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 .
Status of Claims
The preliminary amendment filed 23 December 2024 has been received and examined.
Claims 1-14, 16, 20, 22, 24, 25, and 29 are pending. Claims 3-12, 14, 16, 20, 24, 25, and 29 have been amended. Claims 15, 17-19, 21, 23, 26-28, and 30-41 have been canceled.
Priority
This application is a National Stage entry of International Application No. PCT/US22/50429, filed 18 November 2022, and claims benefit under 35 U.S.C. 120 to US Provisional Application No. 63/280,704, filed on 18 November 2021. Applicant’s claim for benefit is acknowledged.
Information Disclosure Statement
The four information disclosure statements (IDSs) submitted on 27 August 2024, and the IDS submitted on 23 September 2025, have been acknowledged and considered.
Claim Interpretation
Claim 25 recites the word “preventing.” This word is not defined in the instant specification and is therefore given its broadest reasonable interpretation. According to Taber’s Medical Dictionary, “prevention” is defined as “the anticipation of harm, disease, or injury and the measures taken to block their effects” (p. 1945). Claim 25 is interpreted as the definition taken from Taber’s Medical Dictionary.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 25 and 29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating colorectal cancer with compound PDS-0330, does not reasonably provide enablement broadly for preventing colorectal cancer and all diseases or disorders capable of being modulated by claudin-1 inhibition with all compounds of claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” . . . These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Wands factors are analyzed with respect to the claimed invention in turn below.
The breadth of the claim is broad in scope. The claim recites: “A method of treating or preventing a disease or disorder capable of being modulated by claudin-1 inhibition, comprising administering to a subject in need thereof of a therapeutically effective amount of the compound or salt of claim 1.” The term “modulation” is a relative term that encompasses any minimal effect, which means the method extends to nearly any disease or disorder, each with a vast and diverse population of subjects. For example, the specification discloses: “Overexpression and/or hyperactivity of claudin-1 is known to cause many adverse conditions. These include, for example, hepatitis, diabetic nephropathy, ulcerative colitis, Crohn's disease, and cancer. Cancer includes but is not limited to breast, colorectal, pancreatic, liver, nasopharyngeal, ovarian, uterine, lung, brain, skin, gastric, ovary, esophageal, prostate, colon, stomach, or oral squamous cell cancer.” (Spec., p. 22, ¶[00110]). The claim therefore encompasses a method of preventing all diseases or disorders capable of being modulated by claudin-1 (CLDN-1), including Crohn’s disease and ulcerative colitis.
The nature of the invention generally relates to pharmaceutical art and more specifically to compounds of Formula I and methods of using the same in treating or preventing diseases or disorders capable of being modulated by claudin-1. The instant specification states: “ Despite the clear knowledge of the role of claudin-1 in promoting CRC metastasis, there is no available inhibitor of claudin-1. It is therefore desirable to (i) develop novel claudin-1 inhibitors for CRC progression and metastasis, (ii) develop biomarkers capable of risk stratification and (iii) develop novel therapeutics. Further, many traditional chemotherapeutic agents suffer from a narrow therapeutic index that presents as a major drawback in treating cancer, in addition to a lack of specificity, severe side effects, and development of drug resistance. Therefore, compounds that inhibit anti-angiogenesis and/or target mitochondrial oxidative metabolism are appealing targets for treating tumors and assisting in overcoming the side effects of the chemotherapeutic agents. ” (Spec. p.4). Thus, the nature of the invention is sophisticated.
The state of the prior art is discussed in a review article: “The CLDN-1 and CLDN-7 members of the claudin family are primarily found to be downregulated in several invasive cancers including breast, esophageal, and prostate cancers. However, in contrast, overexpression of CLDN-1 has been observed in colon, nasopharyngeal, ovarian and oral squamous cell cancers, while CLDN-3 and -4 are highly overexpressed in ovarian cancer and upregulated in breast, gastric, pancreatic, prostate and uterine cancers.”(Bhat et al., p.3). Table 1 summarizes the various cancers linked to CLDN-1, and the nature of its expression which attributes to the disease (Id., p. 5). In view of the review article, the state of the prior art is ascending for targeting CLDN-1 for inhibiting or increasing its activity, depending on the cancer type. But Examiner is unaware of evidence from the prior art that supports a claim for administering compounds of Formula I to prevent all types of diseases such as cancer, capable of being modulated by CLDN-1 inhibition, including, nasopharyngeal, ovarian and oral squamous cancer cells.
