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 .
Claim Status
Claims 17-22 are cancelled. Claims 1-16 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/US2022/034885 (filed on 06/24/2022) which claims benefit of Provisional U.S. Application No. 63/215,036 (filed on 06/25/2021). 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.
Claims 1-16 have an effective filing date of 06/25/2021 corresponding to Provisional U.S. Application No. 63/215,036.
Information Disclosure Statement
The information disclosure statement(s) filed on 12/20/2023 and 11/12/2025 has/have been considered. Signed copies are enclosed.
Notably, the disclosure statements filed on 12/20/2023 and 11/12/2025 list Search Reports. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Drawings
The drawings are objected to because:
Fig. 6A, 6G, 9H, 14A, and 15A are blurry, causing crucial details to be obscured;
Fig. 18 refers to Fig. 8 in its brief description; and
Fig. 17, 18D, and 19 contain sequences that do not appear in the drawings and/or in the Brief Description of the Drawings.
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.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-16 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Instant claims 1 and 15 are drawn to a method of treating cancer (instant claim 1) or a pharmaceutical composition (instant claim 15) comprising a first inhibitory agent that inhibits the activation of epithelial cell adhesion molecule (EpCAM) signaling and a second inhibitory agent that inhibits the activation of Wnt signaling. Instead of defining the first and second inhibitory agents by their structure, the instant application uses the functional characteristic of inhibition of either EpCAM or Wnt signaling. An inhibitor is not one specific type of molecule, including but not limited to antagonistic antibodies and small molecules. Therefore, the first and second inhibitory agents encompass a large variety of diverse agents that inhibit EpCAM and Wnt signaling respectively via different mechanisms.
Instant claims 2-4 and 16 delineate how EpCAM and WNT signaling are inhibited, including (i) reducing production or release of EpEX and/or blocking binding of EpEX to a Wnt receptor (instant claims 2 and 16), (ii) blocking binding of a Wnt ligand to a Wnt receptor protein (instant claims 3 and 16), and (iii) the Wnt ligand is not EpEX (instant claim 4). While these limitations narrow the mechanisms by which EpCAM and Wnt signaling are inhibited, the instant claims continue to define the inhibitory agents by the results they achieve rather than their structural characteristics.
Instant claim 5 specifies the first inhibitory agent “is an antibody directed to EpEX or an antigen-binding fragment thereof” (line 2). Instant claims 6-7 further specify “the antibody specifically binds to epidermal growth factor (EGF)-like domains I and II” (instant claim 6, lines 1-2) including epitopes “CVCENYKLAVN (aa 27 to 37) (SEQ ID NO: 20) located in the EGF-like domain I, and KPEGALQNNDGLYDPDCD (aa 83 to 100) (SEQ ID NO: 19) located in the EGF-like domain II” (instant claim 7, lines 2-4). This language encompasses a broad genus of structurally distinct antibodies and antigen-binding fragments thereof directed to EpEX.
Instant claim 8 further specifies the antibody or antigen-binding fragment thereof comprises SEQ ID NOs: 2, 4, 6, 9, 11, and 13 for the 6 CDRs. This language does not delineate which fragments retain their function i.e. binding to EpEX.
Instant claim 10 adequately defines the second inhibitory agent as a porcupine inhibitor. However, it relies on instant claim 1 and therefore is included in this rejection as the first inhibitory agent is not well described.
Regarding instant claims 5-8, the instant specification states “the term ‘antibody’ includes not only intact (i.e. full-length) antibody molecules but also antigen-binding fragments thereof retaining antigen binding ability e.g. Fab, Fab′, F(ab′)2 and Fv” (¶ 0059, emphasis added) and “the term ‘antigen-binding fragment’… refers to a portion or region of an intact antibody molecule that is responsible for antigen binding” (¶ 0061). The use of “e.g.” indicated non-limiting examples of antigen-binding fragments. Antibodies and antigen-binding fragments include but not limited to Fabs, scFvs, VHHs, full-length antibodies, and antibody-drug conjugates, which have distinct structures and functions. For example, Sifniotis et al. (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019) state there are numerous formats to address challenges in antibody therapeutics including “[antibody-drug conjugates] as a targeted drug delivery system, bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Pg. 14, ¶ 4, lines 3-5). In addition, antibody fragments include “Fabs and single chain variable fragments (scFv)” (Sifniotis et al., Pg. 9, ¶ 4, line 4). These fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). Therefore, antibodies and antigen-binding fragments encompass a variety of species, each with their own advantages and disadvantages.
Sevy and Meiler (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014) state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antibody or antigen-binding fragment binds EpEX is not a sufficient description (instant claims 5-6).
