifically disclosed chemical structures, the skilled artisan cannot envision the detailed chemical structure of the encompassed targeting moiety, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003).
The scope of the claim is so broad in that it includes any aptamers, peptides, biodegradable materials, antibody-derived epitope binding domains, cellular ligands but also requires that it targets the surface of a cancer cell or treats or prevents cancer. While aptamers, peptides and potentially antibody-derived epitope binding domains might have some structural limitations such as nucleotides or amino acid, the recitation biodegradable material and cellular ligands contains no structural limitations which would indicate what is required in the compounds to target cancer cells. But even within the scope of aptamers, peptides and antibody-derived, the scope is so large that the instant specification lacks written description of the structural requirements for a targeting moiety that is capable of binding to the surface of a cancer cell or treats/prevents cancer. Even Ray et al. teaches that some, such as AS14111, have been discovered serendipitously (section 5).
Therefore, only the above chemically structurally defined chemicals, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
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 1-6 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 the use of papaverine for treating colon cancer and for mammary or lung tumors in combination with radiation therapy by way of the prior art, specifically Benej et al. and Li et al. (see rejection below) does not reasonably provide enablement for treating or preventing any disease or condition or even treating or preventing 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent 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 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims and Nature of the Invention
The claim is very broad insofar as it recites treating or preventing any condition in a subject comprising administering to the subject a pharmaceutical composition comprising an effective amount of an agent that inhibits TCF/LEF transcription activity or TCF/LEF expression. The compounds claimed are structurally diverse with no central core.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides no direction or guidance for how the compounds claimed can be used to treat or prevent any condition in a subject. Fig. 4 shows the claimed compounds and TCF/LEF transcription IC50 as well as cell viability. However, no guidance is provided in the instant specification on the test parameters utilized to determine these values. There is no indication which cells were utilized in the test. No reasonably specific guidance is provided concerning useful therapeutic protocols for treating or preventing the scope of diseases encompassed by the claims, other than stating they can be treated or prevented. None of the data actually shows that administration of the composition in a subject would treat or prevent any condition. Even in a narrower interpretation with a subject with cancer, none of the data actually shows an effect on tumor size reduction or treating/preventing all forms of cancer.
The Relative Skill Level, the State of the Prior Art and The Level of
Predictability in the Art
The relative skill of those in the art is high, that of an MD or PHD. A medicinal chemist who understands both drug design as well as therapeutic protocols.
Amerigo Scientific teaches that the T cell factor (TCF) family is an important switch in controlling cancer. In some tumors, upregulation of TCF factors may cause T cells to suppress tumor immune responses and promote tumor growth and metastasis (overview). TCF1 and LEF1 mainly play a role in immune cell differentiation and T cell development. In leukemia, abnormal activation may promote T cell malignant proliferation. Epigenetic modifications can inhibit TCF3 in some cancer which leads to release of Wnt signal initiation and stimulates cancer progression. High expression of TCF4 can enhance cell stemness and tumor resistance, making cancer cells more invasive (the role of TCF). T-cell factor family members directly linked to several cancer types including colorectal cancer, breast cancer, acute myeloid leukemia, gastric cancer and hepatocellular carcinoma (see table).
Takano et al. is directed to TCF/LEF-mediated transcriptional regulation in the canonical Wnt pathway. The TCF/LEF family consists of sequence-specific transcription factors that serve as the final key regulators in the Wnt/β-catenin pathway. These proteins bind to Wnt response elements (WREs) in target gene enhancers and promoters, thereby determining which genes are regulated by Wnt signaling/ Despite their fundamental similarities, each TCF/LEF family member can generate distinct effects on target genes, shaped by differential expression patterns, alternative splicing events, and protein–protein interactions (PPIs). TCF7 and LEF1 function primarily as activators of Wnt target genes, particularly in colorectal tumors. Dysregulation of these factors contributes to disease. TCF7L2 polymorphisms are associated with type 2 diabetes and upregulation of TCFL2 is observed in neurogenerative conditions such as Alzheimer’s disease (section 3). Multiple Wnt/β-catenin-targeted agents are in development or have been tested previously. Many efforts to pharmacologically manipulate the Wnt pathway have focused on upstream targets using both biologics and small molecules. However, mutations that aberrantly activate the Wnt pathway often occur downstream. Furthermore, the demonstrated clinical toxicity associated with broad upstream perturbation of the Wnt signaling cascade (e.g., Wnt/Fzd inhibition or Porcupine inhibitors) may limit the therapeutic utility of such agents (section 11). It is important to note that many of β-catenin/TCF inhibitors discovered to date contain promiscuous chemical structures, including compounds later identified as pan-assay interference compounds (PAINS), which can cause non-specific interference in assays, as well as an organocopper complex with potential toxicity concerns. Consequently, these initial hits require rigorous counter screen and further structural optimization to validate their specific mechanism of action and assess their therapeutic potential (section 11). Despite the crucial role of Wnt signaling in diseases such as cancer and fibrosis and the demonstrated efficacy of Wnt-targeting therapies in improving pathological conditions in animal models, no drugs that target Wnt signaling have been clinically approved. The intrinsic complexity of the Wnt signaling cascade, along with its extensive cross-talk with multiple pathways, represents a significant obstacle to safe therapeutic targeting. Nevertheless, the clinical efficacy of pharmacological modulation of the Wnt signaling pathway remains high. For example, recent studies have suggested that inhibition of the Wnt/β-catenin pathway, at least in preclinical models, synergizes with immunotherapies, including immune checkpoint inhibitors and CAR-T-cell therapies, through intrinsic effects on immune cells, tumors, and the tumor microenvironment (second to last paragraph).
