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 .
Election/Restrictions
Applicant’s election without traverse of Group I and species which is heavy chain CDR1-3 of SEQ ID NO:43-35 and light chain CDR1-3 of SEQ ID NO:46-48 in the reply filed on 01/22/2026 is acknowledged.
Applicant notes that withdrawn claims 28, 32, 34 and 35 were identified as generic claims; however, they are only generic as to the species of immune effector cell not species of CD5 antibody (see previous Office action pp. 4-6).
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 name of the sequence listing is incorrect and the size must be in bytes instead of kilobytes. Below is the official USPTO receipt information with the correct name and size, but note neither the receipt nor load date is the date for creation, which does not need to be changed if correct.
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154
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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
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
The disclosure is objected to because of the following informalities: The table bridging pages 49-50 is incorrect. It lists Antibody No. #32 as having HCDR3 of SEQ ID NO:51 and VH of SEQ ID NO:36, but SEQ ID NO:51 is not part of SEQ ID NO:36 or the scFv of SEQ ID NO:34; although, SEQ ID NO:49 and 50 are. Table 2 lists SEQ ID NO:51 as ARGNPWYGVD, which does not agree with SEQ ID NO:51 as it appears in the Sequence Listing; although it is found in SEQ ID NO:36. On p. 76, line 4, SEQ ID NO:51 is identified as ARYFSGSAGDY, which agrees with the Sequence Listing but not with SEQ ID NO:36 or 34.
Appropriate correction is required.
The use of the term “Biolegend” on p. 46, line 2, “GenScript” on p. 51, line 2,”Pharmingen” on p. 51, line 9, which is a trade name or a mark used in commerce, 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.
Applicant is encouraged to review the rest of the specification for other trade names or marks.
Claim Objections
Claim 21 is objected to because of the following informalities: Claim 21 recites “CSF2RA”. The first occurrence of an abbreviation should be accompanied by the full name, in this case “colony stimulating factor 2 receptor subunit alpha” (see p. 19, lines 20-21). 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, 21 and 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 is indefinite because in lines 3-4 it recites “an antibody specifically binding to CD5 or a fragment thereof”. It is unclear if the “fragment thereof” is referring to the antibody or CD5. If reference is to the antibody, this rejection could be obviated by using phrasing such as, ‘an antibody or antigen-binding fragment thereof specifically binding CD5’.
Claim 21 recites the limitation "the cleaving peptide" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 21 is also indefinite because it is unclear how the linkage of the CAR to a truncated EGFR (tEGFR) is accomplished by linking to a (the) cleaving peptide and a CSF2RA signal peptide. That is, it is unclear how the linkage between the CAR and the tEGFR is related to a cleaving signal peptide. For example, whether a self-cleavage peptide (e.g.T2A) and signal sequence link the CAR to a tEGFR. It is noted that “cleaving peptide” is referred to on p. 19, lines 4-6, as a “self-cleaving 2A peptide”.
Claim 37 is indefinite because the last sections states, “the fully human antibody comprises a variant of the CDR sequence combination in any one of (1)-(6), wherein compared with the CDR sequence in any one of (1)-(6), the variant has at least 90% sequence identity, or comprises at least 1 and no more than 10 amino acid changes, or no more than 5, 4, 3, 2 or 1 amino acid changes in total in the CDR sequences.” This is confusing for many reasons. It is unclear if the 1-10 amino acid changes and/or 1-5 amino acids changes “in total” are over the CDR sequence combination (all of HCDR1-3 or LCDR1-3) or each CDR sequence (e.g., HCDR1). Further, it is unclear how the antibody can be “fully human” if it comprises one or more variant sequences, in which case it would be a variant of a fully human antibody.
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.
Claim 1, 3, 4, 6, 21, 23, 37, 38, 40, 45 and 46 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 antibody specifically binding CD5 or an antigen-binding fragment thereof or a single chain antibody specifically binding CD5, wherein the antibody comprises a heavy chain variable region (HCVR) comprising CDR1-3 of SEQ ID NO: 43-45, respectively, and a light chain variable region (LCVR) comprising CDR1-3 of SEQ ID NO:46-48, respectively, and for a method of treating a CD5-expressing T-cell or B-cell malignancy with said antibody or antigen-binding fragment thereof that is a CD5-targeting region of a chimeric antigen receptor (CAR) T- or NK-cell, does not reasonably provide enablement for wherein the antibody, fragment thereof and single chain antibody do not comprise a HCVR and LCVR with the above CDR1-3, and for claim 46, wherein the treatment is for other than a T-cell or B-cell CD5-expressing malignancy or for wherein treatment is preventing the disease or condition or for wherein the anti-CD5 antibody or antigen-binding fragment thereof is not part of a CAR T- or NK-cell. 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 use the invention commensurate in scope with these claims.
