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 .
DETAILED ACTION
Claims 1-4, 7-18, and 20-23 are pending and under consideration.
It is noted that prior art does not teach or suggest a nanobody or antigen-binding fragment thereof comprising a CDR1 of SEQ ID NO: 1, a CDR2 of SEQ ID NO: 2, and a CDR3 of SEQ ID NO:3 (see YE-17, HZ-YE-17-01, HZ-YE-17-02, HZ-YE-17-03, HZ-YE-17-04 of Table 1). It is noted that these five nanobodies share the same CDRs 1-3. However, as described in 112(2) rejection, the specification does not support a broad genus of nanobodies or antigen-binding fragments thereof encompassed by the instant claims.
Priority
It is acknowledged that this application is a National Phase of International Application No. PCT/CN2022/125135 filed October 13, 2022, which claims the benefit of priority to Chinese Patent Application No. 202111208871.9 filed October 18, 2021.
Certified copies of foreign priority applications have been received as required by 37 CFR 1.55.
The priority date has been established as October 13, 2022 for the pending claims.
It is noted that the examiner has established a priority date of October 13, 2022 for claims 1-4, 7-18, and 20-23 of the instant application because the priority of the instantly claimed invention is based on the prior filed applications PCT/CN2022/125135 and Chinese Patent Application No. 202111208871.9 which are written Chinese. The prior filed applications have not been translated and the Examiner is unable to determine the information in the document.
If applicant disagrees with any rejection set forth in this action based on examiner's establishment of a priority date of October 13, 2022 for claims 1-4, 7-18, and 20-23, applicant is invited to submit a proper translation of the priority document and to point to page and line where support can be found establishing an earlier priority date. If Applicants choose to file a translation, then the translation must be filed together with a statement that the translation of the certified copy is accurate. See 35 U.S.C. 119 (b)(3), 37 C.F.R. 1.55(g)(3)(4), 37 C.F.R. 1.78(d)(7), and MPEP 1895.01.
Information Disclosure Statement
The Information Disclosure Statements filed on 04/17/2024, 07/17/2024 and 05/01/2026 have been considered and entered by examiner.
Specification
The use of the term nanobody or nanobodies, which is a trade name or a mark used in commerce (see NANOBODY (Ser. No. 85573029, Reg. Date Dec. 13, 2016), has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities: “MSLN” should be “mesothelin (MSLN)” for clarity. Appropriate correction is required.
Claim 9 is objected to because of the following informalities: “the nucleic acid molecule” should be “the isolated nucleic acid molecule” because claim 8 is drawn to an isolated nucleic acid molecule. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: “the nucleic acid molecule” should be “the isolated nucleic acid molecule” because claim 8 is drawn to an isolated nucleic acid molecule. Appropriate correction is required.
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 1-4, 7-18, and 20-23 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 1-4, 7, 8, 11-14, 18, and 20-23, they contain the trade name/ trademark nanobody (see NANOBODY (Ser. No. 85573029, Reg. Date Dec. 13, 2016). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a single domain antibody, accordingly, the identification/description is indefinite.