Benej et al. shows in Figure 2G as administration of PPV (papaverine, a instantly claimed inhibitor) when administered alone to orthotopic EO771 tumors grown in nude mice had no appreciable effect on tumor growth. Radiation was required to be used in combination with PPV in order to obtain any appreciable reduction in tumor growth.
Lofmark et al. (Clin Pharmacol Ther. 2020) teaches that taught that high in vitro drug potency does not necessarily predict in vivo benefit, partly because of poorer pharmacokinetic properties (page 299, left column, first paragraph).
Thus, the state of the art establishes that only in some tumors upregulation of TCF factors may cause T cells to suppress tumor immune responses and promote tumor growth and metastasis. Each TCF/LEF family member can generate distinct effects on target genes and the intrinsic complexity of the Wnt signaling cascade, along with its extensive cross-talk with multiple pathways, represents a significant obstacle to safe therapeutic targeting. Administration of an instantly claimed inhibitor to a specific tumor showed no appreciable reduction of growth tumor. Finally that a high in vitro drug potency does not necessarily predict in vivo benefit.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used to treat or prevent any condition which includes cancer, Alzheimer’s, fibrosis, etc. as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Benej et al. (PNAS, 2018) in view of Li et al. (Oncogene, 2015).
Applicant Claims
The instant application claims a method for treating or preventing condition in a subject, comprising administering to the subject a pharmaceutical composition comprising an effective amount of an agent that inhibits TCF/LEF transcriptional activity, or TCF/LEF expression, wherein said agent is at least one small molecule represented by a compound having the chemical structure of:
PNG
media_image2.png
164
300
media_image2.png
Greyscale
.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Benej et al. is directed to papaverine and its derivatives radiosensitive solid tumors by inhibiting mitochondrial metabolism. Previous work has shown that decreasing oxygen consumption in the cores of 3D tumor spheroids decreases the level of hypoxia that displays radiation resistance. Data shows that a single dose of a safe, FDA-approved drug papaverine inhibits mitochondrial transport chain complex I and transiently reduces tumor hypoxia, providing a clinically manageable therapeutic window to deliver more effective radiation therapy (page 10759-10760 bridging paragraph).
The structure of papaverine (PPV) is shown in Figure 5A:
PNG
media_image4.png
117
132
media_image4.png
Greyscale
Evaluation of the effect of local radiation therapy and/or PPV treatment on model tumor growth is shown in Figure 2F. In mammary tumors in mice, a single dose of PPV had no significant effect but PPV treatment followed 30 minutes later by radiation therapy produced a significant two to four fold enhancement of tumor growth delay over radiation therapy alone (Fig. 2G; pages 10757-10758 bridging paragraph). In lung tumors, PPV before radiation showed a similar effect but treatment with PPV after radiation did not have any effect compared to radiation alone (Fig. 2H and page 10758 first paragraph).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Benej et al. suggest administration of papaverine in combination with radiation therapy to treat solid tumors such as lung or mammary tumors, Benej et al. does not expressly teach inhibition of TCF/LEF. However, this deficiency is cured by Li et al.