The antibody of claim 1 and subsequently that of dependent claim 3 have no required structure other than a set of HCDR1-3 and of LCDR1-3. Further, while the CAR of the claims comprises a CD5-binding domain and the antibody specifically binds CD5, the “fragment thereof” is not required to. For example, because of the open language used in the claims (“comprising”), there may be something else in the CAR that binds CD5. The specification says a “fragment“ may refer to an antigen-binding fragment, but there is no explicit requirement that it does (paragraph bridging pp. 16-17). If the antibody fragment does not bind CD5, one skilled in the art would not know how to use it without further guidance and direction. As to the antibody, by definition in the specification an antibody may have any number of known structures, e.g., comprising two heavy and two light chains interconnected by disulfide bonds (p. 16, lines 20-23), but is not required to. This also pertains to dependent claim 21. Dependent claim 4 specifies at least the HCVR and LCVR sequences; although, there is an issue with mixing-and-matching heavy and light chain sequences as in claim 1. However, while claims 6 and 23 recite single chain Fv (scFv) antibody sequences and CAR sequences, respectively, they also include “a functional variant thereof”, which does not help the issues for enablement. Also claims 3 and 6 further limit the antibody from which the fragment comes not the fragment itself. As discussed below, the claims have significant structural breadth.
Claims 37, 38 and 45 have similar enablement issues. Independent claim 37 is drawn to a CD5-targeting fully human antibody or a single chain antibody or fragment thereof, wherein the fully human antibody is required to comprise a HCVR comprising HCDR1-3 and/or LCVR comprising LCDR1-3 set forth in sections (1)-(6) or any one of (1)-(6) wherein the CDR sequence has at least 90% identity to or comprises 1-10 amino acid changes or no more than 5 amino acid changes in total in the CDR sequences compared to the CDR sequence in any one of (1)-(6). This means that neither the single chain antibody nor the fragment is required to comprise a HCVR, LCVR or any of the recited CDRs thereof because only the fully human antibody has any particular defined structure in the claim (although general structures of a single chain antibody are known). Additionally, the claims require only that the fully human antibody be CD5 targeting not the single chain antibody or fragment thereof. Also, with the variant CDR sequences encompassed in claim 37, there are significant issues of enablement as discussed below. Dependent claim 38 only further defines the HCVR and/or LCVR of the fully human antibody. Neither the single-chain antibody nor fragment have any recited sequence requirements. As with claim 37, the HCVR and LCVR sequences recited for the fully human antibody may be mixed-and-matched.
In reference to the variants recited in claim 37 and encompassed by dependent claims 38, 45 and 46, the elected HCDR1-3 range from 8 to 11 amino acids in length, for a total of 27 amino acids, 90% identity thereto allowing for 2 amino acid changes in the CDRs, which is still significant even for the HCDR3, encompassing more than a million possible sequences. Even if only 5 amino acids in the CDRs are changed, this means 45% of the of HCDR3 amino acids may be changed, including additions, deletions and substitutions for any of the 20 naturally occurring amino acids or potentially including also non-naturally occurring, e.g., D-isomer, amino acids, or the 5 changes may be spread over the three HCVR or LCVR CDRs (p. 20, lines 21-23). In the elected LCVR, CDR1-3 are 9, 3 and 12 amino acids long, respectively. Changing even 1 amino acid in a 3 amino acid LCDR2 is a significant change. There is no guidance or direction for changing amino acids in any CDR while maintaining CD5-targeting function. Nor are there any working examples other than the 6 specific antibody clones, each with defined CDR sequences comprised by full HCVR and LCVR sequences (table bridging pp. 49-50).
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 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 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 CD5 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). There is no reasonable expectation that an antibody comprising a substituted HCDR3 or significantly changed other CDR would bind CD5 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. Further, even though there may be some sequence similarity between CDRs of the disclosed 6 sequenced antibodies, there is no evidence or reasonable expectation that CDRs or heavy and light chain variable regions of different antibody clones could be mixed-and-matched to produce a functional CD5-binding antibody or fragment thereof because as the prior art shows, small changes in CDRs can disrupt antigen binding.