Wong et al. (Ab-Ligity: identifying sequence-dissimilar antibodies that bind to the same epitope, MABS, 2021) teaches that sequence-distant antibodies can target the same epitope (Pg. 1, entire Abstract). Thus, one ordinary skill in the art would not be able to visualize other antibodies or antigen binding fragments encompassed by the claims which bind to specific epitopes e.g. SEQ ID NOs: 19 and 20 of instant claim 7.
Colman (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution within the interface of the antigen binding region of the antibody, i.e. anywhere in the VH and VL, may abolish binding or may have very little effect on the binding affinity (Pg. 35, top of left column; Pg. 33, right column). These teachings indicates perturbation to the VH and VL of the antibody, applicable to a deletion, can have disastrous effects. It would not be predictable to determine which fragments of an antibody retain their function of binding EpEX, even when the 6 CDRs are delineated (instant claim 8).
Regarding antagonistic small-molecules, Cochran (Antagonists of protein–protein interactions, Chemistry & Biology, 2000) states “developing such molecules is far from trivial. Ideally, one wants not only high potency against the target protein, but also low toxicity, few side effects and good bioavailability“ (Pg. R85, column 2, ¶ 2, lines 2-5). “[U]nderstanding molecular recognition of protein surfaces is a challenging physical chemistry problem” (Cochran, Pg. R87, column 1, ¶ 2, lines 1-2), as it is extremely unlikely that every surface of the target protein is suitable for binding of a small molecule. Taken together, Cochran establishes small molecule discovery as a difficult, unpredictable task.
At a minimum, the first and second inhibitory agents of the instant claims are not limited to particular classes of molecules. The two classes alone discussed above, antibodies and small molecules, demonstrate the difficulty in identifying the structures encompasses by the functionally defined genera. This issue is further exacerbated when other inhibitory molecules encompassed by the claim language are considered. Thus, recitation that an agent inhibits EpCAM or Wnt signaling does not permit a person having ordinary skill in the art to predict the structure of said agents.
As such, instant claims 1-16 are drawn to a method of treating cancer or pharmaceutical composition comprising genera of first and second inhibitory agents that inhibit EpCAM and Wnt signaling respectively.
The instant specification teaches EpAb2-6 comprising SEQ ID NOs: 2, 4, 6, 9, 11, and 13 for the 6 CDRs (Fig. 19) in monoclonal and humanized forms (¶ 0135). The instant specification also teaches “the second inhibitory agent (a Wnt inhibitor) is a porcupine inhibitor,” specifically LGK974 (¶ 0095, also referred to as WNT974). The instant specification does not provide examples using other first and second inhibitory agents as recited in the instant claims.
However, Applicant is claiming large and structurally diverse genera of first and second inhibitory agents that inhibit EpCAM and Wnt signaling respectively. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genera claimed, specifically the structures of the first and second inhibitory agents. Applicant uses functional language to define the genera which is not sufficient as detailed above (see Sevy and Meiler and Wong et al. for information regarding difficulties with predicting structure from function in antibodies and antigen-binding fragments; see Cochran for information regarding difficulties with predicting structure from function in small molecules). While instant claim 8 delineates 6 parental CDRs for the first inhibitory agent, it is not predictable which antigen-binding fragments would retain their function of binding EpEX as perturbation to the VH and VL can abolish binding affinity (see Colman).
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has disclosed two species within the genera claimed (i.e. EpAb2-6 and LGK974). However, given the large number of species encompassed by the genera claimed as well as the high level of structure variation that would be displayed by members of the claimed genera, the disclosure of two adequately described species is not sufficiently representative of the entire genus.
Furthermore, Applicant has not disclosed in instant claims 5-7 relevant, identifying characteristics of CDR amino acid sequences that confer upon an antibody the ability to bind EpEX, specifically the epitopes in EGF-like I and II domains. It is well-known in the art that antibodies generally comprise six parental CDRs. While instant claim 8 delineates 6 parental CDRs, it is not clear what portion of the antibody outside of said CDRs can be altered before drastically affecting binding affinity to EpEX. Absent a description of the at least minimal structural features correlating with a functional ability to bind EpEX which are shared by members of a genus of antibodies and antigen-binding fragments, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish what portion of an antibody (i.e. an antigen-binding fragment) that confers the ability to bind EpEX, specifically the epitopes in EGF-like I and II domains.
Although screening techniques can be used to find inhibitory agents to EpCAM and Wnt signaling, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
Accordingly, given the difficulty associated with predicting structures of functionally described inhibitory molecules, and given the lack of particularity with which the genera are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genera to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does 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 (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 USPQ2datl966.
