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
Election/Restriction
REQUIREMENT FOR UNITY OF INVENTION
As provided in 37 CFR 1.475(a), a national stage application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept (“requirement of unity of invention”). Where a group of inventions is claimed in a national stage application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.
The determination whether a group of inventions is so linked as to form a single general inventive concept shall be made without regard to whether the inventions are claimed in separate claims or as alternatives within a single claim. See 37 CFR 1.475(e).
When Claims Are Directed to Multiple Categories of Inventions:
As provided in 37 CFR 1.475 (b), a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories:
(1) A product and a process specially adapted for the manufacture of said product; or
(2) A product and a process of use of said product; or
(3) A product, a process specially adapted for the manufacture of the said product, and a use of the said product; or
(4) A process and an apparatus or means specifically designed for carrying out the said process; or
(5) A product, a process specially adapted for the manufacture of the said product, and an apparatus or means specifically designed for carrying out the said process.
Otherwise, unity of invention might not be present. See 37 CFR 1.475 (c).
This application contains claims directed to more than one species of the generic invention. These species are deemed to lack unity of invention because they are not so linked as to form a single general inventive concept under PCT Rule 13.1.
The species are as follows:
Species of CD70-binding regions comprising:
I) m6-CD70 (Table 1, pg. 64): CDRH1 (SEQ ID NO: 45), CDRH2 (SEQ ID NO: 46), CDRH3 (SEQ ID NO: 47), CDRL1 (SEQ ID NO: 49), CDRL2 (SEQ ID NO: 50), CDRL3 (SEQ ID NO: 51).
II) m7-CD70VH (Table 1, pg. 64): CDRH1 (SEQ ID NO: 53), CDRH2 (SEQ ID NO: 54), CDRH3 (SEQ ID NO: 55), CDRL1 (SEQ ID NO: 57), CDRL2 (SEQ ID NO: 58), CDRL3 (SEQ ID NO: 59).
III) m14-CD70VH (Table 1, pg. 64-65): CDRH1 (SEQ ID NO: 61), CDRH2 (SEQ ID NO: 62), CDRH3 (SEQ ID NO: 63), CDRL1 (SEQ ID NO: 65), CDRL2 (SEQ ID NO: 66), CDRL3 (SEQ ID NO: 67).
Applicant is required, in reply to this action, to elect a single species to which the claims shall be restricted if no generic claim is finally held to be allowable. The reply must also identify the claims readable on the elected species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered non-responsive unless accompanied by an election.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which are written in dependent form or otherwise require all the limitations of an allowed generic claim. Currently, the following claim(s) are generic: none.
The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
Where a single claim defines alternatives of a Markush group, the requirement of a technical interrelationship and the same or corresponding special technical features as defined in Rule 13.2, is considered met when the alternatives are of a similar nature. When the Markush grouping is for alternatives of chemical compounds, the alternatives are regarded as being of a similar nature where the following criteria are fulfilled:
(A) all alternatives have a common property or activity; AND
(B)(1) a common structure is present, that is, a significant structural element is shared by all of the alternatives; OR
(B)(2) in cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
The phrase “recognized class of chemical compounds” means that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention, i.e. each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
Although the chemical compounds of CD70 binding regions share a common structure of having a VH and VL forming an antigen-binding regions, the common structure is not a significant structural element because it represents only a small portion of the compound structures and does not constitute a structurally distinctive portion in view of the fact that the antibody backbone or scaffold may be common to any number of antibodies, but does not confer the particular activity, i.e., antigen specificity, and is not responsible for all pharmacological properties (e.g., cytolytic NK activity [Figs. 11A-11B], or TNF-α or IFNg induction [Fig. 9 and 10]), which are determined principally by the complementarity determining regions. Further, the distinct antigen-binding regions of these groups do not belong to a recognized class of chemical compounds.
During a telephone conversation with Sarah D. Eddy on May 5, 2026, a provisional election was made without traverse to prosecute the species of CD70-binding region comprising the CDR-H1-3 of SEQ ID NO:61-63, respective, and CDR-L1-3 of SEQ ID NO:65-67, respectively. Affirmation of this election must be made by applicant in replying to this Office action.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
The size of the text file is required to be in bytes instead of KB or kilobytes (see 37 CFR 1.52(e)(5)). Also, the name of the sequence listing filed is not the same as listed in the Incorporation by Reference paragraph. Please refer to the table below for the official file name and file size:
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592
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Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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.
