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 .
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 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.
Priority
The instant application, filed on 06/07/2023, is a 371 of PCT/CN2021/138845, filed 12/16/2021, and claims foreign priority to China PCT/CN2020/137164, filed 12/17/2020.
Status of Claims/Application
Applicant’s amendment of 02/12/2024 is acknowledged. Claims 1, 3-4, 6, 8-9, 11-12, 14, 16, 18, 21, 23, 26, 29, 32, 34-35, and 37 are amended and claims 2, 5, 7, 10, 15, 17, 19-20, 22, 24, and 38-40 are cancelled. Claims 1, 3-4, 6, 8-9, 11-14, 16, 18, 21, 23, and 25-37 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/12/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
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, 6, 8-9, 11-14, 16, 18, 21, 23, 25, and 26-37 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.
Claims 1, 4, 14, 16, 18, 21, 23, and 37 recite limitations using the terms “optionally” and “further optionally” as follows:
Claim 1, lines 9-13, “optionally the CDR1….; the CDR2…; and the CDR3…”;
Claim 4, lines 18-20, “optionally the CDR1, CDR2, or CDR3 are determined according to the…”;
Claim 14, lines 3-4, “optionally the transmembrane domain is derived from CD8α”;
Claim 16, lines 3-4, “optionally the primary intracellular signaling domain is derived from CD3ζ”;
Claim 18, lines 2-6, “optionally the co-stimulatory signaling domain is derived from…” and “further optionally the co-stimulatory signaling domain is derived from CD137”;
Claim 21, lines 3-4, “optionally the hinge domain is derived from CD8α”;
Claim 23, lines 2-3, “optionally the signal peptide is derived from CD8α”; and
Claim 37, lines 2-3, “optionally the disease or disorder is colorectal cancer, gastric cancer, or esophageal cancer”
In each of these instances, the limitation following the terms “optionally” or “further optionally” are narrower embodiments of the preceding limitations rendering the limitations indefinite as it is unclear if they are a required feature of the claimed invention or an exemplary embodiment.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In each of the instances above, the claims recite a broad recitation followed by “optionally” or “further optionally” and a narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
Claims 6, 8-9, 11-13, 25, and 26-36 are rejected by virtue of their dependency on a rejected claim as they do not resolve the ambiguity discussed above.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6, 8-9, 11-14, 16, 18, 21, 23, and 25-37 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.
Claim 1 is drawn to an anti-GUCY2C single domain antibody comprising CDRs 1-3 of SEQ ID NOs: 64-66, respectively. As recited in the claim SEQ ID NO:s 64-66 comprise variables in which the CDRs can comprise various combinations of amino acids resulting in various CDR combinations. As such, the claim is drawn to genus of sdAbs comprising various CDRs all of which are claimed to function as anti-GUCY2C antibodies. It is also noted that the optional limitation recited in the claim also allows for various combinations of CDRs which also fall under the claimed function. Claims 35-37 further claim methods in which the sdAb of claim 1 is used to treat a disease or disorder, including a GUCY2C associated disease or disorder, and cancer, further reciting functions that the claimed anti-GUCY2C sdAb must be capable of performing. Claim 27 recites that the isolated nucleic acid of claim 26, which encodes the anti-GUCY2C sdAb of claim 1, comprises “a” nucleic acid sequence of SEQ ID NOs: 11 to 18. In the broadest reasonable interpretation of the limitation, the use of “a” encompasses nucleic acid sequences that comprise as little as two nucleic acids from those recited. As such, claim 27 remains drawn to the genus of claim 1.
Claim 8 depends on claim 1 and recites that the anti-GUCY2C sdAb comprises or consists of an amino acid sequence having “at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity” with any one of SEQ ID NOs: 3-10. Based on the claimed sequence identity, claim 8 is also drawn to a genus of anti-GUCY2C sdAbs which can comprise varying CDRs, all of which are claimed as having the function of being an anti-GUCY2C antibody.
Claim 25 is drawn to a chimeric antigen receptor (CAR) and encompasses CARs with an amino acid sequence having “at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity” with the sequence of any one of SEQ ID NOs: 48-55. As such, the claim is drawn to a genus of CAR sequences that can comprise up to 25% variation within the claimed sequences. A CAR is art recognized as a protein that comprises an extracellular antigen binding domain with intracellular T cell activation signals. Therefore, the claim of the sequences acting as CARs encompasses the functional limitation of the sequences being capable of binding to an antigen.
Claim 30 depends on claim 29, which recites an isolated nucleic acid encoding the CAR of claim 12, which includes an extracellular binding domain comprising the anti-GUCY2C sdAb of claim 1, and recites that the isolated nucleic acid comprises “a” nucleic acid of SEQ ID NOs: 56-63. In the broadest reasonable interpretation of the limitation, the use of “a” encompasses nucleic acid sequences that comprise as little as two nucleic acids from those recited. As such, claim 30 remains drawn to the genus of claim 1.
The instant claims are drawn to a genus of anti-GUCY2C sdAb and CARs all of which are claimed as having the recited functions as discussed in detail above. The instant disclosure, however, does not demonstrate a representative number of species of the claimed genus performing the claimed functions. The disclosure also does not provide a structure-function correlation that could be used to predictably identify which species of the claimed genus would be capable of performing the claimed function, particularly in the absence of a full complement of CDRs (three for single domain antibodies), which are the art recognized binding sites of antibodies.