The specification does not reasonably convey possession of the subject matter of instant claims 1-16. Instant claims 1-16 fail to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
Claims 1-14 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 a method for inducing apoptosis and inhibiting tumor progression of colon cancer comprising administering to a subject in need thereof (i) an effective amount of EpAb2-6; and (ii) an effective amount of LGK974, does not reasonably provide enablement for a method for treating all cancer comprising administering to a subject in need thereof (i) an effective amount of any first inhibitory agent that inhibits the activation of EpCAM signaling; and (ii) an effective amount of any second inhibitory agent that inhibits the activation of Wnt signaling. 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 Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention, (2) the state of the prior art, (3) The relative skill of those in the art, (4) the predictability or unpredictability of the art, and (5) the breadth of the claims
Instant claim 1 is drawn to “[a] method for treating cancer, comprising administering to a subject in need thereof (i) an effective amount of a first inhibitory agent that inhibits the activation of epithelial cell adhesion molecule (EpCAM) signaling; and (ii) an effective amount of a second inhibitory agent that inhibits the activation of Wnt signaling” (lines 1-6).
The instant specification states “the term ‘treatment’ refers to the application or administration of one or more active agents to a subject afflicted with a disorder, a symptom or condition of the disorder, or a progression of the disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptom or condition of the disorder, the disabilities induced by the disorder, or the progression or predisposition of the disorder” (¶ 0071, emphasis added). Therefore, the phrase “treating cancer” encompasses a variety of responses in a subject, including a curative treatment.
Instead of defining the first and second inhibitors by their structure, the instant application uses the functional characteristic of inhibition of either EpCAM or Wnt signaling. An inhibitor is not one specific type of molecule, including but not limited to antagonistic antibodies and small molecules.
Accordingly, instant claim 1 is incredibly broad and drawn to a method for treating all cancer comprising administering to a subject in need thereof (i) an effective amount of any first inhibitory agent that inhibits the activation of EpCAM signaling; and (ii) an effective amount of any second inhibitory agent that inhibits the activation of Wnt signaling, the full scope of which is not enabled by the methods as instantly claimed (the nature of the invention and the breadth of the claims).
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The dependent claims demonstrate that practicing the claimed invention encompasses numerous variables. Dependent claims recite:
functional and structural limitations to the first inhibitory agent that inhibits the activation of EpCAM signaling, including an antibody or antigen-binding fragment that binds EpEX (instant claims 2 and 5-9);
functional and structural limitations to the second inhibitory agent that inhibits the activation of Wnt signaling, including a porcupine inhibitor (instant claims 3-4 and 10);
effects of the cancer treatment (instant claims 11-13); and
the type of cancer treated (instant claim 14).
Collectively, the dependent claims demonstrate that the invention is directed to a method of treating cancer in a subject, subject matter that is highly complex and unpredictable, wherein therapeutic efficacy depends on the identities of the first and second inhibitory agents and the type of cancer targeted.
The following details the state of the prior art and the breadth of the claims concerning cancer treatment with inhibitors to EpCAM and Wnt signaling as instantly claimed:
Inhibitory agents
Antagonistic antibodies and antigen-binding fragments inhibit at the protein level. The instant specification states “the term ‘antibody’ includes not only intact (i.e. full-length) antibody molecules but also antigen-binding fragments thereof retaining antigen binding ability e.g. Fab, Fab′, F(ab′)2 and Fv” (¶ 0059, emphasis added) and “the term ‘antigen-binding fragment’… refers to a portion or region of an intact antibody molecule that is responsible for antigen binding” (¶ 0061). The use of “e.g.” indicated non-limiting examples of antigen-binding fragments.
Antibodies and antigen-binding fragments include but not limited to Fabs, scFvs, VHHs, full-length antibodies, and antibody-drug conjugates, which have distinct structures and functions. For example, Sifniotis et al. (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019) state there are numerous formats to address challenges in antibody therapeutics including “[antibody-drug conjugates] as a targeted drug delivery system, bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Pg. 14, ¶ 4, lines 3-5). In addition, antibody fragments include “Fabs and single chain variable fragments (scFv)” (Sifniotis et al., Pg. 9, ¶ 4, line 4). These fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). Therefore, antibodies and antigen-binding fragments encompass a variety of species, each with their own advantages and disadvantages.
Sevy and Meiler (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014) state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antibody or antigen-binding fragment inhibits EpCAM or Wnt signaling is not sufficient.