Information Disclosure Statement
Reference #186 listed in the IDS filed 12/17/2025 as “CA 3,138,854” (published 2020/11/05) is not the reference that was provided, which instead was CA 3,138,857 (published 2020/11/12). As a result, it has been lined through and not considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested:
IMMUNE CELL ENGAGER AND METHOD OF TREATING.
Claim Interpretation
The following definition is noted in the specification ([0362]): “An "immune cell engager," as used herein, describes any polypeptide having at least one antigen binding region and at least one immune cell binding region.”
Claim Objections
Claim 266 is objected to because of the following informalities: In line 2 of claim 266, it recites “encoding for the immune cell engager”. The word “for” in this context takes away from the clarity of the claim. It is suggested that “for” be deleted. 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.
Claim 254, 265, 266 and dependent claims are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 254 is indefinite because it recites that each CDR is 95% identical to a particular amino acid sequence. However, all the sequences have fewer than 20 amino acids. Therefore, it is unclear what the 95% identity implies. That is, the largest CDR sequence is 12 amino acids (e.g., SEQ ID NO:47), and 95% of that is 11.4, but since one cannot have 0.6 amino acids, it is unclear what effect this limitation has. This rejection could be obviated by removing the 95% identity limitation.
Claim 265 is indefinite because it recites “an scFv from an anti-CD3 antibody.” If the antibody is an immunoglobulin, then no antigen-binding fragment thereof is an scFv, which is a linear antibody form. The scFv has only been defined as a single chain antibody in which the VL and VH are connected by a flexible linker, which forms an antigen-binding fragment ([0115]). Therefore, unless the anti-CD3 antibody is a scFv, the claim is confusing. The phrase could instead recite that the immune cell binding region comprises ‘an anti-CD3 scFv’ or ‘CD3-binding region which is an scFv”, if appropriate.
Claim 266 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: how providing a polynucleotide to a cell leads to expression of the immune cell engager from the polynucleotide. That is, unless the polynucleotide is, e.g., introduced, transduced or transfected into the cell (e.g., [0061] and [0202]), the method is incomplete. Once in the cell, it can then express the immune cell engager under suitable conditions.
Claim 273 is indefinite because it is drawn to “A polynucleotide encoding a CD70-specific engineered receptor” comprising a VH , VL, transmembrane domain (TMD) and intracellular domain (ICD). The claim is confusing because CD70 is not a receptor. The antigen binding region of the claim is a type of antibody not a receptor. The receptor of CD70 is CD27 (Shaffer et al., Blood, 117(14):4304-4314, 2011, cited in the IDS filed 1/30/2025, p. 4304, col. 1, start of second paragraph). What it appears is being claimed is a chimeric antigen receptor (CAR), which according to the specification the CD70-binding polypeptides of the claim can be part of ([0005], [0007]). For example, Jin et al. (Neuro-Oncol. 20(1):55-65, 2016, cited in the IDS filed 1/30/2025, Fig. 5A) teach a CD70 CAR, in which the CD70-binding region is from CD27 and comprises a CD27 TMD and 4-1BB and CD3 ICDs, and Panowski et al. (Canc. Res. 79(13_Suppl):2326, 2019, cited in the IDS filed 1/30/2025) teach a CD70 CAR in which the CD70-binding region is an scFv that binds CD70. This rejection could be obviated by, for example, replacing “engineered” in line 1 with “chimeric antigen”.
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 254-273 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 an immune cell engager polypeptide or antibody comprising or polynucleotide encoding a CD70-binding region comprising a heavy chain variable region (VH) comprising a CDR-H1-3 of SEQ ID NO:45-47, 53-55 or of 61-63 and a light chain variable region (VL) comprising respectively a CDR-L1-3 of SEQ ID NO:49-51, 57-59 or 65-67, including wherein said VH comprising one set of CDRs is 95% identical to SEQ ID NO:44, 52 and 60, respectively, and said VL comprising the set of CDRs from the same disclosed antibody as in the VH is 95% identical to SEQ ID NO: 48, 56 and 64, respectively, and wherein the method of treatment is limited to treating a CD70+ cancer in a subject, does not reasonably provide enablement for wherein the CD70-binding region does not comprise at least all their respective CDR-H1-3 and CDR-L1-3 (SEQ ID NO:45-47 and 49-51, or SEQ ID NO: 53-55 and 57-59, or SEQ ID NO:61-63 and 65-67), or for wherein the cancer in the subject does not express CD70. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
There are two main issues of enablement. One deals with the CD70 binding region which has CDRs that are different from those of each of the respective three disclosed anti-CD70 antibodies. The other is treatment of cancers not expressing CD70.