The lack of enablement for changing antibody sequence of the 6 disclosed antibody clones is supported by Herold et al. (Scientific Reports, 7:12276, DOI:10.1038/s41598-017-12519-9, Sept. 2017), which 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.” It is reported previous studies using CDR grafting for antibody humanization showed the importance of framework residues in the context of antigen binding and stability (p. 14, 1st paragraph). 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.”
Even decades before Herold et al. found the need for compatibility of an antibody HVCR with a LVCR for sufficient antigen binding. 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….” The specification provides no reasonable expectation that HCVRs and LCVRs or the CDRs thereof from different disclosed antibody clones could be substituted one for the other to produce an antibody that bound CD5 with biophysical properties that enabled it to be used.
Claim 37 is drawn to 1) a CD5-targeting fully human antibody or 2) a single chain antibody or 3) fragment thereof, wherein 1) the fully human antibody comprises a heavy chain variable region (HCVR) comprising HCDR1-3 and/or a light chain variable region (LCVR) comprising LCDR1-3 selected from one of (1)-(6) or wherein any of the CDR sequences are 90% identical to the listed sequence or comprising 1-10 amino acid changes or no more than 5 changes in total in the CDR sequences. Because of the use of “and/or” in line 3 of the claim, it requires only a HVCR comprising HCDR1-3 or a LCVR comprising LCDR1-3, wherein the HCDR1-3 or LCDR1-3 are selected from the list in the claim or encompassed variants thereof. Further, as the claim beings, “A CD5-targerting fully human antibody or a single chain antibody or fragment thereof,” there is no requirement for the single chain antibody or fragment to target CD5. While the specification says, “The “fully human antibody or single-chain antibody or fragment thereof” of the present application generally refers to any form of antigen-binding molecule capable of binding to a target antigen.” This is not a limiting definition and in the absence of specifying in the claim that a single chain antibody or fragment thereof binds the antigen, it is not required to. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Also, because they only comprise a HVCR comprising HCDR1-3 or a LCVR comprising LCDR1-3 listed in the claim, they will not inherently have any function related to CD5; although, this would not be the case if they comprised a HVCR comprising HCDR1-3 and a LCVR comprising LCDR1-3 which had been shown to function together to bind C5, e.g., those of SEQ ID NO:61-66, respectively. Additionally, the claim encompasses variants of the CDRs. Claim 38 only limits the HCVR or LCVR, but does not require both to be defined as recited in section (1)-(6). Even though claim 40 depends from claim 37 and recites scFv sequences of the fully human antibody, it does not further limit the single chain antibody of fragment thereof.
Claim 46 depends from claim 37 and is drawn to a method of treating a disease or condition by administering a therapeutically effective amount of the fully human antibody or single chain antibody or fragment thereof of claim 37 to a patient in need thereof to eliminate, inhibit or reduce CD5 activity, thereby preventing, alleviating, improving or inhibiting the disease or condition. This claim has several enablement issues in addition to the issues discussed above related to the structure of the full human antibody, single chain antibody and/or fragment thereof. The first is what diseases or conditions could be treated. The second is what aspect of “treating” is enabled.