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All the factors may not be present in every case, and one or more of them may predominate. Ent. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
The level of predictability in the art is generally unpredictable. The relevant art requires each potential drug candidate to be assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18, 24 (CCPA 1970). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. MPEP § 2164.02(II) explains that a correlation between the claimed invention and the evidence provided in an application, along with a correlation between the evidence and the models recognized in the art, are required:
“Correlation” as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brane, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications).
Further, treatments may be effective for some subjects and ineffective for other subjects. Thus, each candidate for pharmaceutical or veterinary medicine must be evaluated on its own even when a nexus to an existing drug or class of drugs has been established.
The amount of direction provided by the inventor includes information about administering compounds of Formula I in vitro and in vivo: “ The contacting of the cell can occur in vitro or in vivo. In some cases, contacting of the cell occurs in vitro. In other cases, contacting of the cell occurs in vivo. Therefore, the disclosure includes administering one or more of a compound described herein to a subject, such as a human, in need thereof. In some
embodiments, the subject suffers from a disease or disorder associated with aberrant activity of claudin-1. These include, for example, hepatitis, diabetic nephropathy, ulcerative colitis, Crohn's disease, and cancer. Cancer includes but is not limited to breast, colorectal, pancreatic, liver, nasopharyngeal, ovarian, uterine, lung, brain, skin, gastric, ovary, esophageal, prostate, colon, stomach, or oral squamous cell cancer. In some cases, the cancer is colorectal cancer.” (Spec., p. 22). However, the working examples only include in vitro and in vivo models of colorectal cancer, specifically with cell lines SW480 and SW620 (Spec., p. 24, ¶ [00121]).
The existence of working examples relates to methods of treating subjects with PDS-330. For example, xenograft colorectal cancer models of mice were prepared with SW620 (high caudlin-1 expression) cells and SW480cld-1 (overexpressed caudlin-1) cells (Figures 18, 21, and 25). Administration of PDS-330 showed decrease in mean tumor volume over time. Additionally, Figure 13 depicts more effective inhibition of cell survival with PDS-330 compared to dasatinib in SW480cld-1 cells. However, Figure 9 shows compound 19A did not show nearly the same effect as PDS-330 in inhibiting cell survival in SW620 and SW480cld-1 cells. Similarly, Figure 11 compares 19A, PDS-330, 23B, and I-6, and PDS-330 was identified as the most potent effector (Spec., p. 27, ¶ [00130]). The present disclosure does not provide working examples for methods of treating or preventing other types of diseases or disorders capable of being modulated by claudin-1 inhibition. There are no examples for a method of preventing, for example Crohn’s disease or ulcerative colitis, in the specification, only the treatment in vitro and in vivo of colorectal cancer cells using compound PDS-330. Furthermore, only compound PDS-330 showed potent effects to treat colorectal cancer, compared to other compounds of Formula I.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure is extensive, as it includes in vitro and in vivo screening for each specific disease or disorder encompassed by the claims. As claimed, the scope of such diseases is essentially unbound.
Scope of Enablement Conclusion
In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a person having ordinary skill in the art to use the full scope of the claimed invention. The breadth of the claims is broad in scope; the nature of the invention is sophisticated; the state of the prior art is ascending for targeting CLDN-1 for inhibiting or increasing its activity, depending on the cancer type; the level of skill in the art is high; the pharmaceutical art is unpredictable; the direction provided by the inventor is limited to evaluation of compounds as claimed in colorectal cancer cell lines overexpressing claudin-1; and does not exemplify a method of preventing all diseases or disorders within the scope of, “A method of treating or preventing a disease or disorder capable of being modulated by claudin-1 inhibition …”; and the quantify of experimentation needed to practice the claimed invention is extensive. Thus, when the evidence is considered as a whole, undue experimentation would be required to practice the full scope of the claimed invention.
Examiner recommends amending the claim to recite colorectal cancer as the disease or disorder capable of being modulated by claudin-1 inhibition as supported by the disclosure and to omit the term “preventing.”