Regarding claim 1, the phrase "(e.g. a substitution,…)" renders the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 1, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 2, the phrase "(e.g., a substitution,…)" renders the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 2, the phrase "preferably", which is used multiple times (e.g. at lines 8, 9, 12), renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 3, the phrase "(e.g., a substitution,…)" renders the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 3, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 4, the phrases "(e.g., a heavy chain framework region…)", “(e.g., 1, 2, …, or 10)”, and "(e.g., a substitution,…)" render the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 4, the phrase "preferably", which is used multiple times (e.g. on pages 3, 4, and 5), renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 7, the phrases "(e.g., C-terminus)", “(e.g., an IgG1 Fc domain)”, and "(e.g., a substitution,…)" render the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 7, the phrase "preferably", which is used multiple times (e.g., at lines 4, 7, 9), renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 9, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 12, the phrase "preferably", which is used multiple times (e.g., at pages 6 and 7), renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 13, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 13, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 14, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 14, the phrase "(e.g., a T cell)" renders the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 16, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 17, the phrase "(e.g., a T cell or a NK cell)" renders the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 17, the phrase "preferably", which is used multiple times (e.g., at pages 4 and 5), renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 18, the phrase "preferably", which is used multiple times (e.g., at pages 8 and 9), renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 20, the phrase "preferably", which is used multiple times (e.g., at lines 10, 11, 14, and 15), renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 20, the phrase "such as" (at lines 11 and 14) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 20, the phrase "(e.g., an antineoplastic agent)" renders the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 21, the phrases "(e.g., horseradish peroxidase…)", “(e.g., an acridinium…)” and "(e.g., fluorescein or …)" renders the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 21, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 22, the phrase "preferably", which is used multiple times (e.g., at lines 7 and 8), renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 22, the phrase "such as" (at lines 11-12) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 22, the phrases "(e.g., horseradish peroxidase…)", “(e.g., an acridinium…)” and "(e.g., fluorescein or …)" renders the claim indefinite because it is unclear whether the limitations in the parenthesis and following “e.g.” is part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 23, the phrase "preferably", which is used multiple times (e.g., at lines 1, 4, 7, 8, and 15 on page 12), renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is required or just a preferred option.
Regarding claim 23, the phrase "such as" (at line 1 on page 12), “(e.g., …)” (e.g. at lines 2, 10, 11, 12, 15 and 16) and “for example” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 8, 10, 11, and 15 are also rejected because these claims depend on the rejected claims directly or indirectly.
As set forth above, indefinite languages are widely used throughout the claims. Applicant should carefully amend the claims by removing all the indefinite languages, including “preferably”, “such as”, “e.g.”, “for example”.
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 1-4, 7-18, and 20-23 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. This is a WRITTEN DESCRIPTION rejection.
Claim 1 is drawn to a nanobody or antigen-binding fragment thereof capable of specifically binding to MSLN, wherein the nanobody or antigen-binding fragment thereof comprises: a CDR1 or variant thereof, a CDR2 or variant thereof, and a CDR3 or variant thereof contained in the variable region (VHH) as set forth in any one of SEQ ID NOs: 4 and 6-9; wherein, the variant has a substitution, deletion or addition of one or several amino acids (e.g., a substitution, deletion or addition of 1, 2 or 3 amino acids) as compared to the sequence from which it is derived; preferably, the substitution is a conservative substitution; preferably, the CDRs are defined according to the IMGT, Kabat or Chothia numbering system. As evidenced by Table 1, SEQ ID NOs: 4 and 6-9 all have the CDRs 1-2-3 of SEQ ID NOs: 1-2-3. Given Broadest Reasonable Interpretation (BRI), the claim encompasses a broad genus nanobodies or antigen-binding fragments with different CDR regions. For example, give BRI, substituting, deleting or adding one or more amino acids of SEQ ID NO: 1 could generate a CDR1 with any sequences (may be completely different from SEQ ID NO: 1).
The instant specification discloses only one nanobody YE-17, and 4 humanized versions of YE-17: HZ-YE-17-01, HZ-YE-17-02, HZ-YE-17-03, HZ-YE-17-04 (see Table 1, represented as SEQ ID NOs: 4 and 6-9), all of which comprises: CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2 and CDR3 of SEQ ID NO: 3. The specification also teaches that YE-17 and humanized variants bind to CHO cells overexpressing hMSLN (Fig. 3, Table 7 and Example 6), block hMSLN to bind its ligand CA125 (Table 9, and Example 7). The specification does not disclose other nanobodies or antigen-binding fragments thereof with different CDRs 1-3 sequences encompassed by the claims.
Therefore, the specification does not provide sufficient representative examples or adequate description for the entire genus of fusion proteins as broadly claimed. The specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus.