Dong et al (Ann. Med. 57(1): 2519682, 11 pages, 2025, p. 2, col. 1, first full paragraph) is a post filing reference that discusses the role of CD5, a receptor with wide ranging immune modulatory activities, including being a negative regulator of the T cell receptor (TCR)/CD3 complex and B cell receptor signaling, as well as supporting lymphocytes survival and immune tolerance. CD5 is a critical regulator of the immune system and a transmembrane glycoprotein expressed on T cells and the surface of certain B cells. “The capacity of CD5 to mediate both activation and suppression within the immune system renders it a paradoxical entity—simultaneously functioning as a defender against pathogenic insult and a potential contributor to immune-mediated tissue damage.” (p. 2, col. 1, last paragraph) CD5 is expressed on T cells and a subset of B cells (p. 2, first full paragraph). It has been found to be a key receptor facilitating viral entry into T cells (p. 3, col. 1, second paragraph). Dong et al. review the basis for CD5 inhibitor therapy for tumors as CD5 inhibits TCR response, limiting antitumor immunity, as well as reduced tumor-infiltrating lymphocyte (TIL) cytotoxicity with elevated CD5 expression, with CD5 expression by diffuse large B cell lymphoma and chronic lymphocytic leukemia also correlated with poor prognosis (p. 4, section 4 and 4.1). Dong et al. point to work by the instant inventors (Dia et al., 2021, cited in the IDS filed 5/1/23) showing that CD5-binding CAR-T cells showed antitumor activity (p. 8, last paragraph). Also, post-filing study is noted has disclosing CAR-natural killer cells with “excellent anti-tumour efficacy [86]. Despite these advances, further studies are needed to elucidate the molecular mechanisms regulating CD5 expression across various biological processes and to establish whether CD5 can serve as a viable immunotherapeutic target in broader contexts.” (p. 8, col. 1, first paragraph) This shows the unpredictability and complexity of using CD5 as a therapeutic target. Additionally, the working examples of the specification are directed to CD5 CAR-T cytotoxicity of CD5-expressing cells in vitro. The specification discusses expression of CD5 and the use of CD5 CAR T cells as antitumor agents against T-lymphocytic leukemia (T-ALL) and T-cell lymphoma (TCL) (p. 2, first paragraph). It discusses (first paragraph of p. 2) that CD5 is expressed on lymphocyte precursors, mature T-cells and some mature B-cells, including being highly expressed in most acute T-lymphocytic leukemias and T-cell lymphomas and often expressed in mantle cell lymphoma, chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia cells (HCL). It is concluded (p. 2, lines 15-16), “CD5 can serve as a safe and reliable target for T-cell tumors.” What is not disclosed is an antibody, full length or single chain, that can be used to treat a disease or condition, particularly a CD5-expressing T-cell malignancy, that is not part of a CAR T-cell. The solo function of the isolated antibodies is not disclosed aside from binding CD5. That is, there is no showing that the antibodies possess blocking function, which would reasonably be expected at a minimum to be needed for antitumor efficacy. This is supported by the post-filing work of Alotaibi et al. (Front. Immunol. 15:1256766, Feb. 2024), which showed that in mice with poorly immunogenic 4T1 breast tumor homografts, CD5 inhibition by a blocking non-depleting CD5 monoclonal antibody led to enhanced T-cell antitumor activity and delay of tumor growth, acting as immune checkpoint blockade to promote antitumor T cell activity (p. 2, col. 1, 3rd paragraph). Alotaibi et al. acknowledges that anti-CD5 monoclonal antibodies conjugated to a toxin or CD5 CAR T cells have been shown to target CD5-expressing non-solid tumors (p. 5, start of col. 1). The theory is that blocking CD5 leads to reduction of the negative effect of CD5 or TCR signaling (p. 5, col. 2, second paragraph). Without this ability, which appears to be absent from the instantly claimed antibodies, the antibody alone is not enabled for treatment of a disease, including tumors.
The instant method encompasses preventing a disease or condition. However, in order to be able to prevent a disease or disorder such as cancer or rheumatoid arthritis, one must first be able to anticipate its onset and second be able to maintain administration throughout the duration of susceptibility so it does not occur. The term “preventing” generally carries the meaning of keeping something from happening. There is no guidance for or working example of anticipating the diseases encompassed by the instant claims, nor how to maintain treatment for the necessary duration to prevent the eventual onset of the disease or condition.
Therefore, for the reasons discussed above, including the breadth of the claims as they relate to changed amino acids in the CDR(s), ability to mix-and-match CDRs and/or VRs, the lack of function required for fragments, as well as the support by the prior art of the complexity and unpredictability of antigen binding as it relates to the CDR regions, the lack of working examples of any modified CDRs or substituted VRs or CDRs thereof from different antibodies that can function within the context of the claimed antibodies or antibody fragments, 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, in addition to the method of treatment encompassing diseases and conditions of great breadth and prevention, as well as treatment with antibodies outside the context of a CAR, it would require undue experimentation to make and use the invention commensurate in scope with the claims.