The claim 272 is drawn to an anti-CD70 antibody, claim 254 to an immune cell engager comprising an anti-CD70 binding region and an immune cell binding region, and claim 273 to a polynucleotide encoding a CD70-specific engineered receptor. They all have in common the requirement for a CD70 binding domain and all recite the domain in terms of comprising a VH and VL, each with CDR1-3 and with each CDR having at least 95% identity to a specified amino acid sequence (see rejection under 35 USC 112(b) above). Each claim lists 3 possible CDRs for each of CDR1-3. Claims 255-256 depending from independent claim 254 further define the VH and VL as at least 95% identical to one of three specified amino acid sequence. Not only is variability potentially allowed in CDRs, but the claims encompass binding regions having mixing-and-matching of CDRs and consequently VH and VL from different antibodies. Claims 260 and 262 recite respectively VH and VL regions, but the claims still permit pairing a VH from one antibody with the VL of another, which is not enabled for the reasons discussed below.
For an antibody, it is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework (FR) sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Chen et al. (EMBO J. 14 (12): 2784-2794, 1995), which teaches that the substitution of a single amino acid in CDR-H2 of an antibody can totally ablate antigen binding and that the same substitution in closely related antibodies can have opposite effects on binding (e.g., see entire document, including Figure I). The authors compared the effects of identical substitutions in related anti-phosphocholine antibodies DI6 and TI5, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. While other amino acid changes in antibodies produced only small or insignificant changes in binding affinity, the complexity of antigen binding and affinity by antibodies is high. Note in Chen (Fig. 1), even mutants with what instant paragraph [0129] considers a “conservative substitution” had a significant change in binding to respectively T15 and D16 (N53S, mutant M135, decreased binding and comparable to wildtype; V63A, mutant M72, wildtype binding and increased binding). Even though there are some publications which acknowledge that CDR-H3 is important, the conformations of other CDRs as well as framework residues (FRs) influence binding. There is no information in the specification about which amino acids of the CDRs and/or FRs are necessary and/or sufficient for specific CD70 binding. MacCallum et al. (J. Mol. Biol 262:732, 1996) analyzed a variety of antibodies for their interaction with their antigen and found that although CDR3 of the variable heavy chain dominated the interaction, a number of residues outside the CDRs make antigen contact and residues in the CDR which do not contact antigen are important for backbone conformations (e.g., p. 733, section beginning at the end of col. 1, and p. 735, paragraph bridging cols. 1-2). The heavy chain CDR3 of SEQ ID NO:63 is only 10 amino acids. If one amino acid is changed in CDR-H3, that represents a 10% change and 200 possible CDR-H3 sequences (assuming substitution of any of the 20 natural amino acids). This may be multiplied for a variable regions if there are changes in other CDRs. Additionally, the CDR-H3 sequence of either SEQ ID NO:47 or 55 and 63 share only 26% identity, while SEQ ID NO:47 and 55 share 85% identity, but still that is only 8/10 amino acids. This ignores the other CDRs of the VH and VL. There is no reasonable expectation that an antibody comprising a substituted CDR-H3 or significantly changed other CDR would bind CD70 or bind with sufficient affinity to be used, nor does the specification provide guidance or direction about which substitutions, additions or deletions throughout the variable region could be made with a reasonable expectation of successfully maintaining the necessary antibody specificity and function to be used. The application discloses the sequence of only 3 CD70-binding antibodies: m6, m7 and m14 (Tables 1 and 3).