Regarding antagonistic small-molecules, Cochran (Antagonists of protein–protein interactions, Chemistry & Biology, 2000) states “developing such molecules is far from trivial. Ideally, one wants not only high potency against the target protein, but also low toxicity, few side effects and good bioavailability“ (Pg. R85, column 2, ¶ 2, lines 2-5). “[U]nderstanding molecular recognition of protein surfaces is a challenging physical chemistry problem” (Cochran, Pg. R87, column 1, ¶ 2, lines 1-2), as it is extremely unlikely that every surface of the target protein is suitable for binding of a small molecule. Taken together, Cochran establishes small molecule discovery as a difficult, unpredictable task.
As fully described in the 102(a) written description section, instant claims 1-16 are drawn to a method of treating cancer comprising administering to the subject genera of first and second inhibitory agents that inhibit EpCAM and Wnt signaling respectively. At a minimum, the first and second inhibitory agents of the instant claims are not limited to particular classes of molecules. The two classes alone discussed above, antibodies and small molecules, demonstrate the difficulty in identifying the structures encompasses by the functionally defined genera. This issue is further exacerbated when other inhibitory molecules encompassed by the claim language are considered. The instant specification teaches EpAb2-6 comprising SEQ ID NOs: 2, 4, 6, 9, 11, and 13 for the 6 CDRs (Fig. 19) in monoclonal and humanized forms (¶ 0135). The instant specification also teaches “the second inhibitory agent (a Wnt inhibitor) is a porcupine inhibitor,” specifically LGK974 (¶ 0095, also referred to as WNT974). The instant specification does not provide examples using other first and second inhibitory agents as recited in the instant claims. Consequently, the lack of structure delineated in the claims encompass a vast amount of first and second inhibitory agents and thus leads to a lack of enablement as Applicant failed to disclose how to use such molecules in treating cancer.
Cancer treatment
While 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. Even within a given cancer type, “[i]ntertumor and intratumor heterogeneity are important obstacles to overcome when designing the most effective therapeutic strategies for patients with cancer. The genotypic and phenotypic variability of tumors can have important consequences for diagnosis, prognosis, and treatment” (Lovly et al., 2016, Pg. e586, Integrating the Heterogeneity of Cancer in Clinical Decision Making, first paragraph). Therefore, the variability among tumors within a cancer type makes it difficult to predict whether a therapeutic approach effective in one tumor type will be effective in another. Accordingly, the treatment of all cancer remains an unpredictable field in which efficacy cannot be readily extrapolated across different cancers or tumor subtypes.
Regarding a curative cancer treatment, Alberts et al. (Cancer Treatment: Present and Future, Molecular Biology of the Cell, 2002) teaches “[t]he difficulty of curing a cancer is similar to the difficulty of getting rid of weeds. Cancer cells can be removed surgically or destroyed with toxic chemicals or radiation; but it is hard to eradicate every single one of them” (Pg. 1, ¶ 2, lines 1-3). Therefore, a curative treatment is extremely challenging as even a few cancer cells can proliferate and create cancer reoccurrence.
The breadth of the claim exacerbates the complex nature of the subject matter to which instant claim 1 is directed. The claim is extremely broad due to the vast number of possible cancer types represented by the term “treating cancer”. Cooper (The Development and Causes of Cancer, The Cell: A Molecular Approach, 2000) teaches “there are more than a hundred distinct types of cancer, which can vary substantially in their behavior and response to treatment” (Pg. 1 , ¶ 2, lines 2-3). Therefore, cancer is not a single disease and treatment would need to be tailored to the specific type of cancer.
The instant specification teaches a combination treatment of LGK974 and EpAb2-6 leads to “induction of apoptosis..[and] reduction in tumor progression” (¶ 0141) in a colon cancer mouse model. The instant specification does not detail how said combination treatment could eradicate cancer entirely or treatment of cancer besides colon cancer. Therefore, it is concluded that the instant specification provides support for inducing apoptosis and inhibiting tumor progression of colon cancer in a subject comprising administering LGK974 and EpAb2-6.
For a person having ordinary skill in the art, i.e. someone with a PhD and/or MD (the relative skill of those in the art), the predictability of applying any first inhibitory agent that inhibits the activation of EpCAM signaling and any second inhibitory agent that inhibits the activation of Wnt signaling for the treatment of all cancer would be low (the predictability or unpredictability of the art) given that:
Inhibitory agents are not a single type of molecule, including but not limited to antagonistic antibodies, antigen-binding fragments, and small molecules. The structure of said agents cannot be reliably predicted from function alone as taught by Sevy and Meiler, Wong et al., and Cochran. This issue is compounded by the lack of structure delineated in instant claims 1-16 regarding first and second inhibitory agents (see 102(a) written description section). There is a lack of enablement as Applicant failed to disclose how to predictably use such molecules in treating cancer.