Claims 1, 3, 4, 21, 23, 37, 38, 40, 45 and 46 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 the sequence of 6 antibody clones which bind CD5 (table bridging pp. 49-50). These are made into 6 corresponding chimeric antigen receptors (CARs, Table 2). There is no disclosure of substitutions within CDRs or mixing-and-matching of the heavy and light chain variable regions (HCVR and LCVR) of different antibodies or sets of CDRs from one antibody’s HCVR with another’s LCVR CDRs. The prior art supports the specificity of pairing of HCVR and LCVR. There is no disclosure of functional variants of a single chain antibody or CAR comprising CDRs or variable regions from different antibodies (see claims 6 and 23). There is no disclosure of a single chain antibody or fragment thereof that comprises less than an HCVR and LCVR, each comprising the CDR1-3 from one disclosed antibody clone. There is no disclosure of a fully human antibody that comprises less than the full HCRV and LCVR of a single antibody clone, or it would otherwise not be fully human, i.e., having sequences aside from the CDRs which are not from human.
The specification in addressing single chain antibodies (e.g., scFv) also speaks to other antibodies when stating (p. 54, lines 3-5), “[C]onsidering the fact that the scFv that binds the CD5 antigen may not have good activation function, its function on CAR-T cells needs to be further confirmed to select the most active CAR molecules.” This acknowledges that the function of a scFv depends on sequence, i.e., simply because one can envision a generic scFv-type sequence or that of another antibody type does not mean it will function as a CD5-binding antibody. For an antibody, it is expected that all of the heavy and light chain CDRs in their proper order 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. The prior art has long acknowledged that even minor changes in the amino acid sequences of the heavy and light chain 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 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 CD5 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). There is no reasonable expectation that an antibody comprising a substituted HCDR3 or significantly changed other CDR would bind CD5 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. Therefore, the skilled artisan could not immediately envisage the genus of antibodies encompassed by the claims in view of the 6 disclosed antibodies, lack of support in the specification for which changes could be made while still binding CD5 and by the prior art showing that changing amino acids in CDRs may have unpredictable consequences on function. Further, even though there may be some sequence similarity between CDRs of the 6 sequenced antibodies, there is no evidence or reasonable expectation that CDRs or heavy and light chain variable regions of different antibody clones could be mixed-and-matched to produce a functional CD5-binding antibody or fragment thereof because as the prior art shows, small changes in CDRs can disrupt antigen binding. Also, 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). 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.” 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.”
Claims 1, 3, 4, 37, 38, 45 and 46 encompasses choosing a heavy chain variable region and a light chain variable region or CDR1-3 thereof from a list of SEQ ID NOs. This permits mixing-and-matching of heavy and light chain variable regions. Note that claim 37 only requires the HCDR1-3 and/or LCDR1-3 to be selected from one of the listed combinations, not that both the HCDR1-3 and LCDR1-3 be selected from a single combination of one of (1)-(6). The specification does not disclose mixing-and-matching of variable regions or CDRs thereof between disclosed CD5-binding clones. Independent claims 1 and 37 encompass antibody fragments that are not required to bind CD5 or comprise structures that would inherently lead to CD5 binding. There is no structural limitation associated with the fragment, unlike with the antibody from which the fragment comes.
Given the limited structure defined in the claim for each antibody and the limited structural information for only 6 distinct antibodies, the specification does not adequately describe the genus of antibodies claimed. The specification discloses antibody clones 10, 32, 35, 6, 7 and 9 and the variable regions thereof, as well as CARs comprising the CD5-binding regions of the antibodies in the context of a CD5-binding scFv, CD8α hinge/transmembrane region, 4-1BB co-stimulatory molecule and CD3ζ intracellular signaling domain. These 6 antibodies and corresponding CARs meet the written description provision of 35 USC 112(a). However, the claims are directed to or encompass antibodies with alternative CDR sets, or in the case of claims 37 and 38 also alternative CDR sequences, and antibody fragments with no function. None of these antibodies or fragments thereof meets the written description provision of 35 USC 112(a). The CAR structure is described on p. 52, line 9-12: “The CAR structure comprises CD8α signal peptide, scFv, CD8α hinge region, CD8α transmembrane region, 4-1BB co-stimulatory molecule and CD3 and is linked through T2A to a truncated EFGR molecule (EGFRt), which can be used as a safety switch during clinical transformation.” Table 2 provides the structure of each CAR containing individually clone 10, 32, 35, 6, 7 and 9. Each one comprises in order: a CD5-binding scFv, CD8α hinge/transmembrane region, 4-1BB co-stimulatory molecule, CD3ζ, T2A self-cleavage peptide, CSF2RA signal peptide and tEGFR.