Further, even though there may be some sequence similarity between CDRs of the 3 sequenced antibodies, there is no evidence or reasonable expectation that CDRs could be mixed-and-matched between antibodies to produce a functional CD70 binding region because as the prior art shows, small changes in CDRs can disrupt antigen binding. This extends to mixing-and-matching VH and VL from different antibodies. The prior art does not support the reasonable expectation of successfully making a functional antibody or antigen-binding fragment thereof under these circumstances. It has been shown that mixing the heavy chains of an antibody to p-azobenzoate from one rabbit with the light chains of an antibody to the same compound but from a different rabbit produced low activity antibodies. It is concluded (RS Nezlin, Biochemistry of Antibodies, 1970, p. 160), "Thus, to restore activity it is not sufficient that the two chains are combined. It is also necessary that the two chains possess a certain specificity if the antigen-binding capacity is to be restored." Later, Kranz et al. (Proc. Natl. Acad. Sci., USA, 78(9):5807 -5811, 1981) showed that in mixing heavy and light chains from six monoclonal anti-fluorescyl antibodies, heterologous heavy and light chain mixtures did not form anti-fluorescyl active sites (p. 5809, col. 1, first part of second paragraph). In another experiment (supra, p. 5809, col. 1, third paragraph), “Of the 30 possible heterologous H and L chain combinations, 13 did not reassociate within detectable limits…, 13 reassociated but with less affinity than the homologous association,.. and 4 associated with greater affinity than the homologous reassociation….”
Herold et al. (Scientific Reports, 7:12276, DOI:10.1038/s41598-017-12519-9, Sept. 2017), shows by mutating conserved regions of VH and VL, almost all VH mutants led to decreased antigen binding affinity, while the VL was more permissive (p. 4, 2nd and 3rd paragraphs). However, when CDR regions were switched between variable domains, it was found that for the VH binding to antigen not only the CDRs but framework regions were also a determining factor (p 9, 6th paragraph). Also, the interaction between the VH and VL was found to be important as shown by when the VL was absent, the antigen binding loop VH:93-107 showed large fluctuations. “Hence, complex formation of the VL and VH domains appears to lock some of the antigen binding loops into distinct conformations.” (p. 11, first paragraph) It was discussed that (p. 11, start of 3rd paragraph), “The relationship between structure, stability and binding affinity of VH and VL is still unclear. This is an important aspect for understanding antibody architecture both as the basis of our immune system and also in the context of the engineering of antibodies for therapeutic purposes. In this context, it was found that in mutants an increase in affinity is often accompanied by a decrease in stability and vice versa - and these consequences are difficult to predict33–39.” Further (p. 13, start of last paragraph), “It seems that during antibody biogenesis the effect of CDRs on the stability of VH domains is a decisive, so far underappreciated factor…. The grafting constructs revealed that CDRs, in addition to antigen binding, affect variable domain structure strongly.” The reference concludes (p. 14, end of 2nd paragraph and 3rd paragraph), “[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way. (¶) Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding.”
Therefore, for the reasons discussed above and including the breadth of the claims as they relate to substitutions which may be in the CDR(s), the support by the prior art of the complexity and unpredictability of antigen binding as it relates to the CDR and variable regions, the lack of working examples of only 3 distinct anti-CD70 antibodies and lack of any modified CDRs of the antibodies that can function within the context of the claimed CD70-binding region, and the lack of guidance for or direction about which modifications and/or substitutions would reasonably be expected to produce a functional antibody or fragment thereof, it would require undue experimentation to make and use the claimed invention.
A further enablement issue is that of what cancers can be treated with an immune cell engager that binds CD70 with sufficient affinity and binds an immune cell, presumably to bring the cancer cell into sufficient proximity of the immune cell to allow immune cell-mediated cytotoxicity of the cancer cell. By this mechanism, if the CD70-binding region did not bind the cancer cell, it would fail to bring the immune cell sufficiently close to the cancer cell. The in vitro working examples used as cancer cells “Raji and Karpas cells, which have high CD70 expression on their cell surface,” and Mec-1 cells, “which have high CD70 expression” ([0525] and [0528]). In vivo experiments used mice with multiple myeloma MM1 or acute myeloid leukemia MOLM-14 cells, both of which express CD70. Additionally, Shaffer et al. (Blood, 117(14):4304-4314, 2011, cited in the IDS filed 1/30/2025, p. 4306, col. 2, third paragraph, and Fig. 1A) made a CD70-specific CAR, wherein the CD70 binding region contained its receptor, CD27. It was shown that the CD70+ T cells killed CD70-positive target cells but not CD70-negative cells (p. 4307, col. 1, second paragraph). Using primary lymphoma cells which naturally express CD70, it was shown “CD70-specific T cells recognize and kill primary CD70-positive malignant cells in a CD70-specific manner.” (p. 4308, col. 2, end). This was supported by in vivo data (p. 4309, first two paragraphs). Therefore, it reasonably appears that in order for the method of claim 268 to be enabled for treating cancer by administration of the immune cell engager, the cancer must express CD70 (see claim 269).