Claim Rejections - 35 USC § 112(b) – Indefinite
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 and 4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships in compounds of Formula I, is the location of the variable atom X1 within Formula I. The claim defines B as a C6-C10 aryl or 5-10 membered heteroaryl. B can be a naphthyl possessing a variable X1 atom, as shown in claim 2. Appropriate correction is requested.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 5-8, 10, 12-14, 16, 20 and 22 are rejected under 35 U.S.C. 102(a)(1) based upon a public use or sale or other public availability of the invention, namely compound entered the PubChem Database as PubChem SID: 367099690, Deposited: 25 May 2018 (690).
Regarding claims 1-2, 690 is a compound having the structure of Formula I: B is a C6 aryl ring substituted with one R1; L is a linker, wherein Q2 is C=O, Q1 is a bond, and RN is H; X2 and X3 are both CH; R2 is H; and A is a 9 membered heteroaryl comprising two N heteroatoms.
Regarding claim 5, 690 is a compound of claim 1 having a structure of Formula Ib: Q1 is a bond; Q2 is C=O; RN is H; R1 is a methoxy substituent; R2 is H; and A is a 9 membered heteroaryl comprising two N heteroatoms.
Regarding claims 6-8 and 10, 690 is a compound of claim 1 having a structure of Formula I: X2 is CH; X3 is CH; Q1 is a bond; and Q2 is C=O.
Regarding claim 12-14, 690 is a compound of claim 1 having a structure of Formula I: A is a 9 membered heteroaryl comprising two N heteroatoms and R3 is H. The A ring, specifically, is a benzimidazole ring.
Regarding claims 16 and 20, 690 is a compound of claim 1 having a structure of Formula I wherein R1 is H.
Regarding claim 22, 690 and Compound No. 1 share the exact same structure.
Claims 1-4, 6-7, 9, 11, 12-14, 16, 20 and 22 are rejected under 35 U.S.C. 102(a)(1) based upon a public use or sale or other public availability of the invention, namely compound entered the PubChem Database as PubChem SID: 108529656, Deposited: 22 February 2011 (656).
Regarding claim 1, 656 is a compound having the structure of Formula I: B is a C10 aryl ring substituted with one R1; L is a linker, wherein Q2 is C=S, Q1 is C=O, and RN is H; X2 and X3 are both CH; R2 is H; and A is a 9 membered heteroaryl comprising two N heteroatoms.
Regarding claims 2-4, 6-7, 9 and 11-12, 656 is a compound of claim 1: B is the naphthyl group wherein R1 is H and X1 is CH; Q2 is C=S, Q1 is C=O, and RN is H; X2 and X3 are both CH; R2 is H; and A is a 9 membered heteroaryl comprising two N heteroatoms.
Regarding claims 13-14, 656 is a compound of claim 1 with an A ring that is specifically a benzimidazole ring.
Regarding claims 16 and 20, 656 is a compound of claim 1 wherein R1 is H.
Regarding claim 22, 656 and Compound No. 8 share the exact same structure.
Allowable Subject Matter
Claim 24 contains allowable subject matter. The closest prior art is Pope et al. (Pope JL, Bhat AA, Sharma A, et al., Gut 2014;63:622–634), which discloses a villin-claudin-1 transgenic (Cl-1Tg) mouse model to understand the role of claudin-1 in regulation of intestinal epithelial homeostasis (p. 622, Design).
Pope et al. teaches that upregulated claudin-1 expression induces metalloproteinase-9 (MMP-9) and p-ERK signaling, which alters intestinal epithelial cell differentiation decreasing goblet cell counts. (p.622). Three inhibitors, GM6001, pyrvinium, and U0126, were administered to Cl-1Tg mice to examine their effects on, MMP-9 activity, Wnt/β-catenin-signaling, and p-ERK1/2 activity, respectively. No inhibitors of claudin-1 are taught and the structures of the inhibitors taught are not obvious variants of the compounds in the instant application. Pope et al. also states: “Recent studies have demonstrated marked increase in claudin-1 expression in colon cancer as well as the areas of active inflammation and its correlation with neoplastic transformation.” (p. 629). There is motivation in the art to inhibit claudin-1 as it is overexpressed in colon cancer, but no such inhibitors are disclosed. There is no teaching nor suggestion to make such inhibitors in the art, as of the effective filing date of the claimed invention, nor would it be expected that compounds with a N,N-diaryl urea core, produce predictable effects with respect to inhibition of claudin-1. Accordingly, claim 24 is novel and nonobvious over Pope et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHIL CHANDER AGGARWAL whose telephone number is (571)272-7755. The examiner can normally be reached 7am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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