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…” Neither the prior art nor specification support description of a genus of CD5-binding antibodies or fragments thereof commensurate in scope with the claims in view of the showing in the prior art of the effect of amino acid changes can have on antibody function and of the very limited disclosure of the 6 distinct antibodies in specification.
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 6 antibodies referred to above, the skilled artisan cannot envision the detailed chemical structure of the HCVR and LCVR or CDR1-3 thereof of the encompassed antibodies and fragments thereof which bind CD5, 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).
Therefore, only an antibody comprising the HCVR and LCVR of one of clones 10, 32, 35, 6, 7 or 9, or antigen-binding fragment thereof or CAR comprising the HCVR and LCVR of one clone as the CD5-binding domain linked to a CD8α hinge/transmembrane domain linked to a 4-1BB co-stimulatory domain and CD3ζ intracellular signaling domain (with or without a T2A self-cleavage peptide linked to a CSF2RA signal peptide linked to a truncated EGFR sequence), 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).
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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 6, 37, 38, 40, 45 and 46 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2016/172606 A1 (Momokin).
Momokin teaches ([0064]) a CAR comprising a CD5 binding domain, a transmembrane domain and a co-stimulatory domain and intracellular signaling domain, wherein the CD5 binding domain comprises a fragment of an antibody specifically binding to CD5 wherein the fragment is, for example, Ser Ala, comprised by instant HCDR3 of SEQ ID NO:45. It is taught that the disclosed composition can be used to treat cancers expressing CD5 ([0079]-[0080]). The antibody-comprising CAR is also taught in a pharmaceutical composition (e.g. [0068]).
Note that the claiming of “a fragment thereof” is different than “an antigen-binding fragment thereof”, which confers more required structure of the antibody from which it comes. Also note that instant claims 3, 6, 38 and 40 merely further limit the antibody from which the fragment comes not the fragment itself.
Claim(s) 37, 38, 40 and 45 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent 11,306,141 B2 (Lim).
Lim teaches antibodies targeting DLK1, including one with a light chain of SEQ ID NO:100 comprising protein fragments SSNIGAGYD and DNSLSAHYV (amino acids 26-34 and 84-102 of SEQ ID NO:100, which correspond to instant SEQ ID NO:46 and amino acids 4-12 of instant SEQ ID NO:48). Therefore, Lim teaches a fragment of the CD5-targeting fully human antibody comprising the light chain variable region of instant SEQ ID NO:29. Lim also teaches a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier or diluent in col. 21, lines 1-20.
Note the “fragment thereof” in the claims as written is not required to have CD5-binding activity (see rejection under 35 USC 112(a) above).
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
There are many prior art references teaching CD5 antibodies alone and as part of a CAR. However, none teach or make obvious the HCVR and LCVR CDR sequences of the instantly claimed and elected species, with the exception of the antibody fragment (see above under 35 USC 102). Examples of prior art drawn to CD5-binding products are set forth below.
Raikar et al. (Onocoimmunol. 7(3):e1407898, 26 December 2017, cited in the IDS filed 5/1/2023) teaches chimeric antigen receptors targeting T-cell malignancies using two structurally different anti-CD5 antigen binding domains in NK cell lines and T cell lines edited to not express CD5.
Dai et al. (Mol. Ther. 29(9): 2707-2722, July 2021, cited in the IDS filed 5/1/2023) was written by many inventors with the instant application and teaches a CD5-targeting biepitopic FHVH1 and FHVH3 CAR with fully human heavy-chain-only antigen recognition domains.
WO2017/112877 A1 (cited in the IDS filed 9/26/2024) in Fig. 1A-B teaches an anti-CDR5 scFv CAR. It shows the CD5CAR effectively lysed T-ALL cell lines expressing CD5 (Fig. 5A-B), as well as T-ALL cells from patients (Figs. 6A-D).
US 20200405811 A1 teaches CD5 CAR T cells comprising murine antibody H65 (Fig. 1), which the instant application used as the control CAR-T cells (e.g., instant Figs. 5-7, p. 2, lines 17-18, and 40, lines 15-18).