Claims 254-273 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.
The specification discloses three antibodies, m6, m7 and m14, which respectively comprise CDR-H1-3 and CDR-L1-3 of SEQ ID NO: 45-47 and 49-51, 53-55 and 57-59, and 61-63 and 65-67, and have the respective VH/VL sequences of SEQ ID NO: 44/48, 52/56, and 60/64. A CD70-binding region having a set of the 6 CDRs from any one of the three disclosed antibodies meets the written description provision of 35 USC 112(a). However, the claims are directed to or encompass a CD70-binding region comprising CDR sequences that have a recited degree of identity (however, see rejection under 112(b) above) and/or comprising CDRs from more than one disclosed antibody. The specification does not disclose any functional CD70-binding regions made by mixing-and-matching CDRs in this way. Because the CDRs are not shared by the three different receptors and there is no disclosure of the ability to swap CDRs between the antibodies while still maintaining CD70 binding and no support from the art for this ability. None of these binding regions that do not comprise all 6 CDRs from a single disclosed antibody meet the written description provision of 35 USC 112(a).
It is stated in AbbVie Deustschland GmbH v. Janssen Biotechnology, Ltd., 111 USPQ 1780, 1789 (759 F.3d 1285, 1298), (Fed. Cir. 2014) discussing Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005) that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed results and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Again in AbbVie at 1788, reiterating Enzo Biochem., Inc., 323 F.3d at 964, “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date…” In this case, the three anti-CD70 antibodies are structurally distinct with CDRs therein being different and do not support a reasonable structure-function correlation.
For an antibody, it is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain the required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen-binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Chen et al. (EMBO J. 14 (12): 2784-2794, 1995), which teaches that the substitution of a single amino acid in CDR-H2 of an antibody can totally ablate antigen binding and that the same substitution in closely related antibodies can have opposite effects on binding (e.g., see entire document, including Figure 1). The authors compared the effects of identical substitutions in related anti-phosphocholine antibodies DI6 and TI5, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. While other amino acid changes in antibodies produced only small or insignificant changes in binding affinity, the complexity of antigen binding and affinity by antibodies is high. Even though there are some publications which acknowledge that CDR-H3 is important, the conformations of other CDRs as well as FRs influence binding. There is no information in the specification about which amino acids of the CDRs and/or FRs are necessary and/or sufficient for specific CD70 binding other than the full complement of those from antibodies m6, m7 and m14 (Table 1). There is no descriptive support of amino acid substitutions in the CDRs encompassed by 95% identity (however, see the rejection under 35 USC 112(b) above) or wherein the CDRs from one antibody are substituted with that of another. MacCallum et al. (J. Mol. Biol 262:732, 1996) analyzed a variety of antibodies for their interaction with their antigen and found that although CDR-H3 of the variable heavy chain dominated the interaction, CDR-L3 residues also frequently contact the antigen and a number of residues outside the CDRs make antigen contact and residues in the CDRs which do not contact antigen are important for backbone conformations (e.g., p. 733, paragraph bridging cols. 1-2, and p. 735, paragraph bridging cols. 1-2). For larger antigens, such as proteins like CD70, most of CDR-L2 and several residues of CDR-H1 and CDR-L3 typically make contact (p. 733, last paragraph). It is concluded (p. 742, col. 2, middle of second paragraph), “Antigens tend to bind to the antibody residues located at the centre of the combining site where the six CDRs meet….” The instant CDR-H3 of m6, m7 and m14, respectively SEQ ID NO:47, 55 and 63, have different sequences. Also, even if just one amino acid is changed in a CDR-H3, that represents an approximately 10% change and about 200 possible CDR-H3 sequences (assuming substitution of any of the 20 natural amino acids). The number of possible antibody sequences increases considering additional changes to the other 5 CDRs of the binding region. The limited disclosure of specific functional embodiments encompassed by the claims and evidence in the prior art that the effect of amino acid substitutions in CDRs does not allow the skilled artisan to readily envision a representative number of antibody species that bind CD70 to support the broad genus encompassed by the claims, nor does it appear the inventors were in possession of the broadly claimed genus.