Li et al. is directed to phosphodiesterase 10A which is a novel target for selective inhibition of colon tumor cell growth and beta-catenin-dependent TCF transcriptional activity. PDE10 is involved in colon tumorigenesis from studies showing that this enzyme is overexpressed in colon tumor cells compared with colonocytes. PDE10 was found to be essential for colon tumor cell growth as evident by experiments showing anti-proliferative and pro-apoptotic effects from small molecule inhibitors and genetic silencing. Consistent with the differential expression of PDE10 in colon tumor cells compared with colonocytes, the growth inhibitory effects resulting from PDE10 inhibition were only apparent in tumor cells (page 3, first complete paragraph). As shown in Figure 2a PDE10 inhibitors such as papaverine (2b) were evaluated for inhibitor effects on the growth of human colonocytes and colon tumor cell lines. Tumor cell growth inhibitory activity from PDE10 inhibition is associated with suppression of beta-catenin and TCF transcriptional activity (page 6).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Benej et al. and Li et al. and administer a therapeutically effective amount of papaverine in combination with radiation therapy to mice with lung, colon or mammary tumors. One skilled in the art would have been motivated to administer papaverine to this patient population as both Benej et al. and Li et al. suggests administration of papaverine to inhibit growth of cancer tissues. Regarding the claimed subject, Benej et al. teaches administration to a mouse model.
Regarding the claimed at least one small molecule, papaverine has the structure:
PNG
media_image4.png
117
132
media_image4.png
Greyscale
which is the same as instantly claimed (second compound in line 9 of claim 1).
Regarding the claimed inhibition of TCF/LEF transcriptional activity and determining TCF/LEF transcription activity, as taught by Li et al. papaverine is a PDE10 inhibitor and inhibition of PDE10 is associated with suppression of beta-catenin and TCF transcriptional activity. Thus, one skilled in the art would expect that papaverine would inhibit TCF/LEF transcriptional activity based on the teachings of Li et al. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Benej et al. and Li et al. and determine TCF/LEF transcription activity. One skilled in the art would have been motivated to measure this activity as tumor cell growth inhibitor activity is associated with TCF transcriptional activity as taught by Li et al. Therefore, measuring the activity would be obvious to determine effectiveness on tumor cell growth inhibition.
Regarding claim 4, both Benej et al. and Li et al. suggest inhibition of cancer growth.
Claims 2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Benej et al. in view of Li et al. as applied to claims 1, 3-4 and 6 above and in further view of Wu et al. (Mol. Pharmaceutics, 2013).
Applicant Claims
The instant application claims said comprises a targeting moiety capable of binding to the surface of a cancer cell, wherein said targeting moiety is selected from the group consisting of aptamers, peptides, biodegradable materials, antibody-derived epitope binding domains, cellular ligands, and combination thereof.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Benej et al. and Li et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Benej et al. teaches treatment of certain types of cancers with papaverine, Benej et al. does not teach a targeting moiety or nanoparticles with an imaging agent. However, this deficiency is cured by Wu et al.
Wu et al. is directed to nucleolin targeting AS1411 modified protein nanoparticle for antitumor drug delivery. Taught are nanoparticles loaded with drug to which AS1411 was attached to the surface. Compared with just nanoparticles of drug, the uptake of the AS1411 modified nanoparticles was increased in tumor cells while there was a decrease in nontumor cell lines (abstract; page 3556; Fig. 1). The nanoparticles also included a hydrophobic fluorescent dye coumarin aka imaging agent, specifically coumarin-6. The fluorescent nanoparticles were used to display the location of the nanoparticles (page 3559, cellular uptake of Apt-NPs-PTX).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Benej et al., Li et al. and Wu et al. and utilize AS1411 modified nanoparticles comprising papaverine and coumarin-6. One skilled in the art would have been motivated to utilize these nanoparticles in order to deliver the antitumor drug papaverine. One skilled in the art would have been motivated to utilize AS1411 targeted nanoparticles as they are taught by Wu et al. as increasing uptake in tumor cells. One skilled in the art would have been motivated to include coumarin-6 in order to visualize the location of the nanoparticles as taught by Wu et al. Since Wu et al. suggests the use of the nanoparticles for antitumor drug delivery there is a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of copending Application No. 17671515 (USPGPUB No. 20220243282) in view of Yu (Scientific Reports, 2017). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant application claims a method for treating or preventing condition in a subject, comprising administering to the subject a pharmaceutical composition comprising an effective amount of an agent that inhibits TCF/LEF transcriptional activity, or TCF/LEF expression, wherein said agent is at least one small molecule represented by a compound having the chemical structure of:
PNG
media_image1.png
200
400
media_image1.png
Greyscale
(as elected).