Cancer is not a single disease. Currently, there is no known cure or treatment for all cancers (see Lovly et al. in the state of the prior art) utilizing the aforementioned combination. Therefore, a generic anti-cancer treatment would not predictably be effective in all cancers.
Consequently, instant claim 1 is directed to complex and unpredictable fields, where the successful treatment of all cancer comprising administrating to the subject any first inhibitory agent to EpCAM signaling and any second inhibitory agent to Wnt signaling cannot be readily extrapolated from the limited number of disclosed examples in the instant application. Evidence of efficacy of LGK974 and EpAb2-6 for inducing apoptosis and inhibiting tumor progression of colon cancer in a subject is provided in the instant specification.
Therefore, a method for inducing apoptosis and inhibiting tumor progression of colon cancer comprising administering to a subject in need thereof (i) an effective amount of EpAb2-6; and (ii) an effective amount of LGK974 is supported by the specification. However, a method for treating all cancers comprising administering to a subject in need thereof (i) an effective amount of any first inhibitory agent that inhibits the activation of EpCAM signaling; and (ii) an effective amount of any second inhibitory agent that inhibits the activation of Wnt signaling is not supported.
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
The instant specification teaches a combination treatment of LGK974 and EpAb2-6 leads to “induction of apoptosis..[and] reduction in tumor progression” (¶ 0141) in a colon cancer mouse model, wherein LGK974 inhibits Wnt signaling and EpAb2-6 inhibits EpCAM signaling. Therefore, the instant specification provides support for inducing apoptosis and inhibiting tumor progression of colon cancer in a subject comprising administering LGK974 and EpAb2-6.
The specification does not provide any additional examples or guidance on how to use a first inhibitory agent to EpCAM signaling other than EPAb2-6 and a second inhibitory agent to Wnt signaling other than LGK974 to treat cancer besides colon cancer as recited in instant claim 1 (the amount of direction or guidance presented and the presence or absence of working examples). The specification of the instant application does not provide support for the entire scope of the claim.
Inhibitory agents are not a single type of molecule, including but not limited to antagonistic antibodies, antigen-binding fragments, and small molecules. As inhibitory agents have substantial variation, their use in cancer treatment would require extensive screening and testing to determine which agents are effective.
Cancer is not a single disease. Currently, there is no known treatment for all cancer (see Lovly et al. in the state of the prior art). Therefore, even for given inhibitory agents to EpCAM and Wnt signaling, it is not readily established which cancer could be treated with such agents.
The amount of experimentation would not be reasonable because it would require determining which inhibitory agents to EpCAM and Wnt signaling to use for any and all cancer treatment in a subject; this is not routine and would therefore require undue experimentation (the quantity of the experimentation, see MPEP 2164.06).
Instant claim 1 is not enabled because a person having ordinary skill in the art as of the effective filing date of the application would not be able to use (i) an effective amount of any first inhibitory agent that inhibits the activation of EpCAM signaling; and (ii) an effective amount of any second inhibitory agent that inhibits the activation of Wnt signaling to treat all cancer with a predictability of success for the reasons outlined above. Instant claims 2-14 are included in this rejection as they incorporate and/or depend on instant claim 1.
Claim Rejections - 35 USC § 112(b)
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 2 and 16 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.
Regarding claims 2 and 16, the phrase "reduces production (or release)” renders the claims indefinite because it is unclear whether the limitation in the parentheses of the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For the purposes of claim interpretation, the phrase "reduces production (or release)” will be treated as “reduces production or release.”
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over US9187558B2 (published 2015-11-17; hereinafter referred to as Pat. ‘558) in view of Boone et al. (Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974. Lab Invest. 2016 Feb;96(2):249-59; IDS filed on 11/12/2025, Cite No. 3) as evidenced by Panda et al. (Intracellular domain of epithelial cell adhesion molecule induces Wnt receptor transcription to promote colorectal cancer progression. J Biomed Sci. 2024 Jul 15;31(1):72) and Liu et al. (Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9).