Further, the specification does not disclose that CDRs or VH and VL from different antibodies could function to bind CD70 with an affinity sufficient for use. The prior art does not support the reasonable expectation of successfully making a functional antibody or antigen-binding fragment thereof under these circumstances. For example, as shown by Kranz et al., (Proc. Natl. Acad. Sci., USA, 78(9):5807-5811, 1981; p. 5809, col. 1, first part of second paragraph) mixing heavy and light chains from six monoclonal anti-fluorescyl antibodies, heterologous heavy and light chain mixtures did not form anti-fluorescyl active sites. In another experiment Kraz et al. found (supra, p. 5809, col. 1, third paragraph), “Of the 30 possible heterologous H and L chain combinations, 13 did not reassociate within detectable limits…, 13 reassociated but with less affinity than the homologous association,.. and 4 associated with greater affinity than the homologous reassociation….” As discussed above, it has been shown that the pairing of variable heavy and light chain regions is not random, and only specific pairs of VH and VL bind a designated antigen. Herold et al. (Scientific Reports, 7:12276, DOI:10.1038/s41598-017-12519-9, Sept. 2017) showed by mutating conserved regions of VH and VL, almost all VH mutants led to decreased antigen-binding affinity, while the VL was more permissive (p. 4, 2nd and 3rd paragraphs). However, when CDR regions were switched between variable domains, it was found that for the VH binding to antigen not only the CDRs but framework regions were also a determining factor (p 9, 6th paragraph). Herold et al. concludes (p. 14, end of 2nd paragraph and 3rd paragraph), “[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way. (¶) Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding.”
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of the set of 6 CDRs from a single antibody and/or set of VH and VL from a single antibody referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed CD70-binding regions, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Additionally, all working examples directed to treatment or killing of cancer are wherein the cancer is CD70-positive. The in vitro working examples used as cancer cells “Raji and Karpas cells, which have high CD70 expression on their cell surface,” and Mec-1 cells, “which have high CD70 expression” ([0525] and [0528]). Mice with multiple myeloma MM1 or acute myeloid leukemia MOLM-14 cells, both of which express CD70, were treated with CD70-binding CAR cells. Additionally, Shaffer et al. (Blood, 117(14):4304-4314, 2011, cited in the IDS filed 1/30/2025, p. 4306, col. 2, third paragraph, and Fig. 1A) made a CD70-specific CAR, wherein the CD70-binding region contained its receptor, CD27. It was shown that the CD70+ T cells killed CD70-positive target cells but not CD70-negative cells (p. 4307, col. 1, second paragraph). Using primary lymphoma cells which naturally express CD70, Shaffer et al. showed “CD70-specific T cells recognize and kill primary CD70-positive malignant cells in a CD70-specific manner.” (p. 4308, col. 2, end). This was supported by in vivo data (p. 4309, first two paragraphs). Therefore, there is not sufficient support for the method of treating a subject for cancer by administering the claimed immune cell engager if the cancer does not express CD70.
Therefore, only a CD70-binding region comprising the 6 CDRs of SEQ ID NO: 45-47 and 49-51, 53-55 and 57-59, or 61-63 and 65-67, and/or the respective pair of VH/VL sequences of SEQ ID NO: 44/48, 52/56, and 60/64, and wherein the cancer to be treated is a CD70+ cancer, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
There are a number of prior art publications disclosing a CD70-binding region which is an antibody or antigen-binding fragment thereof. However, none of the binding regions meet the limitations of the instant claims. Below are examples.
US 2019/0233528 A1 and 2018/0230224 A1 (cited in the IDS filed 1/30/2025 and 11/3/2025, respectively, see, e.g., claims) teach CD70-binding regions.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
August 6, 2026
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