Clinicaltrail.gov ID. NCT03081910 (https://clinicaltrials.gov/study/NCT03081910?term=NCT03081910&rank=1 , 2025) was first published in 2017 and is drawn to use of CAR T-cells expressing a scFv anti-CD5 CAR for treatment of T-cell malignancies expressing CD5 (Brief Summary)./ The antibody was derived from a mouse anti-CD5 antibody. While this reference makes obvious treatment of a T-cell malignancy with an anti-CD5 CAR, it does not teach or make obvious the antibody or portions thereof required by the instant claims.
Examiner’s Comment
The following claims drafted by the examiner and considered to obviate the issues under 35 USC 112(a) of enablement and written description, with the exception for dependency by claim 46 which requires a CAR structure as discussed under 35 USC 112(a), are presented to applicant for consideration:
1. (Currently Amended) A chimeric antigen receptor (CAR) comprising a CD5-binding domain, a transmembrane domain, a co-stimulatory domain and an intracellular signaling domain, wherein the CD5-binding domain comprises an antibody specifically binding to CD5 or an antigen-binding fragment thereof; the antibody comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2) and a heavy chain complementarity determining region 3 (HCDR3), and the LCVR comprises a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2) and a light chain complementarity determining region 3 (LCDR3), and the HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2 and LCDR3 are selected from one of the following combinations:
(1) the HCDR1 having an amino acid sequence as set forth in SEQ ID NO: 43, the HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 44, and the HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 45, the LCDR1 having an amino acid sequence as set forth in SEQ ID NO: 46, the LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 47, and the LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 48;
(2) the HCDR1 having an amino acid sequence as set forth in SEQ ID NO: 49, the HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 50, and the HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 51, the LCDR1 having an amino acid sequence as set forth in SEQ ID NO: 52, the LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 53, and the LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 54;
(3) the HCDR1 having an amino acid sequence as set forth in SEQ ID NO: 55, the HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 56, and the HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 57, the LCDR1 having an amino acid sequence as set forth in SEQ ID NO: 58, the LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 59, and the LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 60;
(4) the HCDR1 having an amino acid sequence as set forth in SEQ ID NO: 61, the HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 62, and the HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 63, the LCDR1 having an amino acid sequence as set forth in SEQ ID NO: 64, the LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 65, and the LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 66;
(5) the HCDR1 having an amino acid sequence as set forth in SEQ ID NO: 67, the HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 68, and the HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 69, the LCDR1 having an amino acid sequence as set forth in SEQ ID NO: 70, the LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 71, and the LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 72; or
(6) the HCDR1 having an amino acid sequence as set forth in SEQ ID NO: 73, the HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 74, and the HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 75, the LCDR1 having an amino acid sequence as set forth in SEQ ID NO: 76, the LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 77, and the LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 78.
37. (Currently Amended) A CD5-targeting fully human antibody or an antigen binding fragment thereof or a single chain antibody, wherein the fully human antibody comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), and the single chain antibody comprises the HCVR and LCVR of the fully human antibody, and the HCVR comprises a HCDR1, a HCDR2 and a HCDR3, the LCVR comprises a LCDR1, a LCDR2 and a LCDR3, the HCDR1, HCDR2, HCDR3, and the LCDR1, LCDR2 and LCDR3 are selected from one of the following combinations:
(1) the LCDR1 having an amino acid sequence of SGSIARNY (SEQ ID NO: 64);the LCDR2 having an amino acid sequence of EDN (SEQ ID NO: 65);the LCDR3 having an amino acid sequence of QSYDDNTSWV (SEQ ID NO: 66);the HCDR1 having an amino acid sequence of GGTFSSNA (SEQ ID NO: 61);the HCDR2 having an amino acid sequence of IIPMFGTT (SEQ ID NO: 62);the HCDR3 having an amino acid sequence of ARDGGGRHPYYYYGMDV (SEQ ID NO: 63);… or
(6) the LCDR1 having an amino acid sequence of SSNIGNNY (SEQ ID NO: 58); the LCDR2 having an amino acid sequence of DNN (SEQ ID NO: 59); the LCDR3 having an amino acid sequence of GTWDSSLSAVV (SEQ ID NO: 60); the HCDR1 having an amino acid sequence of GFTFSSYA (SEQ ID NO: 55); the HCDR2 having an amino acid sequence of ITDSGDIT (SEQ ID NO: 56); the HCDR3 having an amino acid sequence of ARMSSHWYFSADY (SEQ ID NO: 57).
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
May 1, 2026
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