The examples of the instant disclosure detail the immunization of alpaca for production of anti-GUCY2C VHH (page 131, 6.1 Example 1) as well as the screening of the produced single domain antibodies with GUCY2C protein (page 134). The disclosure identifies exemplary VHH domains in table 2, which includes VHH of SEQ ID NOs: 3-10. The disclosure also provides the following exemplary single domain antibody CDRs:
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The examples of the disclosure further detail the production of CARs from the exemplified VHH (page 139, 6.2 Example 2) as well as their testing in cytotoxicity assays (page 151, 6.3 Example 3 and 6.4 Example 4).
The VHH of SEQ ID NOs: 3-10, and CARs comprising these VHH, with the full complement of three CDRs with 100% identity, including those from Table 7 shown above, represent the single domain antibodies that applicant was in possession of at the time of the effective filing date.
The prior art also does not provide a representative number of species of the claimed genus nor does the prior art provide a structure function correlation that can be used to predictably identify which species of the claimed genus would perform the functions claimed. Rather, the state of the art suggests that antibody structure-function is not predictable, particularly in the absence of a full complement of CDRs.
Bathula, N.V., et al (2021) Nanobodies: The future of antibody-based immune therapeutics Cancer biotherapy and radiopharmaceuticals 36; 109-122 teaches that crystallography studies revealed many dynamic features of VHH domain antibodies, such as it is composed of four framework regions (FR) with nine β-sheets separated by loops, which include three hypervariable regions, or CDRs (page 110, right column). The CDR1, located towards the N-terminal region, has high variability, but nonetheless contributes to the binding strength of the domain in collaboration with CDR2, particularly by formation of an interloop disulfide bond with CDR3. The CDR3 is mainly engaged in antigen recognition and is longer than in the conventional VH domain. The longer CD3 gives increased flexibility for antigen binding and specificity variations. Furthermore, in many nanobodies, CDR3 domains have protruding ends, which improves their ability to reach and interact with the epitopes located in protein crevices and enzyme-active domains. All of these properties contribute to the convex surface of VHH, which supplements its ability to interact with the antigen cavities (page 111, left column, paragraph 3).
Hoey, R.J., et al (2019) Structure and development of single domain antibodies as modules for therapeutics and diagnostics Experimental biology and medicine 244; 1568-1576 teaches that VHH domains typically rely heavily on CDR3 for interactions with antigens. Notably, an elongated CDR3 loop provides VHH significant versatility in its ability to interact with target molecules. Unlike conventional antibodies, VHH domains have been observed to interact with antigens in protruding/extended conformations, which allow the antibody to bind protein clefts/pockets, including enzyme active sites. In addition, the CDR3 loop can produce a structurally flat paratope using CDR1/3, CDR1/2/3, and CDR2/3/FW, with some possessing more convex or concave paratopes (paragraph bridging columns, page 1569).
The teachings of Bathula and Hoey demonstrate that antigen binding specificity and strength of single domain antibodies depends on the full complement 3 CDRs all of which, together, form the paratope of the binding domain.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published approximately two years after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable years after the effective filing date. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1). Teachings which demonstrate that, even years after the effective filing date of the claimed invention, modifications, even those using conservative substitutions, were not predictable.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of anti-GUCY2C single domain antibodies that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable modification of the claimed sequences while maintaining GUCY2C binding function. Therefore, the instant claims are found to not meet the written description requirement.
It is noted that there would be support for variation in the framework regions/other domains of the CARs, if the full complement of 3 CDRs were limited to 100% identity.
Allowable Subject Matter
Claim 3 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The following is a statement of reasons for the indication of allowable subject matter: The instant claim is drawn to an anti-GUCY2C sdAb comprising the recited combinations of CDRs. In searches of the prior art, no antibodies were identified comprising the CDR combinations claimed. The following is considered to be the closest prior art.
WO 2009/080764 A2 (Hoogenboom, H.R.J.M., et al) 02 July 2009 teaches amino acid sequences such as single variable domains for oral or nasal administration and pharmaceutical compositions comprising said compounds (abstract). The single variable domains taught by WO’764 are directed against FcRn, pIgR, or Vit B12 receptor (page 147, claim 1) and are single domain antibodies (page 147, claim 3). WO’764 also teaches that the structure of the sdAb is X-FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4-Y; where FR1 to FR4 are framework regions; CDR1 to CDR3 are the complementarity determining regions; and X and Y are a further unit comprising other groups, residues, or binding units (page 164, claim 96).
WO’764 teaches a single domain antibody comprising SEQ ID NO: 81 (page 42, Table 3) which binds to mouse EpoR/Fc chimera and has the following alignment with instant SEQ ID NOs: 19, 27, and 35, respectively.
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As shown in the alignment above, the sdAb taught by WO’764 has significant misalignments with the instantly claimed CDR combinations. The sdAb taught by WO’764 also has a different binding target than those of the instantly claimed invention.
In prior art searches of the CDR combinations of the instantly claimed invention, no matching structures were identified. Based on the nature of antibody functionality and the sensitivity of antibody affinity to variations in the amino acid sequences, particularly in the CDRs, it would not have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the teachings of the above reference to arrive at the exact antibody structures disclosed in the instant application without undergoing a significant amount of trial and error experimentation. Therefore, it is concluded that there is no teaching, suggestion, or reasonable expectation of success in arriving at the instantly claimed CDR combinations rendering them novel and non-obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693