Vas-Gath, Inc. v" Mahurkar, 19 USPQ2d 1111, makes clear that "to satisfy the written description requirement, an 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, and that the invention, in that context, is whatever is now claimed".
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
In the instant case, the claim encompasses a broad genus of anti-MSLN nanobodies which can have different CDRs. By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). Although nanobodies lacking light chains are small antibody fragments derived from heavy-chain-only antibodies and only have three CDR loops. These three CDRs that make up the binding surface which can be considered synonymous with the paratope of conventional antibodies (see page 237, the bridging paragraph of cols. 1-2 of Salamouni et al., FEBS Open Bio. 15 (2025), 236-253). In addition, mutations disrupting CDR-H3 and the framework residues results in significant loss of affinity and stability (see page 241, col. 1) of Salamouni. Thus, the CDR sequences of specific anti-MSLN nanobody (YE-17) disclosed by the specification would not tell structure of other anti-MSLN nanobodies with different CDRs.
Claim 2 recites “wherein the nanobody or antigen-binding fragment thereof comprises: a CDR1 having the sequence as set forth in SEQ ID NO: 1 or variant thereof, a CDR2 having the sequence as set forth in SEQ ID NO: 2 or variant thereof, and a CDR3 having the sequence as set forth in SEQ ID NO: 3 or variant thereof; wherein, the variant has a substitution, deletion or addition of one or several amino acids (e.g., a substitution, deletion or addition of 1, 2 or 3 amino acids) as compared to the sequence from which it is derived” which would encompass a large number variants. However, the specification does not teach any variant which has the same function of YE-17 as anti-MSLN nanobody.
Claim 3 encompasses nanobodies comprising variants of SEQ ID NO: 4 (YE-17). Given BRI, the variants can have different CDRs compared with SEQ ID NO: 4. As set forth above, the specification lacks support for these variants.
Claims 4, 7-18, and 20-23 also encompass a broad genus of nanobodies and antigen-binding fragments of claim 1.
In addition, claim 4 further recites variation in framework regions of the nanobody. It is well known that in the variable domain of an antibody, even outside the CDRs, can significantly impact antibody binding. Mutations in the framework regions (non-CDR areas) can alter the structure and dynamics of the antibody, affecting its ability to bind to its target antigen. For example, even single amino acid change in antigen-distal framework position can result in different conformational space and potentially different binding functions, see § Significance on page E486 of Koenig (Koenig et al., PNAS, E486-E495, Publication Date: 01/05/2017). For nanobody, Salamouni (Salamouni et al., FEBS Open Bio. 15 (2025), 236-253) teaches that framework regions in nanobody are more conserved than those in conventional antibodies, and are important for the preservation of nanobodies in a monomeric state (page 238, col. 1, para. 1). Thus, for example, allowing 5 amino acids substitution, deletion or addition in each of FR1, FR2, FR3, and FR4 (each of which is only about 10 amino acids in length), the claim would encompass a huge number of framework region variants, which vary significantly compared to the framework region of SEQ ID NO: 4, 6, 7, 8, or 9. Thus, the specification also lacks support for these framework variants.
In addition, regarding claims 8-11, 15-17, 20, and 23, since the specification does not have the written description support for the claimed nanobody or antigen-binding fragment, logically, the specification would not have the support for nucleic acid encoding the components the nanobody or antigen binding fragment, or method of using the antibody or antigen-binding fragment or method of using the nucleic acid.
Taken together, the instant specification has not provided a sufficient description about the correlation between the recited functions and the structure of the nanobody; the recited functions and the structure of the specific tumor-cell-penetration peptide; or the recited function and the structure of the lysosome recognition peptide. Based on the Specification and prior art, one of ordinary skilled in the art would not be able to “visualize or recognize” the components of the claimed nanobody or antigen-binding fragment thereof. Logically, the specification lacks written description for the claimed fusion protein comprising the nanobody, or the isolated nucleic acid encoding the nanobody, or bispecific/multispecific antibody comprising the nanobody, or drug conjugate comprising the nanobody, or chimeric antigen receptor (CAR) comprising the antigen binding domain of the nanobody, or method of using the claimed products.