Regarding the first inhibitory agent in a method of treating cancer as recited in instant claims 1 and 5, Pat. ‘558 teaches a “monoclonal antibody or an antigen-binding fragment thereof that has a specific binding affinity to… the EGF-like domain II of epithelial cell adhesion molecule [EpCAM]” (column 1, lines 37-42; antibody also referred to as humanized EpAb2-6 or hEpAb2-6). As Pat. ‘558 states “EpEx [of EpCAM] is composed of two epidermal growth factor-like domains” (column 19, lines 65-66), this teaching reads on an antibody or antigen binding fragment thereof (i.e. hEpAb2-6) that is directed to EpEX (instant claim 5). Pat. ‘558 further teaches EpCAM is important for tumorigenesis and hEpAb2-6 “displayed effective tumor inhibitory activity” (column 22, lines 45-46), indicating hEpAb2-6 is an inhibitor of EpCAM signaling (instant claim 1). Pat. ‘558 further teaches “a method of inhibiting growth of cancer cells and/or tumor-initiating cells, the method comprising administering to a subject in need thereof” hEpAb2-6 (column 2, lines 49-52) wherein the amount of hEpAb2-6 was effective in “inhibit[ing] tumorsphere formation and tumor growth” (column 17, line 30). These teachings read on a method of treating cancer comprising administering to a subject in need thereof an effective amount of a first inhibitory agent that inhibits the activation of EpCAM signaling (instant claim 1).
Regarding binding EGF-like domain II as recited in instant claims 6-7, Pat. ‘558 further teaches hEpAb2-6 binds “an epitope within the sequence of KPEGALQNNDGLYDPDCDE (SEQ ID NO: 63) located within the EGF-like domain II” (column 1, lines 37-41). SEQ ID NO: 63 of Pat. ‘558 is identical to instant SEQ ID NO: 19, reading on hEpAb2-6 has a specific binding affinity to the epitope of instant SEQ ID NO: 19 (instant claim 7) located in the EGF-like domain II (instant claim 6).
Regarding instant claim 8, Pat. ‘558 further teaches hEpAb2-6 comprises SEQ ID NOs: 4-9 for the 6 CDRs (column 1, lines 52-59), which are identical to instant SEQ ID NOs: 2, 4, 6, 9, 11, and 13 respectively. This teaching reads on the antibody or antigen-binding fragment comprising instant SEQ ID NOs: 2, 4, 6, 9, 11, and 13 for the 6 CDRs (instant claim 8).
Regarding instant claims 11 and 13-14, Pat. ‘558 further teaches the method of treating cancer “exhibits a characteristic of inducing apoptosis of said cancer cells” (column 2, lines 25-26; instant claim 11), “prolonged the lifespan of tumor-bearing mice” (column 17, line 31; instant claim 13), and targets “ovarian cancer cells” (claim 17 of Pat. ‘558; instant claim 14). These teachings read on the method of treating cancer induces apoptosis of cancer cells (instant claim 11), is effective in prolonging the survival of the subject (instant claim 13), and the cancer is ovarian cancer (instant claim 14).
Regarding the first inhibitory agent in a pharmaceutical composition as recited in instant claim 15, Pat. ‘558 teaches the method of treating cancer comprises administering “composition that comprises: (a) the antibody or antigen-binding fragment… and (b) a pharmaceutically acceptable carrier” (claim 13 of Pat. ‘558). This teachings reads on a pharmaceutical composition of a first inhibitory agent that inhibits the activation of EpCAM signaling (instant claim 15).
Pat. ‘558 does not teach:
a method of treating cancer or pharmaceutical composition comprising a second inhibitory agent that inhibits the activation of Wnt signaling (instant claims 1 and 15);
hEpAb2-6 reduces the release of EpEX (instant claims 2 and 16);
the ligand of the second inhibitory agent (instant claims 3-4, 10, and 16);
hEpAb2-6 binds the epitope of instant SEQ ID NO: 20 (instant claim 7) located in the EGF-like domain I (instant claim 6);
hEpAb2-6 inhibits beta-Catenin signaling (instant claim 9); and
the method of treating cancer inhibits tumor progression (instant claim 12).
Regarding the reduction of the release of EpEX and the inhibition of beta-Catenin signaling by the first inhibitory agent as recited in instant claims 2, 9, and 16, Panda et al. teaches “hEpAb2-6… binds to and inhibits the cleavage of EpEX, which impedes shedding of EpICD” (Pg. 6, column 1, last ¶, lines 14-17) wherein “cleavage at the cellular membrane causing release of the extracellular (EpEX) and intracellular (EpICD) domains” (Pg. 2, column 1, ¶ 1, lines 6-8) (instant claims 2 and 16). Panda et al. further teaches soluble EpICD forms a complex with beta-Catenin “to modulate transcription of EpCAM targets” (Pg. 2, column 2, ¶ 1, 16-17), indicating that inhibition of the release of EpICD by hEpAb2-6 also inhibits beta-Catenin signaling (instant claim 9). The examiner notes hEpAb2-6 is identical in both Pat. ‘558, Panda et al., and the instant application, stemming from the same applicant Academia Sinica. This teaching indicates hEpAb2-6 inherently (i) reduces the release of EpEX (instant claims 2 and 16) and (ii) inhibits beta-Catenin signaling (instant claim 9) as evidenced by Panda et al.