Copending ‘515 claims a method for treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising an effective amount of at least one agent that inhibits at least one of EN2 expression or EN2 transcriptional activity, and at least one of SATB2 expression or SATB2 transcriptional activity, wherein SATB2 and EN2 are expressed in the cancer, the cancer is selected from the group consisting of human breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, gastric cancer, liver cancer, lung cancer, cancer stem cells, mesothelioma, brain cancer, ovarian cancer, head and neck cancer, sarcoma, kidney cancer, melanoma, multiple myeloma, leukemia, and lymphoma, and the at least one agent wherein the claimed agents include the same compound as instantly elected is claimed (see page 4, last line, second compound).
Regarding claim 2, copending ‘515 claims the same (claim 2).
Regarding claim 4, copending ‘515 claims the same (claim 4).
Regarding claim 5, copending ‘515 claims the same (claim 5).
Regarding claim 6, copending ‘515 claims the same (claim 6).
The difference between the instant claims and copending ‘515 is that copending ‘515 claims a specific condition (i.e. treating or preventing cancer) and claims that the agent inhibits at least one of EN2 expression or EN2 transcriptional activity and at least one of SATB2 expression or SATB2 transcriptional activity. Copending ‘515 does claim administration of the same compound. Copending ‘515 does not claim TCF/LEF expression. However, this deficiency is cured by Yu et al.
Yu et al. is directed to SAT2/beta-catenin/TCF-LEF pathway which induces cellular transformation by generating cancer stem cells in colorectal cancer. SATB2 is highly expressed in colon cancer cell lines. Silencing of SATB2 inhibits TCF/LEF activity and its targets (page 2, third complete paragraph). IHC data demonstrated that SATB2 expression is positively correlated with β-catenin expression. Examined whether β-catenin/TCF-LEF pathway mediates the effects of SATB2 in CSCs by measuring the expression of β-catenin and TCF-LEF targets, and TCF-LEF transcriptional activity. SATB2 shRNA inhibited the expression of SATB2, and β-catenin expression, and TCF/LEF targets cyclin D1 and Survivin (Fig. 7G). Furthermore, inhibition of SATB2 by shRNA attenuated TCF-LEF transcriptional activity (page 7). Data demonstrate that β-catenin/TCF-LEF pathway mediates the biological effects of SATB2 (page 8).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘515 and Yu et al. and measure the transcriptional activity of TCF/LEF. One skilled in the art would have been motivated to measure this activity as copending ‘515 specifically claims the compounds inhibit SATB2 and Yu et al. demonstrates that SATB2 inhibitors inhibit expression of SATB2 and beta-catenin which attenuated TCF-LEF transcription. Since the data in Yu et al. demonstrates a link between TCF-LEF pathway and SATB2, one skilled in the art would have a reasonable expectation of success.
Claims 1-6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-6, 8 and 11-12 of copending Application No. 17672693 (USPGPUB No. 20220168422) in view of Yu et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘693 claims a method for treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising an effective amount of an agent that inhibits Nanog expression, or Nanog transcriptional activity, wherein Nanog is expressed in the cancer and the agent is the same as instantly elected (first compound listed).
Regarding claim 2, copending ‘693 claims the same (claim 8).
Regarding claim 5, copending ‘693 claims the same (claim 5).
Regarding claim 6, copending ‘693 claims the same (claim 6).
The difference between the instant claims and copending ‘693 is that copending ‘693 claims a specific condition (i.e. treating or preventing cancer) and claims that the agent inhibits Nanog expression or transcription activity. Copending ‘693 does claim administration of the same compound. Copending ‘693 does not claim TCF/LEF expression. However, this deficiency is cured by Yu et al.
Yu et al. is directed to SAT2/beta-catenin/TCF-LEF pathway which induces cellular transformation by generating cancer stem cells in colorectal cancer. The pluripotency maintaining factors (Nanog) regulate self-renewal and survival of stem cells (page 2, first paragraph). Some of the targets of TCF/LEF include pluripotency maintaining factors such as Nanog (page 2, second complete paragraph). SATB2 shRNA inhibited the expression of TCF-LEF target genes, Nanog in colorectal CSCs (page 10, last paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘693 and Yu et al. and measure the transcriptional activity of TCF/LEF. One skilled in the art would have been motivated to measure this activity as copending ‘693 specifically claims the compounds inhibit Nanog and Yu et al. demonstrates that Nanog is a TCF-LEF target gene. Since Nanog is a target gene of TCF-LEF there is a reasonable expectation of success.
Regarding claim 4, Yu et al. teaches that Nanog regulate self-renewal and survival of stem cells. Therefore, administration of the elected compound, which is taught by copending ‘693 as an inhibitor of Nanog would be expected to inhibit cancer stem cell growth.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636