Although Applicants may argue that it is possible to screen for each variants that bind and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. "As we held in Lilly, "[a]n adequate written description of a DNA ... 'requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention." 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171 ). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions." Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed.
Taken together, the instant specification has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between functions and the structure of the nanobody or antigen-binding fragment thereof by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of fusion proteins broadly encompassed by the claimed fusion proteins, or the methods of making and/or using the claimed fusion proteins.
Claim 20 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an ENABLEMENT rejection.
Claim 20 is drawn to a method for preventing and/or treating tumor, comprising administering to a subject in need thereof an effective amount of
the nanobody or antigen-binding fragment thereof according to claim 1, or
a polypeptide construct comprising the nanobody or antigen-binding fragment thereof and an immunoglobulin Fc domain, or
an isolated nucleic acid molecule comprising a nucleotide sequence encoding the nanobody or antigen-binding fragment thereof or the polypeptide construct, or
a bispecific or multispecific antibody comprising the nanobody or antigen-binding fragment thereof or the polypeptide construct, or
a conjugate comprising the nanobody or antigen-binding fragment thereof or the polypeptide construct and a therapeutic agent ligated thereto, or
a chimeric antigen receptor, or
an isolated nucleic acid molecule, or vector, or host cell comprising a nucleotide sequence encoding the chimeric antigen receptor, or
a pharmaceutical composition comprising any of the foregoing;
wherein the chimeric antigen receptor comprises an antigen-binding domain comprising the nanobody or antigen-binding fragment thereof, a spacer domain, a transmembrane domain and an intracellular signaling domain; preferably, the tumor is a MSLN-positive tumor; and/or preferably, the tumor is selected from the group consisting of solid tumors, such as gastric cancer, lung cancer, ovarian cancer, esophageal cancer, pancreatic cancer, cervical cancer, mesothelioma or breast cancer; and/or preferably, the subject is a mammal, such as a human; and/or preferably, the nanobody or antigen-binding fragment thereof, polypeptide construct, isolated nucleic acid molecule, vector, host cell, bispecific or multispecific antibody, conjugate, chimeric antigen receptor, or pharmaceutical composition is administered alone or in combination with an additional pharmaceutically active agent (e.g., an antineoplastic agent).
As set forth above, each option of (i) to (viii) encompasses a broad genus compositions lacking written description support. In addition, neither the specification or the claim limit “tumor”, thus, the claim also encompass a broad genus of tumors. The specification, while being enabling for detecting MSLN in a sample, does not reasonably provide enablement for the claimed compositions ((i) to (viii)) preventing, treating all tumors encompassed by the claims.
To be enabling, 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 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
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 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 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
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 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:
Nature of invention and breadth of the claims:
The claim is drawn to a method for preventing and/or treating tumor, comprising administering to a subject in need thereof an effective amount of options (i) to (viii). Under a broadest reasonable interpretation, the claim thus encompass innumerous tumors and innumerous compositions of (i) to (viii).
Relative skill in the art:
The relative skill of those in the art is high with an MD or a PhD.
Level of unpredictability in the art and State of the prior art:
Cancer is not a single disease, or cluster of closely related disorders. Thus, cancers are highly heterogeneous at both the molecular and clinical level. Dagogo-Jack et al. (Nature Review Clinical Oncology, vol. 15, pp 81-94, February 2018) teach that cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. As a result of this heterogeneity, the bulk tumor might include a diverse collection of cells harboring distinct molecular signatures with differential levels of sensitivity to treatment. This heterogeneity might result in a non-uniform distribution of genetically distinct tumor-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity) (Abstract). Furthermore, Kaiser (Science, 2006, 313: 1370) teaches that 90% of tumor drugs fail in patients. See 3rd col., 2nd to last para. Targeted Cancer Therapies (retrieved from https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet, September 1, 2021) teaches that immunotherapy, as a targeted therapy, act on specific molecule targets that associated with specific cancers (§ What are the targeted cancer therapies). Many targeted cancer therapies have been approved by FDA to treat specific types of cancer (§ What targeted therapies have been approved for specific types of cancer?).