Regarding the first inhibitory agent binding the EGF-like domain I as recited in instant claims 6-7, Pat. ‘558 and the instant application teach the identical antibody hEpAb2-6. Therefore, the functional characteristics of said antibody would be the same as recited in the instant claim and should also bind epitope of the sequence of EGF-like domain I. As is commonly known, “[a] chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present” (MPEP 2112.01). The ability to bind the epitope of instant SEQ ID NO: 20 (instant claim 7) located in the EGF-like domain I (instant claim 6) is an inherent characteristic of hEpAb2-6, inseparable from its chemical structure.
Regarding the method of treating cancer or pharmaceutical composition comprising a second inhibitory agent and its identity as a porcupine inhibitor as recited in instant claims 1, 10, and 15, Boone et al. teach “[t]argeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974” (Pg. 249, Title; instant claim 10) wherein “WNT974 produces cytostatic effects in patient ascites cells” to treat the ovarian cancer (Pg. 249, Abstract, fourth to last line; instant claim 1), indicating an effective amount of WNT974 was utilized. This teaching reads on a method of treating cancer comprising administering to a subject in need thereof an effective amount of an inhibitory agent that inhibits the activation of Wnt signaling (instant claim 1) and said agent is a porcupine inhibitor (instant claim 10). In addition, this teaching gives motivation for using WNT974 in a method of treating ovarian cancer as its cytostatic effects would be beneficial in a treatment to slow or stop cell growth and division of cancer cells. Boone et al. further teach WNT974 was in “[a] stock solution of 10 mM” (Pg. 250, column 1, ¶ 4, line 2), reading on a pharmaceutical composition of said agent (instant claim 15).
Regarding the second inhibitory agent blocks a Wnt ligand that is not EPEX as recited in instant claims 3-4 and 16, Boone et al. does not explicitly teach that WNT974 blocks binding of a Wnt ligand to a Wnt receptor protein (instant claims 3 and 16) and the Wnt ligand is not EpEX (instant claim 4). However, Liu et al. teach “Wnt undergoes posttranslational acylation (palmitoylation) that is mediated by Porcupine (PORCN)… which is required for subsequent Wnt secretion. Loss of PORCN leads to inhibition of Wnt ligand driven signaling” (Pg. 20224, column 2, ¶ 1, lines 6-11) i.e. without this posttranslational modification from porcupine, Wnt is blocked from binding its receptor to initiate signaling. Therefore, a porcupine inhibitor such as WNT974 would block Wnt binding to its receptor. This teaching reads on WNT974 inherently blocks binding of a Wnt ligand to a Wnt receptor protein (instant claims 3 and 16) and the Wnt ligand is not EpEX (instant claim 4) as evidenced by Liu et al.
Boone et al. do not teach the inclusion of an inhibitory agent that inhibits the activation of EpCAM signaling. This deficiency is remedied by the combined teachings of Pat. ‘558 and Panda et al. as described above.
WNT974 was known and used prior to the effective filing date of the application in a method of treating ovarian cancer. In addition, both Pat. ‘558 and Boone et al. are in analogous arts (i.e. treatment of ovarian cancer with an inhibitory agent). Since Boone et al. teach WNT974 has cytostatic effects that would be beneficial in an ovarian cancer treatment to slow or stop cell growth and division of cancer cells, there is motivation for adding WNT974 to a method of treating ovarian cancer in a subject comprising administrating hEpAb2-6 and a pharmaceutical composition of hEpAb2-6 as taught by Pat. ‘558.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome 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.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. Boone et al. teach WNT974 has cytostatic effects that would be beneficial in an ovarian cancer treatment to slow or stop cell growth and division of cancer cells) would have led one of ordinary skill to modify the prior art reference (i.e. a method of treating ovarian cancer in a subject comprising administrating hEpAb2-6 and a pharmaceutical composition of hEpAb2-6 as taught by Pat. ‘558) to arrive at the claimed invention. There is a reasonable expectation of success as WNT974 known and used prior to the effective filing date of the application in a method of treating ovarian cancer. Furthermore, in light of Pat. ‘558 who teaches hEpAb2-6 suppressed tumorsphere formation and tumor growth, there is a reasonable expectation that hEpAb2-6 would successfully inhibit tumor progression as recited in instant claim 12. In addition, both Pat. ‘558 and Boone et al. are in analogous arts (i.e. treatment of ovarian cancer with an inhibitory agent).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to add WNT974 to a method of treating ovarian cancer in a subject comprising administrating hEpAb2-6 and a pharmaceutical composition of hEpAb2-6 as taught by Pat. ‘558. Additionally, hEpAb2-6 would be expected to retain its anti-tumor properties when used in combination with WNT974, thus resulting in inhibiting tumor progression as well.