In addition, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). Although nanobodies lacking light chains are small antibody fragments derived from heavy-chain-only antibodies and only have three CDR loops. These three CDRs that make up the binding surface which can be considered synonymous with the paratope of conventional antibodies (see page 237, the bridging paragraph of cols. 1-2 of Salamouni et al., FEBS Open Bio. 15 (2025), 236-253). In addition, mutations disrupting CDR-H3 and the framework residues results in significant loss of affinity and stability (see page 241, col. 1) of Salamouni. Thus, the compositions ((i) to (viii)) encompassed by the claim could have different properties and therapeutic activities, e.g. binding specificity, affinity, and/or stability.
In addition, Zhang (Zhang et al., CN 110698562 A, cited in IDS of 07/17/2024, English translated version is provided by Applicant) teaches that the biological function of MSLN has not been fully understood, and its relationship with cancers is still unclear (the 2nd paragraph from bottom on page 1).
Collectively, the therapeutic effectiveness for all cancers of the claimed compositions is not a certainty, and is determined empirically.
Direction or guidance and working examples:
MPEP § 608.01 (p) provided that within the specification, "specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. The instant specification does not offer any working examples using any of these claimed compositions for preventing and/or treating any tumor.
The quantity of experimentation needed:
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable."
In order to expand the teaching of the application to prevent or treat all cancers with all claimed nanobodies, a considerable amount of experimentation is needed given the unpredictability on function of antibody and targeted cancer therapy.
Due to the large quantity of experimentation necessary to test the use of claimed compositions to treat various cancers; the lack of direction/guidance presented in the specification regarding which structural features are required in order to provide activity; the state of the prior art which establishes the unpredictability of the nanobody and cancer therapy; and the breadth of the claims, undue experimentation would be required of the skilled artisan to use the claimed invention in its full scope.
Claim Rejections - 35 USC § 102
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 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 1-4, 7-11, 13, 22 and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang (Zhang et al., CN 110698562 A, Publication Date: 01/17/2020, cited in IDS of 07/17/2024, English translated version is provided by Applicant).
Claim interpretation: it is noted that the claims recite variants including changes to several amino acids. Given Broadest Reasonable Interpretation (BRI), several amino acids would encompass any number of amino acids. Thus, the claims encompass nanobodies with sequences different from recited SEQ ID NOs.
Zhang teaches an anti-mesothelin antibody, which is a specific high-affinity nanobody. The nanobody can bind to human MSLN expressed on the cell surface (Abstract, and Summary of the invention on page 2). The nanobody of Zhang would read on the nanobody of instant claims 1-3.
Regarding claim 4, Zhang teaches humanized anti-MSLN antibody (page 5, paras. 1-6).
Regarding claim 7, Zhang teaches that the antibody has a Fc domain (page 5, para. 3).
Regarding claims 8-11, Zhang also teaches a nucleic acid molecule encoding the nanobody, a vector comprising the nucleic acid molecule, a host cell comprising the nucleic acid molecule or the vector, or a kit comprising the nanobody (lines 1-4 of page 3). And method of culture the host cells to isolate the antibody (pages 5-6, § (4) Preparation of human MSLN monoclonal antibody from CHO-K1 cells).
Regarding claim 13, Zhang teaches antibody-conjugated drugs, CART therapy comprising anti-MSLN antibodies (page 3, para. 7).
Regarding claim 22, Zhang teaches a kit comprising the nanobody (page 3, para. 4).
Regarding claim 23, Zhang also teaches the use of the nanobody for detecting the presence or level of MSLN in a sample (lines 5-6 of page 3).
Conclusion
No claims are allowed.
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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/Primary Examiner, Art Unit 1646
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