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 1-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 15, 17, and 19-20 of U.S. Patent No. US9187558B2 (hereinafter referred to as Pat. ‘558) in view of the disclosure of Pat. ‘558 (qualifies as prior art as it was published 2015-11-17) and Boone et al. (Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974. Lab Invest. 2016 Feb;96(2):249-59; IDS filed on 11/12/2025, Cite No. 3) as evidenced by Panda et al. (Intracellular domain of epithelial cell adhesion molecule induces Wnt receptor transcription to promote colorectal cancer progression. J Biomed Sci. 2024 Jul 15;31(1):72) and Liu et al. (Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9).
Instant claims 1-16 are rendered obvious by the combined teachings of the prior art as fully described in the 103 rejection section, the 103s being incorporated here. The addition of the patented claims over above over related subject matter only further supported this obviousness.
Note that Pat. ‘558 was used in the 103 rejection to render the instant claims obvious in view of Boone et al. as evidenced by Panda et al. and Liu et al. The disclosure of Pat. ‘558 qualifies as prior art as it was published 2015-11-17.
Claims 13 and 20 of Pat. ‘558 teach a method of inhibiting growth of cancer cells and/or tumor-initiating cells comprising administering to a subject in need thereof (i.e. a method of treating cancer in a subject; instant claim 1) an antibody or antigen-binding fragment thereof that has a specific binding affinity to an epitope within the sequence of SEQ ID NO: 63 (SEQ ID NO: 63 of Pat. ‘558 is identical to instant SEQ ID NO: 19; instant claim 7) located within the EGF-like domain II of EpCAM (instant claim 6). Claim 15 of Pat. ‘558 teaches the antibody or antigen-binding fragment thereof comprises heavy and light chains that encompass SEQ ID NOs of instant claim 8. Claim 17 of Pat. ‘558 teaches the method targets ovarian cancer cells, reading on the cancer treated is ovarian cancer (instant claim 14). Claim 19 of Pat. ‘558 teaches a composition of the antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier (i.e. a pharmaceutical composition; instant claim 15).
The claims of Pat. ‘558 do not teach:
an inhibitory agent that inhibits the activation of Wnt signaling and its target (instant claims 1, 3-4, 10 and 16);
the downstream effects or targets of the antibody or antigen-binding fragment thereof (instant claims 2, 5, and 9); nor
the effects of the cancer treatment (instant claims 11-13).
These deficiencies are remedied by the disclosure of Pat. ‘558 and Boone et al. as evidenced by Panda et al. and Liu et al. as fully described in the 103 rejection section above.
WNT974 was known and used prior to the effective filing date of the application in a method of treating ovarian cancer. In addition, the instant application, the claims/disclosure of Pat. ‘558, and Boone et al. are in analogous arts (i.e. treatment of ovarian cancer with an inhibitory agent). Since Boone et al. teach WNT974 has cytostatic effects that would be beneficial in an ovarian cancer treatment to slow or stop cell growth and division of cancer cells, there is motivation for adding WNT974 to a method of treating ovarian cancer in a subject comprising administrating hEpAb2-6 and a pharmaceutical composition of hEpAb2-6 as taught by the claims/disclosure of Pat. ‘558.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome 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.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. Boone et al. teach WNT974 has cytostatic effects that would be beneficial in an ovarian cancer treatment to slow or stop cell growth and division of cancer cells) would have led one of ordinary skill to modify Pat. ‘558 (i.e. a method of treating ovarian cancer in a subject comprising administrating hEpAb2-6 and a pharmaceutical composition of hEpAb2-6 as taught by the claims/disclosure of Pat. ‘558) to arrive at the claimed invention. There is a reasonable expectation of success as WNT974 known and used prior to the effective filing date of the application in a method of treating ovarian cancer. In addition, the instant application, the claims/disclosure of Pat. ‘558, and Boone et al. are in analogous arts (i.e. treatment of ovarian cancer with an inhibitory agent).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to add WNT974 to a method of treating ovarian cancer in a subject comprising administrating hEpAb2-6 and a pharmaceutical composition of hEpAb2-6 as taught by the claims/disclosure of Pat. ‘558.
Conclusion
Claims 1-16 are pending. Claims 1-16 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jessica M Priest whose telephone number is (571)272-8469. The examiner can normally be reached Mon-Fri 8am-5pm.
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, Samira Jean-Louis can be reached at (571) 270-3503. 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.
/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
Prosecution Insights